diff --git "a/dataset.csv" "b/dataset.csv" new file mode 100644--- /dev/null +++ "b/dataset.csv" @@ -0,0 +1,774 @@ +input_text,target_text +"Exercise-Associated Muscle Cramps (EAMC) are a common painful condition of muscle spasms. Despite scientists tried to understand the physiological mechanism that underlies these common phenomena, the etiology is still unclear. From 1900 to nowadays, the scientific world retracted several times the original hypothesis of heat cramps. However, recent literature seems to focus on two potential mechanisms: the dehydration or electrolyte depletion mechanism, and the neuromuscular mechanism. The aim of this review is to examine the recent literature, in terms of physiological mechanisms of EAMC. A comprehensive search was conducted on PubMed and Google Scholar. The following terminology was applied: muscle cramps, neuromuscular hypothesis (or thesis), dehydration hypothesis, Exercise-Associated muscle cramps, nocturnal cramps, muscle spasm, muscle fatigue. From the initial literature of 424 manuscripts, sixty-nine manuscripts were included, analyzed, compared and summarized. Literature analysis indicates that neuromuscular hypothesis may prevails over the initial hypothesis of the dehydration as the trigger event of muscle cramps. New evidence suggests that the action potentials during a muscle cramp are generated in the motoneuron soma, likely accompanied by an imbalance between the rising excitatory drive from the muscle spindles (Ia) and the decreasing inhibitory drive from the Golgi tendon organs. In conclusion, from the latest investigations there seem to be a spinal involvement rather than a peripheral excitation of the motoneurons.","Exercise-Associated Muscle Cramps (EAMC) are a common type of muscle spasm, in which a muscle continually contracts without intention, causing pain. Scientists have tried to explain why these cramps happen, but have not been able to. An idea commonly returned to throughout the years is that EAMCs may be caused by heat. Recently, though, more likely explanations are thought to include dehydration, lack of electrolytes, or issues with the nerves connecting to the muscles. The aim of this review is to look at recent research into how and why EAMCs happen. We searched common online resources for papers. For search terms, we used: muscle cramps, neuromuscular hypothesis (or thesis), dehydration hypothesis, Exercise-Associated muscle cramps, nocturnal cramps, muscle spasm, muscle fatigue. The search returned 424 papers. We read and analyzed 69 of them. From the latest evidence, interactions of nerves with muscles explains muscle cramps better than dehydration. Muscle contraction is normally balanced by special cells in the muscles that sense how stretched or contracted the muscles are. Recent findings suggest malfunctions in these sensor cells result in spinal nerves sending unnecessary signals for the muscles to contract. In summary, the signal causing muscles to contract during a spasm seems to come from the spine rather than the nerve endings within the muscles." +"Background: Muscle cramp is a painful, involuntary muscle contraction, and that occurs during or following exercise is referred to as exercise-associated muscle cramp (EAMC). The causes of EAMC are likely to be multifactorial, but dehydration and electrolytes deficits are considered to be factors. This study tested the hypothesis that post-exercise muscle cramp susceptibility would be increased with spring water ingestion, but reduced with oral rehydration solution (ORS) ingestion during exercise. Methods: Ten men performed downhill running (DHR) in the heat (35-36 �C) for 40-60 min to reduce 1.5-2% of their body mass in two conditions (spring water vs ORS) in a cross-over design. The body mass was measured at 20 min and every 10 min thereafter during DHR, and 30 min post-DHR. The participants ingested either spring water or ORS for the body mass loss in each period. The two conditions were counter-balanced among the participants and separated by a week. Calf muscle cramp susceptibility was assessed by a threshold frequency (TF) of an electrical train stimulation to induce cramp before, immediately after, 30 and 65 min post-DHR. Blood samples were taken before, immediately after and 65 min after DHR to measure serum sodium, potassium, magnesium and chroride concentrations, hematocrit (Hct), hemoglobin (Hb), and serum osmolarity. Changes in these varaibles over time were compared between conditions by two-way repeated measures of analysis of variance. Results: The average (�SD) baseline TF (25.6 � 0.7 Hz) was the same between conditions. TF decreased 3.8 � 2.7 to 4.5 � 1.7 Hz from the baseline value immediately to 65 min post-DHR for the spring water condition, but increased 6.5 � 4.9 to 13.6 � 6.0 Hz in the same time period for the ORS condition (P < 0.05). Hct and Hb did not change significantly (P > 0.05) for both conditions, but osmolarity decreased (P < 0.05) only for the spring water condition. Serum sodium and chloride concentrations decreased (< 2%) at immediately post-DHR for the spring water condition only (P < 0.05). Conclusions: These results suggest that ORS intake during exercise decreased muscle cramp susceptibility. It was concluded that ingesting ORS appeared to be effective for preventing EAMC.","Muscle cramps are unconscious contractions of muscles that are painful. When they happen during or after excercise, they are called Exercise-Associated Muscle Cramps (EAMC). There are probably many causes of EAMC, but dehydration and lack of electrolytes (mineral salts dissolved in the blood) are thought to play roles. This study tested whether drinking a special drink called Oral Rehydration Solution (ORS) while exercising made Exercise-Associated Muscle Cramps less likely than drinking spring water. Ten men ran downhill in hot conditions for 40-60 minutes, drinking either spring water or ORS. Their weights were measured 20 minutes into the exercise, then every 10 minutes, and then 30 minutes after the exercise was completed. After each measurement, the men drank enough of either the spring water or ORS to make up for the weight they lost. We did the experiment twice, a week apart, so that each person tried both drinks. We balanced which order they tried the drinks in. Muscle cramps were easier to induce in participants who had drunk spring water than in participants who had drunk ORS. Some electrolytes in the blood decreased for participants who were drinking only spring water. The study showed that the drinking ORS (Oral Rehydration Solution) during exercise made muscle cramps less likely." +"Muscle cramp is a temporary but intense and painful involuntary contraction of skeletal muscle that can occur in many different situations. The causes of, and cures for, the cramps that occur during or soon after exercise remain uncertain, although there is evidence that some cases may be associated with disturbances of water and salt balance, while others appear to involve sustained abnormal spinal reflex activity secondary to fatigue of the affected muscles. Evidence in favour of a role for dyshydration comes largely from medical records obtained in large industrial settings, although it is supported by one large-scale intervention trial and by field trials involving small numbers of athletes. Cramp is notoriously unpredictable, making laboratory studies difficult, but experimental models involving electrical stimulation or intense voluntary contractions of small muscles held in a shortened position can induce cramp in many, although not all, individuals. These studies show that dehydration has no effect on the stimulation frequency required to initiate cramping and confirm a role for spinal pathways, but their relevance to the spontaneous cramps that occur during exercise is questionable. There is a long history of folk remedies for treatment or prevention of cramps; some may reduce the likelihood of some forms of cramping and reduce its intensity and duration, but none are consistently effective. It seems likely that there are different types of cramp that are initiated by different mechanisms; if this is the case, the search for a single strategy for prevention or treatment is unlikely to succeed.","Muscle cramp is a temporary but intense, painful, uncontrollable muscle contraction that can occur for different reasons. The causes of and cures for exercise-related cramps remain unknown. However, some cases may be linked with disturbances of water and salt balance, while others may be from constant abnormal spinal reflex activity linked to fatigue of the affected muscles. Evidence of lack of water comes largely from medical records from large industrial settings. However, it is also supported by one large treatment trial and trials with small groups of athletes. Cramp is very unpredictable, making lab studies difficult, but experiments with electrical stimulation or intense voluntary contractions of small muscles held in a shortened position can cause cramp in many, but not all, individuals. These studies show that dehydration does no affect the stimulation amount needed to start cramping and confirm a role for spinal pathways, but their link to the spontaneous exercise-related cramps that occur is questionable. There is a long history of home remedies for treatment or prevention of cramps. Some may reduce the chance of some forms of cramping and reduce its intensity and length, but none are consistently effective. There may be different types of cramp caused by different mechanisms; if so, finding a single strategy for prevention or treatment is unlikely to work." +"Muscular cramp is a common symptom in healthy people, especially among the elderly and in young people after vigorous or peak exercise. It is prominent in a number of benign neurological syndromes. It is a particular feature of chronic neurogenic disorders, especially amyotrophic lateral sclerosis. A literature review was undertaken to understand the diverse clinical associations of cramp and its neurophysiological basis, taking into account recent developments in membrane physiology and modulation of motor neuronal excitability. Many aspects of cramping remain incompletely understood and require further study. Current treatment options are correspondingly limited.","Muscle cramps are common in healthy people, especially in the elderly and young people after intense exercise. Cramps are in many harmless brain-related disorders. Cramps are common in long-lasting, brain-related disorders like amyotrophic lateral sclerosis which weakens muscles. We reviewed the basis and biological mechanisms of cramps. Future studies are needed to understand cramps. Current treatment is limited." +"Muscle cramps result in continuous, involuntary, painful, and localized contraction of an entire muscle group, individual single muscle, or select muscle fibers. Generally, the cramp can last from minutes to a few seconds for idiopathic or known causes with healthy subjects or in the presence of diseases. Palpating the muscle area of the cramp will present a knot. Exercise-associated muscle cramps are the most frequent condition requiring medical/therapeutic intervention during sports. The specific etiology is not well understood and possible causes depend on the physiological or pathological situation in which the cramps appear. It is important to note that a painful contraction that is limited to a specific area does not mean that the cause of the cramp is necessarily local. A cramp is almost never a local effect but involves the whole body system, such as somatic and emotional.","Muscle cramps cause constant and unintended contraction of muscles, causing pain. They can occur for individual muscles, groups of muscles, or small parts of muscles. A cramp usually lasts seconds or minutes, regardless of cause and how healthy you are. A knot (hard area) can be felt beneath the skin where the cramp is. Muscle cramps are the most common reason for seeking medical help during sports. We still don't know why muscle cramps happen. Causes may also depend on the person and the situation. Importantly, even though the pain of a muscle cramp can be in a specific area, the cause may lie elsewhere. A cramp can almost never be explained just by local effects, and it involves both the whole body and your emotional state." +"The dystonias are a group of disorders characterized by excessive involuntary muscle contractions leading to abnormal postures and/or repetitive movements. A careful assessment of the clinical manifestations is helpful for identifying syndromic patterns that focus diagnostic testing on potential causes. If a cause is identified, specific etiology-based treatments may be available. In most cases, a specific cause cannot be identified, and treatments are based on symptoms. Treatment options include counseling, education, oral medications, botulinum toxin injections, and several surgical procedures. A substantial reduction in symptoms and improved quality of life is achieved in most patients by combining these options.","Dystonias are disorders with a lot of uncontrollable muscle contractions leading to awkward poses and/or repetitive movements. Checking the symptoms can help identify patterns that focus identification testing on possible causes. If a cause is found, specific cause-based treatments may be available. In most cases, a specific cause cannot be found, and treatments are based on symptoms. Treatment includes counseling, education, oral medications, botox (used as a muscle relaxant), and surgeries. A noticeable decrease in symptoms and improved quality of life is achieved in most patients by combining these options." +"Muscle cramps are a common problem characterized by a sudden, painful, involuntary contraction of muscle. These true cramps, which originate from peripheral nerves, may be distinguished from other muscle pain or spasm. Medical history, physical examination, and a limited laboratory screen help to determine the various causes of muscle cramps. Despite the ""benign"" nature of cramps, many patients find the symptom very uncomfortable. Treatment options are guided both by experience and by a limited number of therapeutic trials. Quinine sulfate is an effective medication, but the side-effect profile is worrisome, and other membrane-stabilizing drugs are probably just as effective. Patients will benefit from further studies to better define the pathophysiology of muscle cramps and to find more effective medications with fewer side-effects.","Muscle cramps are a common problem represented by sudden, painful, involuntary muscle contractions. These true cramps, coming from nerves outside the brain and spinal cord, may be identifiable from other muscle pains. Medical history, physical check-up, and lab screenings help determine different causes of muscle cramps. Despite their harmless nature, cramps are uncomfortable for many. Experience and limited medical studies guide treatment. Quinine sulfate (an antimalarial drug) helps, but its side-effects are problematic. Similar drugs may be just as helpful. More studies are needed to better define the effects of muscle cramps and find better medications." +"Dystonia is a complex neurological movement disorder characterized by involuntary muscle contractions. Increasing studies implicate the microbiome as a possible key susceptibility factor for neurological disorders, but the relationship between the gut microbiota and dystonia remains poorly explored. Here, the gut microbiota of 57 patients with isolated dystonia and 27 age- and environment-matched healthy controls was analyzed by 16S rRNA gene amplicon sequencing. Further, integrative analysis of the gut microbiome and serum metabolome measured by high-performance liquid chromatography-mass spectrometry was performed. No difference in ?-diversity was found, while ?-diversity was significantly different, with a more heterogeneous community structure among dystonia patients than among controls. The most significant changes in dystonia highlighted an increase in Clostridiales, including Blautia obeum, Dorea longicatena, and Eubacterium hallii, and a reduction in Bacteroides vulgatus and Bacteroides plebeius. The functional analysis revealed that genes related to tryptophan and purine biosynthesis were more abundant in gut microbiota from patients with dystonia, while genes linked to citrate cycle, vitamin B6, and glycan metabolism were less abundant. The evaluation of serum metabolites revealed altered levels of l-glutamic acid, taurine, and d-tyrosine, suggesting changes in neurotransmitter metabolism. The most modified metabolites strongly inversely correlated with the abundance of members belonging to the Clostridiales, revealing the effect of the gut microbiota on neurometabolic activity. This study is the first to reveal gut microbial dysbiosis in patients with isolated dystonia and identified potential links between gut microbiota and serum neurotransmitters, providing new insight into the pathogenesis of isolated dystonia. IMPORTANCE Dystonia is the third most common movement disorder after essential tremor and Parkinson's disease. However, the cause for the majority of cases is not known. This is the first study so far that reveals significant alterations of gut microbiome and correlates the alteration of serum metabolites with gut dysbiosis in patients with isolated dystonia. We demonstrated a general overrepresentation of Clostridiales and underrepresentation of Bacteroidetes in patients with dystonia in comparison with healthy controls. The functional analysis found that genes related to the biosynthesis of tryptophan, which is the precursor of the neurotransmitter serotonin, were more active in isolated dystonia patients. Altered levels of several serum metabolites were found to be associated with microbial changes, such as d-tyrosine, taurine, and glutamate, indicating differences in neurotransmitter metabolism in isolated dystonia. Integrative analysis suggests that neurotransmitter system dysfunction may be a possible pathway by which the gut microbiome participates in the development of dystonia. The gut microbiome changes provide new insight into the pathogenesis of dystonia, suggesting new potential therapeutic directions.","Dystonia is a complicated brain-related movement disorder with uncontrollable muscle contractions. Many studies imply microorganisms inside us as a possible factor for brain-related disorders, but the link between the gut microorganisms (microbiota) and dystonia remains poorly explored. Here, the gut microbiota of 57 patients with dystonia and 27 age- and environment-matched healthy patients was analyzed by 16S DNA sequencing. Further, we analyzed the gut microbiome and molecules in the blood. No change in some gut-diversity was found, while other gut-diversity was very different, with a more diverse community among dystonia patients than among healthy patients (controls). The most different change in dystonia showed an increase in certain types of microorganisms labeled Clostridiales, including Blautia obeum, Dorea longicatena, and Eubacterium hallii, and a reduction in other microorganisms labeled Bacteroides vulgatus and Bacteroides plebeius. The analysis showed that genes related to the molecules tryptophan and purine creation were more abundant in gut microbiota from patients with dystonia, while genes linked to energy cycles, vitamin B6, and glycan (a specific sugar) breakdown were less abundant. Analyzing blood molecules revealed changed levels of molecules called l-glutamic acid, taurine, and d-tyrosine, suggesting changes in brain signaling molecule metabolism. The most modified molecules decreased with the abundance of microorganism members belonging to the Clostridiales, revealing the effect of the gut microbiota on brain molecule activity. This study is the first to show gut microbial differences in patients with dystonia and found possible links between gut microbiota and blood brain signaling molecules, providing new insight into the causes of dystonia. IMPORTANCE Dystonia is the third most common movement disorder after tremors and Parkinson's disease (a brain disorder affecting movement). However, the cause for many cases is not known. This is the first study so far that reveals significant changes of gut microbiome and links the change of blood molecules with gut changes in patients with dystonia. We show a general overrepresentation of Clostridiales and underrepresentation of Bacteroidetes in patients with dystonia compared to healthy controls. The analysis found that genes related to the creation tryptophan, which makes the brain signaling molecule serotonin, were more active in dystonia patients. Changed levels of several blood molecules were found to be linked with microbial changes, such as d-tyrosine, taurine, and glutamate, indicating differences in brain signaling molecule metabolism in dystonia. Analysis suggests that brain signaling molecule system dysfunction may be a possible pathway by which the gut microbiome participates in the development of dystonia. The gut microbiome changes provide new insight into the cause of dystonia, suggesting new potential treatment directions." +"Dystonia is a neurological condition characterized by abnormal involuntary movements or postures owing to sustained or intermittent muscle contractions. Dystonia can be the manifesting neurological sign of many disorders, either in isolation (isolated dystonia) or with additional signs (combined dystonia). The main focus of this Primer is forms of isolated dystonia of idiopathic or genetic aetiology. These disorders differ in manifestations and severity but can affect all age groups and lead to substantial disability and impaired quality of life. The discovery of genes underlying the mendelian forms of isolated or combined dystonia has led to a better understanding of its pathophysiology. In some of the most common genetic dystonias, such as those caused by TOR1A, THAP1, GCH1 and KMT2B mutations, and idiopathic dystonia, these mechanisms include abnormalities in transcriptional regulation, striatal dopaminergic signalling and synaptic plasticity and a loss of inhibition at neuronal circuits. The diagnosis of dystonia is largely based on clinical signs, and the diagnosis and aetiological definition of this disorder remain a challenge. Effective symptomatic treatments with pharmacological therapy (anticholinergics), intramuscular botulinum toxin injection and deep brain stimulation are available; however, future research will hopefully lead to reliable biomarkers, better treatments and cure of this disorder.","Dystonia is a disorder of the nervous system. It involves unusual posture or parts of your body moving in ways you can't control. Dystonia could be a sign of many underlying disorders, sometimes with other symptoms and sometimes not. We will focus on dystonia without other symptoms. This can be hereditary or have an unknown origin. Dystonia varies in how it appears, but it can affect all age groups, and can significantly impact daily life. We understand more about different types of dystonia since discovering the genes causing it. Some of the most common forms of hereditary dystonia are caused by mutations in genes called TOR1A, THAP1, GCH1 and KMT2B. These mutations may cause: problems with genes turning on or off; problems with sending or receiving dopamine (a neurotransmitter involved in motivation); problems adjusting the connections of brain cells; or problems suppressing unwanted brain activity. Dystonia is mainly diagnosed by signs a doctor can recognize. It is still difficult to diagnose and explain dystonia. Dystonia can be treated with: drugs (specifically anticholinergics, which block a neurotransmitter); injections of botulinum toxin (such as Botox); and insertion of electrodes into the brain. However, we hope that more research will produce better diagnostics, treatments, and maybe cures." +"Background: Skeletal muscle cramps are common and often occur in association with pregnancy, advanced age, exercise or motor neuron disorders (such as amyotrophic lateral sclerosis). Typically, such cramps have no obvious underlying pathology, and so are termed idiopathic. Magnesium supplements are marketed for the prophylaxis of cramps but the efficacy of magnesium for this purpose remains unclear. This is an update of a Cochrane Review first published in 2012, and performed to identify and incorporate more recent studies.","Skeletal muscle cramps are common and occur with pregnancy, old age, exercise or nerve-related, movement disorders (like amyotrophic lateral sclerosis which weakens muscles). Usually, muscle cramps have no obvious cause. Magnesium supplements are used for preventing cramps, but their effectiveness is unclear. " +"Hyperkalemia is a frequent clinical abnormality in patients with chronic kidney disease, and it is associated with higher risk of mortality and malignant arrhythmias. Severe hyperkalemia is a medical emergency, which requires immediate therapies, followed by interventions aimed at preventing its recurrence. Current treatment paradigms for chronic hyperkalemia management are focused on eliminating predisposing factors, such as high potassium intake in diets or supplements, and the use of medications known to raise potassium level. Among the latter, inhibitors of the renin-angiotensin aldosterone system are some of the most commonly involved medications, and their discontinuation is often the first step taken by clinicians to prevent the recurrence of hyperkalemia. While this strategy is usually successful, it also deprives patients of the recognized benefits of this class, such as their renoprotective effects. The development of novel potassium binders has ushered in a new era of hyperkalemia management, with a focus on chronic therapy while magentomaintaining the use of beneficial, but hyperkalemia-inducing medications such as renin-angiotensin aldosterone system inhibitors. This review article examines the incidence and clinical consequences of hyperkalemia, and its various treatment options, with special emphasis on novel therapeutic agents and the potential benefits of their application.","Hyperkalemia (high blood potassium) is common in those with long-lasting kidney disease. It is linked to higher risk of death and a harmful, irregular heart beat. Severe high blood potassium is serious, requires immediate treatment, and should be actively prevented. Current treatment for high blood potassium includes eliminating potassium in diets, supplements, and medications known to raise potassium. Medication that blocks kidney-related monitoring of blood pressure and electrolyte balance are usually removed by clinicians to prevent the return of high blood potassium. While removing kidney-related medication helps, patients do not receive the kidney-protecting benefits of the medication. New potassium binders have greatly influenced high blood potassium monitoring. They allow the continued use of helpful kidney-related medication that may promote high blood potassium. This article reviews the effects of high blood potassium and its treatment." +"Hyperkalemia is a frequent clinical abnormality in patients with chronic kidney disease, and it is associated with higher risk of mortality and malignant arrhythmias. Severe hyperkalemia is a medical emergency, which requires immediate therapies, followed by interventions aimed at preventing its recurrence. Current treatment paradigms for chronic hyperkalemia management are focused on eliminating predisposing factors, such as high potassium intake in diets or supplements, and the use of medications known to raise potassium level. Among the latter, inhibitors of the renin-angiotensin aldosterone system are some of the most commonly involved medications, and their discontinuation is often the first step taken by clinicians to prevent the recurrence of hyperkalemia. While this strategy is usually successful, it also deprives patients of the recognized benefits of this class, such as their renoprotective effects. The development of novel potassium binders has ushered in a new era of hyperkalemia management, with a focus on chronic therapy while magentomaintaining the use of beneficial, but hyperkalemia-inducing medications such as renin-angiotensin aldosterone system inhibitors. This review article examines the incidence and clinical consequences of hyperkalemia, and its various treatment options, with special emphasis on novel therapeutic agents and the potential benefits of their application.","Hyperkalemia is a condition where the potassium level in the blood is higher than normal. Potassium is a very important mineral in the body. Hyperkalemia is often seen in patients with ongoing kidney disease. Hyperkalemia can cause serious problems with your heartbeat and an increased risk of death. Doctors consider severe hyperkalemia a medical emergency and treat it immediately. They also give treatments to try to stop it from coming back. Current treatments for ongoing hyperkalemia include avoiding things that can cause it to come back. Doctors advise not to eat foods or take supplements that are high in potassium and to stop using medicines that are known to increase the potassium level. Some of the most commonly uses medicines that are known to increase potassium levels are a class of drugs that block the renin-angiotensin-aldosterone system (RAAS blockers). The renin-angiotensin-aldosterone system (RAAS) is a hormone system that manages blood pressure and fluid balance in the body. Often as the first step, doctors stop giving patients these medicines to prevent hyperkalemia from coming back. While stopping these medicines usually works well to lower the potassium level, patients miss out on the known kidney protection this class of drugs can give. Newer medicines have now been developed that bind to potassium. These new potassium binders allow doctors to lower the potassium level in a different way. Doctors may now be able to lower potassium levels and still keep their patients on the RAAS blockers for the kidney protection these medicines give. This research studies hyperkalemia and its effects. This work also shows the many (and new) ways of treating hyperkalemia and how the treatment can help the patients." +"Hyperkalemia is a clinically important electrolyte abnormality that occurs most commonly in patients with chronic kidney disease. Due to its propensity to induce electrophysiological disturbances, severe hyperkalemia is considered a medical emergency. The management of acute and chronic hyperkalemia can be achieved through the implementation of various interventions, one of which is the elimination of medications that can raise serum potassium levels. Because many such medications (especially inhibitors of the renin-angiotensin aldosterone system) have shown beneficial effects in patients with cardiovascular and renal disease, their discontinuation for reasons of hyperkalemia represent an undesirable clinical compromise. The emergence of 2 new potassium-binding medications for acute and chronic therapy of hyperkalemia may soon allow the continued use of medications such as renin-angiotensin-aldosterone system inhibitors even in patients who are prone to hyperkalemia. This review article provides an overview of the physiology and the pathophysiology of potassium metabolism and hyperkalemia, the epidemiology of hyperkalemia, and its acute and chronic management. We discuss in detail emerging data about new potassium-lowering therapies, and their potential future role in clinical practice.","Hyperkalemia (high blood potassium) is a medical issue common in patients with long-lasting kidney disease. Since it may promote electrical and heart-related issues, severe high blood potassium is a medical emergency. Certain treatments, like eliminating medications that raise blood potassium, can help manage high blood potassium. Since many kidney-affecting drugs (like blockers of kidney-related monitoring of blood pressure and electrolytes) help patients with heart- and kidney-related diseases, their removal is an issue. The use of 2 new potassium-binding medications for treating high blood potassium may allow the continued use of kidney-affecing medications even in patients prone to high blood potassium. This article reviews the biology, spread, and treatment of potassium metabolism and high blood potassium. We discuss new potassium-lowering treatments." +"Hyperkalemia is a clinically important electrolyte abnormality that occurs most commonly in patients with chronic kidney disease. Due to its propensity to induce electrophysiological disturbances, severe hyperkalemia is considered a medical emergency. The management of acute and chronic hyperkalemia can be achieved through the implementation of various interventions, one of which is the elimination of medications that can raise serum potassium levels. Because many such medications (especially inhibitors of the renin-angiotensin aldosterone system) have shown beneficial effects in patients with cardiovascular and renal disease, their discontinuation for reasons of hyperkalemia represent an undesirable clinical compromise. The emergence of 2 new potassium-binding medications for acute and chronic therapy of hyperkalemia may soon allow the continued use of medications such as renin-angiotensin-aldosterone system inhibitors even in patients who are prone to hyperkalemia. This review article provides an overview of the physiology and the pathophysiology of potassium metabolism and hyperkalemia, the epidemiology of hyperkalemia, and its acute and chronic management. We discuss in detail emerging data about new potassium-lowering therapies, and their potential future role in clinical practice.","Hyperkalemia is a condition where the potassium level in the blood is higher than normal. Potassium is a very important mineral in the body. Hyperkalemia is a important problem that happens mostly in people with long-lasting kidney disease. Severe hyperkalemia is a medical emergency because it can cause problems with the heart beat and the nerves. Doctors will stop the medicines that can cause increases in potassium blood levels as one of many ways to treat hyperkalemia. Many of these medicines that can cause hyperkalemia have also shown good effects on the heart, circulation, and kidneys. These medicines include a class of drugs that block the renin-angiotensin-aldosterone system (RAAS blockers). The RAAS is a hormone system that manages blood pressure and fluid balance in the body. Because these medicines also have good effects, stopping them may not be the best solution. Two newer medicines that bind to potassium are coming out to treat hyperkalemia. These potassium-binding medicines may soon allow doctors to continue to use the RAAS blockers that may increase the blood potassium levels, even in patients who may get hyperkalemia. This research studies the way potassium is handled in the body under normal conditions and in hyperkalemia. it also studies hyperkalemia in the population and how doctors treat rapidly occurring and ongoing hyperkalemia. We thoroughly discuss the information coming out about these new medicines that can lower potassium. We also discuss how doctors can use them in the future." +"In patients with advanced-stage chronic kidney disease (CKD), progressive kidney function decline leads to increased risk for hyperkalemia (serum potassium > 5.0 or >5.5 mEq/L). Medications such as renin-angiotensin-aldosterone system inhibitors pose an additional hyperkalemia risk, especially in patients with CKD. When hyperkalemia develops, clinicians often recommend a diet that is lower in potassium content. This review discusses the barriers to adherence to a low-potassium diet and the impact of dietary restrictions on adverse clinical outcomes. Accumulating evidence indicates that a diet that incorporates potassium-rich foods has multiple health benefits, which may also be attributable to the other vitamin, mineral, and fiber content of potassium-rich foods. These benefits include blood pressure reductions and reduced risks for cardiovascular disease and stroke. High-potassium foods may also prevent CKD progression and reduce mortality risk in patients with CKD. Adjunctive treatment with the newer potassium-binding agents, patiromer and sodium zirconium cyclosilicate, may allow for optimal renin-angiotensin-aldosterone system inhibitor therapy in patients with CKD and hyperkalemia, potentially making it possible for patients with CKD and hyperkalemia to liberalize their diet. This may allow them the health benefits of a high-potassium diet without the increased risk for hyperkalemia, although further studies are needed.","In patients with full-body-spreading, chronic kidney disease (CKD), kidney deterioration leads to higher risk of high blood potassium. Medications that block kidney-related monitoring of blood pressure and electrolytes worsen high blood potassium risk, especially in those with long-lasting kidney disease. When high blood potassium develops, clinicians recommend a lower-potassium diet. This work explores hurdles to continuing a low-potassium diet and its effects on harmful medical outcomes. A potassium-rich diet may have multiple health benefits due to other vitamin, mineral, and fiber content in the foods. These benefits include blood pressure reductions and lower risk of cardiovascular disease and stroke. High-potassium foods may also reduce progression of and risk of death from chronic kidney disease. Supporting treatment with new potassium-binding agents, patiromer and sodium zirconium cyclosilicate, may allow kidney-affecting medication and a less-restricted diet in patients with chronic kidney disease and high blood potassium. New potassium-binding agents may allow the benefits of a high-potassium diet without risk of higher blood potassium. However, more studies are needed." +"In patients with advanced-stage chronic kidney disease (CKD), progressive kidney function decline leads to increased risk for hyperkalemia (serum potassium > 5.0 or >5.5 mEq/L). Medications such as renin-angiotensin-aldosterone system inhibitors pose an additional hyperkalemia risk, especially in patients with CKD. When hyperkalemia develops, clinicians often recommend a diet that is lower in potassium content. This review discusses the barriers to adherence to a low-potassium diet and the impact of dietary restrictions on adverse clinical outcomes. Accumulating evidence indicates that a diet that incorporates potassium-rich foods has multiple health benefits, which may also be attributable to the other vitamin, mineral, and fiber content of potassium-rich foods. These benefits include blood pressure reductions and reduced risks for cardiovascular disease and stroke. High-potassium foods may also prevent CKD progression and reduce mortality risk in patients with CKD. Adjunctive treatment with the newer potassium-binding agents, patiromer and sodium zirconium cyclosilicate, may allow for optimal renin-angiotensin-aldosterone system inhibitor therapy in patients with CKD and hyperkalemia, potentially making it possible for patients with CKD and hyperkalemia to liberalize their diet. This may allow them the health benefits of a high-potassium diet without the increased risk for hyperkalemia, although further studies are needed.","In patients with advanced, long-standing (chronic) kidney disease (CKD), the kidney function continues to decline. This decrease in kidney function leads to an greater risk of hyperkalemia. Hyperkalemia is a condition where the potassium level in the blood is higher than normal. Potassium is a very important mineral in the body. Hyperkalemia is a important problem that happens mostly in people with long-lasting kidney disease. Some drugs can also cause an additional risk of hyperkalemia, especially in patients with chronic kidney disease (CKD). One such class of drugs, is the renin-angiotensin-aldosterone system inhibitors (RAAS blockers). The renin-angiotensin-aldosterone system (RAAS) is a hormone system that manages blood pressure and fluid balance in the body. When hyperkalemia develops, doctors often advise patients to go on a diet that is lower in potassium. This study talks about the things that stop patients from following a low potassium diet. The paper also discusses what the effect of following a strict diet can have on poor patient outcomes. Facts are showing that a diet that includes foods high in potassium is good for your health. These same foods may be good for your health because they also contain other vitamins, minerals, and fiber. These benefits include lowering your blood pressure. The benefits also include lowering the risks for heart disease, blood vessel disease , and stroke. Foods high in potassium may also prevent chronic kidney disease (CKD) from getting worse. High-potassium foods may also decrease the risk of death in patients with CKD. Newer drugs, patiromer and sodium zirconium cyclosilicate, bind and get rid of excess potassium from the body. The use of these drugs may allow for renin-angiotensin-aldosterone system inhibitor (RAAS blocker) therapy in patients with CKD and hyperkalemia. Doctors using these drugs together may make it possible for patients with CKD and hyperkalemia to have more freedom with their diets. This treatment approach may give patients the health benefits of a high-potassium diet without the increased risk for hyperkalemia. Further studies are needed." +"Hyperkalemia is an electrolyte abnormality with potentially life-threatening consequences. Despite various guidelines, no universally accepted consensus exists on best practices for hyperkalemia monitoring, with variations in precise potassium (K+) concentration thresholds or for the management of acute or chronic hyperkalemia. Based on the available evidence, this review identifies several critical issues and unmet needs with regard to the management of hyperkalemia. Real-world studies are needed for a better understanding of the prevalence of hyperkalemia outside the clinical trial setting. There is a need to improve effective management of hyperkalemia, including classification and K+ monitoring, when to reinitiate previously discontinued renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, and when to use oral K+-binding agents. Monitoring serum K+ should be individualized; however, increased frequency of monitoring should be considered for patients with chronic kidney disease, diabetes, heart failure, or a history of hyperkalemia and for those receiving RAASi therapy. Recent clinical studies suggest that the newer K+ binders (patiromer sorbitex calcium and sodium zirconium cyclosilicate) may facilitate optimization of RAASi therapy. Enhancing the knowledge of primary care physicians and internists with respect to the safety profiles of these newer K+ binders may increase confidence in managing patients with hyperkalemia. Lastly, the availability of newer K+-binding agents requires further study to establish whether stringent dietary K+ restrictions are needed in patients receiving K+-binder therapy. Individualized monitoring of serum K+ among patients with an increased risk of hyperkalemia and the use of newer K+-binding agents may allow for optimization of RAASi therapy and more effective management of hyperkalemia.","Hyperkalemia (high blood potassium) is an electrolyte issue with possibly life-threatening effects. No agreement exists for treating high blood potassium. Guidelines vary based on postassium level and management of immediate or long-lasting high blood potassium. This review identifies many issues and needs regarding high blood potassium. Real-world studies are needed to better understand the real-world widespreadness of high blood potassium. Improving treatment of high blood potassium, including classification, potassium monitoring, and specific medication use, is necessary. While monitoring blood potassium should be individualized, increased monitoring should be considered for those with chronic kidney disease, diabetes, heart failure, history of high blood potassium, or enzyme-based therapy which blocks kidney-related monitoring of blood pressure and electrolytes. New potassium binders (patiromer sorbitex calcium and sodium zirconium cyclosilicate) may help renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, which blocks kidney-related monitoring of blood pressure and electrolytes. Improving understanding of these newer potassium binders may increase confidence in helping those with high blood potassium. The availability of newer K+ binders needs more research to determine if more strict dietary K+ restrictions are needed for patients. Personalized blood potassium monitoring in those with high risk of high blood potassium and new potassium-binding agents may improve certain kidney-related, enzyme-based therapies and management of high blood potassium." +"Hyperkalemia is an electrolyte abnormality with potentially life-threatening consequences. Despite various guidelines, no universally accepted consensus exists on best practices for hyperkalemia monitoring, with variations in precise potassium (K+) concentration thresholds or for the management of acute or chronic hyperkalemia. Based on the available evidence, this review identifies several critical issues and unmet needs with regard to the management of hyperkalemia. Real-world studies are needed for a better understanding of the prevalence of hyperkalemia outside the clinical trial setting. There is a need to improve effective management of hyperkalemia, including classification and K+ monitoring, when to reinitiate previously discontinued renin-angiotensin-aldosterone system inhibitor (RAASi) therapy, and when to use oral K+-binding agents. Monitoring serum K+ should be individualized; however, increased frequency of monitoring should be considered for patients with chronic kidney disease, diabetes, heart failure, or a history of hyperkalemia and for those receiving RAASi therapy. Recent clinical studies suggest that the newer K+ binders (patiromer sorbitex calcium and sodium zirconium cyclosilicate) may facilitate optimization of RAASi therapy. Enhancing the knowledge of primary care physicians and internists with respect to the safety profiles of these newer K+ binders may increase confidence in managing patients with hyperkalemia. Lastly, the availability of newer K+-binding agents requires further study to establish whether stringent dietary K+ restrictions are needed in patients receiving K+-binder therapy. Individualized monitoring of serum K+ among patients with an increased risk of hyperkalemia and the use of newer K+-binding agents may allow for optimization of RAASi therapy and more effective management of hyperkalemia.","Hyperkalemia is a condition where the potassium level in the blood is higher than normal. Potassium is a very important mineral (electrolyte) in the body. Hyperkalemia can sometimes lead to death. Although there are many guidelines, all doctors do not agree on the best ways to take care of patients with different types of hyperkalemia. Types of hyperkalemia include acute (coming on rapidly), and chronic (long-lasting). This study discusses the serious issues and needs in the care of patients with hyperkalemia. Real-world studies are needed to understand how many patients have hyperkalemia that are not under research. Doctors need to improve the overall care of patients with hyperkalemia. This care includes knowing the type of hyperkalemia, how often to check the blood potassium levels, when to use the potassium-binder drugs that are taken by mouth, and when doctors can start the RAAS blocker drugs again. The renin-angiotensin-aldosterone system (RAAS) is a hormone system that manages blood pressure and fluid balance in the body. Drugs that block the RAAS (RAAS blockers) have good effects on the cardiovascular system (heart and blood vessels). But the RAAS blockers can cause hyperkalemia. How often blood potassium levels are checked depends on the patient. Doctors should consider checking the blood levels more often in patients with chronic kidney disease, diabetes, heart failure, or a history of hyperkalemia and in patients taking RAAS blockers. Recent patient studies suggest that the newer potassium-binders (patiromer sorbitex calcium and sodium zirconium cyclosilicate) may help using the RAAS blockers and overall good treatment. Confidence in caring for patients with hyperkalemia may increase as primary care and internal medicine doctors learn more about the safety of the newer potassium-binders. More studies are required in order to know if strict low-potassium diets are needed in patients taking potassium-binders. Each patient's blood potassium levels should be checked as needed in patients at increased risk for hyperkalemia. Doing this, and using the newer potassium-binding drugs, may allow the best use of RAAS blockers and better overall care of patients with hyperkalemia." +"Hyperkalemia is a potentially life-threatening metabolic problem caused by inability of the kidneys to excrete potassium, impairment of the mechanisms that move potassium from the circulation into the cells, or a combination of these factors. Acute episodes of hyperkalemia commonly are triggered by the introduction of a medication affecting potassium homeostasis; illness or dehydration also can be triggers. In patients with diabetic nephropathy, hyperkalemia may be caused by the syndrome of hyporeninemic hypoaldosteronism. The presence of typical electrocardiographic changes or a rapid rise in serum potassium indicates that hyperkalemia is potentially life threatening. Urine potassium, creatinine, and osmolarity should be obtained as a first step in determining the cause of hyperkalemia, which directs long-term treatment. Intravenous calcium is effective in reversing electrocardiographic changes and reducing the risk of arrhythmias but does not lower serum potassium. Serum potassium levels can be lowered acutely by using intravenous insulin and glucose, nebulized beta2 agonists, or both. Sodium polystyrene therapy, sometimes with intravenous furosemide and saline, is then initiated to lower total body potassium levels.","Hyperkalemia is a condition where the potassium level in the blood is higher than normal. Potassium is an important mineral in the body. Hyperkalemia is caused by problems with potasium metabolism and it can be life-threatening. It can be caused by a problem with the kidneys getting rid of the potassium through the urine. It can also be caused by a problem moving potassium into the cells from the bloodstream or both. Hyperkalemia that comes on rapidly is usually caused by an illness, dehydration, or by starting medicines that affect normal potassium balance in the body. Hyperkalemia can also be caused by other syndromes or conditions in patients with kidney diseases that are caused by diabetes. Signs that hyperkalemia may be life-threatening include EKG changes that are typically seen with high potassium levels or by a rapid rise in potassium levels on a blood test. Urine tests for potassium, creatinine (a waste product from muscles), and osmolality (the kidney's ability to balance water in urine) should be done as a first step in finding the cause for the hyperkalemia. Finding the cause for the hyperkalemia will have an effect on the ongoing treatment. Giving calcium through an IV can improve the abnormal EKG changes and reduce the risk of abnormal heartbeats, but this treatment does not lower the blood potassium level. Blood potassium levels can be lowered quickly by giving IV insulin and glucose, and by giving medicines called beta2 agonists through an inhaler or both. To then lower total body potassium levels, sodium polystyrene (a potassium-binding medicine) is started, sometimes with IV Lasix and saline." +"Hyperkalemia results either from the shift of potassium out of cells or from abnormal renal potassium excretion. Cell shift leads to transient increases in the plasma potassium concentration, whereas decreased renal excretion of potassium leads to sustained hyperkalemia. Impairments in renal potassium excretion can be the result of reduced sodium delivery to the distal nephron, decreased mineralocorticoid level or activity, or abnormalities in the cortical collecting duct. In some instances, all 3 of these perturbations are present. Excessive intake of potassium can cause hyperkalemia but usually in the setting of impaired renal function. We discuss the clinical manifestations of hyperkalemia and outline an approach to its diagnosis and treatment.","Hyperkalemia is a condition where the potassium level in the blood is higher than normal. Potassium is a very important mineral in the body. Hyperkalemia can be caused by too much potassium coming out of the cells into the blood. It can also be caused when the kidneys are not getting rid of enough potassium from the body through the urine. Hyperkalemia is temporary when too much comes out of the cells into the bloodstream. But, when the kidneys cannot get rid of enough potassium from the body, the hyperkalemia can last a longer time. There can be a few different reasons why the kidneys don't function correctly to get rid of potassium.� In some people, all the reasons are present at the same time. Taking in too much potassium through food or drink can cause hyperkalemia, especially if a person has a kidney problem. In this paper, we talk about how hyperkalemia can effect you. We also talk about how doctors can diagnose and treat it" +"Hypokalemia (ie, potassium levels less than 3.5 mEq/L) occurs in fewer than 1% of healthy individuals, but is present in up to 20% of hospitalized patients, 40% of patients taking diuretics, and 17% of patients with cardiovascular conditions. Hypokalemia often is asymptomatic; symptoms are more common in older adults. Common symptoms are cardiac arrhythmias and muscle weakness or pain. Management consists of intravenous potassium replacement during cardiac monitoring for patients with marked symptoms, echocardiogram (ECG) abnormalities, or severe hypokalemia (ie, level less than 3.0 mEq/L). Oral replacement is appropriate for asymptomatic patients with less severe hypokalemia. Hyperkalemia (ie, level greater than 5.5 mEq/L) also can cause cardiac arrhythmias and muscle symptoms. Urgent management is warranted for patients with potassium levels of 6.5 mEq/L or greater, if ECG manifestations of hyperkalemia are present regardless of potassium levels, or if severe muscle symptoms occur. Urgent management includes intravenous calcium, intravenous insulin, and inhaled beta agonists. Hemodialysis can be used in urgent situations. For patients with less severe hyperkalemia, renal elimination drugs sometimes are used, as are gastrointestinal elimination drugs. For all patients with hypokalemia or hyperkalemia, drug regimens should be reevaluated and, when possible, hypokalemia- or hyperkalemia-causing drugs should be discontinued.","Hypokalemia is a condition where the potassium level in the blood is less than normal. Potassium is a very important mineral in the body. Hypokalemia rarely happens in healthy people. It happens commonly In patients in the hospital, on diuretics, or with heart and circulation conditions. Hypokalemia can happen without patients noticing anything wrong. Older adult more commonly notice some effect (symptom) of hypokalemia. Common effects (symptoms) of hypokalemia are abnormal heart beats and muscle weakness or pain. Doctors treat hypokalemia�with IV potassium while monitoring�the heart� in patients who have significant symptoms, EKG problems, or severe hypokalemia. Doctors treat hypokalemia with potassium by mouth in patients without symptoms or if the hypokalemia is less severe. Hyperkalemia is a condition where the potassium level in the blood is higher than normal. Hyperkalemia can also cause abnormal heart beats and muscle symptoms. Doctors must treat hyperkalemia right away if the blood potassium levels are too high, if EKG changes occur (no matter what the blood potassium levels are), or if severe muscle symptoms occur. This urgent treatment includes IV calcium, IV insulin, and medicines given by an inhalers (called beta-agonists). Kidney dialysis can be used in urgent situations For patients with less severe hyperkalemia, sometimes medicines are used that can get rid of the excess potassium through�the kidneys or the� bowels. For all patients with hypokalemia or hyperkalemia, all drugs taken by the patient should be reviewed by their doctor. When possible, the drugs that cause hypokalemia or hyperkalemia should be stopped." +"Purpose: Emerging treatment options for the management of chronic hyperkalemia in the outpatient setting are reviewed. Summary: Current treatment options for the management of hyperkalemia are limited and often accompanied by serious adverse effects. Two investigational drugs for the treatment of hyperkalemia are being evaluated in Phase III trials: sodium zirconium cyclosilicate and patiromer. Both of these drugs are administered orally and act by enhancing potassium's removal, predominantly through the gastrointestinal tract. The safety and efficacy of sodium zirconium cyclosilicate and patiromer were evaluated in Phase II and III trials. Both agents were studied in patients with chronic mild-to-severe hyperkalemia, chronic kidney disease (CKD), or heart failure as well as those taking a renin-angiotensin system (RAS) inhibitor, an aldosterone antagonist, or both therapies. These clinical trials found that sodium zirconium cyclosilicate and patiromer normalized serum potassium levels quickly and maintained normalized serum potassium levels over several weeks. Both medications caused a rapid decrease in serum potassium, with two studies examining efficacy endpoints for 12 weeks or longer. The overall frequency of adverse effects in these clinical trials was low, with gastrointestinal adverse events being the most commonly observed. Conclusion: Options for the management of hyperkalemia, particularly chronic hyperkalemia in the outpatient setting, are limited. Both sodium zirconium cyclosilicate and patiromer are emerging therapies that may provide long-term management of hyperkalemia, particularly in patients with underlying heart failure or CKD as well as those taking an RAS inhibitor, an aldosterone antagonist, or both.","New treatments for long-lasting (chronic) hyperkalemia to take care of patients not in the hospital (outpatients) are being researched. Current treatments for hyperkalemia are few and often have serious side effects. Two new drugs are being researched for the treatment of hyperkalemia in new patient studies (clinical trials). Their names are sodium zirconium cyclosilicate and patiromer. Both of these drugs are given by mouth. They act by increasing the removal of potassium from the body, mostly through the gastrointestinal tract. The gastrointestinal tract includes the stomach and the bowels. These drugs have already been studied in people for their safety and effectiveness in past clinical trials. These clinical trials included patients with chronic hyperkalemia (ranging from mild to severe), chronic kidney disease, or heart failure. These research trials also included patients taking other drugs at the same time. These other drugs included a class of drugs that block the renin-angiotensin-aldosterone system called RAAS blockers. The renin-angiotensin-aldosterone system is a hormone system that manages blood pressure and fluid balance in the body. These clinical trials found that sodium zirconium cyclosilicate and patiromer brought the blood potassium levels down to normal quickly and kept the blood levels of potassium normal for several weeks. Both drugs caused a fast decrease in blood potassium levels. Two of these patient trials studied the effectiveness for 12 weeks or longer. The overall number of side effects in these patient studies was low. The most common side effects seen were related to the gastrointestinal tract. Doctors don�t have a lot of ways to treat hyperkalemia, especially chronic hyperkalemia if the patient is not in the hospital. Both sodium zirconium cyclosilicate and patiomer are new drugs that may provide long term treatment of hyperkalemia . These drugs may be very helpful in patients who also have heart failure or chronic kidney disease. They may also be helpful in patients taking one or more types of RAAS blockers." +"Patients with end-stage renal disease (ESRD) on maintenance dialysis have a high risk of developing hyperkalemia, generally defined as serum potassium (K+) concentrations of >5.0 mmol/l, particularly those undergoing maintenance hemodialysis. Currently, the key approaches to the management of hyperkalemia in patients with ESRD are dialysis, dietary K+ restriction, and avoidance of medications that increase hyperkalemia risk. In this review, we highlight the issues and challenges associated with effective management of hyperkalemia in patients undergoing maintenance dialysis using an illustrative case presentation. In addition, we examine the potential nondialysis options for the management of these patients, including use of the newer K+ binder agents patiromer and sodium zirconium cyclosilicate, which may reduce the need for the highly restrictive dialysis diet, with its own implication on nutritional status in patients with ESRD, as well as reducing the risk of potentially life-threatening hyperkalemia.","Patients with end-stage renal disease (ESRD) on regular, ongoing (maintenance) dialysis have a high risk of developing hyperkalemia. Hyperkalemia is defined as a potassium level in the blood that is higher than normal. Currently, the main treatments of hyperkalemia in patients with ESRD are dialysis, eating a diet low in potassium, and avoiding medicines that increase the risk of hyperkalemia. In this paper, we focus on the issues and problems associated with the treatment of hyperkalemia in patients on maintenance dialysis. We present a case to illustrate these issues. We also discuss potential treatments, other than dialysis, for these patients. Newer drugs , such as patiromer and sodium zirconium cyclosilicate bind to potassium. These potassium-binding drugs may reduce the need for the very strict dialysis diet. Because the dialysis diet is very strict, there may be problems getting enough nutrition for patients with ESRD. These potassium-binding drugs may also reduce the risk of potentially life-threatening hyperkalemia." +"Purpose of review: Hyperkalemia is a potentially fatal electrolyte disorder, more commonly present when the potassium excretion capacity is imparied. Hyperkalemia can lead to adverse outcomes, especially due to severe cardiac arrhythmias. It can also impair the cardiovascular effects of renin-angiotensin-aldosterone system inhibitors (RAASis) and potassium rich diets, as hyperkalemia frequently leads to their discontinuation. Recent findings: Potassium is a predictor of mortality and should be monitored closely for patients who are at risk for hyperkalemia. Acute hyperkalemia protocols have been revised and updated. Randomized trials have shown that the new anti-hyperkalemic agents (patiromer and zirconium cyclosilicate) are effective hyperkalemia treatment options. The use of anti-hyperkalemic agents may allow for a less restrictive potassium diet and lower RAASi discontinuation rates. Summary: Hyperkalemia should be monitored closely for high-risk patients, as it is associated with adverse outcomes. New therapies have demonstrated effective control, offering hope for potential use in patients that would benefit from diet or medications associated with an increase in serum potassium, indicating that the use of hyperkalemic agents can be associated with better outcomes.","Hyperkalemia is a condition where the potassium level in the blood is higher than normal. Potassium is a very important mineral (electrolyte) in the body. Hyperkalemia is a potentially fatal electrolyte disorder. It more likely occurs when the body cannot get rid of potassium as well as it should. Hyperkalemia can lead to serious problems. Especially because hyperkalemia can cause severe problems with the heart beat. The renin-angiotensin-aldosterone system (RAAS) is a hormone system that manages blood pressure and fluid balance in the body. Drugs that block the RAAS (RAAS blockers) have good effects on the cardiovascular system (heart and blood vessels). But the RAAS blockers can cause hyperkalemia. High-potassium diets can also have good effects on the cardiovascular system. But doctors have to stop giving these RAAS blockers and also recommend low-potassium diets in patients with hyperkalemia. Potassium can predict mortality. Potassium levels should be checked often in patients at risk for hyperkalemia. The rules for treating hyperkalemia that occurs rapidly have been updated. Patient studies have shown that the new drugs to treat hyperkalemia (patiromer and zirconium cyclosilicate) work well to treat hyperkalemia. These new drugs may let doctors continue to use the RAAS blockers more often. Doctors may be able to recommend less strict potassium diets too. Hyperkalemia should be closely watched for in high-risk patients because it can lead to poor outcomes. New drugs have been shown to work well. There is hope that these new drugs can control the blood potassium levels in patients that would benefit from RAAS blockers and diets higher in potassium, leading to better overall treatment results." +"New recommendations for the classification and diagnosis of diabetes mellitus include the preferred use of the terms ""type 1"" and ""type 2"" instead of ""IDDM"" and ""NIDDM"" to designate the two major types of diabetes mellitus; simplification of the diagnostic criteria for diabetes mellitus to two abnormal fasting plasma determinations; and a lower cutoff for fasting plasma glucose (126 mg per dL [7 mmol per L] or higher) to confirm the diagnosis of diabetes mellitus. These changes provide an easier and more reliable means of diagnosing persons at risk of complications from hyperglycemia. Currently, only one half of the people who have diabetes mellitus have been diagnosed. Screening for diabetes mellitus should begin at 45 years of age and should be repeated every three years in persons without risk factors, and should begin earlier and be repeated more often in those with risk factors. Risk factors include obesity, first-degree relatives with diabetes mellitus, hypertension, hypertriglyceridemia or previous evidence of impaired glucose homeostasis. Earlier detection of diabetes mellitus may lead to tighter control of blood glucose levels and a reduction in the severity of complications associated with this disease.","New recommendations for classifying diabetes mellitus include using ""type 1"" and ""type 2"" instead of ""IDDM"" and ""NIDDM"" to identify the two major types of diabetes mellitus; simplifying the criteria for identifying diabetes mellitus to two unusual fasting blood scores; and a lower cutoff for fasting plasma glucose or blood sugar. These changes help improve identification of those at risk from effects of high blood sugar. Currently, only half of those with diabetes mellitus have been identified. Testing for diabetes mellitus should begin at 45 years of age and be repeated every three years in those without health risks. Testing should begin earlier and more often for those with health risks. Health risks include obesity, first-degree relatives with diabetes, high blood pressure, high blood fat, or prior signs of blood sugar imbalance. Earlier detection of diabetes mellitus may improve blood sugar control and health issues from the disease." +"Diagnostic criteria for diabetes in children have not been established with nearly the rigor as that employed in adults. Recently revised American Diabetes Association (ADA) criteria allowed utilization of hemoglobin A(1c) (HbA1c) ? 6.5 % for diagnosis of diabetes. A recent series of pediatric studies appear to show that HbA1c has lower sensitivity than Fasting plasma glucose (FPG) or oral glucose tolerance test (OGTT). However, FPG and OGTT have themselves never been validated in children. Studies to validate diagnostic thresholds in children appear unlikely to take place. Thus, accepting the major ADA diagnostic criteria appears to be the best course of action for the pediatric community. One area in which correlation studies between HbA1c and FPG or OGTT might shed light is in the definition of criteria for intervention in 'pre-diabetes,' as the Diabetes Prevention Program Trial did not use HbA1c. However, such treatment, and the exact diagnostic thresholds at which it should be initiated in children, remains unproven.","Standards of diagnosing diabetes in children have not been established with nearly the same precision as has been used in adults Recently revised American Diabetes Association (ADA) guidelines uses the standard of ? 6.5 % in the HbA1c test as a diagnosis of diabetes. Recent studies in children show that the HbA1c test is not as accurate as other tests that measure glucose in the blood. However, other glucose measuring blood tests have not yet been verified to work in children. Future studies, to see which glucose measuring test is best in children, are unlikely to happen. Accepting the ADA guidelines for diagnosing diabetes in children appears to be the best option for pediatricians. Future studies on blood glucose tests should try to develop a guideline for doctors to treat �pre-diabetes�. However, such treatment, and the best way to diagnose and treat �pre-diabetes�, has not been proven. " +In 1997 the American Diabetes Association lowered the threshold for diagnosis of diabetes from a fasting plasma glucose concentration of 7.8 mmol/l to 7.0 mmol/l and advised that the oral glucose tolerance test no longer be used in routine clinical practice. In 1999 the World Health Organization endorsed the reduction in fasting plasma glucose threshold but recommended retaining the oral glucose tolerance test for anyone with impaired fasting glucose (6.1 mmol/l-6.9 mmol/l). This Review discusses the impact of these changes on the prevalence of diabetes and examines the implications for individuals and specific high-risk groups. The phenotype of those diagnosed with diabetes and the predictive value for the development of complications according to the different criteria are compared. It is clear that these changes in diagnostic criteria have major importance both for individuals and for resource planning at a national level.,In 1997 the American Diabetes Association lowered the threshold for diagnosis of diabetes from a fasting (having not eaten food recently) blood glucose (sugar) level of 7.8 mmol/l to 7.0 mmol/l and advised that the by-mouth glucose tolerance test no longer be used in regular clinical practice. In 1999 the World Health Organization supported the reduction in fasting blood glucose threshold but recommended keeping the by-mouth glucose tolerance test for anyone with affected fasting glucose (6.1 mmol/l-6.9 mmol/l). This Review discusses the effect of these changes on the prevalance of diabetes and checks how it affects individuals and specific high-risk groups. The physical effects of those identified with diabetes and the predictive value for the development of side effects according to the different criteria are compared. It is clear that these changes in identification criteria have major importance both for individuals and for planning at a national level. +"The classification of diabetes was originally limited to only two categories called juvenile-onset diabetes mellitus, now known as type 1 diabetes mellitus, and adult-onset diabetes mellitus, now known as type 2 diabetes mellitus. This has grown to a recognition of more than 50 subcategories caused by various pathogenic mechanisms or accompanying other diseases and syndromes. The diagnosis of diabetes has evolved from physician recognition of typical symptoms to detection of ambient hyperglycemia and, thence, to the definition of excessive plasma glucose levels after an overnight fast and/or following challenge with a glucose load (oral glucose tolerance test or OGTT), and more recently, by measurement of glycated hemoglobin (A1c). Screening has uncovered a much higher prevalence of diabetes in the United States and elsewhere, as well as its enormous public health impact. Modern testing has defined individuals at high risk for the development of diabetes and pregnant women whose fetuses are at increased risk for mortality and morbidity. Diagnostic glycemic criteria for presymptomatic diabetes have been set using diabetic retinopathy as a specific complication of the disease: A1c ?6.5%; fasting plasma glucose (FPG) ?126 mg/dL; or plasma glucose measured 2 hours after an OGTT (2-hour PG) ?200 mg/dL. For patients with typical symptoms, a random plasma glucose ?200 mg/dL is diagnostic. The 2-hour PG yields the highest prevalence and A1c the lowest. A1c is the most convenient and practical test, requiring no preparation, is analytically superior, and has the lowest intraindividual variation. It is more expensive than the FPG, but the same or less than the OGTT. The 2-hour PG is the most burdensome to the patient and has the highest intraindividual variation. Standardized measurement of A1c is not available everywhere. Confirmation of an abnormal test with the same test is recommended. Studies in various populations show inconsistency among the glycemic tests. Of people meeting the A1c criterion, 27%�98% meet plasma glucose criteria. Of people meeting plasma glucose criteria, 17%�78% meet the A1c criterion. These discrepancies occur because each test measures different aspects of hyperglycemia that may vary among patients. While the risk of future diabetes is continuously associated with plasma glucose and A1c, the areas between the upper limits of normal and the diabetes cutpoints have been called �prediabetes� or �high risk for diabetes.� These have been defined categorically as A1c 6.0%�6.4% or 5.7%�6.4%; impaired fasting glucose (IFG), FPG 100�125 mg/dL; and impaired glucose tolerance (IGT), 2-hour PG 140�199 mg/dL. A1c 6.0%�6.4% increases the odds ratio (OR) for progression to diabetes (OR 12.5�16) more than the range of 5.7%�6.4% (OR 9.2). In U.S. studies, the incidence of type 2 diabetes averages approximately 6% per year in people with IGT and can reverse spontaneously. IFG is more prevalent than IGT in the United States, though IGT rises more sharply with age. IFG increases the risk of future diabetes to various degrees in different countries, with odds ratios ranging from 2.9 to 18.5.","Classifying diabetes was originally limited to either juvenile-onset diabetes mellitus, or type 1 diabetes mellitus, and adult-onset diabetes mellitus, or type 2 diabetes mellitus. Classification of diabetes now recognizes over 50 subcategories by disease-causing biological processes or accompanying diseases. Diagnosing diabetes has grown from a physician recognizing typical signs to detecting high blood sugar to defining high blood sugar after an overnight fast and/or tolerance test with glucose (a simple sugar). Recently, the diagnosis involves measuring glycated hemoglobin (A1c), an iron-rich protein in blood joined to a sugar. Testing now shows higher widespreadness of and enormous public health impact of diabetes in the United States and elsewhere. Current testing has detected those at risk for diabetes and pregnant women whose fetuses are at higher risk for death and illness. Diagnostic glycemic (blood sugar) criteria for before-symptom diabetes have been set using diabetic retinopathy (eye-affecting diabetes) as a specific effect of the disease: A1c ?6.5%; fasting plasma glucose (FPG) ?126 mg/dL; or blood glucose (sugar) measured 2 hours after an OGTT (2-hour PG) ?200 mg/dL. For patients with typical symptoms, a random blood glucose ?200 mg/dL is diagnostic. The 2-hour PG (a type of blood sugar measurement) yields the highest prevalence and A1c (another test for diabetes) the lowest. A1c is the most convenient and practical test, needing no preparation, is analytically betterr, and has the lowest variation. It is more expensive than the FPG (a diabetes test), but the same or less than the OGTT (a diabetes test). The 2-hour PG is the most burdensome to the patient and has the highest variation. Comparable measurement of A1c is not available everywhere. Checking an abnormal test with the same test is recommended. Studies in various groups show inconsistency among the glycemic tests. Of people meeting the A1c criterion, 27%�98% meet plasma glucose criteria. Of people meeting plasma glucose criteria, 17%�78% meet the A1c criterion. These discrepancies occur because each test measures different aspects of hyperglycemia (high blood sugar) that may vary among patients. While the risk of future diabetes is continuously associated with plasma glucose and A1c, the areas between the upper limits of normal and the diabetes cutpoints have been called �prediabetes� or �high risk for diabetes.� These have been defined categorically as A1c 6.0%�6.4% or 5.7%�6.4%; impaired fasting glucose (IFG), FPG 100�125 mg/dL; and impaired glucose tolerance (IGT), 2-hour PG 140�199 mg/dL. A1c 6.0%�6.4% increases the odds ratio (OR) for progression to diabetes (OR 12.5�16) more than the range of 5.7%�6.4% (OR 9.2). In U.S. studies, the incidence of type 2 diabetes averages approximately 6% per year in people with IGT and can reverse spontaneously. IFG is more prevalent than IGT in the United States, though IGT rises more sharply with age. IFG increases the risk of future diabetes to various degrees in different countries, with odds ratios ranging from 2.9 to 18.5." +"Polyuria-polydipsia syndrome consists of the three main entities: central or nephrogenic diabetes insipidus and primary polydipsia. Reliable distinction between these diagnoses is essential as treatment differs substantially, with the wrong treatment potentially leading to serious complications. Past diagnostic measures using the classical water deprivation test had several pitfalls and clinicians were often left with uncertainity concerning the diagnosis. With the establishment of copeptin, a stable and reliable surrogate marker for arginine vasopressin, diagnosis of the polyuria-polydipsia syndrome has been newly evaluated. Whereas unstimulated basal copeptin measurement reliably diagnoses nephrogenic diabetes insipidus, two new tests using stimulated copeptin cutoff levels showed a high diagnostic accuracy in differentiating central diabetes insipidus from primary polydipsia. For the hypertonic saline infusion test, osmotic stimulation via the induction of hypernatraemia is used. This makes the test highly reliable and superior to the classical water deprivation test, but also requires close supervision and the availability of rapid sodium measurements to guarantee the safety of the test. Alternatively, arginine infusion can be used to stimulate copeptin release, opening the doors for an even shorter and safer diagnostic test. The test protocols of the two tests are provided and a new copeptin-based diagnostic algorithm is proposed to reliably differentiate between the different entities. Furthermore, the role of copeptin as a predictive marker for the development of diabetes insipidus following surgical procedures in the sellar region is described.","Polyuria-polydipsia syndrome consists of the three main effects: central or nephrogenic (kidney-related) diabetes insipidus (constantly-urinating) and primary polydipsia (great thirst). Reliable differences between these diagnoses is needed as treatment differs greatly, with the wrong treatment potentially leading to serious side effects. Past identification measures using the classical water deprivation test had several pitfalls and clinicians were often left with uncertainity regarding the diagnosis. With the creation of copeptin, a stable and reliable surrogate marker for arginine vasopressin (blood vessel constriction), diagnosis of the polyuria-polydipsia syndrome has been newly evaluated. Whereas unstimulated basal copeptin (specific protein) measurement reliably identifies nephrogenic diabetes insipidus, two new tests using stimulated copeptin cutoffs showed a high identification accuracy in differentiating central diabetes insipidus from primary polydipsia. For the hypertonic (very salty) saline infusion test, water-sucking stimulation via a high salt amount is used. This makes the test highly reliable and superior to the classical water deprivation test, but also requires close watch and the availability of rapid sodium measurements to guarantee the test's safety. Alternatively, arginine infusion (adding a specific protein in) can be used to stimulate copeptin release, opening the doors for an even shorter and safer diagnostic test. The test protocols of the two tests are provided and a new copeptin-based diagnostic method is proposed to reliably identify between the different entities. Furthermore, the role of copeptin as a predictive marker for the development of diabetes insipidus following surgeries in the sellar region (an area of the head) is described." +"Introduction: Maturity onset diabetes of the young (MODY) is a rare form of monogenic diabetes. Being clinically and genetically heterogeneous, it is often misdiagnosed as type 1 or type 2 diabetes, leading to inappropriate therapy. MODY is caused by a single gene mutation. Thirteen genes, defining 13 subtypes, have been identified to cause MODY. A correct diagnosis is important for the right therapy, prognosis, and genetic counselling. Material and methods: Twenty-nine unrelated paediatric patients clinically suspected of having MODY diabetes were analysed using TruSight One panel for next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA) assay. Results: In this study we identified variants in MODY genes in 22 out of 29 patients (75.9%). Using two genetic tests, NGS and MLPA, we detected both single nucleotide variants and large deletions in patients. Most of the patients harboured a variant in the GCK gene (11/22), followed by HNF1B (5/22). The rest of the variants were found in the NEUROD1 and HNF1A genes. We identified one novel variant in the GCK gene: c.596T>C, p.Val199Ala. The applied genetic tests excluded the suspected diagnosis of MODY in two patients and revealed variants in other genes possibly associated with the patient's clinical phenotype. Conclusions: In our group of MODY patients most variants were found in the GCK gene, followed by variants in HNF1B, NEUROD1, and HNF1A genes. The combined NGS and MLPA-based genetic tests presented a comprehensive approach for analysing patients with suspected MODY diabetes and provided a successful differential diagnosis of MODY subtypes.","The study's introduction states that the maturity onset diabetes of the young (MODY) is a rare form of single-gene-causing diabetes. Being clinically and genetically diverse, it is often misdiagnosed as type 1 or type 2 diabetes, leading to inappropriate therapy. MODY is caused by a single gene mutation. Thirteen genes, defining 13 types, have been identified to cause MODY. A correct diagnosis is important for the right therapy, recovery, and genetic counselling. The study's material and methods include twenty-nine unrelated child patients clinically suspected of having MODY diabetes analysed with DNA sequencing. As the results in this study, we identified different types in MODY genes in 22 out of 29 patients (75.9%). Using two genetic tests termed NGS and MLPA, we detected both small mutation types and large gene deletions in patients. Most patients had a different type in the GCK gene (11/22), followed by HNF1B (5/22). The rest of the different types were found in the NEUROD1 and HNF1A genes. We identified one novel gene type in the GCK gene. The applied genetic tests excluded the suspected diagnosis of MODY in two patients and revealed subtypes in other genes possibly linked with the patient's clinical physical characteristics. In conclusion, in our group of MODY patients, most gene types were found in the GCK gene, followed by changes in HNF1B, NEUROD1, and HNF1A genes. The combined genetic tests presented a comprehensive way to analyze patients with possible MODY diabetes and provided a successful diagnosis of MODY subtypes." +"The International Expert Committee recommends that the diagnosis of diabetes be made if hemo globin A1c (HbA1c) level is greater, similar 6.5% and confirmed with a repeat HbA1c test. The committee recommends against ""mixing different methods to diagnose diabetes"" because ""the tests are not completely concordant: using different tests could easily lead to confusion"". Fasting plasma glucose, 2-hour postglucose-load plasma glucose, and oral glucose tolerance tests are recommended for the diagnosis of diabetes only if HbA1c testing is not possible due to unavailability of the assay, patient factors that preclude its inter pretation, and during pregnancy. HbA1c testing has the advantages of greater clinical convenience, preanalytic stability, and assay standardization, but when used as the sole diagnostic criterion for diabetes, it has the potential for systematic error. Factors that may not be clinically evident impact HbA1c test results and may systematically raise or lower the value relative to the true level of glycemia. For this reason, HbA1c should be used in combination with plasma glucose determinations for the diagnosis of diabetes. If an HbA1c test result is discordant with the clinical picture or equivocal, plasma glucose testing should be performed. A diagnostic cut-off point of HbA1c greater, similar 6.5% misses a substantial number of people with type 2 diabetes, including some with fasting hyperglycemia, and misses most people with impaired glucose tolerance. Combining the use of HbA1c and plasma glucose measurements for the diagnosis of diabetes offers the benefits of each test and reduces the risk of systematic bias inherent in HbA1c testing alone.","An international committee recommends diagnosing diabetes if hemoglobin A1c (HbA1c), an iron-rich blood protein joined to a sugar, is at or over 6.5% with multiple tests. The committee recommends not ""mixing different methods to diagnose diabetes"" because ""the tests are not completely concordant [or consistent]: using different tests could easily lead to confusion"". Fasting blood sugar tests and blood sugar tests after simple sugar intake may help identify diabetes only if testing for HbA1c is not possible. HbA1c testing is useful for greater convenience, accuracy, and uniformity, but as the single tool for identification, it may lead to measurement errors. Unknown factors may alter scores of the iron-rich blood protein relative to the actual blood sugar level. Thus, tests for this iron-rich blood protein connected to a sugar should be combined with other blood sugar values for diabetes identification. If a score for HbA1c disagrees with the general reading, blood sugar testing should be performed. A cut-off point at or over 6.5% for HbA1c misses many with type 2 diabetes, high fasting blood sugar, and impaired blood sugar sensitivity. Using tests for HbA1c and blood sugar measurements identifies diabetes better than HbA1c tests alone." +"Diabetes mellitus is a common disease whose complications are severe. For decades, the diagnosis of diabetes and prediabetes was using only fasting glucose or glucose two hours during an oral glucose tolerance test. Recently, it is possible to use HbA1c. Each of these tests has advantages and limitations that must be well known by clinicians for better care for patients. So they could use one, two or three of this tests to reach to a proper diagnosis. The aim of this article is about the strong and weak points of these tests.","Diabetes mellitus is a common disease whose side effects are severe. For decades, the diagnosis of diabetes and prediabetes was using only fasting (without food) glucose or glucose two hours during an by-mouth (oral) glucose sensitivity test. Recently, it is possible to use HbA1c (a simple blood sugar test). Each of these tests has pros and cons that must be well known by clinicians for better care for patients. So they could use one, two or three of this tests to reach a proper diagnosis. This article's aim is about the strong and weak points of these tests." +Objective: The objective of this study was to compare the use of hemoglobin A1C to oral glucose tolerance testing to diagnose overt type 2 diabetes in the first trimester of pregnancy. The study used a nonexperimental descriptive design to compare the use of the hemoglobin A1C test results to oral glucose tolerance test results. Methods: The study used a sample of 45 women at high risk for type 2 diabetes in the first trimester of pregnancy. Participants were consented to draw a hemoglobin A1C with their ordered oral glucose tolerance testing for comparison of the two tests' ability to diagnose overt type 2 diabetes. Results: Hemoglobin A1C tests were highly positively correlated with oral glucose tolerance testing for diagnosis of type 2 diabetes in women in the first trimester of pregnancy. Conclusion: The research provides beginning evidence that the hemoglobin A1C should be considered as a first-tier diagnostic test for overt type 2 diabetes in the first trimester of pregnancy.,"The objective of this study was to compare the use of hemoglobin A1C (a simple blood sugar test) to oral (by-mouth) glucose sensitivity (tolerance) testing to diagnose before-birth type 2 diabetes in the first trimester of pregnancy. The study used a nonexperimental design to compare the use of the hemoglobin A1C test results to oral glucose tolerance test results. The study's methods included a sample of 45 women at high risk for type 2 diabetes in the first trimester of pregnancy. Participants volunteered to draw a hemoglobin A1C with their oral glucose tolerance testing for comparison of the two tests' ability to diagnose type 2 diabetes. For the study's results, hemoglobin A1C tests were highly linked with oral glucose tolerance testing for diagnosis of type 2 diabetes in women in the first trimester of pregnancy. In conclusion, the research provides beginning evidence that the hemoglobin A1C should be considered as an important diagnostic test for before-birth type 2 diabetes in the first trimester of pregnancy." +"Highly sensitive and specific radioimmunoassays have been validated for autoantibodies reacting with the four major autoantigens identified so far in autoimmune diabetes. However, the analysis of this large number of autoantigens has increased the costs and time necessary for complete autoantibody screenings. Our aim was to demonstrate that it is possible to detect the immunoreactivity against a combination of four different autoantigens by a single assay, this representing a rapid, low-cost first approach to evaluate humoral autoimmunity in diabetes. By using this novel multi-autoantigen radioimmunoassay (MAA), in subsequent steps we analysed 830 sera, 476 of known and 354 of unknown diabetes-specific immunoreactivity, collected from various groups of individuals including type 1 and type 2 diabetes patients, autoantibody-positive patients with a clinical diagnosis of type 2 diabetes (LADA), prediabetic subjects, individuals at risk to develop autoimmune diabetes, siblings of type 1 diabetic patients, coeliac patients and healthy control subjects. All sera reacting with one or more of the four autoantigens by single assays also resulted positive with MAA, as well as eight of 24 type 1 diabetic patients classified initially as autoantibody-negative at disease onset based on single autoantibody assays. In addition, MAA showed 92% sensitivity and 99% specificity by analysing 140 blinded sera from type 1 diabetic patients and control subjects provided in the 2010 Diabetes Autoantibody Standardization Program. MAA is the first combined method also able to evaluate, in addition to glutamic acid decarboxylase (GAD) and tyrosine phosphatase (IA)-2, insulin and islet beta-cell zinc cation efflux transporter (ZnT8) autoantibodies. It appears to be particularly appropriate as a first-line approach for large-scale population-based screenings of anti-islet autoimmunity.","Certain precise measuring tools can measure specific, self-made proteins that tag four major markers of autoimmune diabetes (diabetes from the body mistakenly destroying its own cells). However, analysis of these many self-made markers increases costs and time for measurements. We aim to show a quick, low-cost approach for detecting these four self-made markers to check for antibody-related autoimmunity in diabetics. With this new measuring tool, which is called a multi-autoantigen radioimmunoassay (MAA), we measured 830 blood samples, 476 of known and 354 of unknown diabetes type. These samples came from type 1 and type 2 diabetics, slow-progressing type 2 diabetics, prediabetics, individuals at risk to develop autoimmune diabetes, siblings of type 1 diabetics, gluten-sensitive patients, and healthy patients. All blood reacting with one or more of the four self-made markers by other tools also reacts with MAA, along with eight more, type 1 diabetics whose blood did not react with other tools. Also, MAA shows high accuracy for disease detection and no detection after analysing 140 unknown blood samples from type 1 diabetics and healthy patients. MAA is the first to measure multiple self-made tagging proteins. This new tool appears appropriate for checking if a person's cells mistakenly attack their own diabetes-regulating cells." +"Objective: To describe the historical refinements, understanding of physiology and clinical outcomes observed with thyroid hormone replacement strategies. Methods: A Medline search was initiated using the search terms, levothyroxine, thyroid hormone history, levothyroxine mono therapy, thyroid hormone replacement, combination LT4 therapy, levothyroxine Bioequivalence. Pertinent articles of interest were identified by title and where available abstract for further review. Additional references were identified in the course of review of the literature identified. Results: Physicians have intervened in cases of thyroid dysfunction for more than two millennia. Ingestion of animal thyroid derived preparations has been long described but only scientifically documented for the last 130 years. Refinements in hormone preparation, pharmaceutical production and regulation continue to this day. The literature provides documentation of physiologic, pathologic and clinical outcomes which have been reported and continuously updated. Recommendations for effective and safe use of these hormones for reversal of patho-physiology associated with hypothyroidism and the relief of symptoms of hypothyroidism has documented a progressive refinement in our understanding of thyroid hormone use. Studies of thyroid hormone metabolism, action and pharmacokinetics have allowed evermore focused recommendations for use in clinical practice. Levothyroxine mono-therapy has emerged as the therapy of choice of all recent major guidelines. Conclusions: The evolution of thyroid hormone therapies has been significant over an extended period of time. Thyroid hormone replacement is very useful in the treatment of those with hypothyroidism. All of the most recent guidelines of major endocrine societies recommend levothyroxine mono-therapy for first line use in hypothyroidism.","Our objective is to summarize the history, understanding of how they work, and patient health changes seen with thyroid hormone replacement treatments. We searched Medline using the search terms, levothyroxine, thyroid hormone history, levothyroxine mono therapy, thyroid hormone replacement, combination LT4 therapy, levothyroxine Bioequivalence. Both levothyroxine and LT4 are synthetic thryoid hormones. We identified important papers by title and abstract to look at more closely when possible. We found more references while reading the important papers. Doctors have treated overactive and underactive thyroids for more than 2000 years. Taking forms of medicine that come from animal thyroid glands has been described for a long time but only written about in scientific papers for the last 130 years. Improvements in hormone medication preparation, drug production and drug laws continue to this day. Normal body function, disease, and patient health effects are described and updated regularly in scientific papers. Using these hormones to successfully and safely undo changes to body function and improve other symptoms of an underactive thyroid shows our improved understanding of their use. Better patient care has resulted from studies of thyroid hormone metabolism, how it works, and what the body does to it. The use of a single drug, levothyroxine, has become the top thyroid medicine based on recent major guidelines. Thyroid hormone treatments have been developed over a long time period. Thyroid hormone replacement is very useful in treating an underactive thyroid. Levothyroxine is widely accepted as the first treatment for an underactive thyroid." +"Thyroiditis is a general term that encompasses several clinical disorders characterized by inflammation of the thyroid gland. The most common is Hashimoto thyroiditis; patients typically present with a nontender goiter, hypothyroidism, and an elevated thyroid peroxidase antibody level. Treatment with levothyroxine ameliorates the hypothyroidism and may reduce goiter size. Postpartum thyroiditis (occurring within one year of childbirth, miscarriage, or medical abortion) can be short-lived or long-lasting. Release of preformed thyroid hormone into the bloodstream may result in hyperthyroidism. This may be followed by transient or permanent hypothyroidism as a result of depletion of thyroid hormone stores and destruction of thyroid hormone-producing cells. Patients should be monitored for changes in thyroid function. Beta blockers can treat symptoms in the initial hyperthyroid phase; in the subsequent hypothyroid phase, levothyroxine should be considered in women with a serum thyroid-stimulating hormone level greater than 10 mIU per L, or in women with a thyroid-stimulating hormone level of 4 to 10 mIU per L who are symptomatic or desire fertility. Subacute thyroiditis is a transient thyrotoxic state characterized by anterior neck pain, suppressed thyroid-stimulating hormone, and low radioactive iodine uptake on thyroid scanning. Many cases of subacute thyroiditis follow an upper respiratory viral illness, which is thought to trigger an inflammatory destruction of thyroid follicles. In most cases, the thyroid gland spontaneously resumes normal thyroid hormone production after several months. Treatment with high-dose acetylsalicylic acid or nonsteroidal anti-inflammatory drugs is directed toward relief of thyroid pain.","Thyroiditis refers to medical conditions that include thyroid inflammation. The most common type of thyroiditis is Hashimoto thyroiditis. Patients usually have a painless enlarged thyroid, underactive thyroid, and high levels of proteins made by the immune system to fight foreign substances. Taking levothyroxine, a thyroid drug, improves underactive thyroid and may decrease thyroid size. Short-lived or long-lasting thyroiditis can occur postpartum, within one year of childbirth, miscarriage, or medical abortion. Overactive thyroid can be caused by stored thyroid hormone released to the blood. Overactive thyroid may be followed by short-term or permanent underactive thyroid. Patients should be checked for changes in thyroid function. Beta blockers can improve overactive thyroid symptoms. Levothyroxine, a thyroid drug, can improve underactive thyroid symptoms in women with high blood levels of hormones that act as a messenger to the thyroid. Subacute thyroiditis is short-lived and characterized by neck pain, low blood levels of hormones that acts as a messenger to the thyroid, and low thyroid function based on a common test. Many subacute thyroiditis cases follow colds. The thyroid usually returns to normal on its own after many months. High-dose aspirin or similar over-the-counter pain relievers can be taken to relieve thyroid pain." +"Thyroiditis is a general term that encompasses several clinical disorders characterized by inflammation of the thyroid gland. The most common is Hashimoto thyroiditis; patients typically present with a nontender goiter, hypothyroidism, and an elevated thyroid peroxidase antibody level. Treatment with levothyroxine ameliorates the hypothyroidism and may reduce goiter size. Postpartum thyroiditis (occurring within one year of childbirth, miscarriage, or medical abortion) can be short-lived or long-lasting. Release of preformed thyroid hormone into the bloodstream may result in hyperthyroidism. This may be followed by transient or permanent hypothyroidism as a result of depletion of thyroid hormone stores and destruction of thyroid hormone-producing cells. Patients should be monitored for changes in thyroid function. Beta blockers can treat symptoms in the initial hyperthyroid phase; in the subsequent hypothyroid phase, levothyroxine should be considered in women with a serum thyroid-stimulating hormone level greater than 10 mIU per L, or in women with a thyroid-stimulating hormone level of 4 to 10 mIU per L who are symptomatic or desire fertility. Subacute thyroiditis is a transient thyrotoxic state characterized by anterior neck pain, suppressed thyroid-stimulating hormone, and low radioactive iodine uptake on thyroid scanning. Many cases of subacute thyroiditis follow an upper respiratory viral illness, which is thought to trigger an inflammatory destruction of thyroid follicles. In most cases, the thyroid gland spontaneously resumes normal thyroid hormone production after several months. Treatment with high-dose acetylsalicylic acid or nonsteroidal anti-inflammatory drugs is directed toward relief of thyroid pain.","Thyroiditis covers multiple disorders represented by inflammation of the thyroid gland. The most common disorder is Hashimoto thyroiditis. Patients have enlarged thyroids, reduced thyroid function, and increased proteins targeting thyroid products. Levothyroxine (a thyroid hormone treatment) improves thyroid function and size. Post-birth thyroiditis is temporary or lasting thyroid dysfunction occuring within a year of childbirth, miscarriage, or medical abortion. Supplemental thyroid hormone release into the blood may cause excess thyroid function. Temporary or permanent reduced thryoid function may follow excess thyroid function due to thyroid hormone depletion and destruction of hormone-producing cells. Patients should be monitored for changes in thyroid function. Beta blockers (common high blood pressure medication) can treat symptoms of the initial phase of excess thyroid function. Levothyroxine should be considered for later phases in women with high thyroid-stimulating hormone levels. Subacute or fairly rapid thyroiditis (thyroid inflammation) is a temporary, thyroid-hormone-excess state with frontal neck pain, reduced thyroid-stimulating hormone, and low iodine sensitivity. Fairly rapid thyroiditis often follows an upper airway viral illness, thought to trigger inflammatory destruction of thyroid cells. In most cases, the thyroid gland suddenly returns to normal after several months. High-dose aspirin or nonsteroidal anti-inflammatory drugs help give thyroid pain relief." +"In the 1990s, selenium was identified as a component of an enzyme that activates thyroid hormone; since this discovery, the relevance of selenium to thyroid health has been widely studied. Selenium, known primarily for the antioxidant properties of selenoenzymes, is obtained mainly from meat, seafood and grains. Intake levels vary across the world owing largely to differences in soil content and factors affecting its bioavailability to plants. Adverse health effects have been observed at both extremes of intake, with a narrow optimum range. Epidemiological studies have linked an increased risk of autoimmune thyroiditis, Graves disease and goitre to low selenium status. Trials of selenium supplementation in patients with chronic autoimmune thyroiditis have generally resulted in reduced thyroid autoantibody titre without apparent improvements in the clinical course of the disease. In Graves disease, selenium supplementation might lead to faster remission of hyperthyroidism and improved quality of life and eye involvement in patients with mild thyroid eye disease. Despite recommendations only extending to patients with Graves ophthalmopathy, selenium supplementation is widely used by clinicians for other thyroid phenotypes. Ongoing and future trials might help identify individuals who can benefit from selenium supplementation, based, for instance, on individual selenium status or genetic profile.","In the 1990s, selenium was found to be a part of a protein that helps produce thyroid hormone. Since this discovery, many scientists have studied how selenium might help thyroid health. Selenium, which has antioxidant characteristics, is found in meat, seafood and grains. The amount of selenium eaten varies across the world due to different soils and how much of it plants absorb. Eating too much or too little selenium can cause health problems, with a small ideal range for consumption. Studies that look at how often diseases occur in different groups of people and why show a relationship between eating too little selenium and higher rates of inflamed thyroid caused by thyroid cells that are attacked by infection-preventing cells, Graves disease (a disease in which infection-preventing cells attack healthy cells and lead to an overactive thyroid), and enlarged thyroids. Studies of people taking selenium who have long-term inflamed thyroids caused by thyroid cells attacked by infection-preventing cells generally have bloodwork that suggests more normal thyroid function but no improvement in symptoms. In Graves disease, taking selenium might make overactive thyroid go away faster and make quality of life and eye problems better in people with mild thyroid eye disease. Although selenium is only recommended for people with thyroid eye disease, doctors prescribe selenium for other thyroid problems. Current and future studies might help determine who should take selenium based, for example, on blood selenium levels and heredity." +"Hashimoto's thyroiditis (HT) is the most prevalent autoimmune disorder characterized by the destruction of thyroid cells caused by leukocytes and antibody-mediated immune processes accompanied by hypothyroidism. In recent years, evidence has emerged pointing to various roles for vitamin D, including, proliferation and differentiation of normal and cancer cells, cardiovascular function, and immunomodulation. Vitamin D deficiency has been especially demonstrated in HT patients. The aim of this study was to investigate the effect of vitamin D on circulating thyroid autoantibodies and thyroid hormones profile (T4, T3, and TSH) in females with HT. Forty-two women with HT disease were enrolled in this randomized clinical trial study and divided into vitamin D and placebo groups. Patients in the vitamin D and placebo groups received 50 000 IU vitamin D and placebo pearls, weekly for 3 months, respectively. The serum levels of 25-hydroxy vitamin D [25(OH) D], Ca++ion, anti-thyroperoxidase antibody (anti-TPO Ab), anti-thyroglobulin antibody (anti-Tg Ab), T4, T3, and TSH were measured at the baseline and at the end of the study using enzyme-linked immunosorbent assays. The results of this study showed a significant reduction of anti-Tg Ab and TSH hormone in the Vitamin D group compared to the start of the study; however, there was a no significant reduction of anti-TPO Ab in the Vitamin D group compared to the placebo group (p=0.08). No significant changes were observed in the serum levels of T3 and T4 hormones. Therefore, vitamin D supplementation can be helpful for alleviation of the disease activity in HT patients; however, further well controlled, large, longitudinal studies are needed to determine whether it can be introduced in clinical practice.","Hashimoto's thyroiditis (HT) is the most common type of disease caused by thyroid cells that are attacked by infection-preventing cells and results in an underactive thyroid. Recently, science has shown vitamin D can change how normal and cancer cells grow, divide, and change from one cell to another, how the heart works, and how the body's immune system changes. Too little vitamin D is seen in people with Hashimoto's thyroiditis. This study aimed to determine the effect of vitamin D on thyroid autoantibodies (substances that develop when a person's immune system mistakenly attacks the thyroid) and thyroid hormone (T4, T3, and thyroid-stimulating hormone) blood levels in women. We split 42 women with HT disease into two groups and gave one group vitamin D and the other group sham treatment. We gave one group 50,000 international units of vitamin D and the other group sugar pills for 3 months. We measured blood levels of thyroid autoantibodies and thyroid hormones (T4, T3, and thyroid-stimulating hormone) at the beginning and end of the study using a common antibody-measuring tool. Blood levels of one antibody and thyroid-stimulating hormone were lower at the end of the study in the group taking vitamin D. The group taking vitamin D and the group taking sugar pills had similar blood levels of another antibody. Blood levels of T3 and T4 hormones did not change in either group. Therefore, taking vitamin D can help people with Hashimoto's thyroiditis. However, more large studies done over time are needed to see if it can be used in patient care." +"Background: Hashimoto's thyroiditis is an autoimmune disorder and the most common cause of hypothyroidism. The use of Nigella sativa, a potent herbal medicine, continues to increase worldwide as an alternative treatment of several chronic diseases including hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM). The aim of the current study was to evaluate the effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth Factor (VEGF) - 1, Nesfatin-1 and anthropometric features in patients with Hashimoto's thyroiditis. Methods: Forty patients with Hashimoto's thyroiditis, aged between 22 and 50 years old, participated in the trial and were randomly allocated into two groups of intervention and control receiving powdered Nigella sativa or placebo daily for 8 weeks. Changes in anthropometric variables, dietary intakes, thyroid status, serum VEGF and Nesfatin-1 concentrations after 8 weeks were measured. Results: Treatment with Nigella sativa significantly reduced body weight and body mass index (BMI). Serum concentrations of thyroid stimulating hormone (TSH) and anti-thyroid peroxidase (anti-TPO) antibodies decreased while serum T3 concentrations increased in Nigella sativa-treated group after 8 weeks. There was a significant reduction in serum VEGF concentrations in intervention group. None of these changes had been observed in placebo treated group. In stepwise multiple regression model, changes in waist to hip ratio (WHR) and thyroid hormones were significant predictors of changes in serum VEGF and Nesgfatin-1 values in Nigella sativa treated group (P < 0.05). Conclusions: Our data showed a potent beneficial effect of powdered Nigella sativa in improving thyroid status and anthropometric variables in patients with Hashimoto's thyroiditis. Moreover, Nigella sativa significantly reduced serum VEGF concentrations in these patients. Considering observed health- promoting effect of this medicinal plant in ameliorating the disease severity, it can be regarded as a useful therapeutic approach in management of Hashimoto's thyroiditis.","Hashimoto's thyroiditis is caused by thyroid cells that are attacked by infection-preventing cells and is the most common cause of an underactive thyroid. More people around the world are taking Nigella sativa, a powerful herbal medicine, as a nontraditional way to treat many long-term diseases including high cholesterol, high blood pressure and type 2 diabetes. The current study aimed to rate the effects of Nigella sativa on how well the thyroid is working, blood Vascular Endothelial Growth Factor (VEGF) - 1 (a protein that promotes new blood vessels), Nesfatin-1 (a chain of amino acids that affects hunger) and physical body measurements in people with Hashimoto's thyroiditis. We randomly split forty people with Hashimoto's thyroiditis and between 22 and 50 years old into two group and gave one group powdered Nigella sativa and the other group sham treatment for 8 weeks. We measured changes in physical body measurements, what people ate, thyroid function, blood VEGF and Nefastin-1 levels after 8 weeks. Taking Nigella sativa caused lower body weight and body mass index (BMI). People taking Nigella sativa had lower blood levels of thyroid-stimulating hormone and antibodies that target the thyroid and higher levels of blood thyroid hormone (T4) after 8 weeks. People taking Nigella sativa had lower blood levels of VEGF. None of these changes were seen in the group who took the sham treatmentl. Based on a statistical model, changes in the ratio of the waist to the hip and thyroid hormones predicted changes in blood VEGF and Nesgfatin-1 levels in the group who took Nigella sativa. We concluded that powdered Nigella sativa improved thyroid function and physical body measurements in people with Hashimoto's thyroiditis. Nigella sativa lowered blood VEGF levels. Nigella sativa can be a useful non-traditional treatment for people with Hashimoto's thyroiditis to make the disease less severe." +"Background: Hashimoto's thyroiditis is an autoimmune disorder and the most common cause of hypothyroidism. The use of Nigella sativa, a potent herbal medicine, continues to increase worldwide as an alternative treatment of several chronic diseases including hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM). The aim of the current study was to evaluate the effects of Nigella sativa on thyroid function, serum Vascular Endothelial Growth Factor (VEGF) - 1, Nesfatin-1 and anthropometric features in patients with Hashimoto's thyroiditis. Methods: Forty patients with Hashimoto's thyroiditis, aged between 22 and 50 years old, participated in the trial and were randomly allocated into two groups of intervention and control receiving powdered Nigella sativa or placebo daily for 8 weeks. Changes in anthropometric variables, dietary intakes, thyroid status, serum VEGF and Nesfatin-1 concentrations after 8 weeks were measured. Results: Treatment with Nigella sativa significantly reduced body weight and body mass index (BMI). Serum concentrations of thyroid stimulating hormone (TSH) and anti-thyroid peroxidase (anti-TPO) antibodies decreased while serum T3 concentrations increased in Nigella sativa-treated group after 8 weeks. There was a significant reduction in serum VEGF concentrations in intervention group. None of these changes had been observed in placebo treated group. In stepwise multiple regression model, changes in waist to hip ratio (WHR) and thyroid hormones were significant predictors of changes in serum VEGF and Nesgfatin-1 values in Nigella sativa treated group (P < 0.05). Conclusions: Our data showed a potent beneficial effect of powdered Nigella sativa in improving thyroid status and anthropometric variables in patients with Hashimoto's thyroiditis. Moreover, Nigella sativa significantly reduced serum VEGF concentrations in these patients. Considering observed health- promoting effect of this medicinal plant in ameliorating the disease severity, it can be regarded as a useful therapeutic approach in management of Hashimoto's thyroiditis.","Hashimoto's thyroiditis (thyroid inflammation) occurs when immune cells mistakenly attack the body's own healthy cells. It is the most common cause of reduced thyroid function. Nigella sativa, a powerful herbal medicine, increases globally as an alternative treatment for many long-lasting diseases like high blood pressure, high blood fat, and type 2 diabetes mellitus (T2DM). The current work evaluates how Nigella sativa affects thyroid function, blood protein levels, and physical measurements in those with Hashimoto's thyroid inflammation. Forty patients with Hashimoto's thyroid inflammation, aged 22 through 50, were randomly split into two groups receiving powdered Nigella sativa or inactive treatment daily for 8 weeks. Using an herbal medicine reduced body weight and body mass index. Blood levels of thyroid stimulating hormone and anti-thyroid cell proteins decreased while thyroid product levels increased in the Nigella sative-treated group after 8 weeks. The treatment group showed reduced blood vessel signaling protein. No changes occured in the inactive treatment group. Changes in waist to hip ratio and thyroid hormones were linked to changes in certain blood protein levels in the Nigella sative-treated group. Nigella sativa may improve thyroid and general health in those with Hashimoto's thyroiditis (thyroid inflammation). Also, Nigella sativa (an herbal medicine) reduces blood vessel signaling protein in these patients. Due to its health-promoting effect, this medicinal plant can be a useful treatment for Hashimoto's thyroidits." +"Purpose of review: The aim of the article is to present the basics of oral levothyroxine (LT4) absorption, reasons why patients may have persistently elevated serum thyroid stimulation hormone (TSH) levels, and alternative strategies for LT4 dosing. Recent findings: Although oral LT4 tablets are most commonly used for thyroid hormone replacement in patients with hypothyroidism, case studies report that liquid oral LT4, intravenous, intramuscular, and rectal administration of LT4 can successfully treat refractory hypothyroidism. Summary: Hypothyroidism is one of the most common endocrine disorders encountered by primary care physicians and endocrinologists. LT4 is one of the most widely prescribed medications in the world and it is the standard of care treatment for hypothyroidism. Generally, hypothyroid patients will be treated with LT4 tablets to be taken orally, and monitoring will occur with routine serum thyroid tests, including TSH concentrations. However, many patients fail to maintain serum TSH levels in the target range while managed on oral LT4 tablets. A subset of these patients would be considered to have poorly controlled hypothyroidism, sometimes termed refractory hypothyroidism. For these patients, optimization of ingestion routines and alternative formulations and routes of administration of LT4 can be considered, including oral liquid, intravenous, intramuscular, and even rectal formulations.","This article aims to cover the basics of how well levothyroxine (LT4 - a common thyroid medication) is absorbed when taken by mouth, reasons why people may have continuously high blood levels of thyroid stimulating hormone, and other ways to take levothyroxine. Although LT4 tablets taken by mouth are most commonly used for thyroid hormone replacement in people with underactive thyroids, studies show that taking LT4 in liquid-form by mouth, shot to a vein or muscle, and through the rectum can work to treat poorly-controlled underactive thyroid. Underactive thyroid is one of the most common hormone disorders doctors see. LT4 is one of the most commonly prescribed drugs in the world and is the recommended treatment for underactive thyroid. Generally, people with underactive thyroids will take LT4 tablets by mouth and track thryoid levels with common blood thyroid tests, including measuring levels of thyroid-stimulating hormone. Taking LT4 tablets by mouth does not keep blood thyroid-stimulating hormone levels at the right level for many people. Some of these people may have poorly-controlled underactive thyroids, or refractory underactive thyroids. This group of people might need to take LT4 in other forms or other ways, including liquid-form by mouth, shot to a vein or muscle, or even through the rectum." +"Hypothyroidism is one of the most common hormone deficiencies in adults. Most of the cases, particularly those of overt hypothyroidism, are easily diagnosed and managed, with excellent outcomes if treated adequately. However, minor alterations of thyroid function determine nonspecific manifestations. Primary hypothyroidism due to chronic autoimmune thyroiditis is largely the most common cause of thyroid hormone deficiency. Central hypothyroidism is a rare and heterogeneous disorder characterized by decreased thyroid hormone secretion by an otherwise normal thyroid gland, due to lack of TSH. The standard treatment of primary and central hypothyroidism is hormone replacement therapy with levothyroxine sodium (LT4). Treatment guidelines of hypothyroidism recommend monotherapy with LT4 due to its efficacy, long-term experience, favorable side effect profile, ease of administration, good intestinal absorption, long serum half-life and low cost. Despite being easily treatable with a daily dose of LT4, many patients remain hypothyroid due to malabsorption syndromes, autoimmune gastritis, pancreatic and liver disorders, drug interactions, polymorphisms in DIO2 (iodothyronine deiodinase 2), high fiber diet, and more frequently, non-compliance to LT4 therapy. Compliance to levothyroxine treatment in hypothyroidism is compromised by daily and fasting schedule. Many adult patients remain hypothyroid due to all the above mentioned and many attempts to improve levothyroxine therapy compliance and absorption have been made.","Underactive thyroid is one of the most common conditions caused by a lack of specific hormones in adults. Underactive thyroid is usually easily identified and successfully treated. However, small changes in thyroid function determine symptoms that can be caused by many conditions. Primary underactive thyroid caused by a long-term inflamed thyroid, which in turn is caused by thyroid cells that are attacked by infection-preventing cells, is the most common cause of too little thyroid hormones in adults. Central underactive thyroid, which is not very common and has many causes, is when an otherwise normal thyroid makes too little thyroid hormone due to lack of thyroid-stimulating hormone. Thyroid hormone replacement with levothyroxine (LT4) is the normal treatment of primary and central underactive thyroid. Treatment guidelines for an underactive thyroid recommend a single drug, levothyroxine (LT4), because of how well it works, how long it has been used, few side effects, how easy it is to use, how well it is absorbed in the stomach, how long it lasts in the blood, and low cost. Although taking LT4 daily treats underactive thyroid, many people still have underactive thyroids due to conditions that do not allow absorption in the stomach, inflammation of the stomach lining caused by thyroid cells that are attacked by infection-preventing cells, pancreatic and live disease, two or more drugs interacting with each other, gene variations, eating too much fiber, and more commonly, not following the prescribed LT4 treatment. Taking levothyroxine as prescribed for underactive thyroid depends on when and if it is taken on an empty stomach. For all of these reasons, many adults still have underactive thyroids. Doctors have tried many ways to make people take levothyroxine as prescribed and make levothyroxine more easily absorbed in the stomach." +"Objective: Hypothyroidism is relatively common, occurring in approximately 5% of the general US population aged ?12 years. Levothyroxine (LT4) monotherapy is the standard of care. Approximately, 5%-10% of patients who normalise thyroid-stimulating hormone levels with LT4 monotherapy may have persistent symptoms that patients and clinicians may attribute to hypothyroidism. A long-standing debate in the literature is whether addition of levotriiodothyronine (LT3) to LT4 will ameliorate lingering symptoms. Here, we explore the evidence for and against LT4/LT3 combination therapy as the optimal approach to treat euthyroid patients with persistent complaints. Methods: Recent literature indexed on PubMed was searched in March 2017 using the terms ""hypothyroid"" or ""hypothyroidism"" and ""triiodothyronine combination"" or ""T3 combination."" Relevant non-review articles published in English during the past 10 years were included and supplemented with articles already known to the authors. Findings: Current clinical evidence is not sufficiently strong to support LT4/LT3 combination therapy in patients with hypothyroidism. Polymorphisms in deiodinase genes that encode the enzymes that convert T4 to T3 in the periphery may provide potential mechanisms underlying unsatisfactory treatment results with LT4 monotherapy. However, results of studies on the effect of LT4/LT3 therapy on clinical symptoms and thyroid-responsive genes have thus far not been conclusive. Conclusions: Persistent symptoms in patients who are biochemically euthyroid with LT4 monotherapy may be caused by several other conditions unrelated to thyroid function, and their cause should be aggressively investigated by the clinician.","Underactive thyroid is relatively common, occurring in about 5% of the general U.S. population 12 years and older. The recommended treatment is a single drug, levothyroxine (LT4 - a common thyroid medication). About 5%-10% of patients who use LT4 alone to regulate thyroid-stimulating hormone levels may have ongoing symptoms that patients and doctors may think are caused by underactive thyroid. Science disagrees as to whether addition of levotriiodothyronine (LT3 - another thryoid medication) to LT4 will improve these ongoing symptoms. We look at whether combining LT4 and LT3 is the best way to treat patients with normal thyroid function but ongoing symptoms. We searched PubMed in March 2017 using the terms ""hypothyroid"" or ""hypothyroidism"" and ""triiodothyronine combination"" or ""T3 combination."" We looked at English articles in the last 10 years in addition to known articles. We did not find strong proof that combining LT4 and LT3 worked to treat patients with underactive thyroids. Genes that cause less conversion of T4 to T3 may explain unsuccessful treatment with LT4. The benefit of adding LT3 to LT4 treatment is uncertain. Ongoing symptoms in patients with normal thyroid function may be due to other causes. A doctor should determine the cause of the ongoing symptoms." +"Objective: Hypothyroidism is relatively common, occurring in approximately 5% of the general US population aged ?12 years. Levothyroxine (LT4) monotherapy is the standard of care. Approximately, 5%-10% of patients who normalise thyroid-stimulating hormone levels with LT4 monotherapy may have persistent symptoms that patients and clinicians may attribute to hypothyroidism. A long-standing debate in the literature is whether addition of levotriiodothyronine (LT3) to LT4 will ameliorate lingering symptoms. Here, we explore the evidence for and against LT4/LT3 combination therapy as the optimal approach to treat euthyroid patients with persistent complaints. Methods: Recent literature indexed on PubMed was searched in March 2017 using the terms ""hypothyroid"" or ""hypothyroidism"" and ""triiodothyronine combination"" or ""T3 combination."" Relevant non-review articles published in English during the past 10 years were included and supplemented with articles already known to the authors. Findings: Current clinical evidence is not sufficiently strong to support LT4/LT3 combination therapy in patients with hypothyroidism. Polymorphisms in deiodinase genes that encode the enzymes that convert T4 to T3 in the periphery may provide potential mechanisms underlying unsatisfactory treatment results with LT4 monotherapy. However, results of studies on the effect of LT4/LT3 therapy on clinical symptoms and thyroid-responsive genes have thus far not been conclusive. Conclusions: Persistent symptoms in patients who are biochemically euthyroid with LT4 monotherapy may be caused by several other conditions unrelated to thyroid function, and their cause should be aggressively investigated by the clinician.","Low thyroid function occurs in around 5% of the US population aged ?12 years. Levothyroxine (LT4) (a thyroid hormonal drug) is standard treatment. Around 5-10% of patients with regular thyroid-stimulating hormone levels after LT4 may still have symptoms attributable to reduced thyroid funciton. Experts debate if adding levotriiodothyronine (LT3), another manmade thyroid hormone, to LT4 will help lingering symptoms. We explore evidence for and against LT4/LT3 double treatment for best treating patients with lingering thyroid issues. We searched PubMed in March 2017 using the terms ""hypothyroid"" or ""hypothyroidism"" (low thyroid function) and ""triiodothyronine combination"" or ""T3 combination"" (thyroid hormonal drug therapy). Current evidence does not support LT4/LT3 double treatment for those with reduced thyroid function. Variations in genes blueprinting enzymes that convert thyroid hormone from one form to another may explain the lack of improvement with LT4 treatment. However, studies of LT4/LT3 double treatment are not conclusive. Lingering symptoms in patients with normal thyroids from LT4 therapy may be from other thyroid-unrelated causes, which should be investigated by the clinician." +"Hyperthyroidism is an excessive concentration of thyroid hormones in tissues caused by increased synthesis of thyroid hormones, excessive release of preformed thyroid hormones, or an endogenous or exogenous extrathyroidal source. The most common causes of an excessive production of thyroid hormones are Graves disease, toxic multinodular goiter, and toxic adenoma. The most common cause of an excessive passive release of thyroid hormones is painless (silent) thyroiditis, although its clinical presentation is the same as with other causes. Hyperthyroidism caused by overproduction of thyroid hormones can be treated with antithyroid medications (methimazole and propylthiouracil), radioactive iodine ablation of the thyroid gland, or surgical thyroidectomy. Radioactive iodine ablation is the most widely used treatment in the United States. The choice of treatment depends on the underlying diagnosis, the presence of contraindications to a particular treatment modality, the severity of hyperthyroidism, and the patient's preference.","Overactive thyroid is when too much thyroid hormone produced, when too much stored thyroid hormone released, or when there are internal or external thyroid hormone sources outside the thyroid. The most common causes of too much thyroid hormone made are Graves disease, a disease in which infection-preventing cells attack healthy cells and results in an overactive thyroid, or when one or more glandular growths make extra thyroid hormone. The most common causes of too much thyroid hormone released is thyroid inflammation, although the signs are the same as other causes. Overactive thyroid can be treated with drugs that block the formation of thyroid hormone, radiation therapy, or surgery to remove the thyroid. Radiation therapy is the most widely used treatment in the United States. The choice of treatment depends on the diagnosis, reasons not to use a particular method, how serious the overactive thyroid is, and what the patient wants." +"The proper treatment of hyperthyroidism depends on recognition of the signs and symptoms of the disease and determination of the etiology. The most common cause of hyperthyroidism is Graves' disease. Other common causes include thyroiditis, toxic multinodular goiter, toxic adenomas, and side effects of certain medications. The diagnostic workup begins with a thyroid-stimulating hormone level test. When test results are uncertain, measuring radionuclide uptake helps distinguish among possible causes. When thyroiditis is the cause, symptomatic treatment usually is sufficient because the associated hyperthyroidism is transient. Graves' disease, toxic multinodular goiter, and toxic adenoma can be treated with radioactive iodine, antithyroid drugs, or surgery, but in the United States, radioactive iodine is the treatment of choice in patients without contraindications. Thyroidectomy is an option when other treatments fail or are contraindicated, or when a goiter is causing compressive symptoms. Some new therapies are under investigation. Special treatment consideration must be given to patients who are pregnant or breastfeeding, as well as those with Graves' ophthalmopathy or amiodarone-induced hyperthyroidism. Patients' desires must be considered when deciding on appropriate therapy, and dose monitoring is essential.","Successfully treating an overactive thyroid depends on identifying the signs and symptoms of the disease and determining the cause. Graves' disease, a disease in which infection-preventing cells attack healthy cells, is the most common cause of an overactive thyroid. Other common causes of an overactive thyroid include thyroid inflammation, one or more glandular growths making extra thyroid hormone, and side effects of some medications. A common test that measures blood levels of hormones that acts as messengers to the thyroid is the first step in a medical exam. When results of this test are uncertain, a test to measure thyroid function can be used. When the cause is inflammation of the thyroid, treating the symptoms is enough because the overactive thyroid is short-lived. Graves' disease and when one or more growths make extra thyroid hormone can be treated with radiation therapy, drugs that block the formation of thyroid hormone, or surgery. In the United States, radiation therapy to shrink the thyroid is preferred unless there is a reason not to do so. Thyroid removal is an option when other treatments do not work or should not be used, or when an enlarged thyroid is causing pressure or squeezing. New treatments are being studied. People who are pregnant or breastfeeding, and people with thyroid eye disease or overactive thyroids caused by amiodarone, a heart medication, must be given special treatment consideration. We must factor in what patients want when deciding on treatment. Maintaining a safe and effective dose is very important." +"The chemical structure of a neuroleptic does not relaibly predict the exact profile of its therapeutic action. We considered the question whether the biochemical action of a neuroleptic, and specifically the ratio between DA-receptor block and NA-receptor block, might have a higher predictive value in this respect. In this context we carried out a double-blind study of the therapeutic value of clozapine and perphenazine in acute psychoses of varying symptomatology and aetiology. There are strong indications that clozapine has only a slight inhibitory effect on transmission in central DA-ergic neurons, but markedly inhibits transmission in central NA-ergic neurons, and that the reverse applies to perphenazine. In view of these data we expected perphenazine to be a stronger antipsychotic and a weaker sedative than clozapine, and vice versa. The plausibility of this hypothesis was demonstrated. Partly also on the basis of earlier research, we concluded that the biochemical action of a neuroleptic is a more faithful predictor of its therapeutic action profile than the chemical structure.","The chemical structure (arrangement of chemical bonds between atoms in a molecule) of drugs used to treat psychotic disorders does not reliably predict how well the treatment works. We looked into whether the biological and chemical changes made to the body by a drug to treat psychotic disorders might better predict how well the treatment works. We did a study of how well antipsychotics clozapine and perphenazine treat short-term impaired relationships with reality with varying symptoms and causes. Data suggest that clozapine and perphenazine have opposite effects on two types of neurons or brain cells. We thought that perphenazine would be a stronger drug to treat impaired relationships with reality and a weaker sedative than clozapine, and vice versa. This assumption proved reasonable. Partly based on earlier research, we concluded that the biological and chemical changes to the body made by a drug used to treat psychotic disorders better predicts how well the treatment works than the arrangement of chemical bonds between atoms in a molecule." +"CLINICAL experience with tranquilizers has shown the need for prolonged therapy for chronic neurotic and psychotic disorders. Since phenothiazine derivatives such as perphenazine are being employed in this manner and since there have been rare reports of jaundice and leukopenia associated with its administration, questions about a potential deleterious effect of this drug on the liver and blood have to be answered.","Use of tranquilizers on patients has shown the need for long-term treatment of long-term neurotic and pyschotic mental disorders. Because antipsychotic drugs like perphenazine are being used to treat long-term mental disorders and there have been rare cases of yellowing of the skin and a decrease in disease-fighting cells in the blood of people who take it, we must figure out whether this drug harms the liver and blood." +"In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular reference to intersections with the pharmacology of perphenazine. That study identified five areas of potentially beneficial intersection. Data showed seemingly 5 independent perphenazine attributes of benefit to glioblastoma treatment - i) blocking dopamine receptor 2, ii) reducing centrifugal migration of subventricular zone cells by blocking dopamine receptor 3, iii) blocking serotonin receptor 7, iv) activation of protein phosphatase 2, and v) nausea reduction. Perphenazine is fully compatible with current chemoirradiation protocols and with the commonly used ancillary medicines used in clinical practice during the course of glioblastoma. All these attributes argue for a trial of perphenazine's addition to current standard treatment with temozolomide and irradiation. The subventricular zone seeds the brain with mutated cells that become recurrent glioblastoma after centrifugal migration. The current paper shows how perphenazine might reduce that contribution. Perphenazine is an old, generic, cheap, phenothiazine antipsychotic drug that has been in continuous clinical use worldwide since the 1950's. Clinical experience and research data over these decades have shown perphenazine to be well-tolerated in psychiatric populations, in normals, and in non-psychiatric, medically ill populations for whom perphenazine is used to reduce nausea. For now (Summer, 2020) the nature of glioblastoma requires a polypharmacy approach until/unless a core feature and means to address it can be identified in the future. Conclusions: Perphenazine possesses a remarkable constellation of attributes that recommend its use in GB treatment.","To improve how well treatment for glioblastoma, a type of brain cancer, works, we looked at studies on the disease-related processes associated with glioblastoma and their interaction with how the antipsychotic perphenazine affects the body. That study found five areas of possibly helpful interaction. Studies showed 5 independent qualities of perphenazine that might help treat glioblastoma, including changing how cells grow and move and reducing nausea. Perphenazine can be taken with current chemotherapy and radiation treatments and with commonly prescribed glioblastoma drugs. These qualities suggest the addition of perphenazine to current chemotherapy and radiation treatment should be studied. Part of the brain sends out damaged cells that become recurring glioblastoma after they move outward. This paper shows how perphenazine might decrease this activity. Perphenazine is an old, generic, cheap drug used to treat psychotic disorders worldwide since the 1950s. Studies over time have shown perphenazine does not cause many side effects in normal people, people with mental illness, and ill people taking perphenazine to reduce nausea. As of Summer 2020, glioblastoma requires multiple drugs to treat it until and unless it is better understood and a single treatment drug is found. We conclude that perphenazine has many qualities that suggest its use in treating glioblastoma." +"In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular reference to intersections with the pharmacology of perphenazine. That study identified five areas of potentially beneficial intersection. Data showed seemingly 5 independent perphenazine attributes of benefit to glioblastoma treatment - i) blocking dopamine receptor 2, ii) reducing centrifugal migration of subventricular zone cells by blocking dopamine receptor 3, iii) blocking serotonin receptor 7, iv) activation of protein phosphatase 2, and v) nausea reduction. Perphenazine is fully compatible with current chemoirradiation protocols and with the commonly used ancillary medicines used in clinical practice during the course of glioblastoma. All these attributes argue for a trial of perphenazine's addition to current standard treatment with temozolomide and irradiation. The subventricular zone seeds the brain with mutated cells that become recurrent glioblastoma after centrifugal migration. The current paper shows how perphenazine might reduce that contribution. Perphenazine is an old, generic, cheap, phenothiazine antipsychotic drug that has been in continuous clinical use worldwide since the 1950's. Clinical experience and research data over these decades have shown perphenazine to be well-tolerated in psychiatric populations, in normals, and in non-psychiatric, medically ill populations for whom perphenazine is used to reduce nausea. For now (Summer, 2020) the nature of glioblastoma requires a polypharmacy approach until/unless a core feature and means to address it can be identified in the future. Conclusions: Perphenazine possesses a remarkable constellation of attributes that recommend its use in GB treatment.","To try improving treatment in glioblastoma (a brain cancer), this work collected data on the cancer's symptoms and traits along with references to perphenazine (an anti-psychotic medication). This study found five areas of possibly beneficial treatment. 5 perphenazine attributes of benefit to glioblastoma treatment include blocking two target sites for chemical messengers, reducing movement of specific cells, activating certain enzymes, and reducing nausea. Perphenazine works with current chemradiotherapy and common medicines used to treat glioblastoma. Perphenzaine attributes argue for a trial to add it to current standard treatment with temozolomide (an anti-cancer drug) and irradiation. A specific brain region seeds the brain with mutated cells that become reappearing gliobastoma after outward movement. The current work shows how perphenazine may reduce this outward growing brain cancer. Perphenazine is an old, common, cheap antipsychotic drug used clinically worldwide since the 1950's. Perphenzaine has been well-tolerated in psychiatric groups, in healthy groups, and in non-psychiatric but medically ill groups who use perphenazine to reduce nausea. For now (Summer, 2020), glioblastoma needs a multi-drug approach until a core treatment can be identified. Perphenazine has many attributes that recommend its use in glioblastoma treatment." +"Background: Perphenazine is an old phenothiazine antipsychotic with a potency similar to haloperidol. It has been used for many years and is popular in the northern European countries and Japan. Objectives: To examine the clinical effects and safety of perphenazine for those with schizophrenia and schizophrenia-like psychoses. Authors' conclusions: Although perphenazine has been used in randomised trials for more than 50 years, incomplete reporting and the variety of comparators used make it impossible to draw clear conclusions. All data for the main outcomes in this review were of very low quality evidence. At best we can say that perphenazine showed similar effects and adverse events as several of the other antipsychotic drugs. Since perphenazine is a relatively inexpensive and frequently used compound, further trials are justified to clarify the properties of this classical antipsychotic drug.","Perphenazine is an old drug used to treat psychotic disorders with strength similar to haloperidol, another drug to treat psychotic disorders. Perphenazine has been used for many years and is popular in the northern European countries and Japan. We aimed to look at the effects and safety of perphenazine in people with schizophrenia (a reality-distorting mental illness) and schizophrenia-like disorders. We conclude that although perphenazine has been used for more than 50 years, incomplete results and the variety of drugs used to compare perphenazine to make it impossible to make clear judgements. The results used in this review were not reliable. The most we can say is that perphenazine had similar results and side effects as many other drugs used to treat psychotic disorders. Because perphenazine is a cheap and often used drug, more studies are needed to fully understand the drug's properties." +"Background: Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between the various first-generation antipsychotics, however, low-potency first-generation antipsychotic drugs are sometimes perceived as less efficacious than high-potency first-generation compounds by clinicians, and they also seem to differ in their side effects. Authors' conclusions: The results do not show a superiority in efficacy of high-potency perphenazine compared with low-potency first-generation antipsychotics. There is some evidence that perphenazine is more likely to cause akathisia and less likely to cause severe toxicity, but most adverse effect results were equivocal. The number of studies as well as the quality of studies is low, with quality of evidence for the main outcomes ranging from moderate to very low, so more randomised evidence would be needed for conclusions to be made.","Drugs used to treat psychotic disorders are the main treatment for schizophrenia (a reality-distorting mental illness). Treatment recommendations say there is no difference in treatment effect among older drugs used to treat psychotic disorders. However, doctors sometimes think older drugs with lower strength used to treat psychotic disorders do not work as well as older drugs with higher strength, and they also seem to have different side effects. We conclude that the results do not show that the antipsychotic perphenazine with its higher strength works better than older antipsychotics with lower strength. Some evidence exists that perphenazine is more likely to cause restlessness and less likely to cause drug toxicity in the bloodstream requiring hospitalization, but most side effects were the same. More evidence is needed to make judgements, as the number and quality of studies is low with medium- to very low-quality results." +"Endometrial cancer (EC) is one of the most common and fatal gynecological cancers worldwide, but there is no effective treatment for the EC patients of progesterone resistance. Repurposing of existing drugs is a good strategy to discover new candidate drugs. In this text, perphenazine (PPZ), approved for psychosis therapy, was identified as a potential agent for the treatment of both progesterone sensitive and resistant endometrial cancer for the first time. Specifically, perphenazine exhibited good cell proliferation inhibition in Ishikawa (ISK) and KLE cell lines according to the CCK-8 assay and colony formation assay. It also reduced the cell migration of ISK and KLE cell lines in the light of the transwell migration assay. Annexin-V/PI double staining assay suggested that perphenazine could effectively induce ISK and KLE cell apoptosis. Moreover, results of western blot assay indicated perphenazine obviously inhibited the phosphorylation of Akt. Delightedly, PPZ also could significantly attenuate xenograft tumor growth at both 3 mg/kg and 15 mg/kg in mice without influencing the body weights.","Endometrial cancer (EC), cancer of the lining of the uterus, is one of the most common and deadly cancers of the female reproductive system worldwide, but there is no working treatment for EC patients who do not respond to progesterone, a hormone. Trying drugs used for other things is a good way to find new ways to treat conditions. Perphenazine, used to treat psychotic disorders, might treat people with endometrial cancer who are both sensitive to and resistant to progesterone. Perphenazine reduced growth of certain cancer-causing endometrial cells based on common lab tests. Tests showed perphenazine also reduced movement of certain cancer-causing endometrial cells. Tests suggest that perphenazine could kill certain cancer-causing endometrial cells. Perphenazine also could reduce tumor growth in mice without affecting body weight." +"Endometrial cancer (EC) is one of the most common and fatal gynecological cancers worldwide, but there is no effective treatment for the EC patients of progesterone resistance. Repurposing of existing drugs is a good strategy to discover new candidate drugs. In this text, perphenazine (PPZ), approved for psychosis therapy, was identified as a potential agent for the treatment of both progesterone sensitive and resistant endometrial cancer for the first time. Specifically, perphenazine exhibited good cell proliferation inhibition in Ishikawa (ISK) and KLE cell lines according to the CCK-8 assay and colony formation assay. It also reduced the cell migration of ISK and KLE cell lines in the light of the transwell migration assay. Annexin-V/PI double staining assay suggested that perphenazine could effectively induce ISK and KLE cell apoptosis. Moreover, results of western blot assay indicated perphenazine obviously inhibited the phosphorylation of Akt. Delightedly, PPZ also could significantly attenuate xenograft tumor growth at both 3 mg/kg and 15 mg/kg in mice without influencing the body weights.","Endometrial (outer womb) cancer (EC) is a common, fatal female-related cancer worldwide, but there is no treatment for EC patients of progesterone (specific female hormone) resistance. Adapting current drugs is useful to discover new candidate drugs. In this text, perphenazine (PPZ), used for psychosis, may treat patients with both progesterone sensitive and resistant outer womb cancer. Perphenazine (an anti-psychotic) blocked cell growth in two, outer womb cancer cell groups. Perphenazine could effectively cause controlled cell death in two, outer womb cancer cell groups. Also, perphenazine could block phosphorylation of Akt, which activates the Akt enzyme which monitors cell growth. Delightedly, perphenazine could weaken cancer growth from a different-species organ transplant in mice at various doses without affecting body weight." +"Background: Antipsychotic drugs are usually given orally but compliance with medication given by this route may be difficult to quantify. The development of depot injections in the 1960s gave rise to extensive use of depots as a means of long-term maintenance treatment. Perphenazine decanoate and enanthate are depot antipsychotics that belong to the phenothiazine family and have a piperazine ethanol side chain. Objectives: To assess the effects of depot perphenazine decanoate and enanthate versus placebo, oral antipsychotics and other depot antipsychotic preparations for people with schizophrenia in terms of clinical, social and economic outcomes. Authors' conclusions: Depot perphenazine is in clinical use in the Nordic countries, Belgium, Portugal and the Netherlands. At a conservative estimate, a quarter of a million people suffer from schizophrenia in those countries and could be treated with depot perphenazine. The total number of participants in the four trials with useful data is 313. None of the studies observed the effects of oral versus depot antipsychotic drugs. Until well conducted and reported randomised trials are undertaken clinicians will be in doubt as to the effects of perphenazine depots and people with schizophrenia should exercise their own judgement or ask to be randomised.","Drugs used to treat psychotic disorders are usually given by mouth, but it is hard to measure if people take the drugs as instructed. Slow-releasing shots, created in the 1960s, became popular as long-term treatment to keep conditions stable. Perphenazine decanoate and enanthate are slow-release shots used to treat psychotic disorders. We aimed to measure the medical, social, and economic effects of slow-releasing perphenazine decanoate and enanthate shots compared to no treatment, drugs used to treat psychotic disorders by mouth, and other slow-releasing shots used to treat psychotic disorders for people with schizophrenia (a reality-distorting mental illness). We state that slow-releasing perphenazine shots are used in Denmark, Finland, Iceland, Norway, Sweden, Belgium, Portugal, and the Netherlands. At least 250,000 people have schizophrenia in these countries and could be given slow-releasing perphenazine shots. The four trials with useful results had 313 total people. None of the studies compared the effects of antipsychotics taken by mouth to a slow-releasing shot. People with schizophrenia should use their own judgement until more studies are done and doctors know the effects of slow-release perphenazine shots." +"We have found oral perphenazine 8 mg (OP8) useful as follows: (1) as a nonsedating antiemetic; (2) as a preventative measure similar to the antihistamine promethazine against ketamine-induced psychotomimetic effects; and (3) as a safe single-dose drug (only 1.3 extrapyramidal events per 10,000 patients receiving 4�8 mg oral dose, with all events easily treated). Additionally, we evaluated the efficacy of single-dose OP8 to a single 40 mg dose of aprepitant given preoperatively in colorectal surgery patients at our academic center within an enhanced recovery protocol, which was designed to mitigate opioid utilization, reduce Postoperative Nausea and Vomiting (PONV), and optimize patient recovery. In this retrospective study, no differences were noted in antiemetic requirement on postoperative days 0 and 1 between patients receiving OP8 versus aprepitant. As enhanced recovery protocols become more widespread and continue to be applied to other surgical specialties, effective PONV prevention is imperative for improving patient outcomes. OP8 deserves to be properly evaluated (by clinical study, and/or in routine clinical practice) as a part of a cost-effective multimodal enhanced recovery strategy.","Perphenazine 8 mg (OP8) can be taken by mouth for the following uses: (1) as a nonsedating drug to prevent nausea and vomiting; (2) like promethazine, an antihistamine (allergy drug) , to prevent psychotic symptoms caused by ketamine (a pain relief drug); and (3) as a safe one-dose drug. We also rated the success of one-dose OP8 compared to one 40 mg dose of aprepitant, used to prevent nausea and vomiting, given to people before rectum, anus, and colon operations in our center with guidelines designed to help people recover more quickly from surgery, reduce opioid use, and reduce nausea and vomiting after surgery. In this study, we saw no differences in nausea and vomiting prevention on the same day of surgery and one day after surgery between patients who got OP8 versus aprepitant. As guidelines to help people recover more quickly from surgery become more widespread and used for other surgeries, successfully preventing nausea and vomiting after surgery is key to improving patient results. OP8 should be studied as part of a cost-effective, multi-process way to help people recover more quickly from surgery." +"Background and objective: despite the introduction of newer antiemetics in the prevention of postoperative nausea and vomiting (PONV), perphenazine is recommended in current guidelines, as the concept of multimodal management of PONV in high-risk patients requires more than two drugs to be combined. The aim of this quantitative systematic review was to assess the efficacy and safety of perphenazine in the prophylaxis of PONV in adults and children. Results: eleven trials published between 1965 and 1999 including a total of 2081 participants fulfilled the inclusion criteria and were further analysed. In children, perphenazine 0.07 mg kg was effective in preventing vomiting (RR, 0.31; 95% CI, 0.18-0.54), whereas in adults, a dose of about 5 mg was effective for the prevention of PONV (RR, 0.50; 95% CI, 0.37-0.67). When compared with established newer drugs, for example, ondansetron, dexamethasone or droperidol, no significant differences were observed in the pooled analysis with limited data. Reporting of adverse events was poor. Transient sedation was reported in three eligible trials (RR, 0.9; 95% CI, 0.40-2.05). Conclusion: there is evidence that perphenazine is effective in the prevention of PONV in children and adults without serious adverse effects compared with placebo.","Even though there are newer drugs to prevent nausea and vomiting after surgery, current guidelines recommend the drug perphenazine. A multi-process way to prevent nausea and vomiting in high-risk patients requires using more than two drugs. We aimed to rate the success and safety of perphenazine in prevention of nausea and vomiting in adults and children. We looked at eleven studies published between 1965 and 1999 with a total of 2081 people. Perphenazine 0.07 mg kg and 5 mg prevented nausea and vomiting in children and adults, respectively. We saw no big differences compared to newer drugs like ondansetron, dexamethasone or droperidol in studies with limited results. Side effects were not well reported. Short-term sedation occurred in three studies. Studies show that perphenazine prevents nausea and vomiting in children and adults without serious side effects compared to sham treatment." +"Background and objective: despite the introduction of newer antiemetics in the prevention of postoperative nausea and vomiting (PONV), perphenazine is recommended in current guidelines, as the concept of multimodal management of PONV in high-risk patients requires more than two drugs to be combined. The aim of this quantitative systematic review was to assess the efficacy and safety of perphenazine in the prophylaxis of PONV in adults and children. Results: eleven trials published between 1965 and 1999 including a total of 2081 participants fulfilled the inclusion criteria and were further analysed. In children, perphenazine 0.07 mg kg was effective in preventing vomiting (RR, 0.31; 95% CI, 0.18-0.54), whereas in adults, a dose of about 5 mg was effective for the prevention of PONV (RR, 0.50; 95% CI, 0.37-0.67). When compared with established newer drugs, for example, ondansetron, dexamethasone or droperidol, no significant differences were observed in the pooled analysis with limited data. Reporting of adverse events was poor. Transient sedation was reported in three eligible trials (RR, 0.9; 95% CI, 0.40-2.05). Conclusion: there is evidence that perphenazine is effective in the prevention of PONV in children and adults without serious adverse effects compared with placebo.","Despite newer anti-nausea drugs, perphenazine (an anti-psychotic) is still used in multimodal treatment of nausea and vomiting post-operation in high-risk patients that need two or more drugs. This work measures the success and safety of perphenazine in preventing post-operation nausea and vomiting. Eleven trials published between 1965 and 1999 included 2081 total participats for analysis. In children, 0.07 mg kg of perphenzaine prevented vomiting while 5 mg prevented post-operation nausea and vomiting in adults. Compared to newer anti-nausea and -vomiting drugs, no differences were observed. Reporting of harmful events was poor. Three trials reported temporary sedation or a calming effect. Perphenazine may be effective in preventing post-operation nausea and vomiting in children and adults without serious harmful effects." +"We present here a potential new treatment adjunct for glioblastoma. Building on murine studies, a series of papers appeared recently showing that therapeutic irradiation of the ipsilateral subventricular zone (SVZ) retards growth of more peripherally growing cortical glioblastomas in humans, suggesting a tumor trophic function for the SVZ. Further studies showed that SVZ cells migrate out towards a peripheral glioblastoma. Dopamine signaling through D3 subtype receptor indirectly drives this centrifugal migration in humans. Since psychiatry has several drugs with good D3 blocking attributes, such as fluphenazine, or perphenazine, we suggest that adding one of these D3 blocking drugs to current standard treatment of resection followed by temozolomide and irradiation might prolong survival by depriving glioblastoma of the trophic functions previously subserved by dopaminergic signaling on SVZ cells.","We look at a possible new treatment to add to standard treatment for glioblastoma, a type of brain cancer. Based on mouse studies, several recent studies showed that radiation of the part of the brain where brain cells are made reduces growth of some glioblastomas in humans, suggesting this part of the brain might play a role in fueling brain tumors. More studies showed cells from the part of the brain where brain cells are made move outward toward a glioblastoma. Certain molecule signaling causes this cell movement. Because many mental health drugs block molecule signaling, such as fluphenazine, or perphenazine, we suggest adding one of these drugs to the current standard treatment of surgery followed by chemotherapy and radiation to possibly increase survival time by cutting off fuel to the glioblastoma." +"Management of 242 foreign bodies of the upper gastrointestinal tract are reported. Thirty-nine were in the pharynx, 181 in the esophagus, 19 in the stomach, and 3 in the small bowel. The flexible panendoscope was used 211 times (87.2%) to manage these foreign bodies, while the rigid esophagoscope was used 12 times (5.0%). Two hundred thirty-nine foreign bodies (98.8%) were successfully managed endoscopically. The surgery rate was 0.4%. There was no morbidity or mortality. Twenty-five percent of the cases were done under general endotracheal anesthesia. Coins in the esophagus are removed promptly if in the cervical or mid esophagus, and within 12 hours if in the distal esophagus. Once in the stomach, they will usually pass without difficulty. Meat impaction resulting in an obstructed esophagus is an urgent problem and the bolus should be removed within hours. Sharp and pointed foreign bodies can be very difficult to manage. Dry runs with a reproduction of the foreign body are essential to successful removal. Button batteries lodged in the esophagus represent an emergency and should be removed without delay. Once in the stomach, they will usually pass through the gastrointestinal tract without difficulty. The forward-viewing flexible panendoscope has become the instrument of choice in managing foreign bodies in most tertiary medical centers as well as in the community hospitals.","We reported removal of 242 objects that shouldn't be eaten which were stuck in the mouth, throat, esophagus, stomach, and upper part of the small intestine. Thirty-nine objects that shouldn't be eaten were located in the throat, 181 in the esophagus, 19 in the stomach, and 3 in the small intestine. A flexible, telescoping tube with a camera was used 211 times (87.2%) to treat these objects, while the stiff, inflexible tube with a camera was used 12 times (5.0%). Two hundred thirty-nine objects that shouldn't be eaten (98.8%) were successfully removed by putting a long, thin tube directly into the body. 0.4% of people had surgery to remove the object that shouldn't be eaten. Nobody had an illness or died. Twenty-five percent of the cases required people to be put in a sleep-like state with a breathing tube. Coins in the esophagus are removed quickly if they are in the uppermost or mid esophagus, and within 12 hours if in the lower esophagus. If coins makes it to the stomach, they are usually passed easily. Meat that gets stuck and blocks the esophagus is an urgent problem, and the blockage should be removed within hours. Sharp and pointed objects can be hard to remove. Practicing with a similar object is very important. Button batteries in the esophagus are an emergency and should be removed immediately. If button batteries make it to the stomach, they are usually passed easily. A new kind of flexible, telescoping tube with a camera has become the tool to treat objects that shouldn't be eaten in most specialized medical centers and community hospitals." +"Objective: To evaluate management of foreign bodies in the upper gastrointestinal tract. Patients and methods: A total of 103 patients with history of foreign body ingestion were included in this study. X-ray neck and rigid oesophagoscopy was carried out in all patients for diagnosis and removal of foreign bodies. A structured questionnaire was designed to record all information. Results: Dysphagia (92%) and tenderness in neck (60%) were the most common clinical features. Majority (89%) patients had come to the hospital within 24 hours. X-ray of the neck (lateral view) was the most useful investigation with presence of air in the esophagus being a significant finding. Post-cricoid region was the site of impaction of foreign bodies in 84% of the subjects. The procedure of esophagoscopy was successful in 90 patients (97%) and failed in 3 patients (3%). Coins were the most common foreign bodies (60%), followed by meat related foreign bodies (22.5%) and dentures in 5% cases. Complications occurred in 18% patients and were more common in adults (37.1%) compared to children (8.8%). The most serious complication was pneumomediastinum. Maximum complications occurred with dentures (80%) and bone chips (42%). Conclusion: Foreign body in the esophagus is a serious condition and early removal by rigid esophagoscopy is recommended which is a safe and effective procedure.","Our objective is to rate treatment of objects that shouldn't be eaten found in the mouth, throat, esophagus, stomach, and upper part of the small intestine. We included 103 patients who ate objects that shouldn't be eaten. Neck x-rays and a procedure that uses a stiff, inflexible tube with a camera were done to diagnose and remove the objects that shouldn't be eaten. We recorded all information using a questionnaire. Trouble swallowing (92%) and soreness in neck (60%) were the most common symptoms. Most of the patients (89%) had come to the hospital within 24 hours. X-rays of the side of the neck helped the most with air in the esophagus being an important finding. The part of the throat that allows food to pass into the esophagus was where objects that shouldn't be eaten got stuck in 84% of people. Using a flexible tube with a camera worked in 90 patients (97%) and didn't work in 3 patients (3%). Coins were swallowed most often (60%), followed by meat (22.5%) and dentures (5%). Complications happened in 18% of patients and were more common in adults (37.1%) compared to children (8.8%). The most serious complication was air in the center of the chest. People who swallowed dentures (80%) and bone chips (42%) had the most complications. We concluded that objects in the esophagus that shouldn't be eaten are a serious condition and early removal by inserting a flexible tube with a camera is safe and works." +"Objective: To evaluate management of foreign bodies in the upper gastrointestinal tract. Patients and methods: A total of 103 patients with history of foreign body ingestion were included in this study. X-ray neck and rigid oesophagoscopy was carried out in all patients for diagnosis and removal of foreign bodies. A structured questionnaire was designed to record all information. Results: Dysphagia (92%) and tenderness in neck (60%) were the most common clinical features. Majority (89%) patients had come to the hospital within 24 hours. X-ray of the neck (lateral view) was the most useful investigation with presence of air in the esophagus being a significant finding. Post-cricoid region was the site of impaction of foreign bodies in 84% of the subjects. The procedure of esophagoscopy was successful in 90 patients (97%) and failed in 3 patients (3%). Coins were the most common foreign bodies (60%), followed by meat related foreign bodies (22.5%) and dentures in 5% cases. Complications occurred in 18% patients and were more common in adults (37.1%) compared to children (8.8%). The most serious complication was pneumomediastinum. Maximum complications occurred with dentures (80%) and bone chips (42%). Conclusion: Foreign body in the esophagus is a serious condition and early removal by rigid esophagoscopy is recommended which is a safe and effective procedure.","The objective is to rate treatment of foreign objects stuck in the upper digestive tract. 103 patients that swallowed foreign objects were examined. X-ray neck and esophagus checks were carried out in all patients for identifying and removing foreign objects. A structured questionnaire was created to record all information. Difficulty swallowing (92%) and neck tenderness (60%) were the most common medical attributes. Most (89%) patients came to the hospital within 24 hours. Neck x-rays (from the side) were the most useful scan, showing presence of air in the esophagus as an important finding. A specific site near the bottom of the throat was the site of stuck foreign objects in 84% of patients. Inserting a tube with a viewing lens into the esophagus worked in 90 patients (97%) and failed in 3 patients (3%). Coins were the most common foreign objects (60%), followed by meat-related substances (22.5%) and dentures (5%). Issues occured in 18% of patients and were more common in adults (37.1%) compared to children (8.8%). The most serious issue was air trapped in the area between the lungs. Serious issues occured with dentures (80%) and bone chips (42%). Foreign objects in the esophagus is serious and early removal with esophagus checks, which are safe and effective, is recommended." +"Foreign bodies to the ear, nose, and throat often can be managed in the emergency department, particularly if the patient offers a history consistent with foreign body and is calm and compliant with the examination and removal attempts. Tips for success include analgesia, adequate visualization, immobilization of the patient's head, dexterity and experience level of the provider, and minimizing attempts at removal. It is critical to recognize the risks involved with certain retained objects (button batteries or sharp objects) and when to call a consultant to help facilitate safe, successful removal of objects to the ear, nose, and throat.","Objects that shouldn't be found in the ear, nose, and throat can be removed in the emergency room, especially if the information the patient provides lines up with an object that shouldn't be in the body and the patient is calm and agreeable with the exam and efforts to remove the object. Tips for success include painkillers, the ability to see the object, keeping the patient's head still, skill and experience of the doctor, and removing the object with the least number of tries. It is very important to realize the risks involved with certain objects (button batteries or sharp objects) and when to call a specialist to help ensure safe, successful removal of objects to the ear, nose, and throat." +"Background: Patients with foreign bodies in their ear, nose or throat typically present to general practitioners. The safe and timely removal of foreign bodies ensures good patient outcomes and limits complications. Objectives: The aim of this paper is to outline common foreign objects and review the associated anatomy that may make removal difficult. A description of instruments and indications for use is provided, along with circumstances where specialist referral is warranted. Discussion: The use of appropriate techniques for removal of foreign bodies reduces the complications of removal and associated distress, and limits the number of cases that require surgical input.","People with objects in their ear, nose or throat that shouldn't be there usually go to general doctors. The safe and quick removal of objects that shouldn't be swallowed provides good results and reduces complications. We aimed to list common objects that shouldn't be swallowed and look at the parts of the body that may make removing them hard. We described tools and how to use them, along with times when a specialist should see the patient. Using the right ways to remove objects that shouldn't be swallowed lowers the complications of removal and possible pain, and reduces the cases that require surgery." +"Objective: This study was designed to explore the clinical application of video laryngoscopy in the diagnosis and treatment of throat foreign bodies (FBs). Method: In total, 1572 patients diagnosed with throat FBs at the Department of Otolaryngology of Nanjing Drum Tower Hospital were retrospectively analysed. The covariables collected were the time from FB ingestion to admission, age, sex, duration of admission, and site of impaction. Result: The most common FBs were fish bones, which accounted for 1446 (91.98%) of 1572 FBs. Among all 1572 FBs, 1004 (63.87%) were successfully removed by video laryngoscopy without complications. A shorter duration of admission was associated with a higher diagnostic rate under video laryngoscopy. The diagnostic rate of sharp FBs was significantly higher than that of non-sharp FBs. The most common sites of throat FBs were the tongue root (42.29%), epiglottic vallecula (19.40%), tonsil (18.21%), and piriform fossa (10.65%). Conclusion: Video laryngoscopy is a powerful tool for the diagnosis and treatment of throat FBs, allowing for identification of rare locations of FBs as well as refractory FBs.","The study aimed to look at the use of a camera on the tip of a curved blade to diagnose and remove objects in the throat that shouldn�t be eaten. We studied 1572 people who had objects in the throat that shouldn't be eaten. We wrote down the time between eating the object and coming to the hospital, age, gender, how long the patient was in the hospital, and where the object was stuck. The most common objects stuck were fish bones, which made up 1446 (91.98%) of 1572 objects. Among all 1572 objects, 1004 (63.87%) were successfully removed using a camera on the tip of a curved blade without problems. When a camera on the tip of a curved blade was used to diagnose the object, people left the hospital sooner. Diagnosing sharp objects was higher than that of non-sharp objects. The most common place that objects were stuck in the throat were the far back and bottom of the tongue (42.29%), the space between the back of the tongue and the windpipe entrance (19.40%), the tonsil (18.21%), and the bottom of the throat (10.65%). We conclude that using a camera on the tip of a curved blade is a strong tool for the diagnosis and removal of objects in the throat that shouldn't be eaten, allowing for the finding of uncommon locations of objects and of objects not easily removed." +"Objective: This study was designed to explore the clinical application of video laryngoscopy in the diagnosis and treatment of throat foreign bodies (FBs). Method: In total, 1572 patients diagnosed with throat FBs at the Department of Otolaryngology of Nanjing Drum Tower Hospital were retrospectively analysed. The covariables collected were the time from FB ingestion to admission, age, sex, duration of admission, and site of impaction. Result: The most common FBs were fish bones, which accounted for 1446 (91.98%) of 1572 FBs. Among all 1572 FBs, 1004 (63.87%) were successfully removed by video laryngoscopy without complications. A shorter duration of admission was associated with a higher diagnostic rate under video laryngoscopy. The diagnostic rate of sharp FBs was significantly higher than that of non-sharp FBs. The most common sites of throat FBs were the tongue root (42.29%), epiglottic vallecula (19.40%), tonsil (18.21%), and piriform fossa (10.65%). Conclusion: Video laryngoscopy is a powerful tool for the diagnosis and treatment of throat FBs, allowing for identification of rare locations of FBs as well as refractory FBs.","This work explored the use of video viewing of the voice box with a small device to identify and treat throat foreign bodies (FBs) or substances. 1572 total patients with throat foreign substances at the Department of Otolarynology of Nanjing Drum Tower Hospital were analysed. Time from foreign substance consumption to hospital admission, age, sex, duration of admission, and site of blockage were measured. The most common foreign substance was fish bones, seen in 91.98% of patients. Among all 1572 foreign substances, 1004 (63.87%) were removed by video throat treatment with a small device without issues. A shorter hospital stay was linked to higher identification rate by video viewing of the voice box with a small device. The identification rate of sharp foreign substances was higher than that of non-sharp ones. The most common sites of throat foreign substances were areas near the tonsil and bottom of the tongue and throat. Video viewing of the voice box with a small device is powerful for identifying and treating throat foreign substances. It allows identification of rare locations of foreign substances and stubborn ones." +"Foreign bodies in the ear, nose, and throat are occasionally seen in family medicine, usually in children. The most common foreign bodies are food, plastic toys, and small household items. Diagnosis is often delayed because the causative event is usually unobserved, the symptoms are nonspecific, and patients often are misdiagnosed initially. Most ear and nose foreign bodies can be removed by a skilled physician in the office with minimal risk of complications. Common removal methods include use of forceps, water irrigation, and suction catheter. Pharyngeal or tracheal foreign bodies are medical emergencies requiring surgical consultation. Radiography results are often normal. Flexible or rigid endoscopy usually is required to confirm the diagnosis and to remove the foreign body. Physicians need to have a high index of suspicion for foreign bodies in children with unexplained upper airway symptoms. It is important to understand the anatomy and the indications for subspecialist referral. The evidence is inadequate to make strong recommendations for specific removal techniques.","Objects that shouldn't be in the ear, nose, and throat are sometimes seen by family doctors, usually in children. The most common objects are food, plastic toys, and small household items. Diagnosis is often late because the event that caused the object to get stuck wasn't seen, the symptoms are vague, and people often are diagnosed incorrectly at first. Most objects stuck in the ear and nose can be removed by a skilled doctor in the office with low risk of other problems. Common methods to remove the object include the use of forceps, flushing with water, and using a long, flexible suction tube. Objects stuck in the throat or windpipe are emergencies and considered for surgery. X-rays are often normal. Flexible or stiff tubes with cameras are usually needed to make sure the diagnosis is correct and to remove the object. Doctors need to have a good reason to think there might be an object stuck in children with unexplained upper airway symptoms. It is important to understand the body�s structure and reasons to refer to a subspecialist. The available information is not enough to make strong recommendations for specific ways to remove objects." +"Dysphagia is common but may be underreported. Specific symptoms, rather than their perceived location, should guide the initial evaluation and imaging. Obstructive symptoms that seem to originate in the throat or neck may actually be caused by distal esophageal lesions. Oropharyngeal dysphagia manifests as difficulty initiating swallowing, coughing, choking, or aspiration, and it is most commonly caused by chronic neurologic conditions such as stroke, Parkinson disease, or dementia. Symptoms should be thoroughly evaluated because of the risk of aspiration. Patients with esophageal dysphagia may report a sensation of food getting stuck after swallowing. This condition is most commonly caused by gastroesophageal reflux disease and functional esophageal disorders. Eosinophilic esophagitis is triggered by food allergens and is increasingly prevalent; esophageal biopsies should be performed to make the diagnosis. Esophageal motility disorders such as achalasia are relatively rare and may be overdiagnosed. Opioid-induced esophageal dysfunction is becoming more common. Esophagogastroduodenoscopy is recommended for the initial evaluation of esophageal dysphagia, with barium esophagography as an adjunct. Esophageal cancer and other serious conditions have a low prevalence, and testing in low-risk patients may be deferred while a four-week trial of acid-suppressing therapy is undertaken. Many frail older adults with progressive neurologic disease have significant but unrecognized dysphagia, which significantly increases their risk of aspiration pneumonia and malnourishment. In these patients, the diagnosis of dysphagia should prompt a discussion about goals of care before potentially harmful interventions are considered. Speech-language pathologists and other specialists, in collaboration with family physicians, can provide structured assessments and make appropriate recommendations for safe swallowing, palliative care, or rehabilitation.","Trouble swallowing is common but may be underreported. Specific symptoms, not the area where they are thought to come from, should guide the first exam and visual tests. Symptoms of difficulty breathing that seem to come from the throat or neck may actually be caused by damage in the lower esophagus. Difficulty swallowing that happens in the mouth or the throat shows up as difficulty starting swallowing, coughing, choking, or something entering the airway or lungs by accident. It is most often caused by long-term brain conditions such as stroke, Parkinson's, or memory, language, and thinking loss. Symptoms should be looked at closely due to the risk of something entering the airway or lungs by accident. People with problems that happen during swallowing may describe a feeling of food getting stuck after swallowing. Problems that happen during swallowing is most often caused by stomach-related reflux diseases and disorders of the esophagus with symptoms like heartburn and chest pain. A long-term allergic condition of the esophagus is set off by food allergens and is more and more common. To diagnose this condition, a small part of the esophagus should be removed for examination. Dysfunction of the esophagus that causes difficulty swallowing such as a disorder in which your esophagus is unable to move food and liquids down into your stomach are pretty rare and may be overdiagnosed. Dysfunction of the esophagus caused by opioids is becoming more common. Using a flexible tube with a camera to look at the esophagus, stomach and part of the small intestine is used to look at difficulty swallowing that happens in the mouth and throat, together with barium and X-rays. Cancer of the esophagus and other serious conditions are not common, and low-risk people may take acid reducers for 4 weeks before undergoing testing. Many weak older adults with progressive deterioration in functioning have serious but unseen difficulty swallowing, which really increases their risk of pneumonia (lung infection) caused by something entering the airway or lungs by accident and risk of lacking nutrients in the body. In these people, the diagnosis of difficulty breathing should lead to a conversation about what is important to the person before suggesting possibly harmful treatments. People who treat communication and swallowing disorders and other specialists, working with family doctors, can evaluate and make suggestions for safe swallowing, care for people living with a serious illness, or rehab." +"Most swallowing problems can be treated, although the treatment depends on the type of dysphagia. A multidisciplinary team of surgeons, phoniatrists, and speech-language therapists is necessary to develop the appropriate treatment strategy. A thorough medical history, clinical investigation of the swallowing muscles, and fiberoptic endoscopic evaluation of swallowing with foods of different consistencies help to decide whether swallowing exercises alone are sufficient, or whether an additional pharmacologic or surgical treatment is needed to prevent aspiration, malnutrition, and dehydration.","Most swallowing problems can be fixed, although the treatment depends on the type of trouble swallowing. A team of surgeons, doctors who treat organs involved in speech production, and people who treat communication and swallowing disorders is needed to figure out the best treatment. Information provided by the patient, examination of the swallowing muscles, and using a flexible tube with a camera to see swallowing of different foods help decide whether swallowing exercises are enough, or whether drugs or surgery are also needed to prevent something entering the airway or lungs by accident, prevent a lack of nutrients in the body, and prevent a lack of fluid in the body." +"Most swallowing problems can be treated, although the treatment depends on the type of dysphagia. A multidisciplinary team of surgeons, phoniatrists, and speech-language therapists is necessary to develop the appropriate treatment strategy. A thorough medical history, clinical investigation of the swallowing muscles, and fiberoptic endoscopic evaluation of swallowing with foods of different consistencies help to decide whether swallowing exercises alone are sufficient, or whether an additional pharmacologic or surgical treatment is needed to prevent aspiration, malnutrition, and dehydration.","Most swallowing problems can be treated, but the treatment depends on the type of swallowing difficulty. A multi-type team of surgeons, speech-related organ specialists, and speech-language therapists is needed to create appropriate treatment. A clear medical history, swallowing muscle examination, and monitoring with small devices of swallowing of food with various textures help decide if swallowing exercises alone or additional drug or surgical treatment is needed to prevent breathing, eating, and hydration issues." +"Achalasia is an esophageal motility disorder characterized by aberrant peristalsis and insufficient relaxation of the lower esophageal sphincter. Patients most commonly present with dysphagia to solids and liquids, regurgitation, and occasional chest pain with or without weight loss. High-resolution manometry has identified 3 subtypes of achalasia distinguished by pressurization and contraction patterns. Endoscopic findings of retained saliva with puckering of the gastroesophageal junction or esophagram findings of a dilated esophagus with bird beaking are important diagnostic clues. In this American College of Gastroenterology guideline, we used the Grading of Recommendations Assessment, Development and Evaluation process to provide clinical guidance on how best to diagnose and treat patients with achalasia.","Achalasia describes a disorder in which your esophagus is unable to move food and liquids down into your stomach. People often have difficulty swallowing solids and liquids, spitting up undigested or partially digested food from the stomach, and occasional chest pain with or without weight loss. Measuring the strength and muscle coordination of your esophagus when you swallow led to the finding of 3 subtypes of achalasia that have different pressure and contraction patterns. A lot of saliva and puckering where the esophagus is connected to the stomach, seen using a flexible tube with a camera, or a widened esophagus and narrowing where the esophagus is connected to the stomach, that looks like a bird's beak, found by X-raying the esophagus suggest achalasia. In this guideline, we used a popular method to guide doctors on how best to diagnose and treat people with achalasia." +"Objective: In the present study, an attempt was made to examine the effects of aural stimulation with ointment containing capsaicin on swallowing function in order to develop a novel and safe treatment for non-obstructive dysphagia in elderly patients. Patients and methods: The present study included 26 elderly patients with non-obstructive dysphagia. Ointment containing 0.025% capsaicin (0.5 g) was applied to the external auditory canal with a cotton swab under otoscope only once or once a day for 7 days before swallowing of a bolus of colored water (3 mL), which was recorded by transnasal videoendoscopy and evaluated according to the endoscopic swallowing score. Results: After a single application of 0.025% capsaicin ointment to the right external auditory canal, the endoscopic swallowing score was significantly decreased, and this effect lasted for 60 minutes. After repeated applications of the ointment to each external auditory canal alternatively once a day for 7 days, the endoscopic swallowing score decreased significantly in patients with more severe non-obstructive dysphagia. Of the eight tube-fed patients of this group, three began direct swallowing exercises using jelly, which subsequently restored their oral food intake. Conclusion: These findings suggest that stimulation of the external auditory canal with ointment containing capsaicin improves swallowing function in elderly patients with non-obstructive dysphagia. By the same mechanism used by angiotensin-converting enzyme inhibitors to induce cough reflex, which has been shown to prevent aspiration pneumonia, aural stimulation with capsaicin may reduce the incidence of aspiration pneumonia in dysphagia patients via Arnold's ear-cough reflex stimulation.","We looked at the effects of rubbing an ointment with capsaicin, found in different types of hot peppers, on the ears to improve swallowing function and create a new and safe treatment for old people who have the sensation of food stuck in the esophagus without physical blockage. We looked at 26 old people who had the sensation of food stuck in the esophagus without physical blockage. We used a Q-tip to put ointment with 0.025% capsaicin (0.5 g) in the ear only once or once a day for 7 days before drinking 3 mL of colored water, which was recorded using a flexible tube with a camera and rated using a common test that measures how well one swallows. After putting 0.025% capsaicin ointment to the right ear, the common swallowing test showed less difficulty swallowing. This effect lasted for one hour. After putting the ointment on alternating ears once a day for 7 days, the common swallowing test showed less difficulty swallowing in people with more serious sensations of food stuck in the esophagus without physical blockage. Of the eight people fed with tubes in this group, three began direct swallowing exercises using jelly, which then returned their ability to eat food by mouth. We concluded that putting ointment with capsaicin on the ear improves swallowing function in old people who have the sensation of food stuck in the esophagus without physical blockage. In the same way as other methods to stimulate the cough reflex, putting capsaicin on the ears may decrease how often people with difficulty swallowing develop pneumonia, caused by something entering the airway or lungs by accident, through a cough reflex stimulated by a nerve." +"The local, systemic, and referred causes of finger pain are generally recognizable by historical features and physical examination findings, although radiographs and laboratory evaluation are often required to support the diagnostic impression. Most minor traumatic causes of finger pain require only conservative management, including immobilization followed by exercise. Infectious causes of finger pain include cellulitis, tendinitis, paronychia, felon, and infectious emboli, which generally require antibiotics with or without drainage. Certain patients with finger pain resulting from infection should be referred to a hand surgeon. Vascular and ischemic causes of finger pain represent true emergencies, because tissue viability is dependent on prompt intervention. Whereas any sensory neuropathy may present with finger pain, carpal tunnel syndrome is among the most common. Systemic rheumatic disease, such as rheumatoid arthritis or vasculitis, may begin with finger pain. In addition, such pain may be the first manifestation of a serious systemic illness, as in hypertrophic pulmonary osteoarthropathy. Reflex sympathetic dystrophy is an example of referred pain, presumably by way of neural mechanisms. Certain infectious, traumatic, and ischemic causes of finger pain must be diagnosed promptly to avoid significant morbidity; depending upon the cause of the symptoms, referral to a hand surgeon, rheumatologist, or neurologist may be appropriate. Symptomatic and functional improvement may also be hastened by the input of an occupational therapist.","The causes of finger pain can usually be found by learning about the duration and severity of the problem and doing a physical examination. However, x-rays and lab tests are often used to identify the cause of the pain. Most minor traumatic injuries that cause finger pain only need non-invasive (no surgery) therapy, such as resting followed by exercise. Finger pain caused by an infection (germs that build in the body causing illness) usually require medicines that fight bacteria called antibiotics. A process called drainage that removes extra fluid from a wound is sometimes used with antibiotics. Sometimes patients with finger pain from an infection will see a hand surgeon. Limited or no blood flow to or through the tissues in the finger can cause finger pain, are signs of a true emergency, and require immediate attention to prevent more damage to the tissues. Patients with nerve damage may have finger pain. Carpal tunnel syndrome (pain or tingling in the hand or arm caused by a pinched wrist nerve) is a common example of pain caused by nerve damage. Diseases that can cause your immune system to attack your joints, muscles, bones and organs (called systemic rheumatic diseases) can begin with finger pain. In addition, finger pain may be the first sign of a more serious illness, such as in hypertrophic pulmonary osteoarthropathy (a rare disease with irritation around the bone and enlarged fingertips). Reflex sympathetic dystrophy (a disease causing long-lasting pain in one or more limbs) is an example of when an injury in one part to the body causes pain in a different part of the body. Certain infections, traumatic injuries, and blood flow problems that cause finger pain must be identified quickly to prevent long-term or more serious damage. In some cases, going to a hand surgeon, a rheumatologist (doctor who treats arthritis and other joint, muscle, and bone diseases), or a neurologist (brain and nerve doctor) is needed. Progress in reducing pain and improving movement in the finger may come faster with the help of an occupational therapist, people who help patients with injuries, illnesses, and disabilities build or restore their abilities to do everyday tasks in life." +"The local, systemic, and referred causes of finger pain are generally recognizable by historical features and physical examination findings, although radiographs and laboratory evaluation are often required to support the diagnostic impression. Most minor traumatic causes of finger pain require only conservative management, including immobilization followed by exercise. Infectious causes of finger pain include cellulitis, tendinitis, paronychia, felon, and infectious emboli, which generally require antibiotics with or without drainage. Certain patients with finger pain resulting from infection should be referred to a hand surgeon. Vascular and ischemic causes of finger pain represent true emergencies, because tissue viability is dependent on prompt intervention. Whereas any sensory neuropathy may present with finger pain, carpal tunnel syndrome is among the most common. Systemic rheumatic disease, such as rheumatoid arthritis or vasculitis, may begin with finger pain. In addition, such pain may be the first manifestation of a serious systemic illness, as in hypertrophic pulmonary osteoarthropathy. Reflex sympathetic dystrophy is an example of referred pain, presumably by way of neural mechanisms. Certain infectious, traumatic, and ischemic causes of finger pain must be diagnosed promptly to avoid significant morbidity; depending upon the cause of the symptoms, referral to a hand surgeon, rheumatologist, or neurologist may be appropriate. Symptomatic and functional improvement may also be hastened by the input of an occupational therapist.","Causes of finger pain are usually recognizable by past characteristics and findings from a physical checkup. However, radiographs (images created usually by x-rays) and other lab tests are usually required to support the identification. Most minor causes of finger pain need only mild treatment, like restraining the finger from moving and exercise. Causes of finger pain from bacteria include cellulitis (a bacterial skin infection), tendinitis (an irritation of the tendon), paronychia (a bacterial nail infection), felon (a bacterial fingertip infection), and emboli (a blood vessel blockage). These causes generally require antibacterials alomg with or without fluid drainage of the finger. Some patients with finger pain from bacteria should be sent to a hand surgeon. Causes of finger pain related to blood vessels represent real emergencies that depend on quick treatment. When any nerve damage leads to finger pain, a pinched nerve in the wrist is usually the most common. Full-body autoimmune diseases (diseases in which infection-preventing cells attack healthy cells), which may cause joint pain or irritation in the blood vessels, might start with finger pain. Also, finger pain may be the first sign of a serious full-body illness, as in hypertrophic pulmonary osteoarthropathy, a rare disease with irritation around the bone and joints and enlarged fingertips. Reflex sympathetic dystrophy (a disease causing long-lasting limb pain) is an example of pain felt in an area away from its source, possibly by nerve signaling issues. Some bacteria-related, injury-related, and blood vessel-related causes of finger pain must be checked quickly to avoid serious harm. Depending on the cause, help from a hand surgeon, rheumatologist (a doctor who treats musculoskeletal issues), or neurologist (a doctor who treats nerve-related issues) may be needed. Recovery may be quickened with occupational therapists that help patients perform everyday activities." +"When patients present with acute or chronic hand and/or finger pain after an injury, try placing a pencil first over and then under the proximal phalanx of the finger that is generating the pain. Ask the patient to flex and extend the fingers several times. Putting the affected metacarpal phalangeal (MP) joint more relatively flexed or extended than the other MP joints will often take away the pain with active movement with the pencil in place. When this happens, our hand therapist builds a relative motion splint that simulates the effect of the pencil. These are very functional splints that patients wear 24 hours a day, 7 days a week. Most people can work with these splints on.","When a patient has sudden or ongoing hand and/or finger pain after an injury, a hand therapist may place a pencil over and under the first bone of the finger (that starts at the base from the hand) that is causing the pain. The doctor will then ask the patient to flex and extend the fingers several times. Putting the first knuckle (the joint where the finger connects with the hand) in a more flexed and extended position than the other knuckles will often take away the pain with active movement when the pencil is in place. The hand therapist will then build a relative motion splint (a piece of sturdy material to support injured bones and allow some movement) that will have the same effect of the pencil. These types of splints support initial movement and can be worn 24 hours a day, 7 days a week. Most people can work with these splints on." +"Objective: To identify through case study the presentation and possible pathophysiological cause of complex regional pain syndrome and its preferential response to stellate ganglion blockade. Setting: Complex regional pain syndrome can occur in an extremity after minor injury, fracture, surgery, peripheral nerve insult or spontaneously and is characterised by spontaneous pain, changes in skin temperature and colour, oedema, and motor disturbances. Pathophysiology is likely to involve peripheral and central components and neurological and inflammatory elements. There is no consistent approach to treatment with a wide variety of specialists involved. Diagnosis can be difficult, with over-diagnosis resulting from undue emphasis placed upon pain disproportionate to an inciting event despite the absence of other symptoms or under-diagnosed when subtle symptoms are not recognised. The International Association for the Study of Pain supports the use of sympathetic blocks to reduce sympathetic nervous system overactivity and relieve complex regional pain symptoms. Educational reviews promote stellate ganglion blockade as beneficial. Three blocks were given at 8, 10 and 13 months after the initial injury under local anaesthesia and sterile conditions. Physiotherapeutic input was delivered under block conditions to maximise joint and tissue mobility and facilitate restoration of function. Conclusion: This case demonstrates the need for practitioners from all disciplines to be able to identify the clinical characteristics of complex regional pain syndrome to instigate immediate treatment and supports the notion that stellate ganglion blockade is preferable to upper limb intravenous regional anaesthetic block for refractory index finger pain associated with complex regional pain syndrome.","The objective of this case report (a summary of an individual patient's symptoms, diagnosis, and treatment) is to identify the sign or symptoms and causes of complex regional pain syndrome (a form of ongoing pain that affects the arm or leg) and if a pain treatment called stellate ganglion blockade (an injection of medication into nerves at the front of the neck that can relieve pain) has any effect on the pain. Complex regional pain syndrome can occur in the arms or legs after a minor injury, fracture, surgery, or nerve damage. It appears as sudden, random pain, changes in skin temperatures and color, swelling in ankles, feet or legs, and uncontrollable movements in the body. Disease-related physical changes are likely to involve outer and central parts, nerve-related elements, and inflammatory elements, the body's natural response to injury or infection. There is no consistent approach to treatment with a wide variety of specialists involved. Diagnosis can be difficult. Sometimes it is over-diagnosed (diagnosis of a medical condition that would never have caused any symptoms or problems) from too much attention on the pain even though other symptoms are not present. Sometimes it can be under-diagnosed (diagnosed less often than its occurrence) when less obvious symptioms are not recognized. A professional medical association for the study of pain supports the kind of pain block used in stellate ganglion blockade to reduce sensory nerves and relieve pain sympoms. Educational reviews promote stellate ganglion blockade as beneficial. Three blocks (injections) were given at 8, 10 and 13 months after the initial injury under local anaesthesia and clean conditions. Physical therapy was provided after the patient received an injection to allow more movement of the joint and tissues and to help restore use of the injured finger. This case shows that healthcare providers need to be able to identify clinical signs of complex regional pain syndrome to start treatment immediately. It also shows that stellate ganglion blockade is a preferable method to an IV of local anaesthetic (one-time injection of medicine that numbs a small area of the body) in the upper arm to help finger pain associated with complex regional pain syndrome." +"Background and aims: In previous studies, we successfully applied Low Level Laser Therapy (LLLT) in patients with non-specific chronic pain of the shoulder joint and lower back. The purpose of the present study was to assess the effectiveness of LLLT for chronic joint pain of the elbow, wrist, and fingers. Subjects and methods: Nine male and 15 female patients with chronic joint pain of the elbow, wrist, or fingers, who were treated at the rehabilitation outpatient clinic at our hospital from April, 2007 to March, 2009 were enrolled in the study. We used a 1000 mW semiconductor laser device. Each tender point and three points around it were irradiated with laser energy. Each point was irradiated twice for 20 s per treatment, giving a total of three minutes for all 4 points. Patients visited the clinic twice a week, and were evaluated after four weeks of treatment. Pain was evaluated with a Visual Analogue Scale (VAS). Statistical analysis of the VAS scores after laser irradiation was performed with Wilcoxon's signed rank sum test, using SPSS Ver.17. Results: All VAS scores were totaled and statistically analyzed. The average VAS score before irradiation was 59.2�12.9, and 33.1�12.2 after the irradiation, showing a significant improvement in VAS score (p<0.001) after treatment. The treatment effect lasted for about one and a half days in the case of wrist pain, epicondylitis lateralis (tennis elbow), and carpal tunnel syndrome. In other pain entities, it lasted for about three to fifteen hours. No change in the range of motion (ROM) was seen in any of the 24 subjects. Conclusion: We concluded that LLLT at the wavelength and parameters used in the present study was effective for chronic pain of the elbow, wrist, and fingers.","To treat patients with chronic shoulder and low back pain, previous studies have successfully used a treatment called low level laser therapy (LLLT), a laser light used at a low level and applied to the skin of the body to reduce pain or inflammation and help heal wounds, tissues, and nerves. The purpose of this current study is to find out if LLLT also helps patients with chronic joint pain of the elbow, wrist, and fingers. This study included 9 male and 15 female patients with chronic joint pain in the elbow, wrist, or fingers. The tender point (specific area of pain) and three points surrounding the pain were exposed to the LLLT therapy light. Each area was exposed two times for 20 seconds per treatment, giving a total of three minutes for all 4 points. Patients visited the clinic twice a week, and were evaluated after 4 weeks of treatment with LLLT (laser therapy). A tool called the Visual Analogue Scale (VAS) was used to measure pain by asking patients to report how intense their pain is on a scale. The study analyzed VAS scores (how patients described their pain) after they received the LLLT laser treatment. All VAS scores that document pain intensity were totaled and analyzed. There was significant improvement in how much pain patients felt after they received the treatment. The effect of the laser treatment lasted for about one and half days for patients with wrist pain, tennis elbow, and carpal tunnel syndrome (pinched nerve in the wrist). In patients with other types of pain, the effect lasted for about 3-15 hours. There was no change in how far patients could move or stretch the injured part of the body after the treatment. This study found that low level laser therapy was helpful for chronic pain of the elbow, wrist, and fingers." +"Background and aims: In previous studies, we successfully applied Low Level Laser Therapy (LLLT) in patients with non-specific chronic pain of the shoulder joint and lower back. The purpose of the present study was to assess the effectiveness of LLLT for chronic joint pain of the elbow, wrist, and fingers. Subjects and methods: Nine male and 15 female patients with chronic joint pain of the elbow, wrist, or fingers, who were treated at the rehabilitation outpatient clinic at our hospital from April, 2007 to March, 2009 were enrolled in the study. We used a 1000 mW semiconductor laser device. Each tender point and three points around it were irradiated with laser energy. Each point was irradiated twice for 20 s per treatment, giving a total of three minutes for all 4 points. Patients visited the clinic twice a week, and were evaluated after four weeks of treatment. Pain was evaluated with a Visual Analogue Scale (VAS). Statistical analysis of the VAS scores after laser irradiation was performed with Wilcoxon's signed rank sum test, using SPSS Ver.17. Results: All VAS scores were totaled and statistically analyzed. The average VAS score before irradiation was 59.2�12.9, and 33.1�12.2 after the irradiation, showing a significant improvement in VAS score (p<0.001) after treatment. The treatment effect lasted for about one and a half days in the case of wrist pain, epicondylitis lateralis (tennis elbow), and carpal tunnel syndrome. In other pain entities, it lasted for about three to fifteen hours. No change in the range of motion (ROM) was seen in any of the 24 subjects. Conclusion: We concluded that LLLT at the wavelength and parameters used in the present study was effective for chronic pain of the elbow, wrist, and fingers.","In previous studies, we used Low Level Laser Therapy (LLLT), therapy with applying light on the body's surface, in patients with non-specific, long-lasting pain of the shoulder joint and lower back. This work measures the success of this specific light therapy for lasting joint pain of the elbow, wrist, and fingers. Nine male and fifteen female patients with long-lasting joint pain of the elbow, wrist, or fingers were treated at our hospital's recovery clinic from April, 2007 to March, 2009. These patients were employed in the study. Patients visited the clinic twice a week and were checked after four weeks of treatment. Pain was measured with a specific pain scale. The average pain score noticeably improved after treatment. The treatment effect lasted for about one and a half days regarding wrist pain, tennis elbow, and carpal tunnel syndrome, which involves pinched nerves in the wrist. In other pain types, the treatment effect lasted for about three to fifteen hours. No change in the range of motion was seen in any of the 24 patients. LLLT at the settings used in this study was useful for long-lasting pain of the elbow, wrist, and fingers." +"This compilation presents a comprehensive review of the literature on common chronic pain conditions of the hand. It briefly presents these common conditions with their biological background, diagnosis, and common management options. It then presents and compares the latest literature available for injection techniques to treat these diagnoses and compares the available evidence. Results: Hand pain is a common condition with 9.7% prevalence in men and 21.6% in women and can cause significant morbidity and disability. It also carries a significant cost to the individuals and the healthcare system, totaling in $4 billion dollars in 2003. Injection therapy is an alternative when conservative treatment fails. Osteoarthritis is the most common chronic hand pain syndrome and affects about 16% of the population. Its mechanism is largely mechanic, and as such, there is controversy if steroid injections are of benefit. Hyaluronic acid (HA) appears to provide substantial relief of pain and may increase functionality. More studies of HA are required to make a definite judgment on its efficacy. Similarly, steroid ganglion cyst injection may confer little benefit. Carpal tunnel syndrome is a compressive neuropathy, and only temporarily relieved with injection therapy. US-guidance provides significant improvement and, while severe cases may still require surgery, can provide a valuable bridge therapy to surgery when conservative treatment fails. Similar bridging treatments and increased efficacy under US-guidance are effective for stenosing tenosynovitis (""trigger finger""), though, interestingly, inflammatory background is associated with decreased effect in this case. When the etiology of the pain is inflammatory, such as in RA, corticosteroid (CS) injections provide significant pain relief and increased functionality. They do not, however, change the course of disease (unlike DMARDs). Another such example is De-Quervain tenosynovitis that sees good benefit from CS injections, and an increased efficacy with US-guidance, and similarly are CS injections for gout. For Raynaud's phenomenon, Botox injections have encouraging results, but more studies are needed to determine safety and efficacy, as well as the possible difference in effect between primary and secondary Raynaud's. Conclusions: Chronic hand pain is a prevalent and serious condition and can cause significant morbidity and disability and interferes with independence and activities of daily living. Conservative treatment remains the first line of treatment; however, when first-line treatments fail, steroid injections can usually provide benefit. In some cases, Hyaluronic acid or Botox may also be beneficial. US-guidance is increasing in hand injection and almost ubiquitously provides safer, more effective injections. Hand surgery remains the alternative for refractory pain.","This report presents a thorough review of the literature on common chronic pain conditions of the hand. It briefly presents common conditions with their biological background, diagnosis, and common options to treat and manage pain. The report also shows and compares the latest literature available for injection methods to treat these diagnoses and compares the available evidence. Hand pain is a common condition occuring in 9.7% of men and 21.6% of women and can cause significant illness and disability. It is also costly to the individuals and the healthcare system, totaling in $4 billion dollars in 2003. Injection therapy (a treatment that involves inserting a needle into the skin to deliver medicine and reduce pain) is an option when other non-surgical treatments fail. Osteoarthritis (the wearing down of flexible tissue at the end of bones) is the most common chronic hand pain condition and affects about 16% of the population. There is disagreement on whether steroid injections are helpful to osteoarthritis. Injections of hyaluronic acid (a natural lubricant that can relieve pain) appear to provide significant relief of pain and may increase movement. More studies of hyaluronic acid are required before deciding how well it works. Similarly, steroid injection to reduce a ganglion cyst (a swelling or bump on the wrist joint) may have little benefit. Injection therapy provides only short-term relief for carpal tunnel syndrome (pinched nerves in the wrist). While severe cases of hand pain may still require surgery, injection therapy may be an additional treatment step before surgery. Similar treatments under US-guidance are effective for a condition called trigger finger where the finger gets locked in a bent position. When the cause of the pain is inflammation (the body's response to injury or infection often causing swelling, pain, or redness), corticosteroid or steroid injections provide significant pain relief and increased movement. Corticosteroid injections do not, however, change the course of disease. Other conditions such as gout (a type of arthritis that causes sudden pain or swelling, often in the big toe) and De-Quervain tenosynovitis (pain in the tendons in the thumb) may get some benefit from corticosteroid injections. Botox injections show encouraging results for Raynaud's phenomenon (spasms caused by slow blood flow in the fingers and other extremities), but more studies are needed to determine safety and how well the injections work. Chronic hand pain is a common and serious condition, can cause significant illness and disability, and interferes with independence and the activities of daily living. Careful, non-invasive treatment remains the first line of treatment; however, when first-line treatments fail, steroid injections can usually provide benefit. In some cases, Hyaluronic acid or Botox may also be helpful. US-guidance is expanding in hand injections and provides safer, more effective injections. Hand surgery remains the alternative for pain that is not responding to multiple treatments." +"Background: Hand osteoarthritis (OA) is a prevalent joint disease that may lead to pain, stiffness and problems in performing hand-related activities of daily living. Currently, no cure for OA is known, and non-pharmacological modalities are recommended as first-line care. A positive effect of exercise in hip and knee OA has been documented, but the effect of exercise on hand OA remains uncertain. Authors' conclusions: When we pooled results from five studies, we found low-quality evidence showing small beneficial effects of exercise on hand pain, function and finger joint stiffness. Estimated effect sizes were small, and whether they represent a clinically important change may be debated. One study reported quality of life, and the effect is uncertain. Three studies reported on adverse events, which were very few and were not severe.","Hand osteoarthritis is a common joint disease that may lead to pain, stiffness and problems in performing hand-related activities of daily living. Currently, no cure for osteoarthritis is known, and using treatment methods that do not involve medications for pain are recommended as first-line care. A positive effect of exercise in hip and knee osteoarthritis has been documented, but the effect of exercise on hand osteoarthritis remains uncertain. Researchers reviewed results from 5 studies and found low-quality evidence (the findings are difficult to interpret or are considered weak) showing small helpful effects of exercise on hand pain, function and finger joint stiffness. The relationship between hand osteoarthritis and exercise were small in these studies, and it is not clear if any medical practices should change based on these 5 studies. One study reported quality of life, and the effect is uncertain. Three studies reported on unexpected medical problems, which were very few and were not severe." +"Upper extremity neuropathic pain states greatly impact patient functionality and quality of life, despite appropriate surgical intervention. This article focuses on the advanced therapies that may improve pain care, including advanced treatment strategies that are available. The article also surveys therapies on the immediate horizon, such as spinal cord stimulation, peripheral nerve stimulation, and dorsal root ganglion spinal cord stimulation. As these therapies evolve, so too will their placement within the pain care algorithm grounded by a foundation of evidence to improve patient safety and management of patients with difficult neuropathic pain.","Pain felt in the arm that is caused by damaged nerves or a weakening nervous sytem is called neuropathic pain and can greatly impact movement and quality of life, even after a patient has surgery. This article focuses on the new therapies that may improve pain care, including new treatment plans that are available. This article examines new and upcoming therapies, such as spinal cord simulation (electrical treatment to the spinal cord), peripheral nerve simulation (electrical treatment to the nerves), and dorsal root ganglion spinal cord stimulation (electrical treatment to spine cells). As these therapies evolve, so too will their placement within pain care plans." +"Upper extremity neuropathic pain states greatly impact patient functionality and quality of life, despite appropriate surgical intervention. This article focuses on the advanced therapies that may improve pain care, including advanced treatment strategies that are available. The article also surveys therapies on the immediate horizon, such as spinal cord stimulation, peripheral nerve stimulation, and dorsal root ganglion spinal cord stimulation. As these therapies evolve, so too will their placement within the pain care algorithm grounded by a foundation of evidence to improve patient safety and management of patients with difficult neuropathic pain.","Nerve-related, upper hand pain greatly affects patient performance and quality of life, even with proper treatment. This article looks at leading treatments that may improve pain care, including advanced treatments that are available. This article also reviews upcoming therapies, like spinal cord electrical stimulation, peripheral or outer nerve stimulation, and dorsal root ganglion spinal cord stimulation (electrical treatment for specific cells in the spinal cord). As these therapies improve, so will their use in pain care grounded by evidence to improve patient safety and monitoring of patients with complex nerve-related pain." +"Background: Rheumatoid arthritis (RA) is characterized by pain, functional disability, poor quality of life (QoL), high socioeconomic impact, and annual costs of over $56 billion in the United States. Acupuncture (AC) is widely in use; however, studies show severe methodological shortcomings, did not consider the functional diagnosis for the allocation of acupoints and their results showed no differences between verum and control groups. Objective: The authors aimed to objectively assess the safety and efficacy of AC treatments for RA. Methods: 105 RA patients with a functional diagnosis of a ""Pivot syndrome"" or ""Turning Point syndrome"" were randomly assigned to (1) verum-AC (verum acupoints), (2) control-AC (sham acupoints-points outside of the conduits/meridians and of the extra-conduits), or (3) waiting list (each group n = 35). AC groups experienced the exact same number, depth, and stimulation of needles. Assessments took place before and 5 min after AC with follow-ups over 4 weeks. Results: (1) Verum-AC significantly improved self-reported pain (Z = -5.099, p < 0.001) and pressure algometry (Z = -5.086, p < 0.001); hand grip strength (Z = -5.086, p < 0.001) and arm strength (Z = -5.086, p < 0.001); health status improved significantly (p < 0.001, Z = -4.895); QoL improved significantly in 7/8 survey domains; and number of swollen joints (Z = -2.862, p = 0.004) and tender joints (Z = -3.986, p < 0.001) significantly decreased. (2) Control-AC showed no significant changes, except in self-reported pain improvement. (3) Waiting list group showed an overall worsening. Conclusion: This is the first double-blind controlled study on AC in RA of the hand that objectively and specifically assesses positive effects supporting its integration in rheumatology. Acupoint allocation according to Chinese Medicine functional diagnoses is extremely relevant to assess AC effectiveness in a patient group primarily defined by a ""western"" medicine diagnosis. Based on clear allocation criteria for acupoints, the authors minimized the possible bias of unspecific and suggestive effects on the control group, showed the specific effects of the points chosen, improved efficacy, and identified an evidence base for AC.","Rheumatoid arthritis is a disease where the immune system attacks healthy cells in the body by mistake. It can cause pain, decrease movement, lead to poor quality of life, impact the social and economic parts of communities, and cost over $56 billion in the United States every year. Acupuncture involves pricking the skin or tissues with thin needles at key points in the body to reduce pain and is widely used. However, studies show problems in the methods used to measure acupuncture. The aim of this current study is to evaluate the safety and the performance of acupuncture treatments on rheumatoid arthritis. In this study, 105 patients with rheumatoid arthritis and a specific diagnosis were randomly assigned to either the acupuncture group, the sham acupuncture group (where the patient is pricked with thin needles but at different, less key points of the body), or a waiting list group. Each group had 35 patients. The acupuncture groups (both normal and sham) experienced the exact same number, depth, and stimulation of needles. A physical and visual exam of patients took place before and 5 minutes after acupuncture treatment with follow-up visits over 4 weeks. Patients in the acupuncture group showed signficantly improved pain and pain sensitivity, hand grip and arm strength, as well as improved health status. Quality of life significantly improved in 7 out of 8 parts of a survey. The number of swollen joints and tender joints signficantly decreased. In the sham acupuncture group (the group that received needle pricks but outside the key points of the body) did not have any significant changes in their condition except in pain improvement. The waiting list group showed an overall worsening. This is the first double-blind controlled study (where neither the patients nor the researcher knows which treatment participants are getting) on acupuncture for rheumatoid arthritis of the hand. The study shows positive effects supporting acupuncture's inclusion in other treatments for rheumatology (diseases in the joints, muscles, tendons, ligaments). The site of the acupuncture needle is very important to determine acupuncture effectiveness. Because the authors in this study clearly defined the placement of the acupuncture needles on the body, they reduced possible bias, showed how the placement of the needles affects the body, improved performance of acupuncture, and identified evidence to support use of acupuncture." +"Pain and a loss of feeling in your thumb, index finger, middle finger, and part of your ring finger may be a sign of carpal tunnel syndrome. This syndrome and the pain, numbness, tingling, and weakness in your hand that result from it are caused by pressure on the median nerve as it travels through the carpal tunnel. Guidelines published in the May 2019 issue of JOSPT make recommendations, based on best practices from the published literature, for evaluating, diagnosing, and treating carpal tunnel syndrome. For you as a patient, these guidelines outline the best rehabilitation treatment options based on the scientific research. Ultimately, the best care is a combination of the leading science, the clinical expertise of your health care provider, and your input as the patient. These guidelines help inform the first step in that process. Practical Advice: Physical therapists are well trained to assess and evaluate people with carpal tunnel syndrome. Although some patients (anywhere from 28% to 62%) recover without treatment, others (from 32% to 58%) get worse. A key to nonsurgical treatment shown to help those with carpal tunnel syndrome is the use of a night brace; a night brace should hold your wrist in a neutral position and only be worn for short-term symptom relief. If you have mild to moderate carpal tunnel syndrome, stretching exercises and the night brace can help, as can manual therapy of your cervical spine and upper extremity performed by a therapist. Education on the proper setup of your computer, especially the mouse, and how hard you strike the keyboard may also help control your symptoms of pain and loss of feeling. The literature review for these guidelines found that low-level laser therapy, thermal ultrasound, iontophoresis, and magnets provided no consistent benefit in treating carpal tunnel syndrome. If nonsurgical treatment does not help, you may need surgery. Your physical therapist can help guide your recovery, decreasing your symptoms.","Pain and a loss of feeling in the thumb, index finger, middle finger, and part of the ring finger may be a sign of carpal tunnel syndrome (pinched nerves in the wrist). This syndrome and the pain, numbness, tingling, and weakness in the hand is caused by pressure on the main nerve at the front of the forearm as it travels through the carpal tunnel, a narrow passageway at the base of the hand that is made of ligaments and bone. Guidelines from the May 2019 issue of Journal of Orthopaedic & Sports Physical Therapy, a scientific journal, make recommendations for evaluating, diagnosing, and treating carpal tunnel syndrome. For patients, these guidelines outline the best rehabilitation treatment options (care that can help people regain, keep, or improve abilities needed for daily life) based on the scientific research. Ultimately, the best care is a combination of three things: 1) the leading science, 2) the knowledge, experience, and skills of a patient's health care provider, and 3) the patient's own input. These guidelines help inform the first step in that process. Physical therapists are people who help injured or ill people improve movement and manage pain. They are well trained to help people with carpal tunnel syndrome. Although some patients (anywhere from 28% to 62%) recover without treatment, others (from 32% to 58%) get worse. A key to nonsurgical treatment shown to help those with carpal tunnel syndrome is the use of a night brace; a night brace should hold the wrist in a neutral position (where the joints are not being bent) and only be worn for short-term symptom relief. For patients with mild to moderate carpal tunnel syndrome, stretching exercises and the night brace can help. Manual therapy (hands-on therapy without using a machine or device) of the neck and arms performed by a therapist can also help. Education on the proper setup of computers, especially the mouse, and how hard patients should strike the keyboard may also help control symptoms of pain and loss of feeling. Research shows that low-level laser therapy (a laser light used at a low level applied to the skin to reduce pain and help the body heal), thermal ultrasound (a device that provides heat to tissues to increase circulation and reduce pain), iontophoresis (a procedure that uses an electrical current to deliver medicine through the skin), and magnets provided no consistent benefit in treating carpal tunnel syndrome. If nonsurgical treatment does not help, surgery may be needed. A physical therapist can help guide a patient's recovery and decrease symptoms." +"Importance: Hand osteoarthritis is a musculoskeletal problem that is associated with hand pain, stiffness, functional limitation, decreased grip strength, and reduced quality of life. Objective: To evaluate the effectiveness of nighttime orthoses on the second or third finger of the dominant hand in controlling pain in women with symptomatic osteoarthritis (OA) in the interphalangeal joint. Design: Randomized controlled trial. Setting: Outpatient clinic. Participants: Fifty-two women with symptomatic OA and presence of Heberden's and Bouchard's nodes, allocated randomly to the intervention group or the control group. Intervention: The intervention group used a nighttime orthosis on the second or third finger of the dominant hand. Both groups participated in an educational session. Outcomes and measures: The following parameters were measured: pain (numerical rating scale, Australian/Canadian Osteoarthritis Hand Index), grip and pinch strength, function (Cochin Hand Functional Scale), and manual performance (Moberg Pick Up Test). Results: The intervention group showed a statistically significant improvement in pain (p < .001) and hand function. The improvement in pain correlated with Cochin Hand Functional Scale scores and the absence of Bouchard's nodes in the third finger, which are predictors of the best prognosis for treatment with a nighttime orthosis. Conclusions and relevance: This study demonstrates that nighttime orthoses are effective in reducing pain and lead to improvement in hand function in women with hand OA. They are therefore specifically recommended for nonpharmacological treatment of hand OA. What this article adds: Orthoses can be considered, together with manual exercises and joint protection, as an intervention to reduce symptoms and improve hand function in people with hand OA. This study is an important step in empowering occupational therapists to determine appropriate and effective intervention for clients with OA.","Hand osteoarthritis is a problem that is associated with hand pain, stiffness, inability to perform normal functional movements, decreased grip strength, and reduced quality of life. A nighttime orthosis is a device or brace worn at night that supports weak or damaged muscles and limits motion of the wrist. The objective of this study is to evaluate how helpful using nighttime orthoses on the second or third finger of the dominant hand is in controlling pain in women who have osteoarthritis in the hinge joint of the fingers. This study used a randomized controlled trial, a type of study that randomly assigns participants to one of two groups: the intervention group that is receiving the treatment or the comparison group not receiving treatment. The study took place in an outpatient clinic away from a hospital. Fifty-two women with osteoarthritis and who also had bony bumps (also called nodes) on the finger joints closest to the fingernail and in the middle of the finger were randomly assigned to the intervention group or the comparison group. The intervention group used a nighttime orthosis on the second or third finger of the dominant hand. Both groups participated in an educational session. The following were measured in both groups: pain (using a numbered scale), grip and pinch strength, function (measuring the ability to move and use the hand for daily activities), and manual performance (using a timed test that involves picking up, holding, and operating small objects). The intervention group (group that used the orthoses) showed a significant improvement in pain and hand function. The improvement in pain matched with measures of movement and the absence of nodes in the middle of the finger on the third finger. This study shows that nighttime orthoses are effective in reducing pain and lead to improvement in hand function in women with hand osteoarthritis. They are therefore specifically recommended for treatment of hand osteoarthritis that does not involve medications. Orthoses can be considered, together with manual exercises and joint protection, as a way to reduce symptoms and improve hand function in people with hand osteoarthritis. This study is an important step in helping occupational therapists (people who help patients with injuries, illnesses, and disabilities build or restore their abilities to perform the daily tasks of life) find appropriate and useful treatments for clients with osteoarthritis." +"Importance: Hand osteoarthritis is a musculoskeletal problem that is associated with hand pain, stiffness, functional limitation, decreased grip strength, and reduced quality of life. Objective: To evaluate the effectiveness of nighttime orthoses on the second or third finger of the dominant hand in controlling pain in women with symptomatic osteoarthritis (OA) in the interphalangeal joint. Design: Randomized controlled trial. Setting: Outpatient clinic. Participants: Fifty-two women with symptomatic OA and presence of Heberden's and Bouchard's nodes, allocated randomly to the intervention group or the control group. Intervention: The intervention group used a nighttime orthosis on the second or third finger of the dominant hand. Both groups participated in an educational session. Outcomes and measures: The following parameters were measured: pain (numerical rating scale, Australian/Canadian Osteoarthritis Hand Index), grip and pinch strength, function (Cochin Hand Functional Scale), and manual performance (Moberg Pick Up Test). Results: The intervention group showed a statistically significant improvement in pain (p < .001) and hand function. The improvement in pain correlated with Cochin Hand Functional Scale scores and the absence of Bouchard's nodes in the third finger, which are predictors of the best prognosis for treatment with a nighttime orthosis. Conclusions and relevance: This study demonstrates that nighttime orthoses are effective in reducing pain and lead to improvement in hand function in women with hand OA. They are therefore specifically recommended for nonpharmacological treatment of hand OA. What this article adds: Orthoses can be considered, together with manual exercises and joint protection, as an intervention to reduce symptoms and improve hand function in people with hand OA. This study is an important step in empowering occupational therapists to determine appropriate and effective intervention for clients with OA.","Hand osteoarthritis is a musculoskeletal problem involving hand pain, stiffness, practical limitation, decreased grip strength, and reduced quality of life. The objective is to measure the use of nighttime braces on the second or third finger of the dominant hand in controlling pain in women with typical osteoarthritis (OA) in the finger knuckles. Fifty-two women with typical OA and bony lumps in the finger knucles were randomly assigned to the treatment group or the control group. The treatment group used a nighttime brace on the second or third finger of the dominant hand. Both groups took part in an informational session. Pain, grip and pinch strength, funciton, and manual performance were measured. The treatment group showed a noticeable improvement in pain and hand function. The improvement in pain paralleled functionality test scores and the loss of bony lumps in the third finger. They are predictors of the best recovery for treatment with a nighttime brace. Nighttime braces are useful in reducing pain and improving hand function in women with hand osteoarthritis. They are recommended for non-medication treatment of hand osteoarthritis. Braces can be used, along with hand exercises and joint protection, to reduce symptoms and improve hand function in people with hand osteoarthritis. This study can help occupational therapists, who help patients perform everyday activities, choose useful treatments for those with osteoarthritis." +"The main source of energy for brain and other organs is glucose. To obtain energy for all tissue, glucose has to come through glycolysis; then as pyruvate it is converted to acetyl-CoA by pyruvate dehydrogenase complex (PDC) and finally enters citric acid cycle. What happens when one of these stages become disturb? Mutation in genes encoding subunits of PDC leads to pyruvate dehydrogenase deficiency. Abnormalities in PDC activity result in severe metabolic and brain malformations. For better understanding the development and mechanism of pyruvate dehydrogenase deficiency the murine model of this disease has been created. Studies on a murine model showed similar malformation in brain structures as in the patients suffered from pyruvate dehydrogenase deficiency such as reduced neuronal density, heterotopias of grey matter, reduced size of corpus callosum and pyramids. There is still no effective cure for PDC-deficiency. Promising therapy seemed to be ketogenic diet, which substitutes glucose to ketone bodies as a source of energy. Studies have shown that ketogenic diet decreases lactic acidosis and inhibits brain malformations, but not the mortality in early childhood. The newest reports say that phenylbutyrate increases the level of PDC in the brain, because it reduces the level of inactive form of PDH. Experiments on human fibroblast and zebra fish PDC-deficiency model showed that phenylbutyrate is promising cure to PDC-deficiency. This review summarizes the most important findings on the metabolic and morphological effects of PDC-deficiency and research for treatment therapy.","The main source of energy for the brain and other organs is glucose, a type of sugar in the blood that comes from the food people eat. In order for energy to reach all tissues, glucose has to go through a process with several stages. One of these stages is called pyruvate dehydrogenase complex (PDC) which converts molecules and links cells to the final stage of creating energy. What happens when one of these stages is disturbed? Genetic changes in the PDC process leads to pyruvate dehydrogenase deficiency, a disease where the body cannot properly breakdown food to create fuel or energy. Errors in PDC (pyruvate dehydrogenase complex) activity also result in severe disruption of the body's ability to process and distribute nutrients and can create brain malformations where the brain or nervous system is damaged or has not formed properly during pregnancy. To better understand the pyruvate dehydrogenase deficiency, researchers created an experiment that includes common household rats and mice. Studies using an animal experiment showed similar abnormalities in brain structures compared to patients suffering from pyruvate dehydrogenase deficiency. There is still no effective cure for pyruvate dehydrogenase complex-deficiency. Promising therapy may be a low carb, high fat diet called a ketogenic diet, where the body substitutes glucose with ketone bodies (chemicals the body makes when there is not enough glucose) as a source of energy. Studies show that a ketogenic diet decreases lactic acidosis (lactic acid build up that can cause nausea, vomiting, and breathing problems) and slows down brain malformations, but not death in early childhood. The newest reports say that phenylbutyrate, a type of salt in the body that helps remove ammonia and waste from the body, increases the level of pyruvate dehydrogenase complex in the brain. Experiments on human fibroblast (a cell found in connective tissues) and zebra fish showed that phenylbutyrate is a promising cure to dehydrogenase complex deficiency. This review summarizes the most important findings on the effects of PDC-deficiency on metabolism and development of the brain and on research for treatment therapy." +"Objectives: Our aime was to study the short- and long-term effects of ketogenic diet on the disease course and disease-related outcomes in patients with pyruvate dehydrogenase complex deficiency, the metabolic factors implicated in treatment outcomes, and potential safety and compliance issues. Methods: Pediatric patients diagnosed with pyruvate dehydrogenase complex deficiency in Sweden and treated with ketogenic diet were evaluated. Study assessments at specific time points included developmental and neurocognitive testing, patient log books, and investigator and parental questionnaires. A systematic literature review was also performed. Results: Nineteen patients were assessed, the majority having prenatal disease onset. Patients were treated with ketogenic diet for a median of 2.9 years. All patients alive at the time of data registration at a median age of 6 years. The treatment had a positive effect mainly in the areas of epilepsy, ataxia, sleep disturbance, speech/language development, social functioning, and frequency of hospitalizations. It was also safe-except in one patient who discontinued because of acute pancreatitis. The median plasma concentration of ketone bodies (3-hydroxybutyric acid) was 3.3 mmol/l. Poor dietary compliance was associated with relapsing ataxia and stagnation of motor and neurocognitive development. Results of neurocognitive testing are reported for 12 of 19 patients. Conclusion: Ketogenic diet was an effective and safe treatment for the majority of patients. Treatment effect was mainly determined by disease phenotype and attainment and maintenance of ketosis.","A ketogenic diet is a low carb, high-fat diet that can help create fuel for the body when glucose levels are low. The aim of this study is to find the short- and long-term effects of a ketogenic diet on disease progression and disease-related outcomes (changes in health) in patients with pyruvate dehydrogenase complex deficiency, a rare disease that impacts the nervous system. The effects of a ketogenic diet on the body's chemical process to turn food into energy and potential safety issues are also studied. Child patients diagnosed with pyruvate dehydrogenase complex deficiency in Sweden and treated with a ketogenic diet are evaluated in this study. The study includes different tests on development and brain function, recording assessments in patient log books, and a series of questions for both researchers and parents to answer. A review of all relevant research on this topic is also performed. Nineteen patients were included in the study. For most of the patients, the disease developed during pregnancy. Patients were treated with ketogenic diet for about 2.9 years, but this time varied. All patients alive at the time of data registration were about 6 years old, but the age did vary. The treatment has a positive effect mainly in the areas of epilepsy (a disorder that causes seizures), ataxia (loss of control of movement), sleep disturbance, speech/language development, social functioning (the ability to engage with others), and the number of hospitalizations. It is also safe-except in one patient who had to stop because of acute pancreatitis, where the pancreas becomes swollen over a short period of time. Not staying on the diet regularly is connected with returning ataxia (loss of control of movement) and slowing or stopping of the strengthening of bones and muscles and brain development. Ketogenic diet is an effective and safe treatment for the majority of patients. How effective treatment is was mostly determined by physical traits or characteristics of patients and by if the body reaches and maintains ketosis, a process where the body burns stored fat for energy instead of glucose." +"Diets low in carbohydrates and proteins and enriched in fat stimulate the hepatic synthesis of ketone bodies (KB). These molecules are used as alternative fuel for energy production in target tissues. The synthesis and utilization of KB are tightly regulated both at transcriptional and hormonal levels. The nuclear receptor peroxisome proliferator activated receptor ? (PPAR?), currently recognized as one of the master regulators of ketogenesis, integrates nutritional signals to the activation of transcriptional networks regulating fatty acid ?-oxidation and ketogenesis. New factors, such as circadian rhythms and paracrine signals, are emerging as important aspects of this metabolic regulation. However, KB are currently considered not only as energy substrates but also as signaling molecules. ?-hydroxybutyrate has been identified as class I histone deacetylase inhibitor, thus establishing a connection between products of hepatic lipid metabolism and epigenetics. Ketogenic diets (KD) are currently used to treat different forms of infantile epilepsy, also caused by genetic defects such as Glut1 and Pyruvate Dehydrogenase Deficiency Syndromes. However, several researchers are now focusing on the possibility to use KD in other diseases, such as cancer, neurological and metabolic disorders. Nonetheless, clear-cut evidence of the efficacy of KD in other disorders remains to be provided in order to suggest the adoption of such diets to metabolic-related pathologies.","Diets low in carbohydrates and proteins but high in fat stimulate the liver to make fat-related energy molecules called ketone bodies (KB). Ketone bodies are molecules used as alternate fuel to produce energy for tissues in the body. Making and using ketone bodies is carefully controlled within the body at the molecule and hormone level. One hormone, known as the master regulator of the process to develop ketone bodies, helps activate the cell networks that control fatty acids and ketogenesis, the process that creates ketone bodies. New factors, such as circadian rhythms (the natural cycle of mental and physical changes in the body over 24 hours) and paracrine signals (cell signaling to communicate with other cells nearby), are becoming important aspects of this metabolic regulation that controls and monitors cell energy stores. However, ketone bodies are currently considered not only as an energy supply but also as signaling molecules that send messages to other cells or parts of the body. Ketogenic diets are currently used to treat different forms of infantile epilepsy (the onset of seizures in infancy), which is also caused by genetic defects. However, several researchers are now focusing on the possibility to use ketogenic diets in other diseases, such as cancer, brain-related and metabolic disorders. Nonetheless, clear-cut evidence of the performance of ketogenic bodies in other disorders is needed in order to suggest using such diets." +"Diets low in carbohydrates and proteins and enriched in fat stimulate the hepatic synthesis of ketone bodies (KB). These molecules are used as alternative fuel for energy production in target tissues. The synthesis and utilization of KB are tightly regulated both at transcriptional and hormonal levels. The nuclear receptor peroxisome proliferator activated receptor ? (PPAR?), currently recognized as one of the master regulators of ketogenesis, integrates nutritional signals to the activation of transcriptional networks regulating fatty acid ?-oxidation and ketogenesis. New factors, such as circadian rhythms and paracrine signals, are emerging as important aspects of this metabolic regulation. However, KB are currently considered not only as energy substrates but also as signaling molecules. ?-hydroxybutyrate has been identified as class I histone deacetylase inhibitor, thus establishing a connection between products of hepatic lipid metabolism and epigenetics. Ketogenic diets (KD) are currently used to treat different forms of infantile epilepsy, also caused by genetic defects such as Glut1 and Pyruvate Dehydrogenase Deficiency Syndromes. However, several researchers are now focusing on the possibility to use KD in other diseases, such as cancer, neurological and metabolic disorders. Nonetheless, clear-cut evidence of the efficacy of KD in other disorders remains to be provided in order to suggest the adoption of such diets to metabolic-related pathologies.","Diets low in carbs and proteins and high in fat quicken the creation of liver ketone bodies (KB) (particles made from fat breakdown). KB are used for energy creation in certain body parts. The creation and use of KB from fat breakdown are monitored both at the cellular and multi-cellular level. The nuclear receptor peroxisome proliferator activated receptor ? (PPAR?) is a major regulator of the creation of KB made from fat breakdown. It combines diet signals to the start up of cellular systems monitoring fat breakdown and KB creation. New factors, like sleep-wake patterns and cellular signals, may strongly influence this metabolic monitoring. However, KB are not just energy particles but also signaling particles. ?-hydroxybutyrate (a particle made from fat breakdown) blocks some cellular processes. This creates a connection between products of liver fat breakdown and changes in gene expression without changes to the DNA sequence. Ketogenic diets (KD) or low-carb diets are used to treat different forms of infatile epilepsy, a disorder in babies that disturbs brain and nerve activity and causes seizures. Infantile epilepsy is also caused by flaws in gene expression. However, researchers are now focusing on using KD in other diseases, such as cancer, nerve-related and metabolic disorders. More evidence is needed to use KD diets to treat diseases." +"Treatment of PDH deficiency rarely influences the course of the disease. It is usually possible to reverse or minimize systemic lactic acid accumulation by giving a high fat/low carbohydrate ""ketogenic"" diet, but this does not alleviate the neurological symptoms as structural damage in the brain is present from before birth and many patients do not have significant metabolic problems. There is some evidence that dichloroacetate (which inhibits the specific PDH kinase and thereby activates any residual functioning complex) will also reduce the metabolic disturbance in some patients, but, again, this is rarely accompanied by any objective improvement in neurological performance. A more favorable outcome can be expected in the extremely rare patients with a thiamine responsive form of the disease and, for this reason, a short therapeutic trial of thiamine is worth trying in all cases.","Pyruvate dehydrogenase deficiency or shortage is a rare disorder caused by genetic changes, and its progression can rarely be stopped by treatment. It is usually possible to reverse or minimize some symptoms by giving a high fat/low carbohydrate ""ketogenic"" diet, but this does not help with delays in mental and motor development because damage in the brain is present before birth. A chemical in the body called dichloroacetate may also reduce the disturbance on metabolism in some patients, but, again, this is rarely accompanied by any improvement in mental and motor development. In rare cases, a vitamin called thiamine may respond to pyruvate dehydrogenase deficiency, and so a short course of thiamine is worth trying for all cases." +"Objectives: To report 2 additional cases of pyruvate dehydrogenase complex deficiency with reversible deep gray matter lesions following initiation of ketogenic diet and to perform a literature review of serial imaging in patients with pyruvate dehydrogenase complex. Methods: Clinical data on 3 previously unpublished cases of patients with pyruvate dehydrogenase complex deficiency and with serial magnetic resonance imagings (MRIs) before and after institution of ketogenic diet were reported. A systematic literature review was performed to search for published cases of patients with confirmed pyruvate dehydrogenase complex deficiency who underwent serial MRIs. Results: The 3 subjects in this series demonstrated clinical improvement on ketogenic diet. Two subjects showed reversal of some brain lesions on repeat MRI following initiation of ketogenic diet. Of the 21 published cases with serial MRIs, 13 patients underwent some form of treatment, and of this smaller subset 4 patients had repeat MRIs that showed definitive improvement. In both our described cases and those published in the literature, improvement occurred in lesions in the basal ganglia. Conclusions: In patients with pyruvate dehydrogenase complex deficiency, basal ganglia lesions on MRI are reversible with treatment in some cases and could serve as a biomarker for measuring response to treatment.","Pyruvate dehydrogenase complex deficiency or shortage is a rare disorder that can impact metabolism and lead to problems in the nervous sytem. The objective of this study is to describe cases of pyruvate dehydrogenase complex deficiency after starting a ketogenic (low carb/high fat) diet and to review other studies that have images of the brain in patients with the disorder. Medical information from 3 cases of patients with pyruvate dehydrogenase complex deficiency who had magnetic resonance imagings (MRIs), or scans of the brain, taken before and after they started a ketogenic diet are reported. Researchers searched for other published cases of patients with pyruvate dehydrogenase complex deficiency who also had multiple MRIs. The 3 cases in this report showed improvement by being on a ketogenic diet. Two cases showed a reversal of some brain lesions or damage on repeat MRI after starting a ketogenic diet. The study's search for other cases found 13 patients with pyruvate dehydrogenase complex deficiency who had some form of treatment, and of this group 4 patients had repeat MRIs that showed definite improvement. In all cases, improvement occurred in lesions in the basal ganglia, a part of the brain that helps coordinate movement. In patients with pyruvate dehydrogenase complex deficiency, basal ganglia lesions on MRI are reversible with treatment in some cases and could serve as a way to measure how a patient responds to treatment." +"Background: The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results: The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1? subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying what seems to be a private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas the lactate/pyruvate ratio was below 16; enzymatic activities, when compared to control values, indicated to be independent from the genotype and ranged from 8.5% to 30%, the latter being considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed psychomotor retardation/developmental delay, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially include the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, in silico analysis of the missense mutations present in this PDC deficient population allowed to envisage the molecular mechanism underlying these pathogenic variants. Conclusion: The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allow to obtain an insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.","The pyruvate dehydrogenase complex (PDC) is a chemical process in the body that converts molecules and links cells to the final stage of creating energy. PDC deficiency or shortage is a disorder that can be caused by changes in genes. The result of PDC deficiency mainly affects the central nervous system (the spinal cord and brain). This study aims to describe the clinical, biochemical (the chemical processes in living organisms), and genetic information in 13 patients with pyruvate dehydrogenase complex (PDC) deficiency. All 13 patients carry some type of mutation in the genes that are involved in the PDC process. The mutation in the PDHA1 gene (a gene that helps encode a building block of PDC) is the most common. These data support earlier reports describing PDHA1 mutations as the main cause of PDC deficiency. The data also reveal a notable frequency of the PDHX mutation (another gene that helps encode a building block of PDC) among Portuguese patients who seem to carry a mutation in the community or population. The biochemical analysis showed high levels of lactic acid (high levels occur when oxygen in the body decreases) and high levels of pyruvate plasma (a molecule that helps change sugar in the blood to energy when oxygen levels are low). All patients showed developmental delay (delays or slowness in reaching language, thinking, or motor skills). How serious these delays are seems to match up with the type and location of the mutation carried by the patient. Treatment options include a ketogenic diet (low-carb/high-fat diet) and adding a vitamin called thiamine to the diet, although taking a supplement called arginine aspartate (used for helping to build proteins) may be beneficial in some patients. Moreover, computer modeling of these gene mutations in this PDC deficient population created a picture of underlying causes of these mutations. The identification of the disease-causing mutations provides an insight on the severity of their impact on development and the selection of the best therapy." +"Background: The pyruvate dehydrogenase complex (PDC) catalyzes the irreversible decarboxylation of pyruvate into acetyl-CoA. PDC deficiency can be caused by alterations in any of the genes encoding its several subunits. The resulting phenotype, though very heterogeneous, mainly affects the central nervous system. The aim of this study is to describe and discuss the clinical, biochemical and genotypic information from thirteen PDC deficient patients, thus seeking to establish possible genotype-phenotype correlations. Results: The mutational spectrum showed that seven patients carry mutations in the PDHA1 gene encoding the E1? subunit, five patients carry mutations in the PDHX gene encoding the E3 binding protein, and the remaining patient carries mutations in the DLD gene encoding the E3 subunit. These data corroborate earlier reports describing PDHA1 mutations as the predominant cause of PDC deficiency but also reveal a notable prevalence of PDHX mutations among Portuguese patients, most of them carrying what seems to be a private mutation (p.R284X). The biochemical analyses revealed high lactate and pyruvate plasma levels whereas the lactate/pyruvate ratio was below 16; enzymatic activities, when compared to control values, indicated to be independent from the genotype and ranged from 8.5% to 30%, the latter being considered a cut-off value for primary PDC deficiency. Concerning the clinical features, all patients displayed psychomotor retardation/developmental delay, the severity of which seems to correlate with the type and localization of the mutation carried by the patient. The therapeutic options essentially include the administration of a ketogenic diet and supplementation with thiamine, although arginine aspartate intake revealed to be beneficial in some patients. Moreover, in silico analysis of the missense mutations present in this PDC deficient population allowed to envisage the molecular mechanism underlying these pathogenic variants. Conclusion: The identification of the disease-causing mutations, together with the functional and structural characterization of the mutant protein variants, allow to obtain an insight on the severity of the clinical phenotype and the selection of the most appropriate therapy.","The pyruvate dehydrogenase complex (PDC) quickens the permanent conversion of pyruvate (a particle used for energy-production) into acetyl-CoA (another particle used for energy production). PDC shortage can occur from changes in genes involved in creating its components. The resulting physical traits, though very different, mainly affect the brain and spinal cord. This study explores the medical, biochemical and gene-related information from thirteen PDC scarce patients. The study seeks to create possible gene-physical trait connections. The data agrees with earlier reports describing a specfic gene's sequence changes as the main cause of PDC shortage. However, the results also reveal a large presence of another gene's sequence changes among Portuguese patients. Most carry a possibly private gene sequence change. Regarding medical characteristics, all patients show coordination setback, the intensity of which seems to parallel the type and location of the patient's gene sequence change. Treatment options include administration of a low-carb diet and thiamine, although arginine aspartate may also help. Identifying disease-causing gene sequence changes, along with the altered cellular substances, help explain the physical traits caused by the disease and select the best treatment." +"Mitochondria are the energy-producing organelles of the cell, generating ATP via oxidative phosphorylation mainly by using pyruvate derived from glycolytic processing of glucose. Ketone bodies generated by fatty acid oxidation can serve as alternative metabolites for aerobic energy production. The ketogenic diet, which is high in fat and low in carbohydrates, mimics the metabolic state of starvation, forcing the body to utilize fat as its primary source of energy. The ketogenic diet is used therapeutically for pharmacoresistant epilepsy and for ""rare diseases"" of glucose metabolism (glucose transporter type 1 and pyruvate dehydrogenase deficiency). As metabolic reprogramming from oxidative phosphorylation toward increased glycolysis is a hallmark of cancer cells; there is increasing evidence that the ketogenic diet may also be beneficial as an adjuvant cancer therapy by potentiating the antitumor effect of chemotherapy and radiation treatment.","Mitochondria are the parts of cells that produce energy for the body. Ketone bodies are particles made from breaking down fats and can serve as an alternative to generate energy. The ketogenic diet, which is high in fat and low in carbohydrates, forces the body to use fat as its main source of energy. The ketogenic diet is used to help drug resistant epilepsy (seizures that cannot be conrolled with medicine) and for rare diseases that impact metabolism and the process for changing sugar into energy. There is increasing evidence that the ketogenic diet may also be helpful as an additional therapy for cancer." +"Pyruvate dehydrogenase complex deficiency (PDCD) is a rare neurodegenerative disorder associated with abnormal mitochondrial metabolism. Structural brain abnormalities are common in PDCD. A case of a patient with PDCD with an unusual presentation is described. A 20-month-old boy with hypotonia and developmental delay, presented with hypoxia and respiratory distress due to bronchiolitis. During hospitalisation, he was prescribed PediaSure� feeds. Two days after starting these feeds, he developed respiratory arrest requiring intubation. His blood gas before arrest revealed lactate of 8.9 mmol/L despite normal haemodynamics. After stabilisation and a period of compulsory fasting, subsequent feeding with PediaSure� resulted in the recurrence of lactic acidosis. A metabolic workup revealed an elevated serum pyruvate level. Brain MRI was normal. Skeletal muscle biopsy confirmed PDCD. The most common cause of PDCD is a mutation in the X-linked PDHA1 gene. The severity of PDCD can range from neonatal death to more delayed onset of symptoms as in our index case. Normal brain MRI is reported in only 2% of patients with PDCD. There is no effective treatment for PDCD. In patients with proximal muscle weakness and feeding intolerance with glucose-containing feeds, the presence of lactic acidosis should raise the suspicion of PDCD irrespective of the patient's age and normal MRI.","Pyruvate dehydrogenase complex deficiency (PDCD) or shortage is a rare disorder that can impact metabolism and lead to problems in the brain and nerves. Structural brain abnormalities are common in PDCD. A case of a patient with PDCD is described. A 20-month-old boy with hypotonia (low muscle tone) and developmental delay, was seen by doctors and also had hypoxia (low levels of oxygen in tissues) and trouble breathing due to bronchiolitis (a lung infection). While in the hospital, he was prescribed PediaSure� feeds, a child formula or nutritional food product. Two days after starting these feeds, he stopped breathing and needed a tube inserted in his throat to help him breathe. After being stable and fasting (no food or drinks), feeding with PediaSure� resulted in the recurrence of lactic acidosis (lactic acid build up that can cause nausea, vomiting, and breathing problem). The MRI (scanned image) of the brain was normal. Pyruvate dehydrogenase complex deficiency (PDCD) was confirmed by viewing the muscle tissue under a microscope. The most common cause of PDCD is a mutation in one of the genes called PDHA1 (a gene that encodes a building block of PCD). The seriousness of PDCD can range from infant death to more delayed onset of symptoms as in the child case described here. A normal brain MRI is reported in only 2% of patients with PDCD. There is no effective treatment for PDCD. In patients with muscle weakness and who are unable to eat foods with glucose, the presence of lactic acidosis should raise the suspicion of PDCD regardless of the patient's age and normal MRI." +"Metabolic epilepsies arise in the context of rare inborn errors of metabolism (IEM), notably glucose transporter type 1 deficiency syndrome, succinic semialdehyde dehydrogenase deficiency, pyruvate dehydrogenase complex deficiency, nonketotic hyperglycinemia, and mitochondrial cytopathies. A common feature of these disorders is impaired bioenergetics, which through incompletely defined mechanisms result in a wide spectrum of neurological symptoms, such as epileptic seizures, developmental delay, and movement disorders. The ketogenic diet (KD) has been successfully utilized to treat such conditions to varying degrees. While the mechanisms underlying the clinical efficacy of the KD in IEM remain unclear, it is likely that the proposed heterogeneous targets influenced by the KD work in concert to rectify or ameliorate the downstream negative consequences of genetic mutations affecting key metabolic enzymes and substrates-such as oxidative stress and cell death. These beneficial effects can be broadly grouped into restoration of impaired bioenergetics and synaptic dysfunction, improved redox homeostasis, anti-inflammatory, and epigenetic activity. Hence, it is conceivable that the KD might prove useful in other metabolic disorders that present with epileptic seizures. At the same time, however, there are notable contraindications to KD use, such as fatty acid oxidation disorders. Clearly, more research is needed to better characterize those metabolic epilepsies that would be amenable to ketogenic therapies, both experimentally and clinically. In the end, the expanded knowledge base will be critical to designing metabolism-based treatments that can afford greater clinical efficacy and tolerability compared to current KD approaches, and improved long-term outcomes for patients.","Metabolic epilepsies (seizures) arise in the context of rare hereditary or inborn errors of metabolism (IEM) and can be caused in rare disorders. A common feature of these disorders is they cause brain-related symptoms, such as epileptic seizures, developmental delay (delays in reaching language, thinking, social, or motor skills), and movement disorders. The ketogenic diet, a low-carb/high-fat diet, has been successfully used to treat such conditions. How a ketogenic diet exactly impacts inborn errors of metabolism is not known, but it is likely that they influence the negative impacts of genetic mutations. Benefits of a ketogenic diet are broadly grouped into restoration of parts of metabolism that are impaired, improved maintenance of cells and cells processes, reduced pain and swelling, and processes that control gene activity without changing the DNA. It is possible that a ketogenic diet may be useful in other disorders of metabolism that include epileptic seizures. At the same time, there are some disorders where ketogenic diets should be avoided. More research is needed to better describe metabolic epilepsies that would benefit from a ketogenic diet. Expanding knowledge will be important to design metabolism-based treatments." +"Metabolic epilepsies arise in the context of rare inborn errors of metabolism (IEM), notably glucose transporter type 1 deficiency syndrome, succinic semialdehyde dehydrogenase deficiency, pyruvate dehydrogenase complex deficiency, nonketotic hyperglycinemia, and mitochondrial cytopathies. A common feature of these disorders is impaired bioenergetics, which through incompletely defined mechanisms result in a wide spectrum of neurological symptoms, such as epileptic seizures, developmental delay, and movement disorders. The ketogenic diet (KD) has been successfully utilized to treat such conditions to varying degrees. While the mechanisms underlying the clinical efficacy of the KD in IEM remain unclear, it is likely that the proposed heterogeneous targets influenced by the KD work in concert to rectify or ameliorate the downstream negative consequences of genetic mutations affecting key metabolic enzymes and substrates-such as oxidative stress and cell death. These beneficial effects can be broadly grouped into restoration of impaired bioenergetics and synaptic dysfunction, improved redox homeostasis, anti-inflammatory, and epigenetic activity. Hence, it is conceivable that the KD might prove useful in other metabolic disorders that present with epileptic seizures. At the same time, however, there are notable contraindications to KD use, such as fatty acid oxidation disorders. Clearly, more research is needed to better characterize those metabolic epilepsies that would be amenable to ketogenic therapies, both experimentally and clinically. In the end, the expanded knowledge base will be critical to designing metabolism-based treatments that can afford greater clinical efficacy and tolerability compared to current KD approaches, and improved long-term outcomes for patients.","Metabolic epilepsies (a disorder that disturbs brain and nerve activity and causes seizures) are present with rare, inborn errors of metabolism (IEM), especially with deficiencies of certain energy-monitoring molecules. These disorders commonly include weakened energy-monitoring processes, which lead to a range of nerve-related effects, including epileptic seizures, growth delay, and movement disorders. The ketogenic diet (KD) (a low-carb diet) has successfully treated these conditions to some effect. While the reasons for the usefulness of KD or low-carb diets in inborn errors of metabolism is unclear, it may be because certain targets of KD work together to improve the negative effects from gene sequence changes affecting key metabolic particles, cell stress, and cell death. These helpful effects can be grouped into restoration of weakened energy-monitoring processes and nerve-related damage, improved electrical balance, anti-inflammation, and gene-related activity. Therefore, it is possible that KD may help other metabolic disorders with epileptic seizures. However, there are issues with KD use, including fat breakdown disorders. More research is needed to explain metabolic epilepsies (disorders that disturbe brain and nerve activity and cause seizures) that may be treated with low-carb treatments. Ultimately, this new knowledge will be useful to design metabolic treatments that can further help patients compared to current KD approaches, with better long-term outcomes for patients." +"We determined the ability of self-complementary adeno-associated virus (scAAV) vectors to deliver and express the pyruvate dehydrogenase E1alpha subunit gene (PDHA1) in primary cultures of skin fibroblasts from 3 patients with defined mutations in PHDA1 and 3 healthy subjects. Cells were transduced with scAAV vectors containing the cytomegalovirus promoter-driven enhanced green fluorescent protein (EGFP) reporter gene at a vector:cell ratio of 200. Transgene expression was measured 72h later. The transduction efficiency of scAAV2 and scAAV6 vectors was 3- to 5-fold higher than that of the other serotypes, which were subsequently used to transduce fibroblasts with wild-type PDHA1 cDNA under the control of the chicken beta-action (CBA) promoter at a vector:cell ratio of 1000. Total PDH-specific activity and E1alpha protein expression were determined 10 days post-transduction. Both vectors increased E1alpha expression 40-60% in both control and patient cells, and increased PDH activity in two patient cell lines. We also used dichloroacetate (DCA) to maximally activate PDH through dephosphorylation of E1alpha. Exposure for 24h to 5mM DCA increased PDH activity in non-transduced control (mean 37% increase) and PDH deficient (mean 44% increase) cells. Exposure of transduced patient fibroblasts to DCA increased PDH activity up to 90% of the activity measured in untreated control cells. DCA also increased expression of E1alpha protein and, to variable extents, that of other components of the PDH complex in both non-transduced and transduced cells. These data suggest that a combined gene delivery and pharmacological approach may hold promise for the treatment of PDH deficiency.","This study focuses on the ability of self-complementary adeno-associated virus (scAAV) vectors (a gene therapy tool that introduces genetic material using a modified virus to create a normal copy of a damaged gene) to deliver the pyruvate dehydrogenase gene called PDHA1 (a gene involved in the chemical process to create energy for the body) and create proteins. Cell samples of connective tissue from 3 patients with mutations in PDHA1 and 3 healthy patients were collected for the gene therapy process. Cells are given genetic material with scAAV vectors containing a gene that creates proteins. Two types of vectors, the scAAV2 and scAAv6, were found to be the most effective way to deliver the genetic material into cells. Both vectors increase the production of gene proteins in patients with the damaged genes and in patients with healthy cells. Dichloroacetate, a drug used to treat genetic mitochondrial diseases (diseases where the miochondria cannot create enough energy for cells), is also used to activate pyruvate dehydrogenase, (an enzyme used in metabolism to create energy). The use of dichloroacetate did increase productivity of pyruvate dehydrogenase in cells with damaged genes involved in metabolism. Dichloroacetate did increase production of proteins from certain energy-related genes and activity in other parts of pyruvate dehydrogenase (a protein involved in the chemical process that creates energy for the body). This study shows that a combination of gene therapy and drugs may be a promising treatment for people with pyruvate dehydrogenase deficiency or shortage." +"The coronavirus are a wide group of viruses among that the SARS-CoV-2 is included (family Coronaviridae, subfamily Coronavirinae, genus Betacoronavirus and subgenus Sarbecovirus). Its main structural proteins are the membrane (M), the envelope (E), the nucleocapsid (N) and spike (S). The immune response to SARS-CoV-2 involves the cellular and the humoral sides, with neutralizing antibodies fundamentally directed against the S antigen. Although the seroprevalence data are frequently assumed as protection markers, no necessarily they are. In Spain, it is estimated that, to assure the herd immunity, at least four-fifths of the population should be immunoprotected. Due the high fatality rate of COVID-19, the acquisition of the protection only by the natural infection it not assumable and other measures as the mass immunization are required. Currently, there are several vaccine prototypes (including life virus, viral vectors, peptides and proteins and nucleic acid) in different phase of clinical evaluation. Foreseeably, some of these news vaccines would be soon commercially available. In this text, aspects related to these issues are reviewed.","The coronavirus are a wide group of viruses among that the SARS-CoV-2 (the novel breathing-related coronavirus that can lead to COVID-19) is included. Its main structural proteins are the membrane (M) (a thin layer of lipids that protects the cell and acts as a barrier), the envelope (E) (a small membrane protein and is involved in parts of a virus life cycle), the nucleocapsid (N) (an important protein for viral replication and genome packaging) and spike (S) (a protein involved in introducing coronavirus into host cells). The immune response to SARS-CoV-2 involves the cellular (white blood cells that defend the body against infection) and the humoral sides (molecules that create antibodies against a specific antigen and involve substances found in the humors, or body fluids). There are some data of the percentage of people in a population who have antibodies to an infectious virus. These data are sometimes used to find out how well people are protected from a virus. In Spain, it is suggested that to reach herd immunity (a form of indirect protection from an infectious disease that can occur when a sufficient percentage of a population has become immune to an infection), at least four-fifths of a population (about 80%) should have immunity. Due to the high death rate of COVID-19, being protected by getting the virus is not always reliable, and other measures to reach mass immunization are required. There are different vaccine types currently being evaluated. It is expected that these new vaccines will soon be available to the public. This text reviews different issues related to vaccines and immunity." +"Natural killer (NK) cells are important early responders against viral infections. Changes in metabolism are crucial to fuel NK cell responses, and altered metabolism is linked to NK cell dysfunction in obesity and cancer. However, very little is known about the metabolic requirements of NK cells during acute retroviral infection and their importance for antiviral immunity. Here, using the Friend retrovirus mouse model, we show that following infection NK cells increase nutrient uptake, including amino acids and iron, and reprogram their metabolic machinery by increasing glycolysis and mitochondrial metabolism. Specific deletion of the amino acid transporter Slc7a5 has only discrete effects on NK cells, but iron deficiency profoundly impaires NK cell antiviral functions, leading to increased viral loads. Our study thus shows the requirement of nutrients and metabolism for the antiviral activity of NK cells, and has important implications for viral infections associated with altered iron levels such as HIV and SARS-CoV-2.","Natural killer (NK) cells (white blood cells that kill cells infected with a virus) are important early responders against viral infections. Changes in metabolism (the process that creates fuel for the body) are crucial to fuel NK cell responses, and changes in metabolism are linked to NK cells not working correctly in obesity and cancer. However, very little is known about the metabolism requirements of NK cells during short-term or acute retroviral infection (the earliest stage of infection). Using an animal model for study, researchers show that after infection, NK cells increase uptake of nutrients and reprogram how cells in metabolism work. Iron deficiency or shortage significantly impairs the NK cells' abilities to fight viruses and leads to increased viral loads (quantity of virus in a person). Our study thus shows the requirement of nutrients and metabolism for the antiviral activity of NK cells, and is an important finding for viral infections linked with changes in iron levels such as HIV and SARS-CoV-2." +"As COVID-19 continues to spread rapidly worldwide and variants continue to emerge, the development and deployment of safe and effective vaccines are urgently needed. Here, we developed an mRNA vaccine based on the trimeric receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein fused to ferritin-formed nanoparticles (TF-RBD). Compared to the trimeric form of the RBD mRNA vaccine (T-RBD), TF-RBD delivered intramuscularly elicited robust and durable humoral immunity as well as a Th1-biased cellular response. After further challenge with live SARS-CoV-2, immunization with a two-shot low-dose regimen of TF-RBD provided adequate protection in hACE2-transduced mice. In addition, the mRNA template of TF-RBD was easily and quickly engineered into a variant vaccine to address SARS-CoV-2 mutations. The TF-RBD multivalent vaccine produced broad-spectrum neutralizing antibodies against Alpha (B.1.1.7) and Beta (B.1.351) variants. This mRNA vaccine based on the encoded self-assembled nanoparticle-based trimer RBD provides a reference for the design of mRNA vaccines targeting SARS-CoV-2.","As COVID-19, a viral breathing-related disease, continues to spread rapidly worldwide and variants continue to emerge, the development and distribution of safe and effective vaccines are urgently needed. Researchers developed an mRNA vaccine (a vaccine that introduces or copies a piece of messenger RNA - genetic material - that corresponds to a virus) that is based on trimeric receptor-binding domain (RBD) (part of the virus located on the spike protein which is involved in introducing a virus into host cells) and is fused to TF-RBD, tiny molecules that protect the copies called nanoparticles. The TF-RBD nanoparticles delivered humoral immunity (immunity in which molecules create antibodies against a specific antigen and involve substances found in the humors, or body fluids) as well as a cellular response (using white blood cells that are part of the body's natural immune system). Immunization with two shots of a low dose vaccine of TF-RBD provided adequate protection in mice. In addition, the mRNA template of TF-RBD vaccine was easily and quickly changed into a variant vaccine to address SARS-CoV-2 mutations. The TF-RBD vaccine produced neutralizing antibodies (antibodies that defends a cell from an infectious particle by neutralizing any effect it has) against Alpha (B.1.1.7) and Beta (B.1.351) variants. This mRNA vaccine based on self-assembled nanoparticles provides support for future designs of mRNA vaccines targeting SARS-CoV-2." +"As COVID-19 continues to spread rapidly worldwide and variants continue to emerge, the development and deployment of safe and effective vaccines are urgently needed. Here, we developed an mRNA vaccine based on the trimeric receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein fused to ferritin-formed nanoparticles (TF-RBD). Compared to the trimeric form of the RBD mRNA vaccine (T-RBD), TF-RBD delivered intramuscularly elicited robust and durable humoral immunity as well as a Th1-biased cellular response. After further challenge with live SARS-CoV-2, immunization with a two-shot low-dose regimen of TF-RBD provided adequate protection in hACE2-transduced mice. In addition, the mRNA template of TF-RBD was easily and quickly engineered into a variant vaccine to address SARS-CoV-2 mutations. The TF-RBD multivalent vaccine produced broad-spectrum neutralizing antibodies against Alpha (B.1.1.7) and Beta (B.1.351) variants. This mRNA vaccine based on the encoded self-assembled nanoparticle-based trimer RBD provides a reference for the design of mRNA vaccines targeting SARS-CoV-2.","As COVID-19 (a viral respiratory disease) spreads rapidly worldwide and variants emerge, the creation and use of safe, effective vaccines are urgently needed. Here, we created a pre-protein, moleculer vaccine based on a specific molecular region (labeled TF-RBD) of a unique protein combined to iron-containing molecules. Compared to the molecular vaccine binding to the region without iron, vaccines binding the same region but with iron-containing molecules delivered via muscle show vigorous, long-lasting immunity and specific immune responses. After adding the live respiratory virus, immunization with a two-shot low-dose schedule of the TF-RBD vaccine protected infected mice. Also, the molecular template of the TF-RBD vaccine was easily altered to address specific respiratory viral mutations. The TF-RBD, multi-variant-sensitive vaccine created general-purpose antibodies against multiple variants. This molecular vaccine based on a specific, self-created, triple-unit region is a model for creating molecular vaccines targeting the respiratory SARS-CoV-2 virus." +"Coronavirus Disease 2019 (COVID-19) caused by a novel betacoronavirus SARS-CoV-2 has been an ongoing global pandemic. Several vaccines have been developed to control the COVID-19, but the potential effectiveness of the mucosal vaccine remains to be documented. In this study, we constructed a recombinant L. plantarum LP18: RBD expressing the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein via the surface anchoring route. The amount of the RBD protein was maximally expressed under the culture condition with 200 ng/mL of inducer at 33 �C for 6 h. Further, we evaluated the immune response in mice via the intranasal administration of LP18:RBD. The results showed that the LP18:RBD significantly elicited RBD-specific mucosal IgA antibodies in respiratory tract and intestinal tract. The percentages of CD3 + CD4+ T cells in spleens of mice administrated with the LP18:RBD were also significantly increased. This indicated that LP18:RBD could induce a humoral immune response at the mucosa, and it could be used as a mucosal vaccine candidate against the SARS-CoV-2 infection. We provided the first experimental evidence that the recombinant L. plantarum LP18: RBD could initiate immune response in vivo, which implies that the mucosal immunization using recombinant LAB system could be a promising vaccination strategy to prevent the COVID-19 pandemic.","Coronavirus Disease 2019 (COVID-19), a breathing-related disease caused by a novel coronavirus SARS-CoV-2, has been an ongoing global pandemic. Several vaccines have been developed to control the COVID-19, but the potential effectiveness of the mucosal vaccine (vaccines given at moist, inner lining of some organs and body cavities, such as the nose, mouth, lungs, and stomach) remains to be documented. In this study, researchers constructed a lactic acide gene called L. plantarum LP18: RBD that uses information from the receptor-binding domain (RBD) (the part of the virus located on the spike protein which is involved in introducing a virus into host cells) of the SARS-CoV-2 spike protein by anchoring to the surface. Researchers also evaluate the immune response in mice by the intranasal administration (a non-invasive route for drug delivery through the nose) of LP18:RBD. The results show that LP18:RBD significantly brought out IgA antibodies (antibodies that play a crucial role in the immune function of mucous membranes) in the organs involved in breathing and in digesting food. These results show that LP18:RBD may create humoral immune responses (molecules that create antibodies against a specific antigen and involves substances found in the humors, or body fluids) and could be used as a mucosal vaccine against SARS-CoV-2 infection. This study is the first experiment that shows LP18:RBD could start an immune response within a living person or animal and suggests that mucosal vaccines could be a promising vaccine strategy to prevent the COVID-19 pandemic." +"The coronavirus-disease 2019 (COVID-19) was announced as a global pandemic by the World Health Organization. Challenges arise concerning how to optimally support the immune system in the general population, especially under self-confinement. An optimal immune response depends on an adequate diet and nutrition in order to keep infection at bay. For example, sufficient protein intake is crucial for optimal antibody production. Low micronutrient status, such as of vitamin A or zinc, has been associated with increased infection risk. Frequently, poor nutrient status is associated with inflammation and oxidative stress, which in turn can impact the immune system. Dietary constituents with especially high anti-inflammatory and antioxidant capacity include vitamin C, vitamin E, and phytochemicals such as carotenoids and polyphenols. Several of these can interact with transcription factors such as NF-kB and Nrf-2, related to anti-inflammatory and antioxidant effects, respectively. Vitamin D in particular may perturb viral cellular infection via interacting with cell entry receptors (angiotensin converting enzyme 2), ACE2. Dietary fiber, fermented by the gut microbiota into short-chain fatty acids, has also been shown to produce anti-inflammatory effects. In this review, we highlight the importance of an optimal status of relevant nutrients to effectively reduce inflammation and oxidative stress, thereby strengthening the immune system during the COVID-19 crisis.","The coronavirus-disease 2019 (COVID-19), a viral breathing-related disease, was announced as a global pandemic by the World Health Organization. Challenges arise on how to best support the immune system (a complex network of tissues, organs, cells, and proteins that defends the body against infection) in the general population. The best immune response depends on enough food and nutrition in order to keep infections away. For example, eating enough protein is important for producing antibodies (a protective protein used by the immune system in response to an infection). A lack of nutrients (vitamins and minerals) in the body, such as vitamin A or zinc, is associated with an increased risk of infection. Frequently, low nutrient status in the body is associated with inflammation (the body's response to injury or infection often causing swelling, pain, or redness) and oxidative stress (a condition that happens when nutrients and minerals that protect cells are low), which can impact the immune system. Foods that can help relieve inflammation and have antioxidants (vitamins, minerals, and other nutrients that protect and repair cells) have vitamin C, vitamin E, and phytochemicals (compounds found in fruits and vegetables). Several of these foods can interact with proteins in the body that are related to anti-inflammatory and antioxidant effects. Vitamin D in particular may help prevent the viral infection from entering cells. Fiber in foods has also been shown to fight inflammation. This review highlights the importance of the best levels of key nutrients to reduce inflammation and oxidative stress, resulting in a stronger immune system during the COVID-19 crisis." +"Suggested food, vaccination, drugs, and supplementary for the immune system for COVID-19. According to the World Health Organization, healthy foods and hydration are vital. Individuals consuming a well-balanced diet are healthier with a strong immune system and have a reduced risk of chronic illness, infectious diseases. Vitamins and minerals are vital. Vitamin B, insoluble in water, protects from infection. Vitamin C protects from flu-like symptoms. Insufficient vitamin D and vitamin E can lead to coronavirus infection. Vitamin D can be found in sunlight, and vitamin E can be found in, for example, oil, seeds, and fruits. Insufficient iron and excess iron can lead to risk. Zinc is necessary for maintaining the immune system. Food rich in protein should be the top priority because it has immune properties (immunoglobulin production) and potential antiviral activity. Therefore, in a regular meal, individuals should eat fruit, vegetables, legumes, nuts, whole grains, and foods from animal sources. Food from plants containing vitamin A should be consumed, and 8�10 cups of water should be drunk daily. Malnutrition is dangerous for patients with COVID-19 and thus proper nutrition should be provided. Fruit juice, tea, and coffee can also be consumed. Too much caffeine, sweetened fruit juices, fruit juice concentrates, syrups, fizzy drinks, and still drinks must be avoided. Unsaturated fats, white meats, and fish should be consumed. Saturated fat, red meat, more than 5 g salt per day, and industry processed food should be avoided. Along with diet, physical activity is another factor. Individuals should be active and perform physical exercise regularly to boost the immune system and should have proper sleep.","There are suggested food, vaccination, drugs, and supplements for the immune system (a complex network of tissues, organs, cells, and proteins that defends the body against infection) to fight COVID-19, a viral breathing-related disease. According to the World Health Organization, healthy foods and drinking plenty of water are vital. People who eat a well-balanced diet are healthier with a strong immune system and have a reduced risk of chronic (long-lasting or recurring) illness and infectious diseases. Vitamins and minerals in the body are vital. Vitamin B that cannot dissolve in water protects the body from infection. Vitamin C provides protection from flu-like symptoms. Low levels of vitamin D and vitamin E in the body can lead to coronavirus infection, the virus that leads to COVID-19. Vitamin D is found in sunlight, and vitamin E is found in foods such as oil, seeds, and fruits. Low levels of iron (a mineral that helps the body grow and develop) and too much iron can risk infection. Zinc is a key mineral in the body necessary for keeping the immune system healthy. Food rich in protein should be the top priority because it helps the immune system create protective proteins to fight infections and also has the potential to detect or fight viruses. Therefore, in a regular meal, individuals should eat fruit, vegetables, legumes, nuts, whole grains, and foods from animal sources (protein). People should eat food from plants containing vitamin A and drink 8-10 cups of water every day. Poor nutrition is dangerous for patients with COVID-19, so proper nutrition should be provided. Fruit juice, tea, and coffee can also be consumed. However, too much caffeine, sweetened fruit juices, fruit juice concentrates, syrups, fizzy drinks, and some still (non-carbonated) drinks must be avoided. Unsaturated fats (healthy fats), white meats, and fish should be eaten. Saturated fat (unhealthy fats that can lead to health problems), red meat, more than 5 grams of salt per day, and industry processed food should be avoided. Along with diet, physical activity is another factor. Individuals should be active and exercise regularly to boost the immune system and should also get enough quality sleep." +"Suggested food, vaccination, drugs, and supplementary for the immune system for COVID-19. According to the World Health Organization, healthy foods and hydration are vital. Individuals consuming a well-balanced diet are healthier with a strong immune system and have a reduced risk of chronic illness, infectious diseases. Vitamins and minerals are vital. Vitamin B, insoluble in water, protects from infection. Vitamin C protects from flu-like symptoms. Insufficient vitamin D and vitamin E can lead to coronavirus infection. Vitamin D can be found in sunlight, and vitamin E can be found in, for example, oil, seeds, and fruits. Insufficient iron and excess iron can lead to risk. Zinc is necessary for maintaining the immune system. Food rich in protein should be the top priority because it has immune properties (immunoglobulin production) and potential antiviral activity. Therefore, in a regular meal, individuals should eat fruit, vegetables, legumes, nuts, whole grains, and foods from animal sources. Food from plants containing vitamin A should be consumed, and 8�10 cups of water should be drunk daily. Malnutrition is dangerous for patients with COVID-19 and thus proper nutrition should be provided. Fruit juice, tea, and coffee can also be consumed. Too much caffeine, sweetened fruit juices, fruit juice concentrates, syrups, fizzy drinks, and still drinks must be avoided. Unsaturated fats, white meats, and fish should be consumed. Saturated fat, red meat, more than 5 g salt per day, and industry processed food should be avoided. Along with diet, physical activity is another factor. Individuals should be active and perform physical exercise regularly to boost the immune system and should have proper sleep.","The immune system protects against viruses and diseases and makes specific proteins to kill specific disease-causing invaders. This review discusses the protection of the immune system against COVID-19 (a viral respiratory disease); how the immune system works and fights diseases; and the most recent COVID-19 treatment. Various challenges for the immune system are also discussed. At the article's end, phyical exercise and certain dietary suggestions are encouraged. " +"COVID-19 may cause pneumonia, acute respiratory distress syndrome, cardiovascular alterations, and multiple organ failure, which have been ascribed to a cytokine storm, a systemic inflammatory response, and an attack by the immune system. Moreover, an oxidative stress imbalance has been demonstrated to occur in COVID-19 patients. N- Acetyl-L-cysteine (NAC) is a precursor of reduced glutathione (GSH). Due to its tolerability, this pleiotropic drug has been proposed not only as a mucolytic agent, but also as a preventive/therapeutic agent in a variety of disorders involving GSH depletion and oxidative stress. At very high doses, NAC is also used as an antidote against paracetamol intoxication. Thiols block the angiotensin-converting enzyme 2 thereby hampering penetration of SARS-CoV-2 into cells. Based on a broad range of antioxidant and anti-inflammatory mechanisms, which are herein reviewed, the oral administration of NAC is likely to attenuate the risk of developing COVID-19, as it was previously demonstrated for influenza and influenza-like illnesses. Moreover, high-dose intravenous NAC may be expected to play an adjuvant role in the treatment of severe COVID-19 cases and in the control of its lethal complications, also including pulmonary and cardiovascular adverse events.","COVID-19 (a viral breathing-related disorder) may cause diseases such as pneumonia (lung infection), heart-related changes, and multiple organ failure, which has been related to cytokine storm (an immune reaction where the body releases too many cytokines, which play a role in the body's normal immune response, into the blood too quickly), a systematic inflammatory response (the body's natural reaction against injury and infection in which the immune system attacks the body's own tissues), and an attack by the immune system. Also, an oxidative stress imbalance, which can lead to cell and tissue damage, has been shown to occur in COVID-19 patients. N- Acetyl-L-cysteine (NAC) is used to build antioxidants (vitamins, minerals, and other nutrients that protect and repair cells), and its presence may be followed by reduced, or charged, glutathione (GSH), a key antioxidant that protects tissues and cells. NAC may be a potential preventive drug for a variety of disorders that involve GSH depletion and oxidative stress. At very high doses, N- Acetyl-L-cysteine (NAC) is also used as a medicine against paracetamol intoxication (too much of a common oral medication called Acetaminophen used for pain and reducing fevers). NAC may help prevent SARS-CoV-2, the virus leading to COVID-19, from entering cells. NAC taken orally (by mouth) is likely to weaken the risk of developing COVID-19. Also, high-does N- Acetyl-L-cysteine (NAC) taken intravenously (medication delivered through the vein) may play a role in expanding the treatment of severe COVID-19 cases and help control lung and heart complications." +"Vitamin D is a key regulator of the renin-angiotensin system that is exploited by SARS-CoV-2 for entry into the host cells. Further, vitamin D modulates multiple mechanisms of the immune system to contain the virus that includes dampening the entry and replication of SARS-CoV-2, reduces concentration of pro-inflammatory cytokines and increases levels of anti-inflammatory cytokines, enhances the production of natural antimicrobial peptide and activates defensive cells such as macrophages that could destroy SARS-CoV-2.","Vitamin D plays a key role in controlling blood pressure and fluid in the body and is used by SARS-CoV-2, the virus leading to the respiratory disease of COVID-19, for entry into cells. Vitamin D controls several processes of the immune system to minimize the virus. Examples include preventing entry and replication of SARS-CoV-2 (the novel coronavirus that can lead to COVID-19), reducing inflammation (the body's response to infection causing swelling, pain, or redness), and increasing the production of natural defensive cells in the body that could destroy SARS-CoV-2." +"Novel coronavirus (COVID-19) is causing global mortality and lockdown burdens. A compromised immune system is a known risk factor for all viral influenza infections. Functional foods optimize the immune system capacity to prevent and control pathogenic viral infections, while physical activity augments such protective benefits. Exercise enhances innate and adaptive immune systems through acute, transient, and long-term adaptations to physical activity in a dose-response relationship. Functional foods prevention of non-communicable disease can be translated into protecting against respiratory viral infections and COVID-19. Functional foods and nutraceuticals within popular diets contain immune-boosting nutraceuticals, polyphenols, terpenoids, flavonoids, alkaloids, sterols, pigments, unsaturated fatty-acids, micronutrient vitamins and minerals, including vitamin A, B6, B12, C, D, E, and folate, and trace elements, including zinc, iron, selenium, magnesium, and copper. Foods with antiviral properties include fruits, vegetables, fermented foods and probiotics, olive oil, fish, nuts and seeds, herbs, roots, fungi, amino acids, peptides, and cyclotides. Regular moderate exercise may contribute to reduce viral risk and enhance sleep quality during quarantine, in combination with appropriate dietary habits and functional foods. Lifestyle and appropriate nutrition with functional compounds may offer further antiviral approaches for public health.","Novel coronavirus (COVID-19), which leads to a breathing-related viral disease, is causing deaths around the world and lockdowns. A weak immune system is a known risk factor for all viral flu infections. Functional foods are foods that have a potentially positive effect on health beyond providing basic nutrition. Functional foods help the immune system work better to prevent and control viral infections. Physical activity strengthens these benefits. Exercise boosts the immune system, and how often people exercise relates to how much the immune system is strengthened. Functional foods that prevent non-communicable (non-infectious and chronic) disease can be used to protect against respiratory viral infections and COVID-19. Functional foods within popular diets include a number of immune-boosting additives, vitamins, and minerals. Foods with antiviral (infection fighting) effects include fruits, vegetables, fermented foods and probiotics, olive oil, fish, nuts and seeds, herbs, roots, fungi, amino acids, peptides (protein segments), and cyclotides (peptides from plants). Regular moderate exercise (movement that gets the heart beating faster) may help reduce the risk of getting the virus and help people sleep better, in addition to a healthy diet and functional foods. Lifestyle and healthy nutrition with functional foods may offer additional antiviral approaches for public health." +"Novel coronavirus (COVID-19) is causing global mortality and lockdown burdens. A compromised immune system is a known risk factor for all viral influenza infections. Functional foods optimize the immune system capacity to prevent and control pathogenic viral infections, while physical activity augments such protective benefits. Exercise enhances innate and adaptive immune systems through acute, transient, and long-term adaptations to physical activity in a dose-response relationship. Functional foods prevention of non-communicable disease can be translated into protecting against respiratory viral infections and COVID-19. Functional foods and nutraceuticals within popular diets contain immune-boosting nutraceuticals, polyphenols, terpenoids, flavonoids, alkaloids, sterols, pigments, unsaturated fatty-acids, micronutrient vitamins and minerals, including vitamin A, B6, B12, C, D, E, and folate, and trace elements, including zinc, iron, selenium, magnesium, and copper. Foods with antiviral properties include fruits, vegetables, fermented foods and probiotics, olive oil, fish, nuts and seeds, herbs, roots, fungi, amino acids, peptides, and cyclotides. Regular moderate exercise may contribute to reduce viral risk and enhance sleep quality during quarantine, in combination with appropriate dietary habits and functional foods. Lifestyle and appropriate nutrition with functional compounds may offer further antiviral approaches for public health.","A new coronavirus, COVID-19 (a viral respiratory disease), is causing global death and lockdown burdens. A faulty immune system is a known risk factor for all viral influenza infections. Certain foods improve the immune system's ability to prevent and control harmful viral infections, while physical activity improves such protective benefits. Exercise improves general and antibody-related immune systems through immediate, temporary, and long-term changes to physical activity in a proportional relationship. Prevention of non-infectious disease by certain foods can lead to protection against breathing-related viral infections and COVID-19. Certain foods and supplements in popular diets have immune-boosting molecules. Foods with antiviral properties include fruits, vegetables, fermented foods, probiotics, olive oil, fish, nuts and seeds, herbs, roots, fungi, amino acids, and protein units. Regular moderate exercise may reduce viral risk and improve sleep quality during quarantine, along with appropriate diet and foods. Lifestyle and appropriate diet may offer further antiviral approaches for public health." +"The COVID-19 epidemic is the greatest pandemic that human kind experienced for decades, with high morbidity and mortality. Despite recent development of vaccines there is still many severe cases of COVID-19. Unfortunately there is still no standardized therapies and treatment of severe cases is very challenging. The aim of this study is to indicate if herbs administered alone or as a complementary therapy could be used as prophylaxis or treatment of SARS-CoV-2 infection. Over 85% of patients with COVID-19 in China used Traditional Chinese Medicine (TCM), and a most common herb is Glycyrrhiza glabra, which in vitro inhibits replication of different enveloped viruses, including coronaviruses. Glycyrrhizin in vitro connects and changes conformation of ACE2 receptors, which are vital for SARS-CoV-2 penetration into host cells. Pelargonium sidoides show immunomodulatory and antiviral properties in clinical and in vitro studies, and it inhibits replication of HCo-229E coronavirus. Glycyrrhiza glabra in combination with standard therapies significantly reduces the hospitalization rate and occurrence of COVID-19 symptoms. As complementary therapies lianhuaqingwen capsules and jinhua qinggan granules reduces hospitalization rates, time to symptoms recovery and improve patient psychological comfort. In view of SARS-CoV-2 other herbs are not effective, e.g. maxingshigan-yinqiaosan, or therapeutic concentration would be impossible to achieve, e.g. ephedra herb, or there is simply no proper data. Therefore, Liquorice and Pelargonium sidoides are effective against coronaviruses and could be possibly used as prophylaxis and treatment of COVID-19, while lianhuaqingwen capsules and jinhua qinggan granules can be useful as a complementary therapy to conventional treatment.","The COVID-19 epidemic (an outbreak of the viral breathing-related disorder) is the greatest pandemic that human kind experienced for decades, with high numbers of death and illness. Despite recent development of vaccines, there are still many severe cases of COVID-19. Unfortunately, there is still no standard or routine therapy and treatment for these severe cases. This study aims to find out if herbs given by themselves or as part of a combination of treatments can be used to prevent or treat SARS-CoV-2 infection (the novel coronavirus that can lead to COVID-19). A very common herb is Glycyrrhiza glabra (a root also known as liquorice), which in vitro (experiments in test tubes) stops or slows replication of different viruses, including coronaviruses. In experiments outside of the body, liquorice connects and changes the structure of ACE2 receptors, which are proteins that allow SARS-CoV-2 to enter cells. Pelargonium sidoides (an herb from a plant also known as African geranium) is able to change the response of the immune system and has antiviral (infection fighting) properties in clinical and lab studies. It slows or stops replication of HCo-229E coronavirus, a type of coronavirus that infects humans and bats. Glycyrrhiza glabra, or liquorice, in combination with standard therapies significantly reduces hospitalizations and occurrence of COVID-19 symptoms. Additional therapies based on a traditional Chinese medicine, lianhuaqingwen capsules and jinhua qinggan granules, reduces the number of hospitalizations and the time it takes to recover from symptoms. There are some herbs that are either not effective, would be impossible to get enough of into the body safely, or are not usefully documented to fight SARS-CoV-2. Therefore, Liquorice and Pelargonium sidoides are effective against coronaviruses and could be possibly used as prevention and treatment of COVID-19, while lianhuaqingwen capsules and jinhua qinggan granules can be useful as an additional therapy to standard treatment." +"Potassium is mainly an intracellular ion. The sodium-potassium adenosine triphosphatase pump has the primary responsibility for regulating the homeostasis between sodium and potassium, which pumps out sodium in exchange for potassium, which moves into the cells. In the kidneys, the filtration of potassium takes place at the glomerulus. The reabsorption of potassium takes place at the proximal convoluted tubule and thick ascending loop of Henle. Potassium secretion occurs at the distal convoluted tubule. Aldosterone increases potassium secretion. Potassium channels and potassium-chloride cotransporters at the apical membrane also secrete potassium. Potassium disorders are related to cardiac arrhythmias. Hypokalemia occurs when serum potassium levels under 3.6 mmol/L�weakness, fatigue, and muscle twitching present in hypokalemia.","Potassium is mainly an ion (an atom or molecule that carries an electrical charge) within a body of water within cells. A protein pump in cells called the sodium-potassium pump regulates and moves sodium and potassium in and out of cells. In the kidneys, the filtering and moving of potassium takes place at the glomerulus, a cluster of tiny blood cells. Potassium is reabsorbed at the proximal convoluted tubule (in a filtering unit called the nephron that is part of the kidneys) and the thick ascending loop of Henle (a part of the nephron in the kidneys). Potassium is released at the distal convoluted tubule (a portion of the kidney nephron that functions in both absorption and secretion or release). A hormone called aldosterone increases the release of potassium. Potassium is also released through protein channels that allow potassium molecules to pass through the cells and cell boundaries. Potassium disorders are related to cardiac arrhythmias (irregular heart beats). Hypokalemia occurs when there are low potassium levels in the blood and results in weakness, fatigue, and muscle twitching." +"Total-body potassium (K+) content and appropriate distribution of K+ across the cell membrane is vitally important for normal cellular function. Total-body K+ content is determined by changes in excretion of K+ by the kidneys in response to intake levels. Under normal conditions, insulin and ?-adrenergic tone also make important contributions in maintaining internal distribution of K+. However, despite these homeostatic pathways, disorders of altered K+ homeostasis are common. Appreciating the pathophysiology and regulatory influences that determine the internal distribution and external balance of K+ is critical in designing effective treatments to restore K+ homeostasis. We provide an up-to-date review of the regulatory aspects of normal K+ physiology as a preface to highlighting common disorders in K+ homeostasis and their treatment. This review of K+ homeostasis is designed as a resource for clinicians and a tool for educators who are teaching trainees to understand the pivotal factors involved in K+ balance.","The total-body content of potassium (K+) and distribution of K+ across the cell membranes (the thick layer that surrounds cells) is very important for normal functioning of the body's cells. Total-body K+ content (a method for measuring body composition and mass of cells) is determined by changes in the release of K+ by the kidneys in response to how much K+ is taken in. Insulin (a hormone that allows the cells in the muscles, fat, and liver to absorb sugar from the blood) and ?-adrenergic tone (a group of organs and nerves where hormones are able to signal to other cells) also help keep potassium (K+) distribution at normal levels. Despite these different systems, disorders of changing K+ levels are common. Understanding the pathophysiology (physical changes that come with a particular syndrome or disease) and regulating processes that determine how the body distributes and balances K+ is key to developing treatments to restore K+ homeostasis (processes used by the body to maintain a normal potassium concentration in the fluid). Researchers review the normal regulating process of total-body potassium (K+) before highlighting common disorders in K+ homeostasis and their treatment. This review of K+ homeostasis is a resource for health care providers and a tool for educators teaching students to understand key factors involved in K+ balance." +"Total-body potassium (K+) content and appropriate distribution of K+ across the cell membrane is vitally important for normal cellular function. Total-body K+ content is determined by changes in excretion of K+ by the kidneys in response to intake levels. Under normal conditions, insulin and ?-adrenergic tone also make important contributions in maintaining internal distribution of K+. However, despite these homeostatic pathways, disorders of altered K+ homeostasis are common. Appreciating the pathophysiology and regulatory influences that determine the internal distribution and external balance of K+ is critical in designing effective treatments to restore K+ homeostasis. We provide an up-to-date review of the regulatory aspects of normal K+ physiology as a preface to highlighting common disorders in K+ homeostasis and their treatment. This review of K+ homeostasis is designed as a resource for clinicians and a tool for educators who are teaching trainees to understand the pivotal factors involved in K+ balance.","Full-body potassium (K+) content and appropriate distribution of K+ across cell boudaries is important for normal cellular function. Total-body K+ content is measured by changes in the removal of K+ by the kidneys in response to intake levels. Normally, insulin (a blood sugar-monitoring protein) and nerve-related, stimulating activity also contribute to maintaing internal potassium distribution. Despite these balance-maintaining pathways, disorders of altered potassium balance are common. Understanding the biological distribution and balance of K+ is crucial to designing treatments for it. We review the current biology of K+ to introduce common disorders in K+ balance and their treatment. " +"Histone deacetylase (HDAC) enzymes regulate transcription through epigenetic modification of chromatin structure, but their specific functions in the kidney remain elusive. We discovered that the human kidney expresses class I HDACs. Kidney medulla-specific inhibition of class I HDACs in the rat during high-salt feeding results in hypertension, polyuria, hypokalemia, and nitric oxide deficiency. Three new inducible murine models were used to determine that HDAC1 and HDAC2 in the kidney epithelium are necessary for maintaining epithelial integrity and maintaining fluid-electrolyte balance during increased dietary sodium intake. Moreover, single-nucleus RNA-sequencing determined that epithelial HDAC1 and HDAC2 are necessary for expression of many sodium or water transporters and channels. In performing a systematic review and meta-analysis of serious adverse events associated with clinical HDAC inhibitor use, we found that HDAC inhibitors increased the odds ratio of experiencing fluid-electrolyte disorders, such as hypokalemia. This study provides insight on the mechanisms of potential serious adverse events with HDAC inhibitors, which may be fatal to critically ill patients. In conclusion, kidney tubular HDACs provide a link between the environment, such as consumption of high-salt diets, and regulation of homeostatic mechanisms to remain in fluid-electrolyte balance.","Histone deacetylase (HDAC) are enzymes that control transcription (the process of copying a segment of DNA into messenger RNA, or mRNA, for protein creation), but their specific functions in the kidney are unknown. Researchers discovered that the human kidney uses class I HDACs to activate or build molecules or proteins. The slowing or stopping of class I HDACs from the kidney medulla region in rats during high-salt feedings results in diseases such as hypertension (high blood pressure) and hypokalemia (low levels of potassium in the blood). Three new animal studies are used to determine that HDAC1 and HDAC2 in the kidney epithelium (cells that cover the inner surface of organs) are necessary for maintaining electrolyte (minerals in the body) balance when the body takes in increased sodium. Additionally, epithelial HDAC1 and HDAC2 are necessary for activating many sodium or water transporters and channels across cells. In reviewing all relevant studies of serious side effects connected with clinical HDAC inhibitor use, researchers found that HDAC inhibitors (molecules or enzymes that block actions of an enzyme protein) increased the chance of experiencing fluid-electrolyte disorders (a group of conditions caused by a temporary disturbance in the body's levels of fluids and electrolytes), such as hypokalemia. This study provides a greater understanding of potential serious side effects with HDAC inhibitors, which may be fatal to very ill patients. In conclusion, HDACs from the kidney provide a link between the environment, such as consuming high-salt diets, and regulating processes to stay in fluid-electrolyte balance." +"Background: The basolateral potassium channel in the distal convoluted tubule (DCT), comprising the inwardly rectifying potassium channel Kir4.1/Kir5.1 heterotetramer, plays a key role in mediating the effect of dietary potassium intake on the thiazide-sensitive NaCl cotransporter (NCC). The role of Kir5.1 (encoded by Kcnj16) in mediating effects of dietary potassium intake on the NCC and renal potassium excretion is unknown. Methods: We used electrophysiology, renal clearance, and immunoblotting to study Kir4.1 in the DCT and NCC in Kir5.1 knockout (Kcnj16-/- ) and wild-type (Kcnj16+/+ ) mice fed with normal, high, or low potassium diets. Results: We detected a 40-pS and 20-pS potassium channel in the basolateral membrane of the DCT in wild-type and knockout mice, respectively. Compared with wild-type, Kcnj16-/- mice fed a normal potassium diet had higher basolateral potassium conductance, a more negative DCT membrane potential, higher expression of phosphorylated NCC (pNCC) and total NCC (tNCC), and augmented thiazide-induced natriuresis. Neither high- nor low-potassium diets affected the basolateral DCT's potassium conductance and membrane potential in Kcnj16-/- mice. Although high potassium reduced and low potassium increased the expression of pNCC and tNCC in wild-type mice, these effects were absent in Kcnj16-/- mice. High potassium intake inhibited and low intake augmented thiazide-induced natriuresis in wild-type but not in Kcnj16-/- mice. Compared with wild-type, Kcnj16-/- mice with normal potassium intake had slightly lower plasma potassium but were more hyperkalemic with prolonged high potassium intake and more hypokalemic during potassium restriction. Conclusions: Kir5.1 is essential for dietary potassium's effect on NCC and for maintaining potassium homeostasis.","Potassium channels are proteins that allow rapid and careful flow of potassium ions (an atom that carries an electrical charge) across the cell boundary and generates electrical signals in cells. Two potassium channels located in cells of the kidneys called potassium channels Kir4.1 and Kir5.1 play a key role on controlling how potassium from foods affect how salt is reabsorbed. The role of Kir5.1 in how it passes on potassium from foods in the kidneys and how it releases potassium is unknown. Researchers studied Kir4.1 and Kir5.1 in different parts of the kidneys by using two different types of mice (called wild-type mice - or normal mice - and knockout mice - mice without a specific gene like the one encoding Kir5.1) fed with normal, high, or low potassium diets. When compared with the wild-type mice, the knockout mice that were fed a normal potassium diet had higher transmission of potassium, had more negative charges in some cell boundaries or membranes, had higher activation of major salt reabsorption pathways, and had an increase in the release of sodium in the urine. Neither a diet high nor low in potassium affected the potassium channel that is located at the base or sides of the cell or the negative charges in the cell membranes in the knockout mice. Although high potassium reduced activation of major salt reabsorption pathways and low potassium increased activation of major salt reabsorption pathways in wild-type mice, these effects were not found in the knockout mice. High potassium diets slowed or stopped release of sodium in the urine while low potassium diets increased the release of sodium in the urine in wild-type mice but not in knock-out mice. When compared with wild-type mice, knockout mice who had normal potassium level diets had slightly lower plasma potassium (potassium in the blood). However, knockout mice were more hyperkalemic (having a higher than normal level of potassium in the bloodstream) with a long, high potassium diet and hypokalemic (having a lower than normal level of potassium in the blood) with a restricted potassium diet. Kir5.1 is key for the effect of potassium from foods on how salt is reabsorbed and for maintaining a stable balance of potassium." +"Kidneys play a pivotal role in the maintenance and regulation of acid-base and electrolyte homeostasis, which is the prerequisite for numerous metabolic processes and organ functions in the human body. Chronic kidney diseases compromise the regulatory functions, resulting in alterations in electrolyte and acid-base balance that can be life-threatening. In this review, we discuss the renal regulations of electrolyte and acid-base balance and several common disorders including metabolic acidosis, alkalosis, dysnatremia, dyskalemia, and dysmagnesemia. Common disorders in chronic kidney disease are also discussed. The most recent and relevant advances on pathophysiology, clinical characteristics, diagnosis, and management of these conditions have been incorporated.","Kidneys play a major role in the maintenance and control of acid-base homeostasis (having the right amount of acid and base in the blood and other body fluids) and electrolyte homeostasis (the correct concentration of different ions in the body, such as sodium and potassium), which is required for metabolism and other organ functions. Chronic (long-lasting or recurring) kidney diseases weakens the regulatory functions and leads to changes in electrolyte and acid-base balance, which can be life-threatening. In this review, researchers discuss renal (kidney-related) control functions of electrolyte and acid-base balance and several common disorders, such as disorders with too much acid or base in body fluids, or low potassium levels. Common disorders in chronic kidney disease are also discussed. The most recent and important advances on pathophysiology (functional changes that come with a particular syndrome or disease), clinical characteristics (symptoms and results from lab tests), diagnosis, and management of these conditions have been incorporated." +"Kidneys play a pivotal role in the maintenance and regulation of acid-base and electrolyte homeostasis, which is the prerequisite for numerous metabolic processes and organ functions in the human body. Chronic kidney diseases compromise the regulatory functions, resulting in alterations in electrolyte and acid-base balance that can be life-threatening. In this review, we discuss the renal regulations of electrolyte and acid-base balance and several common disorders including metabolic acidosis, alkalosis, dysnatremia, dyskalemia, and dysmagnesemia. Common disorders in chronic kidney disease are also discussed. The most recent and relevant advances on pathophysiology, clinical characteristics, diagnosis, and management of these conditions have been incorporated.","Kidneys play an important role in monitoring acid-base and electrolyte balance, which is a requirement for many metabolic processes and organ functions in the human body. Long-lasting kidney diseases threaten the regulatory functions, leading to changes in electrolyte and acid-base balance that can be life-threatening. We review the kidney's regulation of electrolyte and acid-base balance and disorders involving their imbalances. Common, long-lasting kidney disorders are also discussed. The most recent and relevant treatments on the biology and treatment of these conditions have been included." +"Potassium is the most abundant cation in the intracellular fluid and it plays a vital role in the maintenance of normal cell functions. Thus, potassium homeostasis across the cell membrane, is very critical because a tilt in this balance can result in different diseases that could be life threatening. Both Oxidative stress (OS) and potassium imbalance can cause life threatening health conditions. OS and abnormalities in potassium channel have been reported in neurodegenerative diseases. This review highlights the major factors involved in potassium homeostasis (dietary, hormonal, genetic, and physiologic influences), and discusses the major diseases and abnormalities associated with potassium imbalance including hypokalemia, hyperkalemia, hypertension, chronic kidney disease, and Gordon's syndrome, Bartter syndrome, and Gitelman syndrome.","There is a lot of potassium (a mineral the body needs to function well) in the fluid within cells. It plays a key role in the maintenance of normal cell functions and processes. Therefore, potassium homeostasis (the correct balance of potassium in the body that is important for cell function) is very critical because a change in this balance can lead to different diseases, some that are life-threatening. Oxidative stress (a condition that happens when the body has low antioxidant levels, vitamins, minerals, and other nutrients that protect and repair cells), and potassium imbalance (levels of potassium that are not normal) can cause life threatening health conditions. Oxidative stress and changes in how potassium passes through cells are reported in neurodegenerative diseases (diseases such as Alzheimer's where nerve cells deteriorate or die). This review highlights the major factors involved in potassium homeostasis such as food and genes. It also discusses major diseases associated with potassium imbalance including hypokalemia (low potassium levels) and chronic kidney disease." +"Background: Potassium (K(+)) is the major intracellular cation, with 98% of the total pool being located in the cells at a concentration of 140-150 mmol/l, and only 2% in the extracellular fluid, where it ranges between 3.5 and 5 mmol/l. A fine regulation of the intracellular-extracellular gradient is crucial for life, as it is the main determinant of membrane voltage; in fact, acute changes of K(+) plasma levels may have fatal consequences. Summary: An integrated system including an 'internal' and 'external' control prevents significant fluctuations of plasma levels in conditions of K(+) loading and depletion. The internal control regulates the intra-extracellular shift, a temporary mechanism able to maintain a constant K(+) plasma concentration without changing the total amount of body K(+). The external control is responsible for the excretion of the ingested K(+), and it has the kidney as the major player. The kidney excretes nearly 90% of the daily intake. Along the proximal tubule and the thick ascending limb on Henle's loop, the amount of K(+) reabsorption is quite fixed (about 80-90%); conversely, the distal nephron has the ability to adjust K(+) excretion in accordance with homeostatic needs. The present review analyzes: (1) the main molecular mechanisms mediating K(+) reabsorption and secretion along the nephron; (2) the pathophysiology of the principal K(+) derangements due to renal dysfunction, and (3) the effect of ingested K(+) on blood pressure and renal electrolyte handling. Key messages: Maintaining plasma K(+) levels in a tight range is crucial for life; thus, multiple factors are implicated in K(+) homeostasis, including kidney function. Recent studies have suggested that K(+) plasma levels, in turn, affect renal salt absorption in animal models; this effect may underlie the reduction of blood pressure observed in hypertensive subjects under K(+) supplementation.","There is a large amount of potassium (a mineral the body needs to function properly) in the fluid within cells. Regulating or monitoring how potassium passes in and out of cells is very important, so sudden or major changes of potassium levels in the blood may be life-threatening. The body has a system with 'internal' and 'external' controls that prevents changes of blood levels when potassium is increasing or decreasing. The 'internal' control monitors the change in potassium as it moves in and out of cells to help maintain a stable level of potassium. The 'external' control is responsible for excreting (releasing) the potassium, and the kidney is the main part of this process. The kidney releases nearly 90% of the daily intake of potassium. In some parts within the kidney, potassium is reabsorbed at a fixed or constant amount, but other portions of the kidneys have the ability to adjust the release of potassium based on what is needed to maintain a potassium balance. This review analyzes the following: (1) the cell processes that reabsorb and release potassium along the nephron (a filter located in the kidneys); (2) the pathophysiology (functional changes in the body that come with a particular syndrome or disease) from renal (kidney-related) problems; and (3) the effect of ingested potassium from food on blood pressure and renal electrolytes. Key messages in this review are that maintaining potassium levels in the blood in a tight range is very important for life. Therefore, multiple factors are connected with potassium homeostasis (the correct amount of potassium for the body to function), including kidney function. Recent studies with animals have suggested that potassium levels affect renal (kidney-related) salt absorption and this effect may be the cause of decreased blood pressure in hypertensive (high-blood pressure) patients using potassium supplements." +"Purpose of review: Renal potassium (K) secretion plays a key role in maintaining K homeostasis. The classic mechanism of renal K secretion is focused on the connecting tubule and cortical collecting duct, in which K is uptaken by basolateral Na-K-ATPase and is secreted into the lumen by apical ROMK (Kir1.1) and Ca-activated big conductance K channel. Recently, genetic studies and animal models have indicated that inwardly rectifying K channel 4.1 (Kir4.1 or Kcnj10) in the distal convoluted tubule (DCT) may play a role in the regulation of K secretion in the aldosterone-sensitive distal nephron by targeting the NaCl cotransporter (NCC). This review summarizes recent progresses regarding the role of Kir4.1 in the regulation of NCC and K secretion. Recent findings: Kir4.1 is expressed in the basolateral membrane of the DCT, and plays a predominant role in contributing to the basolateral K conductance and in participating in the generation of negative membrane potential. Kir4.1 is also the substrate of src-family tyrosine kinase and the stimulation of src-family tyrosine kinase activates Kir4.1 activity in the DCT. The genetic deletion or functional inhibition of Kir4.1 depolarizes the membrane of the DCT, inhibits ste20-proline-alanine rich kinase, and suppresses NCC activity. Moreover, the downregulation of Kir4.1 increases epithelial Na channel expression in the collecting duct and urinary K excretion. Finally, mice with low Kir4.1 activity in the DCT are hypomagnesemia and hypokalemia. Summary: Recent progress in exploring the regulation and the function of Kir4.1 in the DCT strongly indicates that Kir4.1plays an important role in initiating the regulation of renal K secretion by targeting NCC and it may serves as a K sensor in the kidney.","Renal (kidney-related) secretion or release plays a key role in maintaining potassium homeostasis (processes used by the body to maintain a normal potassium concentration in the fluid outside the cells). Renal release of potassium mainly takes place within the kidneys through as series of tubes and ducts. Potassium is absorbed through the potassium channel that is located at the base or sides of the cell called the basolateral and is released into a tube called the lumen through potassium channels. Recent studies have suggested that potassium channels 4.1 (Kir4.1 or Kcnj10) located within the kidney at the distal convoluted tubule (DCT) (which connects to the duct system in the kidneys and helps with salt and water reabsorption) may play a role in regulating the release of potassium by targeting the NaCl cotransporter (NCC) (the carrier protein that helps reabsorb sodium and chloride ions from tube fluid into the cells). This review summarizes recent progress on the role of the potassium channel Kir4.1 in the control of NCC and potassium secretion (release). Recent findings show that Kir4.1 is activated in the basolateral membrane (the thin layer surrounding a cell located at the base or sides of the cell) of the distal convoluted tubule (DCT). Kir4.1 plays a major role in helping the basolateral pass potassium through the cell and in helping cell membranes have a negative charge. Kir4.1 also activates proteins that send signals to other cells which in turn activate Kir4.1 activity in the DCT. Kir4.1 depolarizes (changes the internal charge to make the cell less negative) the membrane of the distal convoluted tubule (DCT), slows down other proteins that regulate cell activity, and suppresses NaCl cotransporter activity. Additionally, the decrease in function of Kir4.1 increases activity of the epithelial Na channel (the lining of the outer part of the kidney tubule) in the ducts and potassium release through urine. Finally, mice with low Kir4.1 activity in the DCT are hypomagnesemia (have a low level of the magnesium mineral in the blood) and hypokalemia (have low levels of potassium). In summary, recent progress in exploring the control and function of Kir4.1 in the distal convoluted tubule suggests that Kir4.1 has an important role in starting the regulation of releasing potassium in the kidneys by targeting NaCl cotransporter and may be a potassium sensor in the kidney." +"Purpose of review: Renal potassium (K) secretion plays a key role in maintaining K homeostasis. The classic mechanism of renal K secretion is focused on the connecting tubule and cortical collecting duct, in which K is uptaken by basolateral Na-K-ATPase and is secreted into the lumen by apical ROMK (Kir1.1) and Ca-activated big conductance K channel. Recently, genetic studies and animal models have indicated that inwardly rectifying K channel 4.1 (Kir4.1 or Kcnj10) in the distal convoluted tubule (DCT) may play a role in the regulation of K secretion in the aldosterone-sensitive distal nephron by targeting the NaCl cotransporter (NCC). This review summarizes recent progresses regarding the role of Kir4.1 in the regulation of NCC and K secretion. Recent findings: Kir4.1 is expressed in the basolateral membrane of the DCT, and plays a predominant role in contributing to the basolateral K conductance and in participating in the generation of negative membrane potential. Kir4.1 is also the substrate of src-family tyrosine kinase and the stimulation of src-family tyrosine kinase activates Kir4.1 activity in the DCT. The genetic deletion or functional inhibition of Kir4.1 depolarizes the membrane of the DCT, inhibits ste20-proline-alanine rich kinase, and suppresses NCC activity. Moreover, the downregulation of Kir4.1 increases epithelial Na channel expression in the collecting duct and urinary K excretion. Finally, mice with low Kir4.1 activity in the DCT are hypomagnesemia and hypokalemia. Summary: Recent progress in exploring the regulation and the function of Kir4.1 in the DCT strongly indicates that Kir4.1plays an important role in initiating the regulation of renal K secretion by targeting NCC and it may serves as a K sensor in the kidney.","Kidney-related potassium (K) secretion helps maintain K balance. Kidney-related K removal commonly focuses on specific parts of sub-kidney units. In these units, K is pulled in by outer-facing protein, which transports K and sodium across a boundary, and is secreted into the inner tube by ROMK (Kir1.1), a K-specific transport protein, and calcium-activated K-specific transport channel. Recently, gene-related studies and animal models have shown that inwardly correcting potassium channel 4.1 (Kir4.1 or Kcnj10) in a specific region of sub-kidney units may monitor potassium secretion in the hormone-sensitive, outward sub-kidney unit by targeting the sodium-chloride cotransporter. This review summarizes recent improvements regarding the role of Kir4.1 channel in regulating the sodium-chloride cotransporter and potassium secretion. Kir4.1 is active in the outer-facing boundary of a specific region of the sub-kidney units and helps transport potassium outward and create a negative boundary charge. Kir4.1 is also the target of a high-energy transporting protein. This transporting protein activates Kir4.1 activity in a specific region of sub-kidney units. The gene-related deletion or silencing of Kir4.1 changes the charge of the boundary of a specific region of sub-kidney units, blocks a high-energy transporting protein, and prevents sodium-chloride channel activity. Also, reducing Kir4.1 activity increases boundary-lining sodium channel activity in a specific region of sub-kidney units and K removal via urine. Finally, mice with low Kir4.1 activity in a specific region of sub-kidney units have low blood magnesium and low blood potassium. Recent progress in exploring the monitoring and use of Kir4.1 in a specific region of sub-kidney units shows that Kir4.1 helps begin the monitoring of kidney-related K removal by targeting sodium-chloride channels. Kir4.1 may also be a K sensor in the kidney." +"We recently described a novel thiazide-sensitive electroneutral NaCl transport mechanism resulting from the parallel operation of the Cl-/HCO3- exchanger pendrin and the Na+-driven Cl-/2HCO3- exchanger (NDCBE) in ?-intercalated cells of the collecting duct. Although a role for pendrin in maintaining Na+ balance, intravascular volume, and BP is well supported, there is no in vivo evidence for the role of NDCBE in maintaining Na+ balance. Here, we show that deletion of NDCBE in mice caused only subtle perturbations of Na+ homeostasis and provide evidence that the Na+/Cl- cotransporter (NCC) compensated for the inactivation of NDCBE. To unmask the role of NDCBE, we generated Ndcbe/Ncc double-knockout (dKO) mice. On a normal salt diet, dKO and single-knockout mice exhibited similar activation of the renin-angiotensin-aldosterone system, whereas only dKO mice displayed a lower blood K+ concentration. Furthermore, dKO mice displayed upregulation of the epithelial sodium channel (ENaC) and the Ca2+-activated K+ channel BKCa. During NaCl depletion, only dKO mice developed marked intravascular volume contraction, despite dramatically increased renin activity. Notably, the increase in aldosterone levels expected on NaCl depletion was attenuated in dKO mice, and single-knockout and dKO mice had similar blood K+ concentrations under this condition. In conclusion, NDCBE is necessary for maintaining sodium balance and intravascular volume during salt depletion or NCC inactivation in mice. Furthermore, NDCBE has an important role in the prevention of hypokalemia. Because NCC and NDCBE are both thiazide targets, the combined inhibition of NCC and the NDCBE/pendrin system may explain thiazide-induced hypokalemia in some patients.","Past studies describe a new process to transport and reabsorb sodium and chloride ions (atoms or molecules that carry electrical charges) from one side of the cell to the other. One is called the Na+-driven Cl-/2HCO3- exchanger (NDCBE) that is a protein that exchanges Na+ (sodium) from outside the cell for Cl- (chloride) that is in the cell. There is no lab or test tube experiments that show evidence for the role of Na+-driven Cl-/2HCO3- exchanger (NDCBE) in maintaining a sodium balance. In this present study, researchers show that reducing Na+-driven Cl-/2HCO3- exchanger in mice causes only minor disruptions of sodium homeostasis (processes used by the body to maintain a normal sodium concentration in the fluid outside the cells). Researchers provide evidence that the Na+/Cl- cotransporter (NCC) (the carrier protein that helps reabsorb sodium and chloride ions from tube fluid into the cells) compensated for the lack of action of the Na+-driven Cl-/2HCO3- exchanger. To understand the role of Na+-driven Cl-/2HCO3- exchanger, researchers generated an experiment with Ndcbe/Ncc double-knockout mice, mice without NCC or NDCBE. On a normal diet, Ndcbe/Ncc double-knockout and single-knockout mice showed similar activation of the hormone system that helps regulate blood pressure, electrolytes, and some heart-related function; however, only Ndcbe/Ncc double-knockout mice showed lower potassium in the blood. Also, Ndcbe/Ncc double-knockout mice showed an increase in the surface sodium channels (ENaC) and the potassium channel Ca2+-activated K+ channels BKCa. When sodium-chloride is depleted, only Ndcbe/Ncc double-knockout mice developed altered blood volume contraction, despite increased kidney activity. Notably, the increase in aldosterone (a hormone that regulates sodium and potassium levels) expected from the sodium-chloride loss was weakened in Ndcbe/Ncc double-knockout mice. Single knock-out and Ndcbe/Ncc double-knockout mice had similar blood potassium concentrations when this occurred. In conclusion, the Na+-driven Cl-/2HCO3- exchanger is necessary for maintaining sodium balance and volume of blood when salt is reduced or when Na+/Cl- cotransporter Is turned off in mice. Furthermore, Na+-driven Cl-/2HCO3- exchanger has an important role in preventing hypokalemia (low levels of potassium). Because Na+/Cl- cotransporter and Na+-driven Cl-/2HCO3- exchanger are both targets of thiazide targets (which reduces sodium reabsorption), the combined slowing of Na+/Cl- cotransporter and the Na+-driven Cl-/2HCO3- exchanger/pendrin system (a multifaceted transporter that plays important roles in various functions of the kidney) may explain thiazide generated hypokalemia in some patients." +"STE20 (Sterile 20)/SPS-1 related proline/alanine-rich kinase (SPAK) and oxidative stress-response kinase-1 (OSR1) activate the renal cation cotransporters Na(+) -K(+) -2Cl(-) cotransporter (NKCC2) and Na(+) -Cl(-) cotransporter (NCC) via phosphorylation. Knockout mouse models suggest that OSR1 mainly activates NKCC2, while SPAK mainly activates NCC, with possible cross-compensation. We tested the hypothesis that disrupting both kinases causes severe polyuria and salt-wasting by generating SPAK/OSR1 double knockout (DKO) mice. DKO mice displayed lower systolic blood pressure compared with SPAK knockout (SPAK-KO) mice, but displayed no severe phenotype even after dietary salt restriction. Phosphorylation of NKCC2 at SPAK/OSR1-dependent sites was lower than in SPAK-KO mice, but still significantly greater than in wild type mice. In the renal medulla, there was significant phosphorylation of NKCC2 at SPAK/OSR1-dependent sites despite a complete absence of SPAK and OSR1, suggesting the existence of an alternative activating kinase. The distal convoluted tubule has been proposed to sense plasma [K(+) ], with NCC activation serving as the primary effector pathway that modulates K(+) secretion, by metering sodium delivery to the collecting duct. Abundance of phosphorylated NCC (pNCC) is dramatically lower in SPAK-KO mice than in wild type mice, and the additional disruption of OSR1 further reduced pNCC. SPAK-KO and kidney-specific OSR1 single knockout mice maintained plasma [K(+) ] following dietary potassium restriction, but DKO mice developed severe hypokalaemia. Unlike mice lacking SPAK or OSR1 alone, DKO mice displayed an inability to phosphorylate NCC under these conditions. These data suggest that SPAK and OSR1 are essential components of the effector pathway that maintains plasma [K(+) ].","Two protein enzymes called STE20 (Sterile 20)/SPS-1 related proline/alanine-rich kinase (SPAK) and oxidative stress-response kinase-1 (OSR1) activate the kidney-related cotransporters (carrier proteins that carry two different ions or other species from one side of the cell to the other) Na(+) -K(+) -2Cl(-) cotransporter (NKCC2) and Na(+) -Cl(-) cotransporter (NCC). Knockout mouse models (experiments with mice that lack a specific gene) suggest that OSR1 mainly activates NKCC2, while SPAK mainly activates NCC, and sometimes compensate for one another. Researchers tested the idea that disrupting both enzymes causes severe polyuria (passing unusually large amounts of urine) and salt-wasting by producing SPAK/OSR1 double knockout (DKO) mice - mice without SPAK or OSR1. DKO mice showed lower systolic blood pressure (the top number of blood pressure that indicates how much pressure the blood is exerting against artery walls when the heart beats) compared to SPAK knockout (SPAK-KO) mice, but showed no severe phenotype (observable traits or characteristics) even after salt restriction in food. Phosphorylation (a process of adding a phosphate group, a group of atoms that have different roles and make up DNA and RNA, to a molecule to prepare it to change or do work) of NKCC2 at SPAK/OSR1-dependent sites was lower than in SPAK-KO mice (mice without SPAK), but still much greater than in wild-type or normal mice. In the innermost part of the kidney called the medulla, there was significant phosphorylation of NKCC2 at SPAK/OSR1-dependent sites despite a complete absence of SPAK and OSR1, which suggests the existence of another activating kinase enzyme. The distal convoluted tubule (a part within the kidney that connects to the collecting duct system that refines salt and water reabsorption) has been suggested to sense blood potassium by monitoring sodium delivery to the collecting duct. A lot of phosphorylated Na(+) -Cl(-) cotransporter (pNCC) is dramatically lowered in SPAK-KO mice than in wild type mice, and the additional disruption of OSR1 further reduced pNCC. SPAK-KO and kidney-specific OSR1 single knockout mice (mice without OSR1 only in the kidney) maintained potassium in the blood following restrictions of potassium in food, but DKO mice developed severe hypokalemia (low levels of potassium in the blood). Unlike mice lacking SPAK or OSR1 alone, SPAK/OSR1 double knockout (DKO) mice showed an inability to phosphorylate NCC under these conditions. These data suggest that STE20 (Sterile 20)/SPS-1 related proline/alanine-rich kinase (SPAK) and oxidative stress-response kinase-1 (OSR1) are essential components of the pathway that maintains potassium in the blood." +"Medical nutrition therapy (MNT) plays an important role in the management of gestational diabetes mellitus (GDM), and accordingly, it has a significant impact on women and newborns. The primary objective of MNT is to ensure adequate pregnancy weight gain and fetus growth while maintaining euglycemia and avoiding ketones. However, the optimal diet (energy content, macronutrient distribution, its quality and amount, among others) remains an outstanding question. Overall, the nutritional requirements of GDM are similar for all pregnancies, but special attention is paid to carbohydrates. Despite the classical intervention of restricting carbohydrates, the latest evidence, although limited, seems to favor a low-glycemic index diet. There is general agreement in the literature about caloric restrictions in the case of being overweight or obese. Randomized controlled trials are necessary to investigate the optimal MNT for GDM; this knowledge could yield health benefits and cost savings.","Medical nutrition therapy (MNT) plays an important role in the care of gestational diabetes mellitus (a type of high blood sugar affecting pregnant women), and it has a significant impact on women and newborns. The main objective of MNT is to make sure to have enough pregnancy weight gain and fetus (unborn baby) growth while having stable blood sugar levels (euglycemia) and avoiding ketones (alternative fuels for the body made when blood sugar is low). However, the best diet remains an unanswered question. Overall, the nutritional and food requirements for gestational diabetes mellitus are similar for all pregnancies, but special attention is paid to carbohydrates (foods that provide sugar and energy for the body). Despite the usual care practice of limiting carbohydrates, the latest evidence, although limited, favors a low-glycemic index diet (a diet that helps control blood sugar from spiking). There is general agreement in studies about limiting calories in the case of being overweight or obese. Experimental studies are necessary to investigate the best medical nutrition therapy for gestational diabetes mellitus because this knowledge may provide health benefits and save money." +"Group 1 (All Types of CHO) The intervention followed the American Dietetic Association nutrition practice guidelines for gestational diabetes. Women received an individual food plan based on CHO restriction (40�45% of TEI), using a CHO counting strategy (basic level). Moderate energy restriction was recommended only for overweight and obese women (24?kcal/kg). Breakfast CHO intake was limited to 15�30?g, and adequate fiber intake was promoted (20�35?g/day). Women in this group were advised to choose any type of CHO, except added refined sugars. Energy and CHO prescriptions were revised at every visit and changes were done according to weight gain and whether or not ketonuria was present. If ketones were present and weight gain was subnormal, energy prescription was increased (200 to 300?kcal/day). If weight gain was adequate, energy was not modified and carbohydrates were increased (no more than 45% of TEI). Fat intake recommendation was maintained (<40% of TEI), and protein recommendation adjustment was made accordingly (20�25% of TEI). Group 2 (Low GI CHO) Women in this group received the same intervention as women in Group 1, but were counseled to eliminate all moderate and high GI foods (GI > 55). Tropical fruits, refined breads, breakfast cereals, flour tortilla, white rice, refined cookies and pastries, potatoes, carrots, beets, and refined sugars were eliminated from their plan. Papaya was the only moderate GI fruit permitted because it is one of the most frequently consumed high-fiber foods in this population. Corn tortillas were included only when combined with beans, as well as corn flakes combined with milk, according to some evidence that the combination of these foods decreases their GI. Conclusions. Inclusion of low GI CHO as part of a comprehensive nutrition intervention is equally effective in improving glycemic control as compared to all types of CHO. This strategy had a positive effect in preventing excessive maternal weight gain but increased the risk of prematurity.","Group 1 of a study included all types of carbohydrates and followed the guidelines described by the American Dietetic Association, an organization of food and nutrition professionals, for gestational diabetes, a type of high blood sugar (diabetes) that develops during pregnancy in women who do not already have diabetes. Women each receive a food plan based on limiting carbohydrates, using a method that counts carbohydrates. Limiting the amount of calories and foods that generate energy consumed is recommend only for overweight or obese women. Breakfast carbohydrates eaten is limited, and adequate fiber consumed is increased. Women in this group are advised to choose any type of carbohydrate, except those with added refined sugars (processed sugars added to food). Energy and carbohydrate prescriptions are revised at every visit, and changes are done according to weight gain and whether or not ketonuria (high ketones, which is a chemical made in the liver that helps break down fat, in urine) is present. If ketones are present and weight gain is under the normal level, energy prescription is increased. If weight gain is enough, energy is not modified, and carbohydrates are increased. The recommendation for the amount of fat eaten stays the same, and the protein recommendation is adjusted accordingly. Group 2 focused on carbohydrates with a low glycemic index (a rating system used to measure how much specific foods increase blood sugar levels). Women in this group have the same program as women in Group 1, but are guided to remove all moderate and high glycemic index foods. Tropical fruits, refined (highly processed) breads, breakfast cereals, flour tortilla, white rice, refined cookies and pastries, potatoes, carrots, beets, and refined sugars are eliminated from their plan. Papaya was the only moderate glycemic index fruit permitted because it is one of the most frequently consumed high-fiber foods in this population. Corn tortillas are included only when combined with beans, as well as corn flakes combined with milk, based on some evidence that the combination of these foods decreases their glycemic index. In conclusion, including low glycemic index carbohydrates as part of a well-rounded nutrition program is just as effective in improving glycemic control as compared to all types of carbohydrates. This strategy has a positive effect in preventing too much maternal weight gain but increases the risk of prematurity (a baby born before 37 weeks)." +"Background: Lower carbohydrate diets have the potential to improve glycemia but may increase ketonemia in women with gestational diabetes (GDM). We hypothesized that modestly lower carbohydrate intake would not increase ketonemia. Objective: To compare blood ketone concentration, risk of ketonemia, and pregnancy outcomes in women with GDM randomly assigned to a lower carbohydrate diet or routine care. Methods: Forty-six women aged (mean � SEM) 33.3 � 0.6 y and prepregnancy BMI 26.8 � 0.9 kg/m2 were randomly assigned at 28.5 � 0.4 wk to a modestly lower carbohydrate diet (MLC, ?135 g/d carbohydrate) or routine care (RC, ?200 g/d) for 6 wk. Blood ketones were ascertained by finger prick test strips and 3-d food diaries were collected at baseline and end of the intervention. Results: There were no detectable differences in blood ketones between completers in the MLC group compared with the RC group (0.1 � 0.0 compared with 0.1 � 0.0 mmol/L, n = 33, P = 0.31, respectively), even though carbohydrate and total energy intake were significantly lower in the intervention group (carbohydrate 165 � 7 compared with 190 � 9 g, P = 0.04; energy 7040 � 240 compared with 8230 � 320 kJ, P <0.01, respectively). Only 20% of participants in the MLC group met the target intake compared with 65% in the RC group (P <0.01). There were no differences in birth weight, rate of large-for-gestational-age infants, percent fat mass, or fat-free mass between groups. Conclusions: An intervention to reduce carbohydrate intake in GDM did not raise ketones to clinical significance, possibly because the target of 135 g/d was difficult to achieve in pregnancy. Feeding studies with food provision may be needed to assess the benefits and risks of low-carbohydrate diets.","A low carbohydrate diet (a diet that limits carbohydrates often found in sugary foods, pasta, and bread) has the potential to improve glycemia (blood sugar level) but it may increase ketonemia (an unusually high amount of ketones, a substance that the body makes if cells don't get enough blood sugar) in women with gestational diabetes (a type of high blood sugar affecting pregnant women). Researchers tested the theory that eating a modestly low amount of carbohydrates would not increase ketonemia. The objective of this study is to compare the amount of ketones that are in the blood, the risk of ketonemia, and pregnancy outcomes, such as full-term or premature, in women with gestational diabetes who are randomly assigned to a lower carbohydrate (carb) diet or routine care. In this study, 46 women are randomly assigned to a modestly lower carb diet or to routine care. Ketones, the substance the body makes if cells don't get enough blood sugar, in the blood are measured by finger prick tests. Food diaries are collected at the beginning of the study and at the end. The results show that there are no detectable differences in blood ketones between participants in the modestly lower carb diet group when compared with women in the routine care group, even though carbs and total energy intake are much lower in the modestly low carb diet group. Only 20% of participants in the modestly low carb diet group met the target amount of consumption compared with 65% in the routine care group. There are no differences in birth weight, rate of large-for-gestational-age infants (a newborn who weighs more than 90% of other newborns of the same gestational age at birth), percent of fat in the body, or fat-free mass (muscle mass) between the groups. In conclusion, a change to reduce the amount of carbs consumed by women with gestational diabetes did not raise ketones to a significant level, possibly because the target of the amount of food was difficult to achieve in pregnancy. Feeding studies with provided food may be needed to determine the benefits and risks of low-carbohydrate diets." +"Background: Lower carbohydrate diets have the potential to improve glycemia but may increase ketonemia in women with gestational diabetes (GDM). We hypothesized that modestly lower carbohydrate intake would not increase ketonemia. Objective: To compare blood ketone concentration, risk of ketonemia, and pregnancy outcomes in women with GDM randomly assigned to a lower carbohydrate diet or routine care. Methods: Forty-six women aged (mean � SEM) 33.3 � 0.6 y and prepregnancy BMI 26.8 � 0.9 kg/m2 were randomly assigned at 28.5 � 0.4 wk to a modestly lower carbohydrate diet (MLC, ?135 g/d carbohydrate) or routine care (RC, ?200 g/d) for 6 wk. Blood ketones were ascertained by finger prick test strips and 3-d food diaries were collected at baseline and end of the intervention. Results: There were no detectable differences in blood ketones between completers in the MLC group compared with the RC group (0.1 � 0.0 compared with 0.1 � 0.0 mmol/L, n = 33, P = 0.31, respectively), even though carbohydrate and total energy intake were significantly lower in the intervention group (carbohydrate 165 � 7 compared with 190 � 9 g, P = 0.04; energy 7040 � 240 compared with 8230 � 320 kJ, P <0.01, respectively). Only 20% of participants in the MLC group met the target intake compared with 65% in the RC group (P <0.01). There were no differences in birth weight, rate of large-for-gestational-age infants, percent fat mass, or fat-free mass between groups. Conclusions: An intervention to reduce carbohydrate intake in GDM did not raise ketones to clinical significance, possibly because the target of 135 g/d was difficult to achieve in pregnancy. Feeding studies with food provision may be needed to assess the benefits and risks of low-carbohydrate diets.","Lower carb diets may improve blood sugar but may increase blood ketone bodies (particles made from fat breakdown) in women with gestational diabetes (GDM) (high blood sugar affecting pregnant women). We presume that fairly lower carbohydrate intake would not increase blood ketone bodies. To compare levels of blood ketone made from fat breakdown, risk of high blood ketone bodies, and pregnancy outcomes in women with gestational diabetes randomly given a lower carb diet or regular care. Forty-six women around 33 years of age were randomly split at 28.5 weeks to either a modestly lower carb diet (MLC) or standard, routine care (RC) for 6 weeks. There was no difference in blood ketones between those in the MLC diet group relative to the RC group, even though carb and total energy intake was lower in the diet group. Only 20% in the MLC diet group met the goal intake versus the 65% in the RC group. No differences in birth weight, rate of large-for-prenatal-age infants, percent fat mass, or fat-free mass between groups existed. Reducing carb intake in those with gestational diabetes did not raise ketones made from fat breakdown, possibly because the carb target was difficult to achieve in pregnancy. Feeding studies providing food may have to assess the effects of low-carb diets." +"Nutrient intake plays a significant role in the health outcomes of all pregnant women. In a pregnancy complicated by gestational diabetes mellitus (GDM), excellent glucose control is as foundational as appropriate weight gain and adequate nutrient intake. The controversies in GDM management include the following: how far to manipulate energy intake, dietary composition (carbohydrates and fats), and gestational weight gain. Signs that food restrictions have gone too far include weight loss or lack of weight gain, undereating to avoid insulin therapy, positive urinary ketones, and intentional restriction of healthy foods. If a balance between nutrient needs and glucose control cannot be achieved, then concurrent medication therapy is needed to assist in reducing insulin resistance and supplementing insulin production to provide normoglycemia and improved pregnancy outcomes. Medical nutrition therapy is a self-management therapy. Education, support, and follow-up are required to assist the woman to make lifestyle changes essential to successful nutrition therapy. Women with GDM are at increased risk for type 2 diabetes; learning to manage GDM with lifestyle change provides an opportunity to affect personal risk factors and the health of the whole family.","Eating nutrients (foods or substances that allow the body to grow and develop) plays a major role in the health outcomes of all pregnant women. In a pregnancy that is complicated by gestational diabetes mellitus (a type of diabetes first seen during pregnancy in a woman who did not have diabetes before pregnancy), excellent blood sugar control is as important as healthy weight gain and getting enough nutrients. The disagreement in the care of gestational diabetes mellitus includes the following: how far to change food consumption, how much carbohydrates and fats make up the diet, and how much weight the infant gains during the pregnancy. Signs that limiting food have gone too far include weight loss or lack of weight gain, undereating to avoid insulin (a hormone in the body that allows cells in the muscles, fat, and liver to absorb sugar that is in the blood) therapy to keep blood sugar normal, positive ketones in urine that indicate the body is using fat for fuel instead of sugar, and planned limits of healthy foods. If a balance between nutrient needs and sugar control cannot be reached, then providing medication at the same time is needed to help in reducing insulin resistance (a condition that causes increased blood sugar) and increasing insulin to provide normoglycemia (normal amount of sugar in the blood) and improved pregnancy outcomes. Medical nutrition therapy is a self-management therapy (where the patient is actively engaged in his or her care or treatment). Education, support, and follow-up are required to help the woman make lifestyle changes that are key to successful nutrition therapy. Women with gestational diabetes mellitus are at an increased risk for type 2 diabetes (a condition where the body doesn't use insulin properly); learning to manage gestational diabetes mellitus with lifestyle changes provides an opportunity to impact personal risk factors (such as health and fitness) and the health of the whole family." +"The extent to which given levels of caloric restriction will improve glycemic status but increase plasma ketone bodies in gestational diabetic women has received little attention. After reviewing the underlying physiology, we present data on two feeding studies investigating the question. In the first, a weight-maintaining approximately 2400-kcal/day diet was fed on a metabolic ward to 12 gestational diabetic women for 1 week. In the second week, subjects were randomized to a continuation of the 2400-kcal/day diet or to a 1200-kcal/day diet. Twenty-four-hour mean glucose levels remained unchanged in the control group but declined in the calorie-restricted group (6.7 mM or 121 mg/dl in week 1 vs 5.4 mM or 97.3 mg/dl in week 2) (p less than 0.01). Nine-hour overnight fasting plasma insulin also declined but oral glucose tolerance did not improve with caloric restriction. Fasting plasma beta-hydroxybutyrate rose in the calorie-restricted group, along with an increase in ketonuria, but not in the control group. A second study compared the impact of a 33% calorie-restricted diet or insulin to a full-calorie diet in a similar 2-week experimental design and measured hepatic glucose output and insulin sensitivity with dideuterated glucose before and during an insulin clamp. Diet in three subjects improved fasting and 24-hr mean glucose by 22 and 10%, respectively, whereas prophylactic insulin in three subjects produced 0 and 4% reductions, respectively. On average, ketonuria after a 9-hr fast declined to an equivalent degree with both treatments. Hepatic glucose output and insulin sensitivity were not statistically significantly altered by gestational diabetes or the therapeutic interventions compared to nondiabetic normal weight or obese pregnant controls. In conclusion, 50% caloric restriction improves glycemic status in obese women with gestational diabetes but is associated with an increase in ketonuria, which is of uncertain significance. An intermediate 33% level of caloric restriction (to 1600-1800 kcal daily) may be more appropriate in dietary management of obese woman with gestational diabetes mellitus and more effective than prophylactic insulin. Further studies are required to confirm these findings.","How much caloric restriction (reducing the amount of calories consumed) will improve glycemic status (blood sugar levels) but increase ketone bodies (substances that the body makes if the cells don't get enough blood sugar) in gestational diabetic women (women diagnosed with diabetes for the first time during pregnancy) has received little attention. Data are presented on two studies that monitor and control diets to investigate these questions. In the first study, a diet of 2,400 calories per day is provided to 12 gestational diabetic women for 1 week. In the second week, patients were randomly assigned to either continue the 2,400 calories per day diet or to a 1,200 calories per day diet. The average glucose (blood sugar) levels remained unchanged in the 2,400 calorie diet group but declined in the lower calorie group that had a 1,200 calories per day diet. After fasting (no food) for 9 hours overnight, insulin (a hormone in the body that allows cells in the muscles, fat, and liver to absorb sugar that is in the blood) also declined, but oral glucose tolerance (a test that measures how the body moves sugar from blood to the tissues) did not improve with the reduced calories diet. Beta-hydroxybutyrate (a chemical in the body that provides energy when not enough carbohydrates or sugars have been eaten) increased in the reduced calorie group, along with an increase in ketonuria, high amounts of ketones (substances that your body makes if your cells don't get enough blood sugar) in the urine, but not in the comparison group that had the 2,400 calorie diet. A second study compared the impact of a calorie-restricted diet reduced by 33% or insulin to a full-calorie diet in a similar 2 week experiment. The study measured liver production of sugar and insulin sensitivity with labeled glucose before and during an insulin clamp (used to maintain glucose levels). Diet in 3 patients improved fasting and average glucose levels. Prophylactic insulin (insulin administered to the patient) in 3 people also produced smaller reductions. On average, ketonuria after a 9 hour fast declined in the same amount with both treatments. Liver glucose production and insulin sensitivity were not significantly changed by gestational diabetes or the treatments compared to normal weight or obese pregnant women who did not have diabetes. In conclusion, reducing calories by half improves blood sugar levels in obese women with gestational diabetes but is connected with an increase in high amounts of ketones in the urine, which is of uncertain significance. Reducing calories by 33% (to 1,600 - 1,800 calories daily) may be better in diet management of obese women with gestational diabetes mellitus and more effective than prophylactic insulin. More studies are required to confirm these results." +"Aim: To measure ketonemia in a control population of pregnant women and in a population of women with gestational diabetes (GDM). To define a normal ketonemia threshold for the controls and to determine whether or not this value could play a role in the clinical management of women with GDM. Method: Fifty-six women with a normal OGTT and 49 women with GDM were included and monitored from the 25th to the 37th week of pregnancy. Control subjects agreed to perform glycaemia and ketonemia self-monitoring 3 times a day. In addition, women with GDM were asked to measure their postprandial glycaemia. Glycaemia and ketonemia measurements were performed using Optium meters. Subjects kept a 24-hour food record twice a week. Results: The mean ketonemia was lower in the control group than in the GDM group (0.01+/-0.10 vs. 0.04+/-0.009 mmol/l; P<0.001). Ketonemia values measured before the midday meal and prior to the evening meal were lower for control subjects than for GDM patients (P=0.002 and P=0.005). Fasting ketonemia was unrelated to ketonuria in the GDM group, whereas there was a correlation in the control group (P=0.006). At least one chronic increase in ketonemia levels was observed in 47% of the women with GDM, compared with only 12% of controls. The lowest levels of evening glycaemia correlated with the highest levels of ketonemia; women with GDM reported lower food and carbohydrate intakes than controls (P<0.001). Conclusion: This work has enabled the establishment of ketonemia reference standards in non-diabetic pregnant women. If ketonemia does indeed indicate overly restrictive dietary behavior, this parameter could be employed for monitoring adherence to the nutritional recommendations for GDM.","The aim of this study is to measure ketonemia (amount of ketones, a substance that the body makes if cells don't get enough blood sugar, in the body) in a control (comparison) population of pregnant women and in a population of women with gestational diabetes (women diagnosed with diabetes for the first time during pregnancy). This study also aims to define normal ketonemia levels for the comparison group and to determine whether or not this level could play a role in the care of women with gestational diabetes. This study included 56 women with normal oral glucose tolerance test results (a test that measures how the body moves sugar from blood to the tissues). Women in the comparison group agreed to monitor glycaemia (blood sugar levels) and ketonemia themselves 3 times a day. In addition, women with gestational diabetes were asked to measure their blood glucose after a meal. Glycaemia and ketonemia measurements are performed using a small finger stick device. Study participants keep a 24-hour food diary twice a week. The average ketonemia is lower in the comparison group than in the gestational diabetes group. Ketonemia values measured before the midday meal and before the evening meal are lower for the comparison group than for patients with gestational diabetes. Fasting (no food) ketonemia is unrelated to ketonuria (high amounts of ketones in the urine) in the gestational diabetes group, whereas there is a connection in the comparison group. At least one chronic (recurring) increase in ketonemia levels is observed in 47% of the women with gestational diabetes, compared with only 12% in the comparison group. The lowest levels of evening glycaemia correlated with the highest levels of ketonemia; women with gestational diabetes reported lower food and carbohydrate intakes than the comparison group. In conclusion, this work has established ketonemia standards in pregnant women who do not have diabetes. If ketonemia does indicate overly restrictive dietary behavior, this measure could be used for monitoring how well people stick to the nutritional recommendations for gestational diabetes." +"Aim: To measure ketonemia in a control population of pregnant women and in a population of women with gestational diabetes (GDM). To define a normal ketonemia threshold for the controls and to determine whether or not this value could play a role in the clinical management of women with GDM. Method: Fifty-six women with a normal OGTT and 49 women with GDM were included and monitored from the 25th to the 37th week of pregnancy. Control subjects agreed to perform glycaemia and ketonemia self-monitoring 3 times a day. In addition, women with GDM were asked to measure their postprandial glycaemia. Glycaemia and ketonemia measurements were performed using Optium meters. Subjects kept a 24-hour food record twice a week. Results: The mean ketonemia was lower in the control group than in the GDM group (0.01+/-0.10 vs. 0.04+/-0.009 mmol/l; P<0.001). Ketonemia values measured before the midday meal and prior to the evening meal were lower for control subjects than for GDM patients (P=0.002 and P=0.005). Fasting ketonemia was unrelated to ketonuria in the GDM group, whereas there was a correlation in the control group (P=0.006). At least one chronic increase in ketonemia levels was observed in 47% of the women with GDM, compared with only 12% of controls. The lowest levels of evening glycaemia correlated with the highest levels of ketonemia; women with GDM reported lower food and carbohydrate intakes than controls (P<0.001). Conclusion: This work has enabled the establishment of ketonemia reference standards in non-diabetic pregnant women. If ketonemia does indeed indicate overly restrictive dietary behavior, this parameter could be employed for monitoring adherence to the nutritional recommendations for GDM.","The aim is to measure blood ketone bodies (particles made from fat breakdown) in a baseline group of pregnant women and group with gestational diabetes (high blood sugar affecting pregnant women). To define a normal baseline level of blood ketone bodies, made from fat breakdown, and determine if this value could aid management of pregnant women with gestational diabetes or high blood sugar. Fifty-six standard women and 49 with gestational diabetes were measured from the 25th to 37th week of pregnancy. Standard women performed measurements of blood sugar and blood ketone bodies 3 times a day. Also, pregnant gestational diabetics with high blood sugar were asked to measure after-meal blood sugar. Blood and ketone measurements were recorded. Patients kept a 24-hour food record twice a week. Average blood ketone bodies were lower in the standard group than the group with gestational diabetes. Blood ketone bodies measured before the midday and evening meals were lower for standard patients than gestational diabetics. Fasting blood ketone bodies were unrelated to urinary ketone bodies in the pregnant gestational diabetics, unlike the standard group. At least one long-lasting increase in blood ketone bodies occured in 47% of pregnant women with gestational diabetes compared to only 12% of standard patients. The lowest levels of evening blood sugar paralleled the highest levels of blood ketone bodies. Pregnant gestational diabetics with high blood sugar reported lower food and carb intakes than standard women. This work created baselines of blood ketone bodies in non-diabetic pregnant women. If blood ketone bodies do indicate restricting diets, this value may monitor faithfulness to diet recommendations for pregnant gestational diabetics with high blood sugar." +"Introduction: Nutrition therapy is an integral part of the management of gestational diabetes mellitus (GDM). Most women with GDM are treated by nutritional management alone. The goal of our study was to compare low and high carbohydrate diets in their effectiveness, safety and tolerability in women with GDM. Material and methods: The study group consisted of 30 Caucasian women newly diagnosed with GDM, with a mean age of 28.7 +/- 3.7 years and pregnancy duration of 29.2 +/- 5.4 weeks. The patients were randomised into two groups: those on a low and those on a high carbohydrate diet (45% vs. 65% respectively of energy supply coming from carbohydrates). The presence of urine ketones was controlled every day. After two weeks daily glucose profiles and compliance with the recommended diets were analysed. Results: Glucose concentration before implementation of the diet regimen did not differ between groups. No changes in fasting blood glucose were noticed in the group that had followed a low carbohydrate diet, although a significant decrease in glucose concentration was observed after breakfast (102 +/- 16 vs. 94 +/- 11 mg/dl), lunch (105 +/- 12 vs. 99 +/- 9 mg/dl) and dinner (112 +/- 16 vs. 103 +/- 13 mg/dl) (p < 0.05). In the high carbohydrate diet group fasting and after-breakfast glucose concentration did not change. A significant decrease in glycaemia was noticed after lunch (106 +/- 15 vs. 96 +/- 7 mg/dl) and dinner (107 +/- 12 vs. 97 +/- 7 mg/dl) (p < 0.05). Ketonuria was not observed in either group. Obstetrical outcomes did not differ between groups. Conclusions: Both high and low carbohydrate diets are effective and safe. A diet with carbohydrate limitation should be recommended to women who experience the highest glycaemia levels after breakfast.","Nutrition therapy (treatment that uses food to prevent and reverse disease) is a key part of the care of gestational diabetes mellitus (GDM) (women diagnosed with diabetes for the first time during pregnancy). Most women with GDM are treated only by managing their nutrition. The goal of this study is to compare low and high carbohydrate (carbohydrates that provide fuel for the body often found in sugary foods, pasta, and bread) diets. The study group has 30 white women newly diagnosed with gestational diabetes mellitus. The patients are randomly put into two groups: those on a low carbohydrate (carb) diet and those on a high carb diet. The presence of urine ketones (substances that the body makes if cells don't get enough blood sugar) is controlled every day. After two weeks, how well women stayed on the recommend diets and daily blood sugar measures were analyzed. Blood sugar levels before starting the new diets did not differ between the two groups. No changes in fasting blood sugar (blood sugar levels after not eating for set amount of time) are noticed in the group that has a low carb diet, although a significant decrease in blood sugar is seen after breakfast, lunch, and dinner. In the high carb diet group, fasting and after breakfast blood sugar levels did not change. A significant decrease in glycaemia (concentration of blood sugar) is noticed after lunch. Ketonuria (high amounts of ketones in the urine) is not observed in either group. Pregnancy outcomes did not differ between the two groups. In conclusion, both high and low carb diets are effective and safe. A diet that limits carbs should be recommended to women who experience the highest concentration of blood sugar levels after breakfast." +"Objective: The object of the study was to determine whether time of day, interval after a standard meal, and maternal body mass influence plasma glucose concentrations in women with gestational diabetes mellitus. Study design: Identical mixed meals were administered on 2 separate occasions 1 week apart to 30 women with dietarily treated gestational diabetes and pregnancies between 28 and 38 weeks' gestation. One meal was administered at 7 AM (morning meal) and the other was administered at 9 PM (evening meal), each after a fast of >/=5 hours. The order of the meals (morning first versus evening first) was assigned randomly. Sixteen of the women had a body mass index >/=27 kg/m(2) (overweight) and 14 women had a body mass index <27 kg/m(2) (lean). Venous plasma concentrations of glucose, insulin, free fatty acids, beta-hydroxybutyrate, and bound and free cortisol were measured hourly for 9 hours after each of the test meals. Results: When all women were considered together glucose concentrations after the morning meal were significantly greater at 1 hour, were not different at 2 hours, and were significantly lower from 3 through 9 hours postprandially than those at corresponding times after the evening meal. Plasma beta-hydroxybutyrate and free fatty acid concentrations were higher between 5 and 9 hours after the morning meal than at the same times after the evening meal. Total and free cortisol levels were higher for the first 7 hours after the morning feeding, reflecting known diurnal variation in cortisol concentrations. Overweight patients' glucose values were significantly greater than those of lean subjects during the last 4 hours of the overnight fast. Conclusions: Among women with dietarily treated gestational diabetes the glucose concentrations were significantly higher from 3 to 9 hours after an evening meal, whereas suppression of free fatty acids and beta-hydroxybutyrate was less sustained after a morning feeding. The mechanisms underlying these differences remain to be determined but may involve diurnal influences of counterregulatory hormones. The relationships between measurements of maternal glycemia and maternal and perinatal outcomes in pregnancies complicated by gestational diabetes may be clarified by establishing a uniform duration of a fast and by developing meal-specific preprandial and postprandial maternal glucose targets for these patients.","The objective of this study is to determine whether time of day, the interval after a standard meal, and maternal body mass (body fat based on height and weight) influence the amount of blood sugar in women with gestational diabetes mellitus (a type of diabetes first seen during pregnancy in a woman who did not have diabetes before pregnancy). Identical mixed meals are given on 2 separate occasions 1 week apart to 30 women with gestational diabetes being treated by diet and who are pregnant. One meal is given at 7 am (morning meal) and the second meal is given at 9 pm (evening meal), each after a fast (no food) of 5 or more hours. The order of the meals (morning first versus evening first) is assigned randomly. Based on body mass index, 16 of the women are considered overweight, and 14 women are lean. Blood sugar from the vein, insulin (a hormone in the body that allows cells in the muscles, fat, and liver to absorb sugar that is in the blood), free fatty acids (lipids from fats and oils that are a source of energy for the body), beta-hydroxybutyrate (a chemical in the body that provides energy when not enough carbohydrates or sugars have been eaten), and bound and free cortisol (a stress hormone that is bound to proteins or free in the blood) are measured hourly for 9 hours after each of the test meals. When all women are measured together, blood sugar after the morning meal is much greater at 1 hour, are not different at 2 hours, and are much lower 3 through 9 hours after the meal than measurements taken at the same times after the evening meal. The chemical beta-hydroxybutyrate and free fatty acid levels are higher between 5 and 9 hours after the morning meal than at the same times after the evening meal. Levels of the stress hormone cortisol are higher for the first 7 hours after the morning meal, reflecting known daily variation in cortisol concentrations. Overweight patients' blood sugar levels are much greater than those of lean patients during the last 4 hours of the overnight fast. In conclusion, among women with gestational diabetes, the blood sugar levels are much higher from 3 to 9 hours after an evening meal, whereas slowing or stopping free fatty acid and beta-hydroxybutyrate use is less stable after a morning meal. The process causing these differences remain to be found but may involve daily influences of hormones that increase blood sugar. The relationships between measurements of blood sugar in pregnant women and maternal and perinatal (before and after birth) outcomes in pregnancies complicated by gestational diabetes may be cleared up by creating a standard time to fast and by developing meal-specific maternal blood sugar levels to aim to reach before and after meals for these patients." +"Objective: To determine the effect of carbohydrate restriction on perinatal outcome in patients with diet-controlled gestational diabetes mellitus (GDM). Methods: Women with diet-controlled GDM were divided non-randomly into two groups based on their dietary carbohydrate content: those with low dietary carbohydrate content (below 42%) and those with high dietary carbohydrate content (exceeding 45%). Subjects kept dietary accounts and were followed with daily fasting and postprandial glucose assessments. Subjects also were tested daily for urinary ketones. Glycosylated hemoglobin, mean fasting and postprandial glucose values, incidence of macrosomia and large for gestational age (LGA) infants, cesarean deliveries for cephalopelvic disproportion and macrosomia, and need for insulin therapy were compared between the groups. Results: The two groups were identical in terms of demographic characteristics. Significant reductions in the postprandial glucose values were seen among subjects in the low-carbohydrate group (P < .04). Fewer subjects in the low-carbohydrate group required the addition of insulin for glucose control (P < .047; relative risk [RR] 0.14; 95% confidence interval [CI] 0.02, 1.00). The incidence of LGA infants was significantly lower in the low-carbohydrate group (P < .035; RR 0.22; 95% CI 0.05, 0.91). Subjects in the low carbohydrate group also had a lower rate of cesarean deliveries for cephalopelvic disproportion and macrosomia (P < .037; RR 0.15; 95% CI 0.04, 0.94). Conclusion: Carbohydrate restriction in patients with diet-controlled GDM results in improved glycemic control, less need for insulin therapy, a decrease in the incidence LGA infants, and a decrease in cesarean deliveries for cephalopelvic disproportion and macrosomia.","The objective of this study is to determine the effect of limiting carbohydrates (carbs) on perinatal (time before and after birth) outcomes in patients with diet-controlled gestational diabetes mellitus (diagnosed with diabetes for the first time during pregnancy). Women with diet-controlled gestational diabetes mellitus are divided non-randomly into two groups based on the amount of carbs in their diet: those with low carbs in the diet (below 42%) and those with high carbs in the diet (exceeding 45%). Patients keep food diaries and are followed with assessments of daily fasting (no food) and blood sugar levels after meals. Patients also were tested daily for urinary ketones (chemicals in uring made from the liver that indicate the body is using fat for fuel instead of sugar). Glycosylated hemoglobin (a blood test that measures the percent of a protein found in blood red cells), average fasting and after meals blood sugar numbers, number of macrosomia (a newborn who is much larger than average) and large for gestational age infants (newborns who weighs more than 90% of other newborns of the same gestational age at birth), cesarean deliveries (C-section) for cephalopelvic disproportion (when a baby's head is too large to fit through the mother's pelvis) and macrosomia, and need for insulin therapy (a hormone in the body that allows cells in the muscles, fat, and liver to absorb sugar that is in the blood) are compared between the groups. The two groups are identical in terms of demographic characteristics such as age, race/ethnicity, geographic area, and income. Major decreases in the after meal blood sugar numbers are seen among patients in the low-carb group. Fewer patients in the low-carb group needed the additional insulin to control blood sugar. The number of large for gestational age infants was much lower in the low-carb group. Patients in the low-carb group also have lower rates of cesarean deliveries due to cephalopelvic disproportion (in which the baby's head is too large to fit through the mother's pelvis) and macrosomia (in which the newborn who is much larger than average). In conclusion, limiting carbohydrates in patients with diet-controlled gestational diabetes mellitus results in improved blood sugar control, less need for insulin therapy, a decrease in the number of large for gestational age infants, and a decrease in cesarean deliveries for cephalopelvic disproportion and macrosomia." +"Objective: To determine the effect of carbohydrate restriction on perinatal outcome in patients with diet-controlled gestational diabetes mellitus (GDM). Methods: Women with diet-controlled GDM were divided non-randomly into two groups based on their dietary carbohydrate content: those with low dietary carbohydrate content (below 42%) and those with high dietary carbohydrate content (exceeding 45%). Subjects kept dietary accounts and were followed with daily fasting and postprandial glucose assessments. Subjects also were tested daily for urinary ketones. Glycosylated hemoglobin, mean fasting and postprandial glucose values, incidence of macrosomia and large for gestational age (LGA) infants, cesarean deliveries for cephalopelvic disproportion and macrosomia, and need for insulin therapy were compared between the groups. Results: The two groups were identical in terms of demographic characteristics. Significant reductions in the postprandial glucose values were seen among subjects in the low-carbohydrate group (P < .04). Fewer subjects in the low-carbohydrate group required the addition of insulin for glucose control (P < .047; relative risk [RR] 0.14; 95% confidence interval [CI] 0.02, 1.00). The incidence of LGA infants was significantly lower in the low-carbohydrate group (P < .035; RR 0.22; 95% CI 0.05, 0.91). Subjects in the low carbohydrate group also had a lower rate of cesarean deliveries for cephalopelvic disproportion and macrosomia (P < .037; RR 0.15; 95% CI 0.04, 0.94). Conclusion: Carbohydrate restriction in patients with diet-controlled GDM results in improved glycemic control, less need for insulin therapy, a decrease in the incidence LGA infants, and a decrease in cesarean deliveries for cephalopelvic disproportion and macrosomia.","The objective is to determine how carb restriction affects births in diet-controlled gestational diabetics, in which high blood sugar affects pregnant women. Diet-controlled, pregnant gestational diabetics with high blood sugar were divided non-randomly based on dietary carb intake: a low-carb intake group (below 42%) or high-carb intake group (over 45%). Subjects kept diet records and were followed with daily blood sugar measurements. Subjects also were tested daily for ketones in urine. Certain blood sugar and birth-related measurements were compared between groups. The two groups had identical socioeconomic traits. The low-carb group had reduced after-meal glucose levels. Less patients in the low-carb group needed insulin for glucose control. The frequency of large-for-prebirth-age infants was lower in the low-carb group. The low-carb group also had less cesarean deliveries for large-head babies and large-body babies. Carb restriction in diet-controlled, pregnant gestational diabetics with high blood sugar improves blood sugar control, reduces need for insulin, reduces frequency of large-for-prebirth-age infants, and reduces cesarean deliveries for large-head and large-body babies." +"Current controversies for medical nutrition therapy in pregnancies complicated by diabetes include the composition and amount of carbohydrates and fats as well as optimal gestational weight gain and energy restriction. Although carbohydrate is the macronutrient with the greatest effect on glycemic control, there is little evidence for a recommended amount and type of carbohydrate or its distribution. This lack of evidence prompts an issue of debate among practitioners over the type of carbohydrate and its percent distribution throughout the day. The best indicators at this time are the results of self-monitoring of blood glucose, ketone testing, food records, and weight gain. A review of the literature provides the most current information available for medical nutrition therapy during a pregnancy complicated by diabetes and reinforces the need for further research in the form of randomized controlled trials to answer questions regarding carbohydrate modification and distribution, energy needs, and weight gain.","Current controversies and arguments for nutrition therapy (treatment based on food) in pregnancies that are complicated by diabetes (a chronic health condition that affects how the body turns food into energy) include the amount of carbohydrates (carbs) and fats, the best amount of weight to gain during pregnancy, and the best way to limit calories. There is little evidence for a recommended amount and type of carb or how it is distributed. This lack of evidence creates a disagreement among health care providers over the type of carb and amount that should be eaten throughout the day. The best measures at this time are the results of self-monitoring of blood sugar, testing for ketones (substances that the body makes if cells don't get enough blood sugar), food diaries, and weight gain. A review of the published studies provides the most current information available for medical nutrition therapy during a pregnancy complicated by diabetes. The review supports the need for further research to answer questions regarding carbohydrate changes and distribution in the diet, energy needs, and weight gain." +"Background: No clinical trials have been specifically designed to compare medical treatments after surgery in Parkinson's disease (PD). Objective: Study's objective was to compare the efficacy and safety of levodopa versus dopamine agonist monotherapy after deep brain stimulation (DBS) in PD. Methods: Thirty-five surgical candidates were randomly assigned to receive postoperative monotherapy with either levodopa or dopamine agonist in a randomized, single-blind study. All patients were reevaluated in short- (3 months), mid- (6 months), and long-term (2.5 years) follow-up after surgery. The primary outcome measure was the change in the Non-Motor Symptoms Scale (NMSS) 3 months after surgery. Secondary outcome measures were the percentage of patients maintaining monotherapy, change in motor symptoms, and specific non-motor symptoms (NMS). Analysis was performed primarily in the intention-to-treat population. Results: Randomization did not significantly affect the primary outcome (difference in NMSS between treatment groups was 4.88 [95% confidence interval: -11.78-21.53, P = 0.566]). In short- and mid-term follow-up, monotherapy was safe and feasible in more than half of patients (60% in short- and 51.5% in mid-term follow-up), but it was more often possible for patients on levodopa. The ability to maintain dopamine agonist monotherapy was related to optimal contact location. In the long term, levodopa monotherapy was feasible only in a minority of patients (34.2%), whereas dopamine agonist monotherapy was not tolerated due to worsening of motor conditions or occurrence of impulse control disorders. Conclusions: This trial provides evidence for simplifying pharmacological treatment after functional neurosurgery for PD. The reduction in dopamine receptor agonists should be attempted while monitoring for occurrence of NMSs, such as apathy and sleep disturbances.","No clinical trials with patients have been developed to compare medical treatments after surgery in Parkinson's disease (a brain disorder that affects movement and coordination). The objective of this study is to compare the performance and safety of levodopa (a drug that enters the brain and helps replace missing dopamine, a chemical that carries signals between brain cells) versus dopamine agonist (a drug that imitates the actions of dopamine in the body) single therapy after deep brain stimulation (surgery that implants devices to stimulate certain areas of the brain) in patients with Parkinson's disease. In this study, 35 patients who are planning to undergo surgery are randomly assigned to receive either levodopa or dopamine agonist after surgery. All patients are evaluated in short (3 months), mid (6 months), and long-term (2.5 years) follow-up appointments after the surgery. The key outcome (result) researchers planned to evaluate is the change in the Non-Motor Symptoms Scale, a scale to count and measure severity of non-motor (unrelated to movement) symptoms such as pain and tiredness, 3 months after surgery. A second outcome is the percent of patients staying on only one drug, change in motor (movement) symptoms, and specific non-motor symptoms. The analysis mainly focuses on the patients who were enrolled and randomly assigned to treatment. Being randomly assigned into treatments did not significantly affect the key outcome from the Non-Motor Symptoms Scale between the two treatment groups. In the 3-month and 6-month follow-up appointments, single therapy (only one drug) is safe and practical in more than half of patients, but it was more often possible for patients on levodopa. The ability to maintain dopamine agonist as the only treatment drug is related to the best contact location. In the 2.5 year follow-up, levodopa single therapy is feasible only in a small number of patients, whereas dopamine agonist single therapy is not tolerated (unable to handle side effects) due to worsening of motor conditions or occurrence of impulse control disorders (disorders in which temptations or thoughts cannot be resisted). In conclusion, this study provides evidence for simplifying drug treatment after brain surgery for Parkinson's disease. The reduction in dopamine agonists should be attempted while monitoring for development of non-motor symptoms, such as lack of motivation and sleep disturbances." +"The natural pattern of progression of Parkinson's disease is largely unknown because patients are conventionally followed on treatment. As Parkinson's disease progresses, the true magnitude of the long-duration response to levodopa remains unknown, because it can only be estimated indirectly in treated patients. We aimed to describe the natural course of motor symptoms by assessing the natural OFF in consecutive Parkinson's disease patients never exposed to treatment (drug-na�ve), and to investigate the effects of daily levodopa on the progression of motor disability in the OFF medication state over a 2-year period. In this prospective naturalistic study in sub-Saharan Africa, 30 Parkinson's disease patients (age at onset 58 � 14 years, disease duration 7 � 4 years) began levodopa monotherapy and were prospectively assessed using the Unified Parkinson's disease Rating Scale (UPDRS). Data were collected at baseline, at 1-year and 2-years follow-up. First-ever levodopa intake induced a significant improvement in motor symptoms (natural OFF versus ON state UPDRS-III 41.9 � 15.9 versus 26.8 � 15.1, respectively; P < 0.001). At 1-year follow-up, OFF state UPDRS-III score after overnight withdrawal of levodopa was considerably lower than natural OFF (26.5 � 14.9; P < 0 .001). This effect was not modified by disease duration. At the 2-year follow-up, motor signs after overnight OFF (30.2 � 14.2) were still 30% milder than natural OFF (P = 0.001). The ON state UPDRS-III at the first-ever levodopa challenge was similar to the overnight OFF score at 1-year follow-up and the two conditions were correlated (r = 0.72, P < 0.001). Compared to the natural progression of motor disability, levodopa treatment resulted in a 31% lower annual decline in UPDRS-III scores in the OFF state (3.33 versus 2.30 points/year) with a lower model's variance explained by disease duration (67% versus 36%). Using the equation regressed on pretreatment data, we predicted the natural OFF at 1-year and 2-year follow-up visits and estimated that the magnitude of the long-duration response to levodopa ranged between 60% and 65% of total motor benefit provided by levodopa, independently of disease duration (P = 0.13). Although levodopa therapy was associated with motor fluctuations, overnight OFF disability during levodopa was invariably less severe than the natural course of the disease, independently of disease duration. The same applies to the yearly decline in UPDRS-III scores in the OFF state. Further research is needed to clarify the mechanisms underlying the long-duration response to levodopa in Parkinson's disease. Understanding the natural course of Parkinson's disease and the long-duration response to levodopa may help to develop therapeutic strategies increasing its magnitude to improve patient quality of life and to better interpret the outcome of randomized clinical trials on disease-modifying therapies that still rely on the overnight OFF to define Parkinson's disease progression.","The natural development of Parkinson's disease (a brain disorder that affects movement and coordination) is largely unknown because patients are usually evaluated while on treatment. As Parkinson's disease progresses, the true impact of the long-term response to levodopa (a drug that enters the brain and helps replace missing dopamine, a chemical that carries signals between brain cells) remains unknown because it can only be estimated indirectly in treated patients. Researchers aimed to describe the natural progression of motor (movement) symptoms such as tremors, rigidity, and slowness of movement by evaluating the natural OFF state (when symptoms return) in patients with Parkinson's disease who have never taken drugs to treat the disease. Researchers also aimed to investigate the effects of daily levodopa on the progression of motor disability (partial or total loss of movement in part of the body) in the OFF medication state over a 2-year period. In this study in sub-Saharan Africa, 30 Parkinson's disease patients started levodopa and are assessed using the Unified Parkinson's disease Rating Scale (UPDRS), a rating tool used to measure the severity and progression of Parkinson's disease in patients. Data are collected at the start of the study and at 1-year and 2-year follow-up appointments. Taking levodopa for the first time has a significant improvement in motor symptoms. At 1-year follow-up, OFF state (when symptoms return) UPDRS-III score after overnight withdrawal of levodopa was considerably lower than natural OFF. This effect does not change based on how long the person has the disease. At the 2-year follow-up, motor signs after overnight OFF are still milder than natural OFF. The ON state (patient feels energetic and can move) UPDRS-III at the first-ever levodopa challenge is similar to the overnight OFF score at 1-year follow-up, and the two conditions are connected. Compared to the natural progression of motor disability, levodopa treatment resulted in a lower annual decline in UPDRS-III scores in the OFF state with a lower number than expected, which is explained by disease duration. Using data taken from before treatment started, researchers made predictions of the natural OFF at 1-year and 2-year follow-up visits and estimated that the magnitude of how long patients have a response to levodopa ranged between 60% and 65% of benefit on motor ability provided by levodopa, independently of how long patients had the disease. Although levodopa is linked to changes in motor ability, overnight OFF disability (when symptoms return) during levodopa is less severe than the natural course of the disease, independently of how long patients had the disease. The same applies to the yearly decline in UPDRS-III scores in the OFF state. Further research is needed to clarify the processes underlying the long-duration response to levodopa in Parkinson's disease. Understanding the natural course of Parkinson's disease and how long motor improvements last while on levodopa may help to develop treatment strategies, increasing its impact to improve patient quality of life and to better understand the outcome of clinical studies on therapies that still rely on the overnight OFF to define Parkinson's disease progression." +"The natural pattern of progression of Parkinson's disease is largely unknown because patients are conventionally followed on treatment. As Parkinson's disease progresses, the true magnitude of the long-duration response to levodopa remains unknown, because it can only be estimated indirectly in treated patients. We aimed to describe the natural course of motor symptoms by assessing the natural OFF in consecutive Parkinson's disease patients never exposed to treatment (drug-na�ve), and to investigate the effects of daily levodopa on the progression of motor disability in the OFF medication state over a 2-year period. In this prospective naturalistic study in sub-Saharan Africa, 30 Parkinson's disease patients (age at onset 58 � 14 years, disease duration 7 � 4 years) began levodopa monotherapy and were prospectively assessed using the Unified Parkinson's disease Rating Scale (UPDRS). Data were collected at baseline, at 1-year and 2-years follow-up. First-ever levodopa intake induced a significant improvement in motor symptoms (natural OFF versus ON state UPDRS-III 41.9 � 15.9 versus 26.8 � 15.1, respectively; P < 0.001). At 1-year follow-up, OFF state UPDRS-III score after overnight withdrawal of levodopa was considerably lower than natural OFF (26.5 � 14.9; P < 0 .001). This effect was not modified by disease duration. At the 2-year follow-up, motor signs after overnight OFF (30.2 � 14.2) were still 30% milder than natural OFF (P = 0.001). The ON state UPDRS-III at the first-ever levodopa challenge was similar to the overnight OFF score at 1-year follow-up and the two conditions were correlated (r = 0.72, P < 0.001). Compared to the natural progression of motor disability, levodopa treatment resulted in a 31% lower annual decline in UPDRS-III scores in the OFF state (3.33 versus 2.30 points/year) with a lower model's variance explained by disease duration (67% versus 36%). Using the equation regressed on pretreatment data, we predicted the natural OFF at 1-year and 2-year follow-up visits and estimated that the magnitude of the long-duration response to levodopa ranged between 60% and 65% of total motor benefit provided by levodopa, independently of disease duration (P = 0.13). Although levodopa therapy was associated with motor fluctuations, overnight OFF disability during levodopa was invariably less severe than the natural course of the disease, independently of disease duration. The same applies to the yearly decline in UPDRS-III scores in the OFF state. Further research is needed to clarify the mechanisms underlying the long-duration response to levodopa in Parkinson's disease. Understanding the natural course of Parkinson's disease and the long-duration response to levodopa may help to develop therapeutic strategies increasing its magnitude to improve patient quality of life and to better interpret the outcome of randomized clinical trials on disease-modifying therapies that still rely on the overnight OFF to define Parkinson's disease progression.","The natural progress of Parkinson's disease (a brain-related disorder affecting movement) is largely unknown because patients are usually examined during treatment. As Parkinson's disease progresses, the effect of the long-lasting response to levodopa (common Parkinsons's medication) remains unknown since it is measured indirectly in treated patients. We tried to describe the natural course of movement symptoms by measuring the OFF state when symptoms occur in patients never given treatment (drug-na�ve) for Parkinson's disease. For 2 years, we also explored how daily levodopa affects the progression of movement symptoms in the OFF state after treatment wears off. In this lengthy, observational study in sub-Saharan Africa, 30 patients with Parkinson's disease (age at onset 58 � 14 years, disease duration 7 � 4 years) began levodopa therapy and were later measured with a specific disease scale for Parkinson's. Data were collected at start, 1-year, and 2-year follow-up. First-time levodopa intake improved movement symptoms. After 1 year, severity of symptoms of Parkinson's disease was lower after overnight withdrawal of levodopa than without it at all. The lowered severity by levodopa was not altered by disease length. After 2 years, movement signs after overnight withdrawal of medication was still 30% milder than movement signs with no treatment ever. The no-symptom state after first-time levodopa was similar and related to the overnight typical-symptom state after 1 year. Compared to the natural progression, levodopa reduces symptom severity via a 31% annual decline with some leeway due to disease duration. We calculated that the response to levodopa involved a possible 60-65% benefit of total motor activity, regardless of disease duration. While levodopa relates to movement fluctuations, the typical-symptom state after overnight levodopa withdrawal was less severe than without medication at all, regardless of disease duration. A yearly decline in symptom severity during the typical-symptom state also exists. We need more research to explain the mechanisms for the response to levodopa in Parkinson's disease. Understanding how Parkinson's disease progresses and the response to levodopa may help create better treatments and better assess clinical trials for Parkinson's disease." +"Degradation of striatal dopamine in Parkinson's disease (PD) may initially be supplemented by increased cognitive control mediated by cholinergic mechanisms. Shift to cognitive control of walking can be quantified by prefrontal cortex activation. Levodopa improves certain aspects of gait and worsens others, and cholinergic augmentation influence on gait and prefrontal cortex activity remains unclear. This study examined dopaminergic and cholinergic influence on gait and prefrontal cortex activity while walking in PD. A single-site, randomized, double-blind crossover trial examined effects of levodopa and donepezil in PD. Twenty PD participants were randomized, and 19 completed the trial. Participants were randomized to either levodopa + donepezil (5 mg) or levodopa + placebo treatments, with 2 weeks with treatment and a 2-week washout. The primary outcome was change in prefrontal cortex activity while walking, and secondary outcomes were change in gait and dual-task performance and attention. Levodopa decreased prefrontal cortex activity compared with off medication (effect size, -0.51), whereas the addition of donepezil reversed this decrease. Gait speed and stride length under single- and dual-task conditions improved with combined donepezil and levodopa compared with off medication (effect size, 1 for gait speed and 0.75 for stride length). Dual-task reaction time was quicker with levodopa compared with off medication (effect size, -0.87), and accuracy improved with combined donepezil and levodopa (effect size, 0.47). Cholinergic therapy, specifically donepezil 5 mg/day for 2 weeks, can alter prefrontal cortex activity when walking and improve secondary cognitive task accuracy and gait in PD. Further studies will investigate whether higher prefrontal cortex activity while walking is associated with gait changes.","Dopamine is a chemical messenger that carries signals between brain cells and affects mood, motivation, and movement. The breakdown and inactivation of dopamine in Parkinson's disease (PD) may initially be addressed by increased cognitive (thought-related) control brought about by cholinergic mechanisms (types of drugs that inhibit, enhance, or imitate the action of the neurotransmitter acetylcholine, the primary signaling molecule of nerve cells). Shift to cognitive control of walking can be measured by prefrontal cortex activation (activating the part of the brain that controls behavior, such as decision-making). Levodopa (a drug that enters the brain and helps replace missing dopamine, a chemical that carries signals between brain cells) improves certain aspects of gait (how a person walks) and worsens others. Cholinergic influence on gait and prefrontal cortex activity remains unclear. This study examines dopaminergic (drugs that increase dopamine activity) and cholinergic influence on gait and prefrontal cortex activity while walking in PD. A clinical study examines the effects of levodopa and donepezil (a type of drug that helps mental function) in Parkinson's disease. In this study, 20 people with Parkinson's disease were randomly put in treatment groups, and 19 completed the study. Participants were randomly put in either the group that received both levodopa + donepezil or the group that received levodopa + placebo (sham) treatments, with 2 weeks spent on treatment and a 2-week washout (the study phase when the drug is stopped and no other drug is used). The main outcome (result) is change in prefrontal cortex activity while walking. Secondary outcomes are change in gait, dual-task performance (doing two tasks at the same time), and attention. Levodopa decreased prefrontal cortex activity (the part of the brain that controls behavior, such as decision-making) compared with off medication, whereas the addition of donepezil reversed this decrease. Gait speed and stride length while doing single- and dual-task conditions improved with combined donepezil and levodopa compared with off medication. Dual-task reaction time was quicker with levodopa compared with off medication, and accuracy improved with the combined donepezil and levodopa drugs. Cholinergic drugs, specifically donepezil for 2 weeks, can alter prefrontal cortex activity when walking and improve secondary cognitive task accuracy and gait in Parkinson's disease. Further studies will investigate whether higher prefrontal cortex activity while walking is associated with gait changes." +"Introduction: Long-term treatment of Parkinson's disease (PD) with levodopa is hampered by motor complications related to the inability of residual nigrostriatal neurons to convert levodopa to dopamine (DA) and use it appropriately. This generated a tendency to postpone levodopa, favoring the initial use of DA agonists, which directly stimulate striatal dopaminergic receptors. Use of DA agonists, however, is associated with multiple side effects and their efficacy is limited by suboptimal bioavailability. Areas covered: This paper reviewed the latest preclinical and clinical findings on the efficacy and adverse effects of non-ergot DA agonists, discussing the present and future of this class of compounds in PD therapy. Expert opinion: The latest findings confirm the effectiveness of DA agonists as initial treatment or adjunctive therapy to levodopa in advanced PD, but a more conservative approach to their use is emerging, due to the complexity and repercussions of their side effects. As various factors may increase the individual risk to side effects, assessing such risk and calibrating the use of DA agonists accordingly may become extremely important in the clinical management of PD, as well as the availability of new DA agonists with better profiles of safety and efficacy.","Long-term treatment of Parkinson's disease with levodopa (a drug that enters the brain and helps replace missing dopamine, a chemical that carries signals between brain cells) is slowed down by motor (movement) complications related to the inability of neurons to convert levodopa to dopamine (a chemical messenger that carries signals between brain cells and affects mood, motivation, and movement) and use it appropriately. This problem often leads to delaying the use of levodopa and using dopamine agonists (a medication that imitates the actions of dopamine in the body to relieve symptoms related to low levels of dopamine), which directly stimulates dopamine receptors or target sites in the brain. Using dopamine agonists, however, is connected with multiple side effects. Their performance is limited by the drug not being completely available to the intended part of the body. This paper reviews the latest findings from animal and human studies on the performance and negative effects of non-ergot dopamine agonists (newer types of drugs that imitate the effects of dopamine), discussing the present and future of this type of drug in Parkinson's disease. The latest findings confirm the effectiveness of dopamine agonists as the first treatment and as an additional drug to use with levodopa in advanced Parkinson's disease, but a more moderate approach to their use is emerging due to their side effects. As different factors may increase the risk to side effects, evaluating such risk and adjusting the use of dopamine agonists may become extremely important in the care of Parkinson's disease, as well as the availability of new dopamine agonists drugs with better safety and performance documented." +"Parkinson's disease (PD), the second most frequent neurodegenerative disease, has been linked to increased central and peripheral inflammation. Although the response of the immune system to dopaminergic treatment remains to be fully understood, dopaminergic agonists are known to exhibit immunoregulatory properties which may, at least in part, explain their therapeutic effect in PD. This highlights the need of analyzing immune parameters in longitudinal studies on PD patients receiving specific therapeutic regimes. In this work, PD patients were included in a two-year prospective study comparing the effect of levodopa alone and a levodopa/pramipexole combo therapy on several regulatory and pro-inflammatory immune cell populations. We demonstrated that PD patients show decreased circulating levels of several important regulatory subpopulations, as determined by flow cytometry. Notably, when administered alone, levodopa decreased the levels of functional Bregs and SLAMF1+ tolerogenic DCs and increased the levels of total and HLA-DR+ classical monocytes, while the pramipexole/levodopa combo may promote Treg- and tolerogenic DC-mediated regulatory responses. These results suggest that a regime based on levodopa alone may promote a pro-inflammatory-type response in PD patients, but when combined with pramipexole, it promotes a clinically beneficial regulatory-type environment.","Parkinson's disease, the second most frequent brain disorder that impacts movement and coordination, is linked to increased central (brain and spinal cord) and peripheral (nerves) inflammation (the body's natural reaction against injury and infection). Although the response of the immune system to dopamine drugs is not fully understood, dopaminergic agonists (a medication that imitates the actions of dopamine in the body to relieve symptoms related to low levels of dopamine) are known to show immune system-regulating characteristics which may, at least in part, explain their effect in Parkinson's disease. There is a need to analyze immune characteristics in long-term studies on Parkinson's disease patients who are receiving specific drugs. In this study, patients with Parkinson's disease are included in a two-year prospective study (a study that takes a set number of subjects and follows them over a long period). This study compares the effect of levodopa (a drug that enters the brain and helps replace missing dopamine) alone and a combination of levodopa and pramipexole (dopamine-promoting) drugs on several regulating and pro-inflammatory (capable of causing inflammation) immune cells in the body. Researchers demonstrate that patients with Parkinson's disease show decreased levels of important cells that regulate the immune system. In particular, when given alone, levodopa decreases the levels of functional Bregs (a type of regulating immune cell) and SLAMF1+ tolerogenic DCs (immune receptors and cells that direct and regulate the immune response) and increases the levels of total and HLA DR+classical monocytes (molecules that produce antigens and fight inflammation). The combination of levodopa and pramipexole drugs may promote Treg- and tolerogenic DC responses (cells that regulate responses and may suppress immune response). These results suggest that treatment plans based on levodopa alone may promote a pro-inflammatory type of response in patients with Parkinson's disease, but when combined with pramipexole, it promotes a clinically helpful regulatory-type environment." +"Parkinson's disease (PD), the second most frequent neurodegenerative disease, has been linked to increased central and peripheral inflammation. Although the response of the immune system to dopaminergic treatment remains to be fully understood, dopaminergic agonists are known to exhibit immunoregulatory properties which may, at least in part, explain their therapeutic effect in PD. This highlights the need of analyzing immune parameters in longitudinal studies on PD patients receiving specific therapeutic regimes. In this work, PD patients were included in a two-year prospective study comparing the effect of levodopa alone and a levodopa/pramipexole combo therapy on several regulatory and pro-inflammatory immune cell populations. We demonstrated that PD patients show decreased circulating levels of several important regulatory subpopulations, as determined by flow cytometry. Notably, when administered alone, levodopa decreased the levels of functional Bregs and SLAMF1+ tolerogenic DCs and increased the levels of total and HLA-DR+ classical monocytes, while the pramipexole/levodopa combo may promote Treg- and tolerogenic DC-mediated regulatory responses. These results suggest that a regime based on levodopa alone may promote a pro-inflammatory-type response in PD patients, but when combined with pramipexole, it promotes a clinically beneficial regulatory-type environment.","Parkinson's disease (PD) (a brain-related disease affecting movement) is the second most frequent brain-related disease and is linked to increased full-body inflammation. While the immune-related effects of dopamine, a chemical messenger, remain unknown, dopamine imitators treat Parkinson's disease partly via immune-related effects. This therapeutic effect supports analysis of immune scores of patients with Parkinson's disease receiving certain treatments. In this work, patients with Parkinson's were in a two-year study comparing how levodopa (a Parkinson's medication) alone and a levodopa/pramipexole (dopamine imitator) combo affects immune cell subtypes. Patients with Parkinson's have reduced blood levels of important regulatory cell subtypes. Levodopa alone may promote a pro-inflammatory response in patients with Parkinson's, but with pramipexole, it promotes a helpful immune environment." +"Purpose: To investigate the comparative effectiveness of dopamine agonists and monoamine oxidase type-B (MAO-B) inhibitors available for treatment of Parkinson's disease. Methods: We performed a systematic literature search identifying randomized controlled trials investigating 4 dopamine agonists (cabergoline, pramipexole, ropinirole, rotigotine) and 3 MAO-B inhibitors (selegiline, rasagiline, safinamide) for Parkinson's disease. We extracted and pooled data from included clinical trials in a joint model allowing both direct and indirect comparison of the seven drugs. We considered dopamine agonists and MAO-B inhibitors given as monotherapy or in combination with levodopa. Selected endpoints were change in the Unified Parkinson's Disease Rating Scale (UPDRS) score, serious adverse events and withdrawals. We estimated the relative effectiveness of each dopamine agonist and MAO-B inhibitor versus comparator drug. Results: Altogether, 79 publications were included in the analysis. We found all the investigated drugs to be effective compared with placebo when given as monotherapy except safinamide. When considering combination treatment, the estimated relative effects of selegiline, pramipexole, ropinirole, rotigotine, cabergoline, rasagiline and safinamide were 2.316 (1.819, 2.951), 2.091 (1.889, 2.317), 2.037 (1.804, 2.294), 1.912 (1.716, 2.129), 1.664 (1.113, 2.418), 1.584 (1.379, 1.820) and 1.179 (1.031, 1.352), respectively, compared with joint placebo and levodopa treatment. Conclusions: Dopamine agonists were found to be effective as treatment for Parkinson's disease, both when given as monotherapy and in combination with levodopa. Selegiline and rasagiline were also found to be effective for treating Parkinson's disease, and selegiline was the best option in combination with levodopa among all the drugs investigated.","The purpose of this study is to compare the effectiveness of dopamine agonists (medication that imitates the actions of dopamine in the body to relieve symptoms related to low levels of dopamine) and monoamine oxidase type-B (MAO-B) inhibitors (medications that prevent enzymes in the body from breaking down dopamine which allows more dopamine available in the brain) for Parkinson's disease. Researchers performed a thorough review of published studies to identify clinical trials investigating 4 dopamine agonists and 3 MAO-B inhibitors for Parkinson's disease. Data are pulled together from the published studies in a computer analysis that allows different comparisons of the 7 drugs. Researchers created the model to include dopamine agonists and MAO-B inhibitors being given as single therapy (only one drug used) or in combination with levodopa. The main outcomes (results) are Unified Parkinson's Disease Rating Scale (UPDRS) scores (rating tool used to measure the severity and progression of Parkinson's disease in patients), serious adverse events (unfavorable or unintended changes in health), and withdrawals (symptoms after a person stops taking a drug). The effectiveness of each dopamine agonist and MAO-B inhibitor versus a comparison drug is estimated. Altogether, 79 published studies are included in the analysis. All the investigated drugs are effective compared with placebos (inactive substances that look like the drug being tested in the experiment) when given as single therapy (the only drug given) except the MAO-B inhibitor, safinamide. In conclusion, dopamine agonists are found to be effective as treatment for Parkinson's disease, both when given in a single therapy and in combination with levodopa. The MAO-B inhibitors selegiline and rasagiline are also found to be effective for treating Parkinson's disease, and selegiline is the best option in combination with levodopa among all the drugs investigated." +"Parkinson's disease (PD) is diagnosed where bradykinesia occurs together with rigidity or tremor, in the presence of supporting features. The diagnosis is clinical, and attention should be paid to exclusion criteria indicating an alternative diagnosis and to 'red flag' features. There is no cure or disease-modifying treatment for PD, and the rate of progression is variable. The most effective symptomatic treatment remains levodopa, which has superior benefits for quality of life in early PD compared to other therapies. Motor fluctuations and dyskinesia later in the disease course can be improved with adjunctive treatments. Around 10% of patients per year with refractory motor fluctuations may be eligible for advanced therapies, including deep-brain stimulation surgery. There is emerging evidence for the management of non-motor symptoms in PD, and the importance of multidisciplinary care. In this article, the evidence base for optimal diagnosis and management of PD is discussed.","Parkinson's disease is diagnosed when bradykinesia (slowness of movement) occurs together with rigidity or tremors, along with other characteristics. The diagnosis is based on the signs, symptoms, and health history of the patient. Attention should be paid to other criteria that might indicate another diagnosis and to 'red flag' (investigate further) features. There is no cure or treatment that can reduce the activity and progression for Parkinson's disease, and the rate of progression varies among patients. The most effective treatment to help symptoms is levodopa (a drug that enters the brain and helps replace missing dopamine), which has superior benefits for quality of life in early Parkinson's disease compared to other therapies. Changes in the ability to move and dyskinesia (involuntary and uncontrollable movements) later in the disease's development can be improved by adding another treatment that assists the primary treatment. Around 10% of patients per year with motor (movement) changes that are not responding to treatment may be able to take advanced therapies, including deep-brain stimulation surgery (surgery that implants devices to stimulate certain areas of the brain). There is emerging evidence for the management of non-motor symptoms (symptoms unrelated to movement such as lack of pain or tiredness) in Parkinson's disease, and the importance of multidisciplinary care (when professionals from different fields work together to deliver comprehensive care that addresses the patient's needs). In this article, the evidence foundation for the best diagnosis and care of Parkinson's disease is discussed." +"Objective: We tested the hypothesis that there are 2 distinct phenotypes of Parkinson tremor, based on interindividual differences in the response of resting tremor to dopaminergic medication. We also investigated whether this pattern is specific to tremor by comparing interindividual differences in the dopamine response of tremor to that of bradykinesia. Methods: In this exploratory study, we performed a levodopa challenge in 76 tremulous patients with Parkinson tremor. Clinical scores (Movement Disorders Society-sponsored version of the Unified Parkinson's Disease Rating Scale part III) were collected ""off"" and ""on"" a standardized dopaminergic challenge (200/50 mg dispersible levodopa-benserazide). In both sessions, resting tremor intensity was quantified using accelerometry, both during rest and during cognitive coactivation. Bradykinesia was quantified using a speeded keyboard test. We calculated the distribution of dopamine-responsiveness for resting tremor and bradykinesia. In 41 patients, a double-blinded, placebo-controlled dopaminergic challenge was repeated after approximately 6 months. Results: The dopamine response of resting tremor, but not bradykinesia, significantly departed from a normal distribution. A cluster analysis on 3 clinical and electrophysiologic markers of tremor dopamine-responsiveness revealed 3 clusters: dopamine-responsive, intermediate, and dopamine-resistant tremor. A repeated levodopa challenge after 6 months confirmed this classification. Patients with dopamine-responsive tremor had greater disease severity and tended to have a higher prevalence of dyskinesia. Conclusion: Parkinson resting tremor can be divided into 3 partially overlapping phenotypes, based on the dopamine response. These tremor phenotypes may be associated with different underlying pathophysiologic mechanisms, requiring a different therapeutic approach.","Researchers tested the idea that there are 2 distinct phenotypes (observable traits or characteristics) of Parkinson tremor based on differences among people in how the resting tremor (a tremor when the muscle is relaxed) responds to dopamine medication. Researchers also investigated whether this pattern is specific to tremor by comparing differences in the dopamine response of the tremor to that of bradykinesia (slowness of movement). In the study, we performed a levodopa (a drug that enters the brain and helps replace missing dopamine) challenge (when a drug is used to confirm a diagnosis of Parkinson's disease if the patient's symptoms improve while taking the medication) in 76 patients with Parkinson tremor. Clinical scores using a tool that evaluates the severity of Parkinson's disease are collected in stages of ""off"" (when symptoms return) and ""on"" (when patient feels energetic and can move) during a standard dopamine challenge. In both sessions, resting tremor intensity was measured using accelerometry (a device that records motion and non-motion) both during rest and while doing another mental task at the same time. Bradykinesia is measured using a speeded keyboard test. The distribution (the movement of a drug to and from the blood and different tissues of the body) of dopamine-responsiveness for resting tremor and bradykinesia is calculated. In 41 patients, a dopamine challenge is repeated after about 6 months. The dopamine response of resting tremor, but not bradykinesia, significantly departed from normal in the body. An analysis of brain activity revealed 3 clusters: dopamine-responsive, intermediate, and dopamine-resistant tremor. A repeated levodopa challenge after 6 months confirmed these clusters. Patients with dopamine-responsive tremor have greater disease severity and tend to have a higher amount of dyskinesia (involuntary and uncontrollable movements). In conclusion, Parkinson resting tremor can be divided into 3 partially overlapping characteristics based on dopamine response. These tremor characteristics may be connected with different underlying functional changes that come with Parkinson's disease, requiring a different treatment approach." +"Objective: We tested the hypothesis that there are 2 distinct phenotypes of Parkinson tremor, based on interindividual differences in the response of resting tremor to dopaminergic medication. We also investigated whether this pattern is specific to tremor by comparing interindividual differences in the dopamine response of tremor to that of bradykinesia. Methods: In this exploratory study, we performed a levodopa challenge in 76 tremulous patients with Parkinson tremor. Clinical scores (Movement Disorders Society-sponsored version of the Unified Parkinson's Disease Rating Scale part III) were collected ""off"" and ""on"" a standardized dopaminergic challenge (200/50 mg dispersible levodopa-benserazide). In both sessions, resting tremor intensity was quantified using accelerometry, both during rest and during cognitive coactivation. Bradykinesia was quantified using a speeded keyboard test. We calculated the distribution of dopamine-responsiveness for resting tremor and bradykinesia. In 41 patients, a double-blinded, placebo-controlled dopaminergic challenge was repeated after approximately 6 months. Results: The dopamine response of resting tremor, but not bradykinesia, significantly departed from a normal distribution. A cluster analysis on 3 clinical and electrophysiologic markers of tremor dopamine-responsiveness revealed 3 clusters: dopamine-responsive, intermediate, and dopamine-resistant tremor. A repeated levodopa challenge after 6 months confirmed this classification. Patients with dopamine-responsive tremor had greater disease severity and tended to have a higher prevalence of dyskinesia. Conclusion: Parkinson resting tremor can be divided into 3 partially overlapping phenotypes, based on the dopamine response. These tremor phenotypes may be associated with different underlying pathophysiologic mechanisms, requiring a different therapeutic approach.","We tested if there are 2 different types of Parkinson tremors, or body shakes due to a brain-related disease affecting movement, based on individualized responses to medication altering levels of dopamine, a chemical messenger. We checked if these patterns are tremor-specific by comparing individualized responses of dopamine by tremors to those by bradykinesia (a slowing of movement). We tested responsiveness to levodopa (a Parkinson's medication) in 76 patients with Parkinson tremors, or shakes by a brain-related disease affecting movement. In 41 patients, a dopamine-sensitivty test was repeated after around 6 months. The dopamine response of resting tremor, but not bradykinesia, was atypical. There were 3 types of tremor dopamine-responsiveness: dopamine-responsive, intermediate, and dopamine-resistant tremor. A levodopa sensitivity test 6 months later matched these tremor response categories. Patients with dopamine-responsive tremors had higher disease severity and frequency of impaired movement. Parkinson resting tremors has 3 physical trait types, based on dopamine response. These tremor patterns may be linked with unrevealed biological processes and need different treatments." +"A vast advancement has been made in the treatment related to central nervous system disorders especially Parkinson's disease. The development in therapeutics and a better understanding of the targets results in upsurge of many promising therapies for Parkinson's disease. Parkinson's disease is defined by neuronal degeneration and neuroinflammation and it is reported that the presence of the neurofibrillary aggregates such as Lewy bodies is considered as the marker. Along with this, it is also characterized by the presence of motor and non-motor symptoms, as seen in Parkinsonian patients. A lot of treatment options mainly focus on prophylactic measures or the symptomatic treatment of Parkinson's disease. Neuroinflammation and neurodegeneration are the point of interest which can be exploited as a new target to emphasis on Parkinson's disease. A thorough study of these targets helps in modifications of those molecules which are particularly involved in causing the neuronal degeneration and neuroinflammation in Parkinson's disease. A lot of drug regimens are available for the treatment of Parkinson's disease, although levodopa remains the choice of drug for controlling the symptoms, yet is accompanied with significant snags. It is always suggested to use other drug therapies concomitantly with levodopa. A number of significant causes and therapeutic targets for Parkinson's disease have been identified in the last decade, here an attempt was made to highlight the most significant of them. It was also found that the treatment regimen and involvement of therapies are totally dependent on individuals and can be tailored to the needs of each individual patient.","A major advancement has been made in the treatment related to central nervous system disorders (disorders impacting the brain and spinal cord), especially Parkinson's disease. New medications and more information on how they change proteins in the body lead to new interest in many promising therapies for Parkinson's disease. Parkinson's disease is defined by neuronal degeneration (the loss of nerve cells in the brain) and neuroinflammation (inflammatory response within the brain or spinal cord due to the immune system responding to injury or infection). The presence of the neurofibrillary aggregates (accumulation of a protein inside neurons) is considered as the trait to help diagnose. Additionally, it is also characterized by the presence of motor (movement) and non-motor (unrelated to movement such as pain and tiredness) symptoms, as seen in patients with Parkinson's disease. Many treatment options mainly focus on prevention measures or on treating the symptoms of Parkinson's. Neuroinflammation and neurodegeneration are the areas of interest to focus on in Parkinson's disease. A thorough study of these areas helps address changing molecules that cause the neuronal degeneration and neuroinflammation in Parkinson's disease. Many drugs are available for the treatment of Parkinson's disease, although levodopa (a drug that enters the brain and helps replace missing dopamine) is the preferred drug because it controls symptoms. However, it also has side effects. It is always suggested to use other drug therapies with levodopa. A number of major causes and therapeutic targets for Parkinson's disease have been identified in the last 10 years. This text highlights the most significant of them. It is also found that structured treatment plans and therapies depend on the individual and should be made specifically for the individual patient's needs." +"Objectives: Parkinson's disease (PD) features both motor and non-motor symptoms that substantially impact quality of life (QoL). Levodopa-carbidopa intestinal gel (LCIG) reduces motor complications and improves some non-motor symptoms in advanced PD (APD). Change in patients' health-related quality of life (hrQoL) is a common endpoint in PD trials and has become an important factor in judging overall effect of LCIG. However, hrQoL is considered to be only one dimension of QoL. The primary aim of this prospective observational study was to observe the effects of LCIG on individual quality of life (iQoL) in PD and caregivers. The secondary aim was to investigate its effects on patients' motor and non-motor symptoms as well as effects on caregiver burden. Materials & methods: Utilizing the Schedule for the Evaluation of Individual Quality of Life-Questionnaire (SEIQoL-Q) and the Personal Wellbeing Index-Adult (PWI-A), twelve patients with advanced PD and their caregivers were followed for six months after initiation of LCIG treatment. Results: At the final follow-up, improvements of iQoL for patients (median SEIQoL index improvement 0.16, P < .05) and caregivers (median SEIQoL index improvement 0.20, P < .05) were seen together with improvements of motor and non-motor symptoms. There were no significant improvements of hrQoL. Conclusions: The study results indicate that LCIG improves iQoL in PD in addition to the improvement of motor and non-motor symptoms. Furthermore, this study signals that LCIG may also contribute to improvement of iQoL in caregivers.","Parkinson's disease has both motor (movement) and non-motor (unrelated to movement such as pain) symptoms that impact quality of life (patient's ability to enjoy normal, everyday activities including physical, social, and emotional aspects of life). Levodopa-carbidopa intestinal gel (LCIG) is a gel delivered to patients through a soft tube in the stomach to provide medication. It reduces movement complications and improves some non-motor symptoms in advanced Parkinson's disease. Change in patients' health-related quality of life (how health impacts a person's quality of life) is a common primary outcome in Parkinson's disease studies and has become an important factor in judging overall effect of LCIG. However, health-related quality of life is considered to be only one part of quality of life. The primary aim of this study is to observe the effects of LCIG on individual quality of life in patients with Parkinson's disease and caregivers (people who provide care to a person with short or long-term limitations due to disease or injury). The second aim is to investigate its effects on patients' motor and non-motor symptoms as well as effects on caregiver burden. Researchers interviewed patients on individual quality of life and also gave patients questions to answer on their own on personal wellbeing in different areas, such as relationships, life achievements, and safety. Twelve patients with advanced Parkinson's disease and their caregivers were followed for 6 months after starting levodopa-carbidopa intestinal gel treatment. At the final follow-up appointment, improvements in individual quality of life for patients and caregivers were seen together with improvements in motor and non-motor symptoms. There were no significant improvements of health-related quality of life. In conclusion, these results suggest that levodopa-carbidopa intestinal gel improves individual quality of life in patients with Parkinson's disease in addition to the improvement of motor and non-motor symptoms. Additionally, this study signals that levodopa-carbidopa intestinal gel may also help with improvement of individual quality of life in caregivers." +"Background: Depression is the single largest contributor to non-fatal health loss worldwide. Second-generation antidepressants are the first-line option for pharmacological management of depression. Optimising their use is crucial in reducing the burden of depression; however, debate about their dose dependency and their optimal target dose is ongoing. We have aimed to summarise the currently available best evidence to inform this clinical question. Findings: 28 554 records were identified through our search (24 524 published and 4030 unpublished records). 561 published and 121 unpublished full-text records were assessed for eligibility, and 77 studies were included (19 364 participants; mean age 42�5 years, SD 11�0; 7156 [60�9%] of 11 749 reported were women). For SSRIs (99 treatment groups), the dose-efficacy curve showed a gradual increase up to doses between 20 mg and 40 mg fluoxetine equivalents, and a flat to decreasing trend through the higher licensed doses up to 80 mg fluoxetine equivalents. Dropouts due to adverse effects increased steeply through the examined range. The relationship between the dose and dropouts for any reason indicated optimal acceptability for the SSRIs in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents. Venlafaxine (16 treatment groups) had an initially increasing dose-efficacy relationship up to around 75-150 mg, followed by a more modest increase, whereas for mirtazapine (11 treatment groups) efficacy increased up to a dose of about 30 mg and then decreased. Both venlafaxine and mirtazapine showed optimal acceptability in the lower range of their licensed dose. These results were robust to several sensitivity analyses. Interpretation: For the most commonly used second-generation antidepressants, the lower range of the licensed dose achieves the optimal balance between efficacy, tolerability, and acceptability in the acute treatment of major depression.","Depression is the single largest contributor to non-fatal health loss worldwide. New antidepressants, also called second-generation antidepressants, (medications used to treat depression and other disorders and can improve mood, sleep quality, and concentration) are the first-line option for managing depression using medication. Their use is important to reduce the burden of depression; however, there is ongoing debate about their dose dependency (when the effects of a drug change when the dose of the drug is changed) and the best target dose (the dose that achieves a target effect). We have aimed to summarize the best available evidence to inform this clinical question. Researchers found 28,554 records by searching published and unpublished records. Among those records, 561 published and 121 unpublished records that have complete text are reviewed, and 77 are included in the final analysis. For SSRIs or selective serotonin reuptake inhibitors (a type of antidepressant that can increase the amount of serotonin, a mood stabilizer), the dose-efficacy curve (relationship between an effect of a drug and the amount of drug given) showed a gradual increase up to doses between 20mg and 40mg fluoxetine (a type of SSRI also called prozac), and a flat to decreasing trend through the higher doses up to 80 mg fluoxetine equivalents. Some patients dropped out due to side effects. The relationship between the dose of the drug and dropouts for any reason suggests the best acceptability for using SSRIs is in the lower licensed range between 20 mg and 40 mg fluoxetine equivalents. Venlafaxine (a type of antidepressant) has an initially increasing relationship between dose amount and drug performance up to 75-150mg, followed by a more modest increase, whereas for another antidepressant called mirtazapine, performance increased up to a dose of about 30 mg and then decreased. Both venlafaxine and mirtazapine worked well in the lower range of their licensed dose. These results performed well in several sensitivity analyses to assess strength and uncertainty in a study. For the most common newer antidepressants, the lower range of the dose achieves the best balance between performance, tolerability (the degree to which drugs' negative effects can be handled by patients), and acceptability in the treatment of major depression." +"Background: Although several studies have examined the long-term efficacy of antidepressants, relatively little attention has been paid to the management of relapses or recurrences during continued antidepressant treatment. This study examined whether depressed patients who had recovered and then relapsed on fluoxetine 20 mg/day would benefit from an increase in fluoxetine dose. Method: Eighteen patients who relapsed on fluoxetine 20 mg/day during long-term treatment with fluoxetine as part of a placebo-controlled study had their fluoxetine dose raised to 40 mg/day and were followed for at least 1 month (mean time = 4.7 months). Results: Twelve (67%) were full responders, 3 (17%) partial responders, and 3 (17%) dropped out because of side effects (e.g., insomnia and agitation). Of those patients who had either full or partial response (N = 15; 83%), 3 complete responders had a recurrence on 40 mg/day after a mean of 5.8 months and 1 partial responder had a recurrence 11 months later. Overall, 11 (61%) of 18 patients maintained their response during their follow-up while taking the higher dose of fluoxetine. Conclusion: An increase in dose of fluoxetine to 40 mg/day appears to be an effective strategy in the treatment of relapse among depressed patients who had initially responded to fluoxetine 20 mg/day.","Antidepressants are medications used to treat depression and other disorders and can improve mood, sleep quality, and concentration. Although several studies have examined how well antidepressants work long-term, there is little attention on how to manage relapses (the worsening of a medical condition that had previously improved) or recurrences (when symptoms return months or years after a person has recovered from the last episode) during continued use of antidepressant drugs. This study examined whether depressed patients who had recovered and then relapsed on fluoxetine (a type of antidepressant also called prozac) at 20 mg/day will benefit from an increase dose of fluoxetine. In this study, 18 patients who relapsed on fluoxetine 20 mg/day during long-term treatment with fluoxetine as part of a larger study had their fluoxetine dose raised to 40 mg/day and were followed for at least 1 month. Twelve (67%) were full responders (patients who reached the expected improvement), 3 (17%) partial responders (patients who reached only part of the expected improvement), and 3 (17%) dropped out of the study because of side effects (e.g. insomnia and agitation). Of those 15 patients who had either full or partial response, 3 complete responders had a recurrence on 40 mg/day after an average of 5.8 months and 1 partial responder had a recurrence 11 months later. Overall, 11 (61%) of 18 patients still reacted to the drug during their follow-up while taking the higher dose of fluoxetine. In conclusion, an increase in dose of fluoxetine to 40 mg/day appears to be an effective way to help treat relapse among people with depression who had initially responded to fluoxetine at 20 mg/day." +"Patients with major depressive disorder remain at risk for relapse following remission and often continue to experience subthreshold symptoms. This study examined whether depressed patients who had recovered and then relapsed on fluoxetine 20 mg/day would benefit from an increase in fluoxetine dose. A total of 132 outpatients with major depressive disorder who achieved remission with 8 weeks of treatment with fluoxetine 20 mg had the dose increased to 40 mg. They were randomized to receive cognitive therapy or medication management alone and were followed for up to 28 weeks for depressive relapse and change in depressive symptoms. A total of 47 (35.6%) out of 132 patients did not complete the 28-week continuation phase. Rates of discontinuation or relapse did not differ significantly between the groups. Change in residual symptoms or wellbeing as measured by Hamilton Depression Scale score or Symptom Questionnaire self-report also did not differ between groups. In this sample of outpatients in continuation phase treatment for major depressive disorder, the combination of cognitive therapy and fluoxetine 40 mg failed to yield any significant benefit in symptoms or relapse rates over fluoxetine 40 mg alone during 28 weeks of follow-up.","Patients with major depressive disorder (a mental health disorder where a person is in a constant depressed mood or has a loss of interest in activities) remain at risk for relapse (the worsening of a medical condition that had previously improved) following remission (a period of improvement where the patient is mostly asymptomatic) and often continue to experience subthreshold symptoms in which a person has symptoms but the symptoms do not meet the full criteria for a medical diagnosis. This study examines whether depressed patients who had recovered and then relapsed while on fluoxetine (a type of antidepressant also called prozac) at 20 mg/day would benefit from an increase in fluoxetine dose. A total of 132 patients with major depressive disorder who achieved remission with 8 weeks of treatment with fluoxetine at 20 mg had the dose increased to 40mg. They are randomly put in groups to receive cognitive therapy (a type of behavior therapy that focuses on challenging negative thoughts that can worsen emotional difficulties) or to receive medication only. Patients are followed for up to 28 weeks to check for depressive relapse and changes in depressive symptoms. A total of 47 out of 132 patients did not complete the 28 weeks phase of the study. Rates of stopping the drug or relapsing did not differ significantly between the group receiving cognitive therapy and the group only receiving medication. Changes in subthreshold symptoms or wellbeing did not differ between groups. In this sample of patients being treated for major depressive disorder, the combination of cognitive therapy and fluoxetine at 40 mg failed to lead to any significant benefit in symptoms or in relapse rates over fluoxetine 40 mg alone during the 28 week follow-up period." +"Patients with major depressive disorder remain at risk for relapse following remission and often continue to experience subthreshold symptoms. This study examined whether depressed patients who had recovered and then relapsed on fluoxetine 20 mg/day would benefit from an increase in fluoxetine dose. A total of 132 outpatients with major depressive disorder who achieved remission with 8 weeks of treatment with fluoxetine 20 mg had the dose increased to 40 mg. They were randomized to receive cognitive therapy or medication management alone and were followed for up to 28 weeks for depressive relapse and change in depressive symptoms. A total of 47 (35.6%) out of 132 patients did not complete the 28-week continuation phase. Rates of discontinuation or relapse did not differ significantly between the groups. Change in residual symptoms or wellbeing as measured by Hamilton Depression Scale score or Symptom Questionnaire self-report also did not differ between groups. In this sample of outpatients in continuation phase treatment for major depressive disorder, the combination of cognitive therapy and fluoxetine 40 mg failed to yield any significant benefit in symptoms or relapse rates over fluoxetine 40 mg alone during 28 weeks of follow-up.","Those with depression may fall back after temporary improvement and still experience minor symptoms. This work compares the rate of re-suffering depression and the frequency of depressive symptoms between patients treated with fluoxetine (an antidepressant medication) alone or with thought therapy. 132 patients with temporary improvement from depression after 8 weeks with 20 mg of fluoxetine had the dose increased to 40 mg. The patients randomly received either cognitive or thought therapy or medication management and were monitored for changes in symptoms or regression for 28 weeks. 47 patients did not complete the 28-week phase. Rates of non-completion or regression did not differ between groups. Change in depressive symptoms did not differ between groups. In this work, cognitive or thought therapy with 40 mg of fluoxetine did not give additional benefit compared to fluoxetine 40 mg alone during the 28 weeks of follow-up." +"Objective: A large number of people experience misophonia. In 2013, the Amsterdam Study Group recommended diagnostic criteria for misophonia. However, misophonia is not yet included in the Diagnostic and Statistical Manual of Mental Disorders. This report is the first report on drug use that directly affects misophonia and demonstrates a 14-year-old adolescent girl with misophonia successfully treated with fluoxetine. Methods: The patient's misophonia symptoms had been continuing for approximately 2 years, and her quality of life was significantly reduced. Psychotherapy conditions could not be applied, and fluoxetine 10 mg/d was started and increased to 20 mg/d after a week. At the second-month follow-up, because of partial improvement, fluoxetine dose was increased to 30 mg/d. Results: At the fourth-month follow-up, there was a 40% decrease in Amsterdam Misophonia Scale score with a 70% decrease in the children's global assessment scale scores. By the 16th week, the overall functionality level was good at the end. Conclusions: Fluoxetine may be used as an effective drug in the treatment of misophonia.","A large number of people experience misophonia (having a strong reaction to specific sounds). In 2013, the Amsterdam Study Group recommended criteria, such as signs and symptoms, to diagnose misophonia. However, misophonia is not yet included in the Diagnostic and Statistical Manual of Mental Disorders, a handbook for health care providers to guide the diagnosis of mental disorders. This report is the first report on drug use that directly affects misophonia and shows a 14-year old girl with misophonia who is successfully treated with fluoxetine (a type of antidepressant also called prozac). The patient's misophonia symptoms had been continuing for approximately 2 years, and her quality of life (a patient's ability to enjoy normal, everyday activities) was significantly reduced. Fluoxetine 10 mg/day was started and increased to 20 mg/day after a week. At the second-month follow-up with the patient, because of partial improvement, the fluoxetine dose was increased to 30 mg/day. At the fourth-month follow-up, there was a 40% decrease in Amsterdam Misophonia Scale score (a rating scale to measure how severe symptoms are) with a 70% decrease in the children's global assessment scale scores (a score that measures overall level of functioning). By the 16th week, the overall functionality level was good at the end. In conclusion, fluoxetine may be used as an effective drug in the treatment of misophonia." +"Objective: Although continuing antidepressant treatment after patients have responded to medication has been shown to greatly reduce the risk of relapse, this risk is not eliminated. A number of theories have been proposed to account for this apparent loss of efficacy. A common initial approach to managing relapse is to increase the dose of antidepressant. We prospectively evaluated the likelihood of response to increasing the fluoxetine doses in patients relapsing during a long-term efficacy study of two fluoxetine dosing regimens. Method: Patients meeting the DSM-IV criteria for major depressive disorder with modified HAMD17 scores > or =18 and CGI-severity scores > or =4 were treated for 13 weeks with open-label 20 mg/day fluoxetine in a multicenter US study. Responders (n = 501) were randomized to 20 mg fluoxetine daily, placebo, or 90 mg enteric-coated fluoxetine weekly for 25 weeks of double-blind continuation treatment. If the patients relapsed during the continuation phase, they were offered a 25-week optional rescue treatment phase during which the study medication dose was increased as follows: (1) patients on placebo had treatment with fluoxetine 20 mg/day reinitiated, (2) patients on fluoxetine 20 mg/day had their dose increased to 40 mg/day, and (3) patients on a 90-mg weekly dose had their dose increased to 90 mg twice a week. The results of the rescue phase for the latter two groups who relapsed while on continuation treatment with fluoxetine are reported. Response was defined as a 50% reduction in the modified HAMD17 score since time of relapse and a CGI-severity score < or =2. Additional efficacy analyses included HAMD and CGI-severity changes from baseline to endpoint. Safety measures included assessment of treatment-emergent adverse events, vital signs, and laboratory measures. Results: Overall, patients relapsing during the continuation treatment responded to an increased dose (57% of the 40-mg-daily group and 72% of the enteric-coated 90-mg-twice-weekly group). Mean modified HAMD17 scores decreased from a mean of approximately 20 to below 8 and were maintained for up to 6 months in the responders. Thirty-five percent of patients either did not respond or initially responded but again relapsed after augmentation of medication. Conclusions: The patients relapsing after initially responding to fluoxetine can benefit from an increase in fluoxetine dose. These results also generally support increasing dose as a first-line treatment strategy for a patient who has relapsed while taking a previously effective dose of an antidepressant. Increasing enteric-coated fluoxetine 90 mg once weekly to twice weekly appeared to be as well-tolerated and effective in restoring response as increasing a daily fluoxetine dose from 20 to 40 mg.","Continuing treatment with antidepressants after patients have responded to medication has been shown to greatly reduce the risk of relapse, which is when a medical condition that had previously improved starts to worsen. However, the risk of a relapse is not completely eliminated. A number of theories have been suggested to account for this possible decline in how well antidepressant medicines work. A common first approach to help a patient who is relapsing is to increase the dose of the antidepressant medicine. Researchers evaluated the chance patients will respond to an increase in the dose of fluoxetine (a type of antidepressant also called prozac) in patients relapsing during a long-term study of two different dosing plans of fluoxetine. Patients who have major depressive disorder are treated for 13 weeks with 20 mg/day of fluoxetine in a large US study. The 501 patients who responded to the medicine are randomly put into either the group receiving 20 mg/day of fluoxetine, the group receiving sham treatment that has the appearance of the drug but is not the real medicine, or 90 mg of fluoxetine weekly. They will be in these groups for 25 weeks during a part of the study called the continuation phase. If the patients relapse during the continuation phase, they are offered a different 25-week treatment plan called a rescue phase where the study medication dose is increased as 1) patients on placebo will restart fluoxetine at 20 mg/day, 2) patients on fluoxetine 20 mg/day will have their dose increased to 40 mg/day, and 3) patients on the 90-mg weekly dose will have their dose increased to 90-mg twice a week. The results of the rescue phase the patients in group 2 (who received 20 mg/day) and group 3 (who received the 90-mg weekly). Researchers used scoring tools that measure depression severity and seeing how much the depression scores are reduced since the time of the last relapse. Additional analyses to evaluate how well the medicine worked include changes in these scoring tools from the start of the study to the end. Safety checks include assessment of unexpected side effects, vital signs (e.g. blood pressure, temperature), and tests done in a lab. Overall, patients relapsing during the continuation treatment phase responded to an increased dose (57% of the 40-mg-daily group and 72% of the 90-mg-twice-weekly group). The average score of the tool that measure depression severity decreased and was maintained for up to 6 months in the people who responded. There are 35 patients who either did not respond or responded at first but then relapsed after increasing medication. In conclusion, patients who relapsed after first responding to fluoxetine can benefit from an increase in the dose amount of fluoxetine. These results also generally support increasing the dose as a first-line treatment plan for a patient who has relapsed while taking a previously effective dose of an antidepressant. Increasing fluoxetine 90 mg once weekly to twice weekly appears to have side effects that patients can handle and is just as effective in restoring response as when daily fluoxetine dose is increased from 20 mg to 40 mg." +"Selective serotonin reuptake inhibitors (SSRIs) are a recently developed class of drugs with significantly greater antidepressant efficacy than placebo. Generally, in double-blind comparative trials, all SSRIs demonstrated antidepressant efficacy similar to that of the 'standard' tricyclic antidepressants amitriptyline and imipramine; a meta-analysis of controlled trials found the efficacy of the SSRIs to be equivalent to that of the 2 tricyclics. Nevertheless, because of small patient numbers included in most studies that compare SSRIs with other antidepressants, no definitive statements about relative efficacy can be made. In these studies it is simply possible to state that no statistically significant differences were identified between SSRIs and the comparative antidepressants. Importantly, differences in clinical characteristics exist between the SSRIs-differences in elimination half-life (t1/2 beta) between fluoxetine and/or its metabolite (total t1/2 beta = 330 hours) and other SSRIs (t1/2 beta range = 15 to 30 hours), for example. This has implications in terms of potential drug interactions and must be considered when patients have to be switched to treatment with monoamine oxidase inhibitors. Studies with fluvoxamine have been conducted in both in- and outpatients, whereas trials with other SSRIs have been confined largely to outpatient populations. Fluvoxamine has been associated with a high incidence of nausea (37%), although this may have resulted from high initial dosages (rather than upward dose titration protocols) used in early trials. Of further interest, fluoxetine doses of 20mg may be sufficient to produce a satisfactory antidepressant response, and this SSRI may be particularly useful in patients with chronic retarded depression. More clinical data are required before the efficacy of sertraline and citalopram relative to standard antidepressants can be clearly defined. Preliminary data indicate that SSRIs are effective in the treatment of panic disorder, obsessive-compulsive disorder (OCD), eating (e.g. anorexia and bulimia) and personality disorders (e.g. anger, impulsiveness) and substance abuse (e.g. alcoholism); early results with fluvoxamine in the treatment of panic disorder and OCD, and with fluoxetine in the treatment of bulimia, personality disorders and alcohol abuse, have been encouraging. SSRIs have a more favourable tolerability profile than tricyclic antidepressants and, unlike the tricyclics, are not associated with anticholinergic adverse effects, sedation, cardiotoxicity or weight gain. SSRIs are associated with a relatively high incidence of nausea, particularly if high doses are used at the start of treatment. However, the incidence of nausea appears to decrease as treatment is continued.","Selective serotonin reuptake inhibitors (SSRIs) are a recently developed type of drugs that works better as an antidepressant than a placebo, a type of substance that looks like a real pill but is not the real medicine. In clinical studies, all SSRIs showed that they have similar effectiveness as standard antidepressants that are older types of medicines. However, because of the small patient numbers in most studies that compare SSRIs with other antidepressants, no definite statements on how the effectiveness compares between the two types of drugs can be made. In these studies, it is simply possible to state that no significant differences based on data analysis are identified between SSRIs and the other type of antidepressants they are being compared to. Importantly, differences in medical features and measures exist between the SSRIs, including differences in the time it takes for the amount of the drug in the body to be reduced to half its starting amount between fluoxetine (a type of antidepressant also called prozac) and other SSRIs. The findings from these existing studies may lead to other effects, including how two or more drugs react to one another which must be considered when patients are switched to treatment with an earlier antidepressant. The structure of clinical studies differs between fluvoxamine, which includes inpatients and outpatients, and other SSRIs which mainly take place in outpatient settings. Fluvoxamine is associated with a high frequency of nausea (37%), although this may be the result from patients starting with a high dose that are often used in early trials instead of the standard dose. Additionally, fluoxetine doses of 20mg may be enough to produce a satisfactory antidepressant response, and this SSRI may be particularly useful in patients with chronic retarded depression, a depression disorder where symptoms include slow movement and toneless speech. More clinical data are needed before the effectiveness of sertraline and citalopram (two other SSRIs) relative to standard antidepressants can be clearly defined. Early data suggests that SSRIs are effective in the treatment of panic disorder, obsessive-compulsive disorder (OCD), eating (e.g. anorexia and bulimia) and personality disorders (e.g. anger, impulsiveness) and substance abuse (e.g. alcoholism). There are encouraging early results with fluvoxamine in the treatment of panic disorder and OCD, and with fluoxetine in the treatment of bulimia, personality disorders and alcohol abuse. Patients are able to handle the side effects of SSRIs better than tricyclic antidepressants and, unlike the tricyclics, SSRIs are not associated with adverse effects of anticholinergic drugs that treat a number of health problems, sedation, damage to the heart, or weight gain. SSRIs are associated with a high count of nausea, particularly if high doses are used at the start of treatment. However, the frequency of nausea appears to decrease as treatment is continued." +"Selective serotonin reuptake inhibitors (SSRIs) are a recently developed class of drugs with significantly greater antidepressant efficacy than placebo. Generally, in double-blind comparative trials, all SSRIs demonstrated antidepressant efficacy similar to that of the 'standard' tricyclic antidepressants amitriptyline and imipramine; a meta-analysis of controlled trials found the efficacy of the SSRIs to be equivalent to that of the 2 tricyclics. Nevertheless, because of small patient numbers included in most studies that compare SSRIs with other antidepressants, no definitive statements about relative efficacy can be made. In these studies it is simply possible to state that no statistically significant differences were identified between SSRIs and the comparative antidepressants. Importantly, differences in clinical characteristics exist between the SSRIs-differences in elimination half-life (t1/2 beta) between fluoxetine and/or its metabolite (total t1/2 beta = 330 hours) and other SSRIs (t1/2 beta range = 15 to 30 hours), for example. This has implications in terms of potential drug interactions and must be considered when patients have to be switched to treatment with monoamine oxidase inhibitors. Studies with fluvoxamine have been conducted in both in- and outpatients, whereas trials with other SSRIs have been confined largely to outpatient populations. Fluvoxamine has been associated with a high incidence of nausea (37%), although this may have resulted from high initial dosages (rather than upward dose titration protocols) used in early trials. Of further interest, fluoxetine doses of 20mg may be sufficient to produce a satisfactory antidepressant response, and this SSRI may be particularly useful in patients with chronic retarded depression. More clinical data are required before the efficacy of sertraline and citalopram relative to standard antidepressants can be clearly defined. Preliminary data indicate that SSRIs are effective in the treatment of panic disorder, obsessive-compulsive disorder (OCD), eating (e.g. anorexia and bulimia) and personality disorders (e.g. anger, impulsiveness) and substance abuse (e.g. alcoholism); early results with fluvoxamine in the treatment of panic disorder and OCD, and with fluoxetine in the treatment of bulimia, personality disorders and alcohol abuse, have been encouraging. SSRIs have a more favourable tolerability profile than tricyclic antidepressants and, unlike the tricyclics, are not associated with anticholinergic adverse effects, sedation, cardiotoxicity or weight gain. SSRIs are associated with a relatively high incidence of nausea, particularly if high doses are used at the start of treatment. However, the incidence of nausea appears to decrease as treatment is continued.","Selective serotonin reuptake inhibitors (SSRIs), which increase serotonin, are recent, notable antidepressant drugs. SSRIs show similar success to other common antidepressants like amitriptyline and imipramine. Still, since the studies have small patient samples, no definite statements about the relative antidepressant success of SSRIs can be made. In these studies, no difference was identified between SSRIs and other antidepressants. Importantly, SSRIs have differences like effect duration among other antidepressant medications like fluoxetine. This distinct effect duration may alter the drug's success and should be considered when switching patients' treatments. Studies with fluvoxamine (an antidepressant SSRI) occured with patients in and out of hospitals, while studies with other SSRIs occured largely with patients out of hospitals. Using fluvoxamine (an antidepressant drug) may lead to nausea, but this may be due to using high starting doses rather than steadily-increasing dosages for use in early trials. 20 mg of flueoxetine may give a decent antidepressant response and be useful for those with long-lasting, movement-inhibiting depression. More data is needed to define the success of other antidepressant selective serotonin reuptake inhibitors like sertraline and citalopram. SSRIs like fluvoxamine and fluoxetine seem to help treat a variety of mental illnesses other than depression. Patients put up with SSRIs better than other non-SSRI antidepressants and without notable side effects, sleepiness, heart damage, or weight gain. SSRIs can lead to nausea, especially with high starting doses. However, the frequency of nausea may decrease as treatment continues." +"Objective: Since several recent meta-analyses report a dose-response relationship for the antidepressant effect of the selective serotonin reuptake inhibitors (SSRIs), we investigated how these drugs are dosed in clinical practice. Methods: Through linkage of nation- or region-wide registers, we describe SSRI doses in 50,365 individuals residing in Region V�stra G�taland, Sweden, with an incident diagnosis of depression and initiating SSRI treatment between 2007 and 2016. The primary question was to elucidate to what extent these individuals had been prescribed a daily dose that according to recent meta-analyses is required to elicit the maximum antidepressant effect, that is >20 mg citalopram, >10 mg escitalopram, >10 mg fluoxetine, >10 mg paroxetine or >50 mg sertraline. Results: In all, 21,049 (54%) out of 38,868 individuals <65 years of age, and 9,131 (79%) out of 11,497 individuals ?65 years of age, never received an SSRI dose reported to exert maximum antidepressant effect. These prescribing practices were seen for citalopram, escitalopram and sertraline, but not for fluoxetine and paroxetine, and were frequent in both primary and secondary/tertiary care. Suggesting that doses here defined as maximum efficacy doses, when prescribed, are usually not intolerable, between 59% and 68% of individuals <65 years of age received such a dose also for the subsequent prescription, that is as frequently as in those prescribed a sub-maximum efficacy dose (52-69%). Conclusion: Most patients being prescribed an SSRI to treat their depression never receive the dose that according to recent meta-analyses is most likely to effectively combat their condition. The lack of consensus regarding effective dosing of SSRIs may have contributed to this state of affairs.","Several analyses using data from multiple studies have found a relationship between the amount of a medicine given (dose) and its effect in a type of antidepressant called selective serotonin reuptake inhibitors (SSRIs). The objective of this study is to investigate how these SSRI drugs are dosed in doctor's offices and health clinics. Researchers describe SSRI doses in 50,365 people living in a specific region in Sweden, with a diagnosis of depression and starting SSRI treatment between 2007 and 2016. The main question is to explain the extent these people are prescribed a daily dose that is expected to get a peak response that would not go higher with a higher dose, which is > 20 mg of citalopram, >10 mg escitalopram, >10 mg fluoxetine, >10 mg paroxetine or >50 mg sertraline - all SSRIs. Overall, 21,049 (54%) out of 38,868 individuals <65 years of age, and 9,131 (79%) out of 11,497 individuals ?65 years of age, never receive an SSRI dose reported to bring about a maximum antidepressant effect. These dosing practices are seen for citalopram, escitalopram and sertraline, but not for fluoxetine and paroxetine, and are frequent in both general care and specialized care. Between 59% and 68% of individuals <65 years of age received the maximum efficacy dose (the dose where an increased dose given would not lead to improvement) for the next prescription. That percent is as frequently as in those prescribed a sub-maximum efficacy dose which is the dose that has a lower response despite an increase in the dose amount. In conclusion, most patients taking an SSRI to treat their depression never receive the dose that is most likely to effectively fight their condition based on detailed reviews of available data. The lack of agreement on the effective dose amount of SSRIs may have contributed to this conclusion." +"Pediatric generalized anxiety disorder (GAD) is characterized by excessive and uncontrollable worry about a variety of events and is accompanied by physical symptoms such as headaches, tension, restlessness, gastrointestinal distress, and heart palpitations. Symptoms impose marked distress and interfere with social, emotional, and educational functioning. GAD occurs in over 10% of children and adolescents, has an average age of onset of 8.5 years, and is more often reported in girls. Common co-occurring conditions include separation anxiety disorder and social phobia. Assessment involves a multi-informant, multi-method approach involving the child, parents, and school teachers. A clinical interview should be conducted to assess for the three primary ways anxiety presents: behaviors, thoughts, and somatic symptoms. Several semi-structured diagnostic interviews are available, and the Anxiety Disorders Interview Schedule is increasingly used. Rating scales completed by the patient, caregivers, and teachers provide useful information for diagnosis and symptom monitoring. Several scales are available to assess patients for the Diagnostic and Statistical Manual of Mental Disorders (4th Edition) GAD diagnosis; however, instruments generally cannot distinguish children with GAD from children with similar anxiety disorders. Both cognitive-behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) have demonstrated efficacy for the treatment of pediatric anxiety disorders including GAD. Evidence suggests that the combination of CBT plus sertraline offers additional benefit compared with either treatment alone. With pharmacotherapy, systematic tracking of treatment-emergent adverse events such as headaches, stomach aches, behavioral activation, worsening symptoms, and emerging suicidal thoughts is important. Recommended starting doses are fluvoxamine 25 mg/day, fluoxetine 10 mg/day, and sertraline 25 mg/day, though lower starting doses are possible. Dosing can be adjusted as often as weekly with the goal of achieving a high-quality response, while minimizing side effects. Long-term treatment with medication has not been well studied; however, to achieve optimal long-term outcome extended use of medication may be required. It is recommended to continue medication for approximately 1 year following remission in symptoms, and when discontinuing medication to choose a stress-free time of the year. If symptoms return, medication re-initiation should be considered seriously.","In children, generalized anxiety disorder (GAD) includes having more than normal and uncontrollable worry about different events and is also includes physical symptoms such as headaches, tension, restlessness, digestive problems, and a racing heartbeat. Symptoms interfere with social, emotional, and educational experiences. GAD occurs in over 10% of children and adolescents and usually starts at the age of 8.5 years. GAD is more often reported in girls. Common conditions that occur with GAD include getting very anxious when separated from family or the main caregiver and social phobia, an intense fear of being in front of others or being watched or judged. Multiple methods are used to test for GAD and includes the child, parents, and school teachers. An interview is recommended to look for the three main ways anxiety is shown: behaviors, thoughts, and somatic (physical) symptoms. Several interview formats to make a diagnosis are available. The Anxiety Disorders Interview Schedule is increasingly used. Ratings scales are completed by the patient, caregivers, and teachers and provide useful information for diagnosis and symptom monitoring. Several scales are able to make a GAD diagnosis which is a diagnosis based on the well-known handbook of mental disorders used by many providers; however, interview tools usually cannot make the distinction between children with GAD and children with similar anxiety disorders. Cognitive-behavioral therapy, which is a type of therapy that focuses on challenging negative thoughts that can worsen emotional difficulties, is shown to be a part positive effect for the treatment of GAD. Additionally, a type of antidepressant called selective serotonin reuptake inhibitors (SSRIs) also show benefits for the treatment of pediatric anxiety disorders including GAD. Evidence suggests that the combination of cognitive-behavioral therapy plus sertraline (an SSRI medication) offers additional benefit when compared with either treatment alone. When using medications for treatment, it is important to monitor and track negative side effects that occur such as headaches, stomach aches, behavioral activation, worsening symptoms, and emerging suicidal thoughts. Recommended starting doses of SSRIs are fluvoxamine 25 mg/day, fluoxetine 10 mg/day, and sertraline 25 mg/day, though starting with lower doses is possible. Dosing can be changed as often as weekly with the goal of achieving a high-quality response, while minimizing side effects. Long-term treatment with medication has not been well studied; however, to reach the best long-term outcome, extended use of the medication may be required. It is recommended to continue medication for about 1 year after remission in symptoms, and to choose a stress-free time of the year when stopping medication. If symptoms return, restarting the medication should be considered seriously." +"Twenty-five patients with a primary DSM-III-R diagnosis of panic disorder with or without agoraphobia were treated openly with the serotonin uptake inhibitor fluoxetine for up to 12 months. For most patients, treatment was initiated at 5 mg/day to minimize adverse effects previously reported with initiation at higher doses. Nineteen (76%) experienced moderate to marked improvement in panic attacks. Four (16%) were unable to tolerate fluoxetine due to adverse effects. Initiating treatment of panic disorder with low doses of fluoxetine may increase its acceptability and permit more patients to benefit from fluoxetine.","Fluoxetine is a type of antidepressant that is also called prozac. Twenty-five patients with a diagnosis of panic disorder, a type of anxiety with unexpected events of intense fear, who either did or did not have agoraphobia (an intense fear of open spaces or leaving the home) are treated openly with fluoxetine for up to 12 months. For most patients, treatment is started at 5 mg/day to minimize side effects that is connected with starting the medication at a higher dose. Nineteen (76%) experienced small to major improvement in panic attacks. Four (16%) were unable to handle fluoxetine because of side effects. Starting treatment of panic disorder with low doses of fluoxetine may increase its acceptability and allow more patients to benefit from fluoxetine." +"Twenty-five patients with a primary DSM-III-R diagnosis of panic disorder with or without agoraphobia were treated openly with the serotonin uptake inhibitor fluoxetine for up to 12 months. For most patients, treatment was initiated at 5 mg/day to minimize adverse effects previously reported with initiation at higher doses. Nineteen (76%) experienced moderate to marked improvement in panic attacks. Four (16%) were unable to tolerate fluoxetine due to adverse effects. Initiating treatment of panic disorder with low doses of fluoxetine may increase its acceptability and permit more patients to benefit from fluoxetine.","Twenty-five patients with panic disorder were treated with the serotonin uptake inhibitor fluoxetine (a common antidepressant) for up to 12 months. For most, treatment started with 5 mg/day to reduce side effects. Nineteen (76%) showed improvement in panic attacks. Four (16%) could not stand fluoxetine due to its side effects. Using low starting doses of fluoxetine for panic disorders may improve its acceptability and use." +"Fluoxetine (FLX) has a unique pharmacokinetic profile. Its major metabolite, norfluoxetine (NFLX), possesses FLX's antidepressant efficacy and a half-life of 7 to 15 days, suggesting the possibility of nonstandard dosing strategies. This study examined the tolerability of a weekly dose and its equivalence to daily dosing of FLX for the continuation phase of treatment for major depressive disorder (MDD). One hundred fourteen subjects initially received open-label treatment with 20 mg of FLX daily for 7 weeks. Subsequently, 70 subjects with a score on the Hamilton Rating Scale for Depression (HAM-D) of 12 or less were randomly assigned in a double-blind design to one of three treatment groups: 20 mg FLX daily (N = 21), 60 mg FLX weekly (N = 28), or placebo (N = 21) and were followed for 7 weeks. HAM-D scores and blood levels of FLX and NFLX were analyzed using a repeated-measures analysis of variance. During the double-blind phase, blood levels for both FLX and NFLX differed across the treatment groups, yet no statistically significant difference in HAM-D scores was observed. There was no difference in the dropout rate across the groups. Subjects could not correctly identify the treatment group into which they were assigned. Weekly dosing of FLX seems to be well tolerated and possibly as effective as daily dosing in maintaining the therapeutic response in subjects with MDD.","Fluoxetine is a type of antidepressant that is also called prozac. There is the possibility that fluoxetine can be given to patients in dose amounts that is different from the regular doses of other medications. In order to study the treatment for major depressive disorder, this study examined how well patients handled a weekly dose of fluoxetine and then monitored the same amount but given daily during a following phase of the study. In this study, 114 patients first receive treatment with 20 mg of fluoxetine daily for 7 weeks. Next, 70 patients are randomly assigned to one of three treatment groups: 20 mg fluoxetine daily with 21 subjects, 60 mg fluoxetine weekly with 28 patients, or placebo of an inactive substance that looks like the drug with 21patients and are followed for 7 weeks. Scores for depression using a rating scale and blood levels of fluoxetine and norfluoxetine, another form of fluoxetine, are analyzed. Blood levels for both fluoxetine and norfluoxetine differ across the three treatment groups, but there are no major differences in the scores for depression observed. There is no difference in the rate of patients who dropped out of the study across the groups. Patients cannot correctly identify the treatment group into which they were assigned. Weekly dosing of fluoxetine seems to be handled well by patients and is possibly as effective as daily dosing for treating patients with major depressive disorder." +"Groin hernias are caused by a defect of the abdominal wall in the groin area and comprise inguinal and femoral hernias. Inguinal hernias are more common in men. Although groin hernias are easily diagnosed on physical examination in men, ultrasonography is often needed in women. Ultrasonography is also helpful when a recurrent hernia, surgical complication after repair, or other cause of groin pain (e.g., groin mass, hydrocele) is suspected. Magnetic resonance imaging has higher sensitivity and specificity than ultrasonography and is useful for diagnosing occult hernias if clinical suspicion is high despite negative ultrasound findings. Herniography, which involves injecting contrast media into the hernial sac, may be used in selected patients. Becoming familiar with the common types of surgical interventions can help family physicians facilitate postoperative care and assess for complications, including recurrence. Laparoscopic repair is associated with shorter recovery time, earlier resumption of activities of daily living, less pain, and lower recurrence rates than open repair. Watchful waiting is a reasonable and safe option in men with asymptomatic or minimally symptomatic inguinal hernias. Watchful waiting is not recommended in patients with symptomatic hernias or in nonpregnant women.","Digestive organs (e.g., intestines) coming out through a weak point or tear in the abdomen causes groin hernias and includes inguinal (groin area) and femoral (upper thigh area) hernias. Inguinal hernias happen more in men. Although groin hernias are easily seen in a physical exam in men, ultrasound is often needed in women. Ultrasound is also helpful when a doctor thinks a hernia has returned, there is a complication after surgery to repair the hernia, or there is another cause of pain (e.g., groin mass, fluid collection in the scrotum). MRI has higher accuracy for detection and no detection than ultrasound and is useful for diagnosing hidden hernias if a doctor thinks it is hernia even if an ultrasound does not show one. Injecting a substance into the hernia sac to improve visibility in x-rays may be used in some patients. Learning about the common types of surgeries can help family doctors improve care after surgery and look for complications, including the hernia returning. Minimally invasive repair has a shorter recovery time, earlier return to daily activities, less pain, and lower return rates than traditional repair. Men with inguinal hernias and with few to no symptoms can reasonably and safely watch the hernia without treatment unless symptoms appear or change. Watching without treatment unless symptoms appear or change is not suggested in people with hernias with symptoms or in nonpregnant women." +"Purpose: Hiatal hernias are a common finding on radiographic or endoscopic studies. Hiatal hernias may become symptomatic or, less frequently, can incarcerate or become a volvulus leading to organ ischemia. This review examines latest evidence on the diagnostic workup and management of hiatal hernias. Methods: A literature review of contemporary and latest studies with highest quality of evidence was completed. This information was examined and compiled in review format. Results: Asymptomatic hiatal and paraesophageal hernias become symptomatic and necessitate repair at a rate of 1% per year. Watchful waiting is appropriate for asymptomatic hernias. Symptomatic hiatal hernias and those with confirmed reflux disease require operative repair with an anti-reflux procedure. Key operative steps include the following: reduction and excision of hernia sac, 3 cm of intraabdominal esophageal length, crural closure with mesh reinforcement, and an anti-reflux procedure. Repairs not amenable to key steps may undergo gastropexy and gastrostomy placement as an alternative procedure. Conclusions: Hiatal hernias are commonly incidental findings. When hernias become symptomatic or have reflux disease, an operative repair is required. A minimally invasive approach is safe and has improved outcomes.","Hiatal hernias, which occur when the upper part of the stomach pushes up through the diaphragm into the chest, are often found by x-ray and using a long, thin tube with a camera to look inside the body. Hiatal hernias may cause symptoms or, less often, can become trapped or twisted, cutting off blood flow to organs. This review looks at the latest studies on the diagnosis and treatment of hiatal hernias. We reviewed the strongest current and most recent studies. We studied this information and put it in an easily reviewable format. We found that hiatal hernias without symptoms develop symptoms and need repair at a rate of 1% per year. Watching without treatment unless symptoms appear or change is suggested for people with hernias with no symptoms. Hiatal hernias with symptoms and those with stomach acid reflux disease need surgery with an anti-reflux procedure. Surgery has key steps. When these key steps can't be done, stitching the stomach to the diaphragm and inserting a feeding tube is another option. We conclude that hiatal hernias are often found when looking for something else. When hernias cause symptoms or have reflux disease, surgery is needed. A minimally invasive treatment is safe and has improved results." +"Purpose: Hiatal hernias are a common finding on radiographic or endoscopic studies. Hiatal hernias may become symptomatic or, less frequently, can incarcerate or become a volvulus leading to organ ischemia. This review examines latest evidence on the diagnostic workup and management of hiatal hernias. Methods: A literature review of contemporary and latest studies with highest quality of evidence was completed. This information was examined and compiled in review format. Results: Asymptomatic hiatal and paraesophageal hernias become symptomatic and necessitate repair at a rate of 1% per year. Watchful waiting is appropriate for asymptomatic hernias. Symptomatic hiatal hernias and those with confirmed reflux disease require operative repair with an anti-reflux procedure. Key operative steps include the following: reduction and excision of hernia sac, 3 cm of intraabdominal esophageal length, crural closure with mesh reinforcement, and an anti-reflux procedure. Repairs not amenable to key steps may undergo gastropexy and gastrostomy placement as an alternative procedure. Conclusions: Hiatal hernias are commonly incidental findings. When hernias become symptomatic or have reflux disease, an operative repair is required. A minimally invasive approach is safe and has improved outcomes.","Hiatal hernias, in which the stomach bulges into the chest, are common clinical findings. Hiatal hernias can lead to unwanted symptoms, trapped or twisted intestines, and reduced blood flow to certain body parts. This review examines the latest works on identifying and managing these stomach bulges into the chest. No-symptom stomach or organ bulges into the chest acquire symptoms and need repair at a rate of 1% per year. Watchful waiting is appropriate for these no-symptom organ bulges into the chest. Hiatal hernias with unwanted symptoms and stomach acid reflux into throat need special, anti-reflux surgery. Key surgery steps include: cutting out the bulging sac, 3 cm of the lower esophagus, closing the site with mesh, and an anti-acid reflux operation. Repairs not possible with common surgery may need stitching and opening of the stomach instead. Hiatal hernias are common. When organ bulges lead to awful symptoms or stomach acid reflux, surgery is needed. A small incision surgery is safe and has improved outcomes." +"A Spigelian hernia (or lateral ventral hernia) is a hernia through the spigelian fascia, which is the aponeurotic layer between the rectus abdominis muscle medially, and the semilunar line laterally. So far, about 1000 cases have been reported worldwide. These hernias are difficult to diagnose as they do not present with a subcutaneous swelling and have high risk of going for strangulation. We discuss the case of a 36 year old female who presented with history of pain and lumpiness in left lower abdomen, both of which decreased on lying down. She presented to emergency with an episode severe pain at same site which subsided spontaneously. Diagnosis was confirmed on CT scan, plication and onlay prolene mesh repair performed. Spigelian hernias are rare, interparietal type of hernias which have high risk undergoing strangulation. Knowledge of symptoms and signs is vital to diagnosis and treatment of these rare type of hernias.","A Spigelian hernia (or lateral ventral hernia involving bulging of digestive organs) develops through muscles found in the abdominal wall. So far, about 1000 of these hernia cases have been seen worldwide. These hernias are hard to diagnose, because they do not cause swelling and often can cut off blood supply to one or more essential organs (e.g., small or large intestine). We look at the case of a 36-year-old female with a history of pain and lumpiness in her left lower stomach, both of which got better when she lay down. She came to the emergency room with severe pain at the same place that went away on its own. A CT scan showed a Spigelian hernia, and a doctor performed surgery. Spigelian hernias are rare and often can cut off blood supply to one or more essential organs. Knowledge of symptoms and signs is important to diagnose and treat these rare hernias." +"Richter's hernia, also called a partial enterocele, involves a protrusion of peritoneum with subsequent strangulation or incarceration of only part of the lumen of the anti-mesenteric portion of the small bowel through a fascial defect. We report a rare presentation of incarcerated incisional Richter's hernia of the cecum in a 39-year-old female. The patient presented with acute abdominal pain that gradually improved. Physical examination revealed right lower quadrant tenderness and nodularity just above an abdominoplasty scar. Subsequent computed tomography scan demonstrated a 1 cm by 1 cm hypovascular pocket arising from the cecum with protrusion into the anterior abdominal wall. The hernia was successfully repaired surgically with resolution of symptoms. It is essential for clinicians to be mindful of the diagnosis of Richter's hernia on the differential for abdominal pain as the risk of detrimental outcomes increases with delayed surgical intervention.","Richter's hernia, also called a partial enterocele, occurs when the tissue that lines your abdominal wall pushes out through a weak point or tear and traps or cuts off blood supply to only one side of one part of the small bowel. We report a rare case of Richter's hernia trapped at the area of a healing surgical scar at the first part of the small intestine in a 39-year-old female. The patient had sudden and sharp stomach pain that gradually got better. Physical exam showed tenderness in the lower right corner of the stomach and nodules just above a tummy tuck scar. A CT scan showed a 1 cm by 1 cm area with a small number of blood vessels coming from the first part of the small intestine pushing into the front abdominal wall. Surgery to repair the hernia worked, and symptoms went away. Doctors must consider the diagnosis of Richter's hernia as a cause of abdominal pain since the risk of harmful effects goes up with delayed surgery." +"Internal hernias are rare, and a delayed diagnosis can lead to dangerous complications. A 75-year-old male with no previous surgical history presented with right upper abdominal pain and vomiting. On examination, he had guarding in the right hypochondrium with a positive Murphy's sign. However, ultrasonography of the gall bladder was normal with dilated bowel loops. Contrast-enhanced CT (CECT) revealed a falciform hernia with evidence of obstruction. Segmental resection of the gangrenous ileum was done with a double-barrel stoma. Later on, stoma reversal was also done with no complications.","Internal hernias, bulging of digestive organs which cannot be seen from outside the body, are rare, and a delayed diagnosis can cause dangerous complications. A 75-year-old man who had never had surgery had pain in the right upper stomach and vomiting. He had tensing of the muscles in the right upper stomach with a physical exam test showing pain. However, ultrasound of the gall bladder was normal with larger than normal bowel loops. A CT scan showed a falciform hernia, caused by a weakening in the falciform ligament - or connecting tissue - of the liver, with signs of blockage. The dead portion of the last part of the small intestine was removed with a temporary opening in the abdominal wall made during surgery. Later on, the abdominal wall opening was reversed with no complications." +"Internal hernias are rare, and a delayed diagnosis can lead to dangerous complications. A 75-year-old male with no previous surgical history presented with right upper abdominal pain and vomiting. On examination, he had guarding in the right hypochondrium with a positive Murphy's sign. However, ultrasonography of the gall bladder was normal with dilated bowel loops. Contrast-enhanced CT (CECT) revealed a falciform hernia with evidence of obstruction. Segmental resection of the gangrenous ileum was done with a double-barrel stoma. Later on, stoma reversal was also done with no complications.","Internal organ (e.g., stomach) bulging is rare. Delayed identification can lead to dangerous issues. A 75-year-old male patient with no prior surgeries had right upper ab pain and vomiting. He had tension in the upper right ab area with pain in the same area. However, medical imaging of the gall bladder was normal with bloated bowel loops. Enhanced X-rays showed a possibly obstructing bulge of the ligament connecting the liver to the abdomen wall. The dead part of the small intestine was surgically removed, while an alternate intestinal pathway was temporarily created and used. Later, the alternate, temporary, intestinal pathway was reversed without any issue." +Acute traumatic abdominal wall hernia (TAWH) is a rare type of hernia that occurs after a low or high velocity impact of the abdominal wall against a blunt object with few cases reported. Perforations of the hollow viscera commonly follow abdominal trauma and likely require surgery for hemorrhage and sepsis source control. We report a case where a high velocity impact of the abdominal wall against the stump of a felled tree caused a TAWH with concomitant gastric perforation in a 20-year-old male patient who required exploratory laparotomy with primary repair of the stomach and fascia. The physical examination findings without previous history of abdominal hernia and pneumoperitoneum in the chest X-ray made suspect our diagnosis and it was confirmed intraoperatively. At 3 months postoperatively the patient has a strong abdominal wall. It is imperative to emphasize the importance of the physical examination goal of not losing diagnosis of TAWH.,"Acute traumatic abdominal wall hernia (TAWH) is a rare type of hernia that happens when the stomach wall hits a smooth object at low or high speed with few cases reported. Tears in the stomach wall that allow stomach contents to spill out often result from stomach injury and likely require surgery for bleeding and controlling the source of the body's extreme response to the spillage. We report a case where a high-speed impact of the stomach wall against a tree stump caused a TAWH with stomach tearing in a 20-year-old man who needed abdominal surgery and repair of the wound. The physical exam, no history of stomach hernia, and air in the stomach suggested TAWH, which was confirmed during surgery. The patient had a strong stomach wall 3 months after surgery. It is important to not rule out TAWH based on the physical exam." +"Introduction and importance: A Littre's hernia (LH) is defined by the presence of Meckel's diverticulum (MD) in any kind of hernia sac. Preoperative diagnosis of LH is a challenge because of its rarity and the absence of specific radiological findings and clinical presentation. Surgery is the appropriate treatment of complicated LH that is an extremely rare condition with approximately 50 cases reported in the literature over the past 300 years. Case presentation: A 46-year-old Caucasian female was admitted to the Emergency Department with a two-day history of abdominal pain. Physical examination revealed an irreducible and painfull mass in umbilical region. Abdominal computed tomography scan showed the protrusion of greater omentum and small bowel loop through the umbilical ring. Laboratory tests were unremarkable. After diagnosis of strangulated umbilical hernia, the patient underwent exploratory laparotomy: the irreducible umbilical hernial sac was opened with presence of incarcerated and strangulated omentum and uncomplicated MD. Resection of incarcerated and ischemic greater omentum alone was performed. The postoperative course of patient was uneventful. Clinical discussion: Meckel's diverticulum (MD) is a vestigial remnant of the omphalomesenteric duct, representing the most common congenital malformation of the gastrointestinal tract. Preoperative diagnosis of LH is very difficult and surgery represents the correct treatment of complicated LH. Conclusion: LH represents an extremely rare complication of MD difficult to diagnose and suspect because of the lack of specific radiological findings and clinical presentation. Surgery represents the appropriate treatment of abdominal wall hernias and complicated MD.","A Littre's hernia (LH) is characterized by Meckel's diverticulum (MD; a pouch on the wall of the lower part of the small intestine present at birth) in any kind of hernia or bulging organ sac. Diagnosing LH before surgery is difficult because it is rare and lacks distinguishing features on x-ray and exam. Surgery is the best treatment for inflamed LH, a very rare condition with about 50 cases reported in scientific papers over the past 300 years. A 46-year-old white woman went to the emergency room after two days of stomach pain. Physical exam showed an irreversible and painful lump near the belly button. Stomach CT scan showed the tissue that covers the intestines and loop of the small intestine pushing out through the muscle that surrounds the belly button. Lab tests were normal. After diagnosis of a hernia near the belly button cutting off blood supply, the patient had abdominal surgery. Doctors opened the irreversible hernia sac and saw tissue that covers the intestines trapped and cut off from blood supply along with uninflamed MD. Parts of the tissue that covers the intestines that were trapped or cut off from blood supply and were removed. The patient recovered normally from surgery. MD is the most common abnormality of the GI tract present at birth. Diagnosing LH before surgery is difficult and surgery is the best treatment of inflamed LH. We conclude that LH is a very rare complication of MD and is difficult to diagnose because it lacks distinguishing features on x-ray and exam. Surgery is the best treatment for stomach wall hernias and inflamed MD." +"Inguinal hernia is the most frequently diagnosed hernia and during their lifetime one third of males are diagnosed with an inguinal hernia. The age distribution is bimodal with the highest incidence in childhood and after 50 years of age. Diagnosis is usually reached through clinical examination of a lump in the inguinal region although some patients can present with intestinal obstruction. Inguinal hernia repair is the only definitive treatment and is one of the most common surgical procedures performed. It is usually performed as an elective procedure in local, spinal or general anasthesia. The repair constitutes of reinforcing the posterior wall of the inguinal canal, often using a polypropylene mesh; either via an open anterior approach or posteriorly from within the abdomen with laparoscopy. The most common complications following a hernia repair are recurrent hernia and chronic -discomfort but recurrence rates have improved with the use of mesh and laparoscopic techniques. This evidence based review describes the -epidemiology and etiology of inguinal hernia together with the most common surgical procedures; focusing on recent innovations.","Inguinal hernia, a bulging of digestive organs occurring in the groin area, is the most often diagnosed hernia. During their lifetime one third of males are diagnosed with an inguinal hernia. People are most likely to get an inguinal hernia in childhood and after 50 years old. Doctors usually diagnose an inguinal hernia by a lump in the groin region although some patients can have blocked intestines. Inguinal hernia repair is the only treatment and is one of the most common surgeries done. Surgery is usually non-urgent and done under anesthesia. The repair involves strengthening the area of the groin, often using a plastic mesh; either by traditional or minimally invasive surgery. The most common complications after a hernia repair are the hernia returning and long-term discomfort, but the rate of a hernia returning has gone down with the use of mesh and minimally invasive surgery. This data-driven review describes the spread, contributing factors, and causes of inguinal hernias and the most common surgeries, focusing on recent methods." +"Inguinal hernia is the most frequently diagnosed hernia and during their lifetime one third of males are diagnosed with an inguinal hernia. The age distribution is bimodal with the highest incidence in childhood and after 50 years of age. Diagnosis is usually reached through clinical examination of a lump in the inguinal region although some patients can present with intestinal obstruction. Inguinal hernia repair is the only definitive treatment and is one of the most common surgical procedures performed. It is usually performed as an elective procedure in local, spinal or general anasthesia. The repair constitutes of reinforcing the posterior wall of the inguinal canal, often using a polypropylene mesh; either via an open anterior approach or posteriorly from within the abdomen with laparoscopy. The most common complications following a hernia repair are recurrent hernia and chronic -discomfort but recurrence rates have improved with the use of mesh and laparoscopic techniques. This evidence based review describes the -epidemiology and etiology of inguinal hernia together with the most common surgical procedures; focusing on recent innovations.","Inguinal hernias, or organ bulging at the lower ab area, is the most frequent hernia afflicting one third of males. These lower-ab organ bulges occur most frequently in childhood and after 50 years. Clinicians identify these inguinal hernias by a lump in the lower-ab area or when patients have intestinal blockage. Surgery of the lower-ab organ bulge is the only treatment and is very common. Surgery of the lower-ab organ bulge is usually performed with anasthesia. The surgery involves reinforcing the lower abdomen wall with mesh. While long-lasting discomfort and reappearing hernias or organ bulges may follow a hernia repair, the rate of reappearance has improved with mesh and small-incisions. The article reviews the spread and causes of inguinal hernia along with common surgical treatments." +"Purpose: The aim of the study was to determine which diagnostic modality [Computerized Tomography (CT), Magnetic Resonance Imaging (MRI), or ultrasound (US)] is more precise in terms of sensitivity and specificity in diagnosing inguinal hernia and sub-type of inguinal hernia (direct or indirect). Results: Bubble charts depicting the size of each patient cohort and percentual range for both sensitivity and specificity showed that US was better than CT and MRI in diagnosing inguinal hernia. Bubble charts for US and CT depicted high values within the studies that reported sensitivity and specificity in diagnosing type of hernia. Conclusions: We found that US had the highest sensitivity and specificity. However, it must be taken into consideration that performance is highly dependent on the operator's level of expertise. Based on this systematic review, ultrasound may be the preferred imaging modality when physical examination is inconclusive, given that local expertise in performing US examination for hernia disease is adequate.","We aimed to find which diagnostic tool (CT, MRI, or ultrasound) is more accurate for detection and no detection in diagnosing a hernia (bulging of organs) in the groin area and sub-type (direct or indirect; based on location within the groin). Results showed that ultrasound was better than CT and MRI in accuracy for detection and no detection in diagnosing a hernia in the groin region. Results showed ultrasound and CT were very accurate for detection and no detection in diagnosing type of hernia. We found that ultrasound was the most accurate for detection and no detection. One must remember that the expertise level of the person using the diagnostic tool can determine how well the tool works. Based on this review, ultrasound may be the best option when physical exam is uncertain, given that ultrasound is done acceptably at the local level." +"Hiatus hernia refers to conditions in which elements of the abdominal cavity, most commonly the stomach, herniate through the oesophageal hiatus into the mediastinum. With the most common type (type I or sliding hiatus hernia) this is associated with laxity of the phrenooesophageal membrane and the gastric cardia herniates. Sliding hiatus hernia is readily diagnosed by barium swallow radiography, endoscopy, or manometry when greater than 2 cm in axial span. However, the mobility of the oesophagogastric junction precludes the reliable detection of more subtle disruption by endoscopy or radiography. Detecting lesser degrees of axial separation between the lower oesophageal sphincter and crural diaphragm can only be reliably accomplished with high-resolution manometry, a technique that permits real time localization of these oesophagogastric junction components without swallow or distention related artefact.","Hiatus hernia refers to when the upper part of the stomach pushes up through the diaphragm into the chest. The most common type (type 1 or sliding hiatus hernia), looseness of the ligament that attaches the esophagus to the diaphragm, causes the part of the stomach that is closest to the esophagus to push up. Sliding hiatus hernia is easily diagnosed by a swallowing test during x-ray, a flexible tube with a light and camera attached, or an esophagus test when more than 2 cm along an axis. However, the movement of the junction between the esophagus and stomach doesn't allow for dependable detection of smaller abnormalities using a flexible tube with a light and camera attached or x-ray. Detecting lesser separation between the esophagus and the diaphragm can only be done reliably with a high-resolution esophagus test, which allows a real time location of the parts of the junction between the esophagus and stomach without misrepresentation due to movement." +"Phenylketonuria (PKU) is an autosomal recessive inborn error of phenylalanine metabolism caused by deficiency in the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. If left untreated, PKU results in increased phenylalanine concentrations in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. PKU management differs widely across Europe and therefore these guidelines have been developed aiming to optimize and standardize PKU care.","Phenylketonuria (PKU) is a disorder inherited from both parents in which the body cannot properly turn food into energy. This is caused by not enough of a specific protein (phenylalanine hydroxylase, PAH) that changes one molecule into another molecule. If not treated, PKU causes higher phenylalanine levels in the blood and brain, which causes intellectual disability, seizure disorder and behavioral problems. The European guidelines on PKU were made to improve and reduce the variation or differences in care because PKU treatment differs a lot across Europe." +"Phenylketonuria (PKU) is considered to be a paradigm for a monogenic metabolic disorder but was never thought to be a primary application for human gene therapy due to established alternative treatment. However, somewhat unanticipated improvement in neuropsychiatric outcome upon long-term treatment of adults with PKU with enzyme substitution therapy might slowly change this assumption. In parallel, PKU was for a long time considered to be an excellent test system for experimental gene therapy of a Mendelian autosomal recessive defect of the liver due to an outstanding mouse model and the easy to analyze and well-defined therapeutic end point, that is, blood l-phenylalanine concentration. Lifelong treatment by targeting the mouse liver (or skeletal muscle) was achieved using different approaches, including (1) recombinant adeno-associated viral (rAAV) or nonviral naked DNA vector-based gene addition, (2) genome editing using base editors delivered by rAAV vectors, and (3) by delivering rAAVs for promoter-less insertion of the PAH-cDNA into the Pah locus. In this article we summarize the gene therapeutic attempts of correcting a mouse model for PKU and discuss the future implications for human gene therapy.","Phenylketonuria (PKU) is a model of a disorder controlled by a single gene in which the body cannot properly turn some food into energy. However, scientists didn't consider transferring genetic material into a PKU patient's cells due to other working treatments. However, unexpected mental function improvements after long-term treatment of adults with PKU by substituting a substance that is lacking in the PKU patient's body might change this belief. In the same way, PKU was thought to be a great test for trying to transfer genetic material into a patient's cells to help a liver disorder inherited from both parents due to a great mouse model and measurable blood levels of l-phenylalanine (a substance transformed by the missing protein in PKU). Lifelong treatment by focusing on the mouse liver (or skeletal muscle) was done using three different approaches. In this paper, we summarize future impacts for transferring genetic material into a patient's cells." +"Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, the main clinical feature is intellectual disability. Treatment, which includes a low Phe diet supplemented with amino acid formulas, commences soon after diagnosis within the first weeks of life. Although dietary treatment has been successful in preventing intellectual disability in early treated PKU patients, there are major issues with dietary compliance due to palatability of the diet. Other potential issues associated with dietary therapy include nutritional deficiencies especially vitamin D and B12. Suboptimal outcomes in cognitive and executive functioning have been reported in patients who adhere poorly to dietary therapy. There have been continuous attempts at improving the quality of medical foods including their palatability. Advances in dietary therapy such as the use of large neutral amino acids (LNAA) and glycomacropeptides (GMP; found within the whey fraction of bovine milk) have been explored. Gene therapy and enzyme replacement or substitution therapy have yielded more promising data in the recent years. In this review the current and possible future treatments for PKU are discussed.","Phenylketonuria (PKU) is a disorder inherited from both parents in which the body cannot properly turn food into energy due to lack of a specific protein (phenylalanine hydroxylase, PAH) in the liver. PKU can cause intellectual disability if not treated. Treatment, which includes a low phenylalanine diet with formulas containing molecules that form proteins, begins soon after diagnosis within the first weeks of life. Although treatment diets prevent intellectual disability in PKU patients treated early, many patients do not follow the diets because they do not taste good. Treatment diets also may lack certain nutrients, especially vitamin D and B12. Patients who do not follow the diets generally show poorer performance in some mental skills. Work has been done to improve the quality of medical diets including their taste. Using certain molecules that form certain proteins are examples of ways to improve medical diets. Transferring genetic material into a patient's cell and replacing or substituting a substance that is lacking in the PKU patient's body have been successful in recent years. In this review, we discuss current and possible future treatments for PKU." +"Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by a deficiency in the hepatic enzyme phenylalanine hydroxylase (PAH). If left untreated, the main clinical feature is intellectual disability. Treatment, which includes a low Phe diet supplemented with amino acid formulas, commences soon after diagnosis within the first weeks of life. Although dietary treatment has been successful in preventing intellectual disability in early treated PKU patients, there are major issues with dietary compliance due to palatability of the diet. Other potential issues associated with dietary therapy include nutritional deficiencies especially vitamin D and B12. Suboptimal outcomes in cognitive and executive functioning have been reported in patients who adhere poorly to dietary therapy. There have been continuous attempts at improving the quality of medical foods including their palatability. Advances in dietary therapy such as the use of large neutral amino acids (LNAA) and glycomacropeptides (GMP; found within the whey fraction of bovine milk) have been explored. Gene therapy and enzyme replacement or substitution therapy have yielded more promising data in the recent years. In this review the current and possible future treatments for PKU are discussed.","Phenylketonuria (PKU) is an inherited, metabolic disorder caused by a lack of a specific liver enzyme or protein. If left untreated, phenylketonuria may lead to intellectual disability. Treating PKU includes a diet low in the molecule Phenylalanine and completed with other molecules. The diet starts within the first weeks of life after identification. While dietary treatment prevents intellectual disability in patients with early treated PKU, the diet is hard to follow due to its taste. Other issues with dietary treatment include deficiencies in vitamin D and B12. Patients that do not follow the diet experience low cognitive function. There have been many attempts to improve the diet including its taste. Changes like using new amino acids and protein units have been explored. Gene therapy and enzyme replacement have been more promising recently. This article reviews current and possible treatments for PKU." +"Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414 Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C> T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G> A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408 Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.","Phenylketonuria (PKU), caused by genetic alterations in the phenylalanine hydroxylase (PAH) gene, is the most common disorder inherited from both parents in which the degree the body can properly turn food (and the protein phenylalanine) into energy can be predicted from genetic makeup. Severe PKU leads to an inability to properly convert food. We estimated that 0.45 million individuals have PKU worldwide at a given point in time, occurring in 1 in 23,930 live births (range: 1 in 4,500 [Italy]-1 in 125,000 [Japan]). Comparing genetic makeups and observable PKU symptoms from 16,092 affected people showed differences in disease seriousness in 51 countries from 17 world regions, with the worldwide observable PKU symptoms being 62% classic PKU, 22% mild PKU, and 16% mild elevated phenylalanine blood levels. Observable PKU symptoms and genetic makeups differ across Europe, from classic PKU in the east to mild PKU in the southwest and mild elevated phenylalanine blood levels in the south. A specific genetic alteration can be followed from Northern to Western Europe, from Sweden through Norway, to Denmark, to the Netherlands. The part of the population with classic PKU at any point in time increases from Europe (56%) through the Middle East (71%) to Australia (80%). Of 758 genetic alterations, three were the most common (22.2%, 6.4%, and 5.5%, respectively) and caused two widespread genetic types at any point in time (11.4% and 2.6%, respectively). Most genetic makeups (73%) were compound heterozygous (both forms of the gene have different mutations), 27% were homozygous (both forms of the gene have the same mutation), and 55% of 3,659 different genetic makeups happened in only one person. Genetic alterations associated with PAH were scored and connected with pre-treatment blood phenylalanine levels (6,115 patients) and results from a test to predict long-term treatment responsiveness (4,381 patients). This allowed prediction of both observable PKU symptoms based on genetic makeup and treatment responsiveness. This study shows that large databases of genetic makeups allow correct prediction of observable PKU symptoms, which allows doctors to choose the right therapies to improve patient results." +"Detection of individuals with phenylketonuria (PKU), an autosomal recessively inherited disorder in phenylalanine degradation, is straightforward and efficient due to newborn screening programs. A recent introduction of the pharmacological treatment option emerged rapid development of molecular testing. However, variants responsible for PKU do not all suppress enzyme activity to the same extent. A spectrum of over 850 variants, gives rise to a continuum of hyperphenylalaninemia from very mild, requiring no intervention, to severe classical PKU, requiring urgent intervention. Locus-specific and genotypes database are today an invaluable resource of information for more efficient classification and management of patients. The high-tech molecular methods allow patients' genotype to be obtained in a few days, especially if each laboratory develops a panel for the most frequent variants in the corresponding population.","Checks for conditions that affect newborns make finding individuals with phenylketonuria (PKU), a disorder inherited from both parents in which the body cannot properly turn a substance (phenylalanine) into energy, easy and effective. A recent drug treatment option brought fast development of a lab method that checks for certain genes, proteins, or other molecules that may be a sign of a disease. However, genetic alternations that cause PKU do not equally reduce protein activity. A range of over 850 genetic alterations causes elevated phenylalanine blood levels from very mild with no treatment to severe PKU, which needs immediate treatment. Databases of physical gene locations and alterations carried in a gene allow effective classification and treatment of patients. The lab method that checks for certain genes, proteins, or other molecules determines a patient's genetic alterations in a few days, especially if each lab comes up with a test to look for alterations in more than one gene for the most common alterations in a group of people." +"""Inborn errors of metabolism,"" first recognized 100 years ago by Garrod, were seen as transforming evidence for chemical and biological individuality. Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype, was identified in 1934 by Asbj�rn F�lling. It is a disease with impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (HPA). Its metabolic phenotype is accountable to multifactorial origins both in nurture, where the normal nutritional experience introduces L-phenylalanine, and in nature, where mutations (>500 alleles) occur in the phenylalanine hydroxylase gene (PAH) on chromosome 12q23.2 encoding the L-phenylalanine hydroxylase enzyme (EC 1.14.16.1). The PAH enzyme converts phenylalanine to tyrosine in the presence of molecular oxygen and catalytic amounts of tetrahydrobiopterin (BH4), its nonprotein cofactor. PKU is among the first of the human genetic diseases to enter, through newborn screening, the domain of public health, and to show a treatment effect. This effect caused a paradigm shift in attitudes about genetic disease. The PKU story contains many messages, including: a framework on which to appreciate the complexity of PKU in which phenotype reflects both locus-specific and genomic components; what the human PAH gene tells us about human population genetics and evolution of modern humans; and how our interest in PKU is served by a locus-specific mutation database (http://www.pahdb.mcgill.ca; last accessed 20 March 2007). The individual Mendelian PKU phenotype has no ""simple"" or single explanation; every patient has her/his own complex PKU phenotype and will be treated accordingly. Knowledge about PKU reveals genomic components of both disease and health.","""Inborn errors of metabolism,"" or inherited disorders in which the body cannot properly turn food into energy, first seen by a doctor 100 years ago, were important support for the idea that people have different chemical and biological makeups. Phenylketonuria (PKU), a disorder inherited from both parents, was discovered in 1934 by a doctor. It causes intellectual disability from damage to the brain caused by too much phenylalanine in the blood. Observable PKU symptoms vary due to nurture, where normal foods contain L-phenylalanine, and in nature, where many changes happen in the gene for phenylalanine hydroxylase (PAH) that controls the L-phenylalanine hydroxylase protein, which helps convert phenylalanine into energy. The PAH protein converts phenylalanine, one molecule, to tyrosine, another molecule. Through checks for conditions that affect newborns, PKU is one of the first inherited diseases to be prevented in the community with successful treatments. Successful treatments caused a change in thinking about inherited disease. The history of PKU provides a lot of information including a way to grasp how complicated the disease is and where observable symptoms depend on both gene location and makeup; what the human PAH gene tells us about the genetics and evolution of humans; and how our understanding of PKU is helped by a database on where gene changes happen. Observable PKU symptoms have no ""simple"" or single explanation; every patient is different and will be treated at an individual level. PKU knowledge shows that genes play a role in both disease and health." +"""Inborn errors of metabolism,"" first recognized 100 years ago by Garrod, were seen as transforming evidence for chemical and biological individuality. Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype, was identified in 1934 by Asbj�rn F�lling. It is a disease with impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia (HPA). Its metabolic phenotype is accountable to multifactorial origins both in nurture, where the normal nutritional experience introduces L-phenylalanine, and in nature, where mutations (>500 alleles) occur in the phenylalanine hydroxylase gene (PAH) on chromosome 12q23.2 encoding the L-phenylalanine hydroxylase enzyme (EC 1.14.16.1). The PAH enzyme converts phenylalanine to tyrosine in the presence of molecular oxygen and catalytic amounts of tetrahydrobiopterin (BH4), its nonprotein cofactor. PKU is among the first of the human genetic diseases to enter, through newborn screening, the domain of public health, and to show a treatment effect. This effect caused a paradigm shift in attitudes about genetic disease. The PKU story contains many messages, including: a framework on which to appreciate the complexity of PKU in which phenotype reflects both locus-specific and genomic components; what the human PAH gene tells us about human population genetics and evolution of modern humans; and how our interest in PKU is served by a locus-specific mutation database (http://www.pahdb.mcgill.ca; last accessed 20 March 2007). The individual Mendelian PKU phenotype has no ""simple"" or single explanation; every patient has her/his own complex PKU phenotype and will be treated accordingly. Knowledge about PKU reveals genomic components of both disease and health.","""Inborn errors of metabolism,"" first identified 100 years ago by Garrod, are metabolic errors from birth and important evidence for chemical and biological individuality. Asbj�rn F�lling identified phenylketonuria (PKU), an inherited physical disorder, in 1934. PKU impairs cognitive development due to toxic buildup of a specific molecule, phenylalanine. The metabolic characteristics of PKU occur due to nurture, in which a normal diet includes the molecule L-phenylalanine, and nature, where DNA mutations influence the gene that creates the L-phenylalanine breakdown enzyme. The phenylalanine breakdown enzyme converts PKU into another molecule, tyrosine, using oxygen and non-protein helpers. PKU is among the first genetic diseases to enter, via newborn testing, publich health and demonstrate the use of successful treatment. This success of treatment has shifted attitudes about genetic diseases. PKU shows how DNA and genes affect physical traits, how modern humans have evolved, and how genetic databases now exist to document genetic mutations. Every individual has unique, physical characteristics involving PKU that require unique treatment. PKU shows the genetic components of disease and health." +"Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH) deficiency) is an autosomal recessive disorder of phenylalanine metabolism, in which especially high phenylalanine concentrations cause brain dysfunction. If untreated, this brain dysfunction results in severe intellectual disability, epilepsy and behavioural problems. The prevalence varies worldwide, with an average of about 1:10,000 newborns. Early diagnosis is based on newborn screening, and if treatment is started early and continued, intelligence is within normal limits with, on average, some suboptimal neurocognitive function. Dietary restriction of phenylalanine has been the mainstay of treatment for over 60 years and has been highly successful, although outcomes are still suboptimal and patients can find the treatment difficult to adhere to. Pharmacological treatments are available, such as tetrahydrobiopterin, which is effective in only a minority of patients (usually those with milder PKU), and pegylated phenylalanine ammonia lyase, which requires daily subcutaneous injections and causes adverse immune responses. Given the drawbacks of these approaches, other treatments are in development, such as mRNA and gene therapy. Even though PAH deficiency is the most common defect of amino acid metabolism in humans, brain dysfunction in individuals with PKU is still not well understood and further research is needed to facilitate development of pathophysiology-driven treatments.","Phenylketonuria (PKU; also known as phenylalanine hydroxylase (PAH) deficiency or shortage) is a disorder inherited from both parents in which the body cannot properly turn food into energy because it cannot process a molecule (phenylalanine). Very high phenylalanine levels damage the brain. If not treated, the damage to the brain causes serious intellectual disability, a seizure disorder, and behavioral problems. The part of the population who has PKU at a given point in time varies worldwide, with an average of about 1 in 10,000 newborns. Early diagnosis is based on checks for conditions that affect newborns, and if treatment is started early and continued, intelligence is usually normal with some decreased mental function. Low-phenylalanine diets have been the go-to treatment for over 60 years and have worked, although results could be better and patients have trouble following the diets. Drugs are available, such as tetrahydrobiopterin, which only works in a small number of patients (usually with milder PKU), and pegylated phenylalanine ammonia lyase, which requires daily shots and causes harmful effects of the body's defense system. Given the drawbacks and disadvantages of these treatments, other treatments are being developed, such as enabling the body to produce PAH proteins and replacing problematic genes with healthy ones. Even though not enough PAH is the most common molecular (amino acid) metabolism disorder, damage of the brain in people with PKU is not well understood, and more research is needed to develop treatments." +"Phenylketonuria (PKU) is an autosomal recessive disorder caused by a large number of mutations at the phenylalanine hydroxylase (PAH) locus, most of which are strongly associated with specific RFLP or VNTR haplotypes. One of the major questions remaining in PKU research is why this apparently maladaptive disorder has been maintained at a frequency of approximately 1 in 10,000 among Caucasians. A growing number of studies have provided evidence that both the relatively high frequency of PKU and the strong mutation/haplotype associations might reflect the existence of multiple founding populations for PKU. Examples of putative founding populations for PKU in both Europe and Asia will be presented. Some PAH mutations are associated with multiple haplotypes, suggesting recurrence. Evidence for and against recurrence as the mechanism responsible for the association of the R408W mutation with RFLP haplotypes 1 and 2 will be discussed.","Phenylketonuria (PKU) is a disorder inherited from both parents caused by many changes at the location of the phenylalanine hydroxylase (PAH) protein. It is a disorder in which the body cannot properly turn food into energy because it cannot process a molecule (phenylalanine). One of the main questions scientists still have is why PKU happens in roughly 1 in 10,000 white people at any point in time. More and more studies have suggested that both the high amount of the population with PKU at any point in time and the strong gene changes that go with this set of changes and variations might show more than one group of people in which PKU first developed. We will show populations thought to be where PKU first developed in both Europe and Asia. Some PAH changes go with many sets of gene variations, suggesting these changes happen more than once. We will discuss information that supports and rejects these changes happening more than once, causing one change to happen in two sets of gene changes." +"Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype (OMIM 261600), is an inborn error of metabolism that can result in impaired postnatal cognitive development. The phenotypic outcome is multifactorial in origin, based both in nature, the mutations in the gene encoding the L-phenylalanine hydroxylase enzyme, and nurture, the nutritional experience introducing L-phenylalanine into the diet. The PKU story contains many messages including a framework to appreciate the complexity of this disease where phenotype reflects both locus-specific and genomic components. This knowledge is now being applied in the development of patient-specific therapies.","Phenylketonuria (PKU), a disorder inherited from both parents, is when the body cannot properly turn food into energy and can cause intellectual disability. Observable PKU symptoms vary, due to nature, the changes in the gene for the L-phenylalanine hydroxylase protein which converts L-phenylalanine to energy, and nurture, the amount of L-phenylalanine eaten. The history of PKU provides a lot of information including a way to grasp how complicated the disease is and where observable symptoms depend on both gene location and makeup. This information is now being used to come up with treatments designed for an individual patient." +"Phenylketonuria (PKU), a Mendelian autosomal recessive phenotype (OMIM 261600), is an inborn error of metabolism that can result in impaired postnatal cognitive development. The phenotypic outcome is multifactorial in origin, based both in nature, the mutations in the gene encoding the L-phenylalanine hydroxylase enzyme, and nurture, the nutritional experience introducing L-phenylalanine into the diet. The PKU story contains many messages including a framework to appreciate the complexity of this disease where phenotype reflects both locus-specific and genomic components. This knowledge is now being applied in the development of patient-specific therapies.","Phenylketonuria (PKU), an inheritable disorder, is an inborn (i.e, existing from birth) error of metabolism that can lead to impaired cognitive development. The physical effects of PKU come from nature, with DNA mutations in a gene that makes a certain protein, and nurture, with the protein L-phenylalanine in food. PKU demonstrates the complexity of a disease where physical traits reflect genetic components. Patient-specific therapies are being developed for diseases like PKU." +"Phenylketonuria (PKU) is an inborn error of metabolism (IEM) most often caused by missense mutations in the gene encoding phenylalanine hydroxylase (PAH) which catalyzes the hydroxylation of phenylalanine (Phe) generating tyrosine (Tyr). PKU belongs to a class of amino acid aminoacidopathies termed �toxic accumulation-IEMs� where the circulating toxin is an amino acid or its metabolites. Mutations in an enzyme, such as PAH, are recessive since one functioning enzyme with the wild-type allele is sufficient. Tetrahydrobiopterin (BH4) binds to the catalytic domain of PAH and is a cofactor for this reaction. PAH is primarily a hepatic enzyme. Elevated blood Phe levels and decreased Tyr levels characterize PKU. Newborns with PKU can appear normal at birth with the first signs appearing after several months. These signs can include musty odor from skin and urine, fair skin, eczema, seizures, tremors, and hyperactivity.","Phenylketonuria (PKU) is a disorder in which the body cannot properly turn food into energy often caused by not enough of a specific protein (phenylalanine hydroxylase, PAH) that changes one molecule (phenylalanine, Phe) into another molecule (tyrosine, Tyr). PKU is a type of molecular (amino acid) metabolism disorder called ""toxic accumulation IEMs,"" in which the buildup of the molecule is toxic. Changes to DNA of a protein, such as PAH, are made in both copies of the gene that is altered, because one working copy of the gene allows the protein to function. PAH is mainly a liver protein. PKU is associated with high blood Phe levels and low Tyr levels. Newborns with PKU can look normal at birth with the first signs showing many months later. Signs of PKU can include a musty smell from skin and pee, fair skin, red and itchy skin, seizures, tremors, and an active and disruptive behavior." +"An 18 year-old woman presented to an outside hospital with seizure activity after a massive ingestion of lamotrigine, bupropion, trazodone, buspirone, and possibly isoretinoin. Her initial vital signs were remarkable for tachycardia (120 bpm). She was intubated for airway protection. For treatment of status epilepticus, she received a total of 12 mg of IV lorazepam along with a lorazepam infusion titrated to 15 mg/hr, a propofol infusion of unknown dosing, and phenobarbital 650 mg. She was transferred to a receiving hospital. Her initial ECG at the receiving hospital showed a QRS of 117 ms which narrowed with 50 mEq of sodium bicarbonate after approximately 6 hours. She required norepinephrine intermittently for blood pressure support for approximately 2 days. The patient had no dysrhythmias. EEG showed no epileptiform activity from approximately 11 hours-32 hours post ingestion. At the receiving hospital, her serum lamotrigine concentration was 109 mcg/mL (reference 3.0-14.0 mcg/mL) 7 hours after ingestion. Her bupropion concentration was 92 ng/mL (reference 50-100 ng/mL). She was extubated on hospital day 5 and discharged to a psychiatric facility on hospital day 13.","An 18-year-old woman went to one hospital with seizures after swallowing a large amount of lamotrigine (anti-seizure), bupropion (antidepressant), trazodone (antidepressant), buspirone (anti-anxiety), and possibly isoretinoin (acne). She had a high heart rate (120 beats per minute). A breathing tube was put in her windpipe to make sure she continued to breathe. To treat a seizure lasting longer than 5 minutes or seizures occurring close together without recovery in between, she was given lorazepam (anti-seizure), propofol (anesthesia), and phenobarbital (anti-seizure). She was transferred to another hospital. The patient did not have an irregular heartbeat. Her breathing tube was removed and she was sent to a psychiatric facility after 13 days in the hospital." +"Buspirone hydrochloride (HCl)1 is a new anxiolytic with a unique chemical structure. Its mechanism of action remains to be elucidated. Unlike the benzodiazepines, buspirone lacks hypnotic, anticonvulsant and muscle relaxant properties, and hence has been termed 'anxioselective'. As evidenced by a few double-blind clinical trials, buspirone 15 to 30 mg/day improves symptoms of anxiety assessed by standard rating scales similarly to diazepam, clorazepate, alprazolam and lorazepam. Like diazepam, buspirone is effective in patients with mixed anxiety/depression, although the number of patients studied to date is small. In several studies, a 'lagtime' of 1 to 2 weeks to the onset of anxiolytic effect has been noted; hence motivation of patient compliance may be necessary. Sedation occurs much less often after buspirone than after the benzodiazepines; other side effects are minor and infrequent. In healthy volunteers, buspirone does not impair psychomotor or cognitive function, and appears to have no additive effect with alcohol. Early evidence suggests that buspirone has limited potential for abuse and dependence. Thus, although only wider clinical use for longer periods of time will more clearly define some elements of its pharmacological profile, with its low incidence of sedation buspirone is a useful addition to the treatments available for generalised anxiety. It may well become the preferred therapy in patients in whom daytime alertness is particularly important.","Buspirone hydrochloride (HCL)1 is a new anti-anxiety drug with a unique molecular makeup. How it works is not yet fully understood. Unlike benzodiazepines, another type of drug to treat anxiety, buspirone is �anxioselective�; that is, it relieves anxiety without the side effects of benzodiazepines (sedation and muscle relaxation). As shown by a few clinical trials, buspirone 15 to 30 mg/day improves symptoms of anxiety using a standard questionnaire similarly to diazepam, clorazepate, alprazolam and lorazepam - other drugs that treat anxiety. Like diazepam, buspirone works in patients with anxiety and depression, although the number of patients studied is small. In many studies, it takes 1 to 2 weeks for anxiety relief after starting buspirone, so doctors may need to encourage patients to keep taking buspirone. Sedation happens much less often with buspirone than benzodiazepines, and other side effects are mild and uncommon. In healthy people, buspirone does not decrease mental processes and physical movement, and seems to not change with drinking alcohol. Early studies suggest buspirone is not likely to be abused or cause dependence. Although only more people taking buspirone for longer will show exactly how it works, it is another option to treat generalized anxiety because it rarely causes sedation. It could become the top treatment in patients who must be alert during the day." +"Buspirone hydrochloride (HCl)1 is a new anxiolytic with a unique chemical structure. Its mechanism of action remains to be elucidated. Unlike the benzodiazepines, buspirone lacks hypnotic, anticonvulsant and muscle relaxant properties, and hence has been termed 'anxioselective'. As evidenced by a few double-blind clinical trials, buspirone 15 to 30 mg/day improves symptoms of anxiety assessed by standard rating scales similarly to diazepam, clorazepate, alprazolam and lorazepam. Like diazepam, buspirone is effective in patients with mixed anxiety/depression, although the number of patients studied to date is small. In several studies, a 'lagtime' of 1 to 2 weeks to the onset of anxiolytic effect has been noted; hence motivation of patient compliance may be necessary. Sedation occurs much less often after buspirone than after the benzodiazepines; other side effects are minor and infrequent. In healthy volunteers, buspirone does not impair psychomotor or cognitive function, and appears to have no additive effect with alcohol. Early evidence suggests that buspirone has limited potential for abuse and dependence. Thus, although only wider clinical use for longer periods of time will more clearly define some elements of its pharmacological profile, with its low incidence of sedation buspirone is a useful addition to the treatments available for generalised anxiety. It may well become the preferred therapy in patients in whom daytime alertness is particularly important.","Buspirone hydrochloride (HCl)1 is a new anxiety-reducing drug with a unique chemical structure. The mechanism of action for this anxiety-reducing drug is unknown. Unlike other anxiety-reducing drugs like benzodiazepines, buspirone lacks hypnotic, seizure-reducing, and muscle relaxant traits. Thus, the drug treats anxiety specifically. As shown in a few studies, 15 to 30 mg/day of buspirone improves anxiety symptoms similarly to other common anxiety-reducing drugs. Like anxiety-reducing diazepam, buspirone helps patients with mixed anxiety/depression. However, the number of patients studied is small. In many studies, the anxiety-reducing effect manifests after 1 to 2 weeks, so motivating patients to comply may be needed. Sedation is less frequent with buspirone than with other anxiety-reducing drugs. Other side effects are minor and infrequent. In healthy volunteers, buspirone does not affect movement or thought. It also appears to not strengthen the effects of alcohol. Buspirone may have limited potential for abuse and dependence. Thus, while more use will better define its effects, buspirone rarely leads to sedation and is a useful a treatment option for anxiety. Buspirone may become the preferred treatment for patients who demand daytime alertness." +"Background: Several medications commonly used to treat generalized anxiety disorder (GAD) have been designated ""potentially inappropriate"" for use in patients aged > or =65 years because their risks may outweigh their potential benefits. The actual extent of use of these agents in clinical practice is unknown, however. Methods: Using a database with information from encounters with general practitioners (GP) in Germany, we identified all patients, aged > or =65 years, with any GP office visits or dispensed prescriptions with a diagnosis of GAD (ICD-10 diagnosis code F41.1) between 10/1/2003 and 9/30/2004 (""GAD patients""). Among GAD-related medications (including benzodiazepines, tricyclic antidepressants [TCAs], selective serotonin reuptake inhibitors, venlafaxine, hydroxyzine, buspirone, pregabalin, and trifluoperazine), long-acting benzodiazepines, selected short-acting benzodiazepines at relatively high dosages, selected TCAs, and hydroxyzine were designated ""potentially inappropriate"" for use in patients aged > or = 65 years, based on published criteria. Results: A total of 975 elderly patients with GAD were identified. Mean age was 75 years, and 72% were women; 29% had diagnoses of comorbid depression. Forty percent of study subjects received potentially inappropriate agents - most commonly, bromazepam (10% of all subjects), diazepam (9%), doxepin (7%), amitriptyline (5%), and lorazepam (5%). Twenty-three percent of study subjects received long-acting benzodiazepines, 10% received short-acting benzodiazepines at relatively high doses, and 12% received TCAs designated as potentially inappropriate. Conclusion: GPs in Germany often prescribe medications that have been designated as potentially inappropriate to their elderly patients with GAD - especially those with comorbid depressive disorders. Further research is needed to ascertain whether there are specific subgoups of elderly patients with GAD for whom the benefits of these medications outweigh their risks.","Many drugs often used to treat generalized anxiety disorder (GAD) have been labeled ""potentially inappropriate"" for use in patients 65-years-old and above because they may cause more risks than benefits. However, it is not known how often these drugs are given to patients. From a database of patients in Germany, we identified all patients 65-years-old and above with GAD who had seen a primary care doctor or received a prescription between 10/1/2003 and 9/30/2004. Among drugs to treat GAD (including benzodiazepines, tricyclic antidepressants [TCAs], SSRIs, venlafaxine, hydroxyzine, buspirone, pregabalin, and trifluoperazine), long-acting benzodiazepines, some short-acting benzodiazepines at relatively high doses, some TCAs, and hydroxyzine were categorized ""potentially inappropriate"" for people 65-years-old and above. We looked at 975 elderly patients with GAD. Average age was 75 years, and 72% were women; 29% were also diagnosed with depression. Forty percent of people in the study were given inappropriate anxiety-treating drugs - most often, bromazepam (10% of all subjects), diazepam (9%), doxepin (7%), amitriptyline (5%), and lorazepam (5%). Twenty-three percent of people in the study were given long-acting benzodiazepines, 10% were given short-acting benzodiazepines at relatively high doses, and 12% were given TCAs categorized as potentially inappropriate. We conclude that German doctors often prescribe drugs labeled as potentially inappropriate to their elderly patients with GAD, especially those also diagnosed with depression. More research is needed to understand whether certain groups of elderly patients with GAD exist with whom the benefits outweigh the risks of these drugs." +"A drug interaction refers to an event in which the usual pharmacological effect of a drug is modified by other factors, most frequently additional drugs. When two drugs are administered simultaneously, or within a short time of each other, an interaction can occur that may increase or decrease the intended magnitude or duration of the effect of one or both drugs. Drugs may interact on a pharmaceutical, pharmacokinetic or pharmacodynamic basis. Pharmacodynamic interactions arise when the alteration of the effects occurs at the site of action. This is a wide field where not only interactions between different drugs are considered but also drug and metabolites (midazolam/alpha-hydroxy-midazolam), enantiomers (ketamine), as well as phenomena such as tolerance (nordiazepam) and sensitization (diazepam). Pharmacodynamic interactions can result in antagonism or synergism and can originate at a receptor level (antagonism, partial agonism, down-regulation, up-regulation), at an intraneuronal level (transduction, uptake), or at an interneuronal level (physiological pathways). Alternatively, psychotropic drug interactions assessed through quantitative pharmaco-EEG can be viewed according to the broad underlying objective of the study: safety-oriented (ketoprofen/theophylline, lorazepam/diphenhydramine, granisetron/haloperidol), strictly pharmacologically-oriented (benzodiazepine receptors), or broadly neuro-physiologically-oriented (diazepam/buspirone). Methodological issues are stressed, particularly drug plasma concentrations, dose-response relationships and time-course of effects (fluoxetine/buspirone), and unsolved questions are addressed (yohimbine/caffeine, hydroxizyne/alcohol).","A drug interaction is when other things change the usual effects of a drug, most often other drugs. When two drugs are taken at the same time, or within a short time of each other, an interaction can happen that may change the size or length of the effect of one or both drugs. Drugs may interact based on what the drugs do to each other (pharmaceutical), what the body does to the drugs (pharmacokinetic), and what the drugs do to the body (pharmacodynamic). Pharmacodynamic interactions occur when the change in effect happens at the site the drug works at in the body. Phamacodynamics is a wide field. Pharmacodynamic interactions can cause drugs to work together or against each other and can happen at different levels of the body. Drugs that affect the mind, emotions, and behavior measured through a well known tool for finding and characterizing drug effects on the central nervous system (quantitative pharmaco-EEG) can be used based on the aim of the study: safety (ketoprofen/theophylline, lorazepam/diphenhydramine, granisetron/haloperidol), drug properties (benzodiazepine receptors), or brain function (diazepam/buspirone). We focus on methods, especially drug blood levels, response as a function of dosage, and varying activity of the drug over time (fluoxetine/buspirone) and talk about unsolved questions." +"Objective: Patients with generalized anxiety disorder (N=107) who had been long-term benzodiazepine users (average duration of use=8.5 years) were enrolled in a benzodiazepine discontinuation program that assessed the effectiveness of concomitant imipramine (180 mg/day) and buspirone (38 mg/day) compared to placebo in facilitating benzodiazepine discontinuation. Method: After a benzodiazepine stabilization period taking either diazepam, lorazepam, or alprazolam, patients were treated for 4 weeks with imipramine, buspirone, or placebo under double-blind conditions while benzodiazepine intake was kept stable (treatment phase). Patients then entered a 4-6 week benzodiazepine taper and a 5-week posttaper phase with imipramine, buspirone, and placebo treatment being continued until 3 weeks into the posttaper phase, at which time all patients were switched to placebo for 2 weeks. Benzodiazepine plasma levels were assayed weekly. Benzodiazepine-free status was assessed 3 and 12 months posttaper. Results: Study subjects were long-term benzodiazepine users with an average of three unsuccessful prior taper attempts. The success rate of the taper in this study was significantly higher for patients who received imipramine (82.6%), and nonsignificantly higher for patients who received buspirone (67.9%), than for patients who received placebo (37.5%). The imipramine effect remained highly significant even after the analysis adjusted for three other independent predictors of taper success: benzodiazepine dose, level of anxious symptoms at baseline, and duration of benzodiazepine therapy. Conclusions: Management of benzodiazepine discontinuation can be facilitated significantly by co-prescribing imipramine before and during the benzodiazepine taper. Daily benzodiazepine dose, severity of baseline symptoms of anxiety and depression, and duration of benzodiazepine use were additional significant predictors of successful taper outcome.","We enrolled 107 patients with generalized anxiety disorder who had been long-term benzodiazepine users (average length of use=8.5 years) in a program to discontinue benzodiazepines to measure how well other anxiety-reducing drugs like imipramine (180 mg/day) and buspirone (38 mg/day) helped patients wean or discontinue benzodiazepines compared to sugar pills. After a period to stabilize benzodiazepine levels taking either diazepam, lorazepam, or alprazolam, patients took imipramine, buspirone, or sugar pills for 4 weeks while the amount of benzodiazepines taken were kept the same (treatment phase). Patients then slowly decreased the amount of benzodiazepines taken for 4-6 weeks, took imipramine, buspirone, and sugar pills for the next 3 weeks, and then took sugar pills for 2 weeks. Blood benzodiazepine levels were measured weekly using a common lab test. We measured how many patients no longer had benzodiazepine in their blood 3 and 12 months after the last sugar pill. Study participants had used benzodiazepines for a long time and had tried an average of three times to decrease the amount of benzodiazepines taken. Patients who took imipramine were significantly more successful in decreasing the amount of benzodiazepines taken (82.6%), nonsignificantly more successful regarding patients who took buspirone (67.9%), than for patients who took sugar pills (37.5%). Imipramine helped even after factoring in other factors to weaning success: amount of benzodiazepines taken, level of anxious feelings prior to weaning, and how long benzodiazepines have been taken. We concluded that discontinuing benzodiazepines can be done more easily by giving patients imipramine before and during the process of slowly decreasing the amount of benzodiazepines taken over time. Amount of benzodiazepines taken daily, level of anxiety and depression prior to weaning, and how long benzodiazepines have been taken also predicted success of slowly decreasing the amount of benzodiazepines taken." +"Objective: Patients with generalized anxiety disorder (N=107) who had been long-term benzodiazepine users (average duration of use=8.5 years) were enrolled in a benzodiazepine discontinuation program that assessed the effectiveness of concomitant imipramine (180 mg/day) and buspirone (38 mg/day) compared to placebo in facilitating benzodiazepine discontinuation. Method: After a benzodiazepine stabilization period taking either diazepam, lorazepam, or alprazolam, patients were treated for 4 weeks with imipramine, buspirone, or placebo under double-blind conditions while benzodiazepine intake was kept stable (treatment phase). Patients then entered a 4-6 week benzodiazepine taper and a 5-week posttaper phase with imipramine, buspirone, and placebo treatment being continued until 3 weeks into the posttaper phase, at which time all patients were switched to placebo for 2 weeks. Benzodiazepine plasma levels were assayed weekly. Benzodiazepine-free status was assessed 3 and 12 months posttaper. Results: Study subjects were long-term benzodiazepine users with an average of three unsuccessful prior taper attempts. The success rate of the taper in this study was significantly higher for patients who received imipramine (82.6%), and nonsignificantly higher for patients who received buspirone (67.9%), than for patients who received placebo (37.5%). The imipramine effect remained highly significant even after the analysis adjusted for three other independent predictors of taper success: benzodiazepine dose, level of anxious symptoms at baseline, and duration of benzodiazepine therapy. Conclusions: Management of benzodiazepine discontinuation can be facilitated significantly by co-prescribing imipramine before and during the benzodiazepine taper. Daily benzodiazepine dose, severity of baseline symptoms of anxiety and depression, and duration of benzodiazepine use were additional significant predictors of successful taper outcome.","107 patients with diagnosed anxiety and who used anxiety-reducing benzodiazepine drugs (for 8.5 years on average) entered a program that ended their drug use. The program measured how antidepressant imipramine (180 mg/day) and anxiety-reducing busprione (38 mg/day) helps end benzodiazepine use compared to inactive treatment. After using either diazepam, lorazepam, or alprazolam (anxiety-reducing benzodiazepines) for a period of time, patients used imipramine, busprione, or an inactive placebo for 4 weeks while benzodiazepine usage was stable. For 4-6 weeks, patients lessened benzodiazepine use. Then, for 5 weeks, patients kept using imipramine, busiprone, and inactive treatment until 3 weeks in this 5-week phase, at which all patients switched to inactive treatment for 2 weeks. Benzodiazepine blood levels were measured weekly. Benzodiazepine-free status was checked 3 and 12 months after treatment. Patients were long-term benzodiazepine users with an average of three failed attempts to lessen drug use. Success rate for lessening drug use was higher for patients taking imipramine (82.6%) and not much higher for patients taking buspirone (67.9%) compared to patients taking the inactive placebo (37.5%). The imipramine effect was still high even after accounting for benzodiazepine dose, baseline level of anxious symptoms, and duration of benzodiazepine treatment. Ending benzodiazepine drug use can be helped by using imipramine before and during the period of benzodiazepine drug use reduction. Daily benzodiazepine dose, severity of starting symptoms of anxiety and depression, and length of benzodiazepine use help predict successful reduction of drug use." +"In this double-blind, placebo-controlled 10-week trial, the anxiolytic properties of the nonbenzodiazepine buspirone were compared with the benzodiazepine lorazepam and placebo in 125 outpatients with generalized anxiety disorder according to DSM-III. After a 3- to 7-day wash-out period, patients were allocated at random to receive orally 3 x 5 mg buspirone (n=58), 3 x 1 mg lorazepam (n=57), or placebo (n=10) over a 4-week period. The study also comprised a 2-week taper period and a 4-week placebo-control period to assess the stability of clinical improvement. The patient's clinical state was estimated on entry and at weekly intervals by general practitioners using the Hamilton Rating Scale for Anxiety (HAM-A) and Clinical Global Impression (CGI) assessment and by a self-rating scale (State Trait Anxiety Inventory X2=STAI-X2). Lorazepam treatment resulted in descriptively, but not significantly, greater improvement on the Hamilton Rating Scale for Anxiety during the whole treatment (week 0-4) and taper period (week 5, 6) than did buspirone. After treatment with active drugs had been discontinued, the 4-week placebo control period showed buspirone-treated patients to display a stability of clinical improvement, while the symptoms of lorazepam-treated patients worsened at week 7-10. Both buspirone and lorazepam were more efficacious in reducing anxiety symptoms than placebo during the treatment and taper period; however, in contrast to the active drugs (buspirone, lorazepam), patients of the placebo group showed further clinical improvement during the control period, especially in the HAM-A score, so differences between placebo and active drugs became smaller at the end of the study.","Over 10 weeks, we compared the anti-anxiety drug characteristics of the nonbenzodiazepine buspirone with the benzodiazepine lorazepam and sugar pills in 125 patients outside the hospital with generalized anxiety disorder based on the third edition of the Diagnostic and Statistical Manual of Mental Disorders. After a 3- to 7-day period for the body to eliminate drugs in the system, patients were randomly given 5 mg buspirone 3 times a day (58 patients), 1 mg lorazepam 3 times a day (57 patients), or sugar pills (10 patients) for four weeks. The study also included a 2-week period when drug amounts were slowly decreased and a 4-week period when all patients took sugar pills to measure the consistency of improvements in anxiety symptoms. Doctors estimated severity of anxiety symptoms at the beginning of the study and weekly using common questionnaires. Patients taking lorazepam showed slightly greater improvement in symptoms than those taking buspirone on one of the questionnaires during the whole treatment (weeks 0-4) and when drug amounts were slowly decreased (weeks 5,6), though not significantly. After patients stopped taking the studied drugs, the 4-week period when patients took sugar pills showed patients who took buspirone showed consistent improvements in anxiety symptoms, while patients who took lorazepam showed worse symptoms at weeks 7-10. Both buspirone and lorazepam worked better than sugar pills to improve anxiety symptoms during treatment and when drug amounts were slowly decreased. However, patients who took sugar pills showed improvements in anxiety symptoms when all patients took sugar pills, especially in one questionnaire, so differences between sugar pills and drugs became smaller at the end of the study." +"This multicentre study was conducted to evaluate the efficacy and consequences of progressive or abrupt withdrawal of clobazam in the treatment of Generalized Anxiety Disorder in a double blind study in comparison to lorazepam and buspirone. 128 outpatients suffering from Generalized Anxiety Disorder according to DMS III criteria were included in the study and treated for three weeks. They were randomly divided into 4 groups: group 1: 32 patients receiving clobazam, abruptly withdrawn and replaced by a placebo; group 2: 29 patients receiving clobazam with progressive withdrawal over 3 weeks, clobazam being replaced by a placebo; group 3: 33 patients receiving lorazepam with progressive withdrawal over 3 weeks, lorazepam being replaced by a placebo; group 4: 34 patients receiving buspirone, abruptly withdrawn and replaced by a placebo. The dosages were increased progressively during the first week of treatment. At the end of this time, the patients received either 30 mg clobazam or 30 mg buspirone or 3 mg lorazepam daily. After the first week, the Hamilton Anxiety Rating Scale (HARS) showed a significant improvement in clobazam and lorazepam groups but not in buspirone group. All the drugs were equally effective after three weeks of treatment. The anti-anxiety activity persisted after withdrawal of the studied drug in the 4 groups, without any signs of rebound anxiety or withdrawal syndrome. No clinically relevant differences were found between the 4 groups regarding safety. The side-effects reported were mainly drowsiness in clobazam and lorazepam groups, nausea and headache in buspirone group. In conclusion, clobazam like lorazepam improved anxiety more quickly than buspirone; after 3 weeks of therapy, efficacy was comparable with the 3 drugs and persisted after treatment discontinuation.","We rated the effectiveness and effects of gradual or fast withdrawal of clobazam (a benzodiazepine which helps treat anxiety) in treating generalized anxiety disorder compared to lorazepam and buspirone, other anxiety-treating drugs. 128 patients with generalized anxiety disorder based on the third edition of the Diagnostic and Statistical Manual of Mental Disorders participated in the study and received treatment for three weeks. We divided patients into 4 groups: 32 patients taking clobazam, quickly withdrawn and replaced with sugar pills; group 2: 29 patients taking clobazam, gradually withdrawn over 3 weeks and replaced with sugar pills; group 3: 33 patients taking lorazepam, gradually withdrawn over 3 weeks and replaced with sugar pills; group 4: 34 patients taking buspirone, quickly withdrawn and replaced with sugar pills. The amount taken was increased gradually during the first week of treatment. At the end of this time, the patients took either 30 mg clobazam, 30 mg buspirone, or 3 mg lorazepam every day. After the first week, a common questionnaire measuring severity of anxiety symptoms showed improvement in people taking clobazam and lorazepam but not in people taking buspirone. All the drugs worked equally well after three weeks of treatment. The anti-anxiety effects lasted after withdrawal of the studied drug in the 4 groups, with no signs of anxiety symptoms returning or withdrawal symptoms. We found no relevant difference in safety between the 4 groups. Drowsiness in patients taking clobazam and lorazepam and nausea and headache in patients taking buspirone were the main side effects reported. We conclude that clobazam, like lorazepam, improved anxiety more quickly than buspirone; after 3 weeks of treatment, effectiveness of the 3 drugs was similar and lasted after patients stopped taking the drugs." +"1. The purpose of this study was to compare the effects and abrupt discontinuation of buspirone 15 or 20 mg tid and lorazepam 3 or 4 mg tid following 8 weeks of treatment. A total of 43 outpatients with generalized anxiety disorder were included in the study and 39 entered the withdrawal phase. 2. Clinical assessments were performed at baseline, 2, 4, 6 and 8 weeks (active phase) and after 9 and 10 weeks (withdrawal phase). These included the Hamilton anxiety scale, the visual analogue scale, the CHESS 84 (a check list for the evaluation of somatic symptoms) and the Lader tranquilizer withdrawal scale (translated in french). 3. Results show similar efficacy for lorazepam and buspirone during the active phase with a higher significant difference for buspirone on the CHESS 84 in relation with neurovegetatives symptoms: lorazepam D0 :16.30 +/- 3.14 D56: 5.10 +/- 0.93 (p < or = 0.01) buspirone D0 :18.82 +/- 3.4 D56: 4.73 +/- 1.18 (p < or = 0.001). No withdrawal phenomena was observed for both drugs using HAM-A lorazepam D63 :12.59 +/- 2.26 D70: 12.0 +/- 1.75 (p = ns) buspirone D63 :10.05 +/- 1.28 D70: 10.32 +/- 1.82 (p = ns) and the same significant difference using Lader scale: lorazepam D63 :4.44 +/- 0.89 D70: 6.96 +/- 1.28 (p < or = 0.05) buspirone D63 :2.95 +/- 0.66 D70: 4.15 +/- 0.92 (p < or = 0.05) 4. This study confirmed that buspirone was as effective as lorazepam at D56 in monitored outpatients with generalized anxiety disorder. There are some evidences that these two drugs differed in efficacy against the various somatic symptoms encountered in generalized anxiety disorder.","This study's purpose was to compare the effects and sudden termination of buspirone 15 or 20 mg three times a day and lorazepam 3 or 4 mg three times a day, common anxiety-reducing drugs. We included 43 patients outside the hospital with generalized anxiety disorder in the study, and 39 quickly stopped taking medication. We collected information from patients at the beginning of the study, at 2, 4, 6 and 8 weeks (active phase), and after 9 and 10 weeks (withdrawal phase). These assessments included common questionnaires measuring severity of anxiety symptoms. Results show lorazepam and buspirone worked similarly well during the active phase with one questionnaire favoring buspirone for physical symptoms of anxiety (e.g., fatigue). No withdrawal symptoms were seen for both lorazepam and buspirone using one of the questionnaires, and the same significant difference was seen using another questionnaire. This study showed that buspirone worked as well as lorazepam 56 days into the study in patients with generalized anxiety disorder. Some results suggest that lorazepam and buspirone did not work the same against the physical symptoms seen in generalized anxiety disorder." +"1. The purpose of this study was to compare the effects and abrupt discontinuation of buspirone 15 or 20 mg tid and lorazepam 3 or 4 mg tid following 8 weeks of treatment. A total of 43 outpatients with generalized anxiety disorder were included in the study and 39 entered the withdrawal phase. 2. Clinical assessments were performed at baseline, 2, 4, 6 and 8 weeks (active phase) and after 9 and 10 weeks (withdrawal phase). These included the Hamilton anxiety scale, the visual analogue scale, the CHESS 84 (a check list for the evaluation of somatic symptoms) and the Lader tranquilizer withdrawal scale (translated in french). 3. Results show similar efficacy for lorazepam and buspirone during the active phase with a higher significant difference for buspirone on the CHESS 84 in relation with neurovegetatives symptoms: lorazepam D0 :16.30 +/- 3.14 D56: 5.10 +/- 0.93 (p < or = 0.01) buspirone D0 :18.82 +/- 3.4 D56: 4.73 +/- 1.18 (p < or = 0.001). No withdrawal phenomena was observed for both drugs using HAM-A lorazepam D63 :12.59 +/- 2.26 D70: 12.0 +/- 1.75 (p = ns) buspirone D63 :10.05 +/- 1.28 D70: 10.32 +/- 1.82 (p = ns) and the same significant difference using Lader scale: lorazepam D63 :4.44 +/- 0.89 D70: 6.96 +/- 1.28 (p < or = 0.05) buspirone D63 :2.95 +/- 0.66 D70: 4.15 +/- 0.92 (p < or = 0.05) 4. This study confirmed that buspirone was as effective as lorazepam at D56 in monitored outpatients with generalized anxiety disorder. There are some evidences that these two drugs differed in efficacy against the various somatic symptoms encountered in generalized anxiety disorder.","This study compares the effects and abrupt stoppage of anxiety-reducing buspirone drug use (15 or 20 mg three times a day) and anxiety-reducing lorazepam drug use (3 or 4 mg three times a day) after 8 weeks of treatment. 43 patients with diagnosed anxiety participated in the study. 39 entered the drug withdrawal phase. Clinical measurements were taken at start, 2, 4, 6, and 8 weeks (active phase) and after 9 and 10 weeks (withdrawal phase). Lorazepam and buspirone had similar effectiveness when used. However, buspirone affected sleep, appetite, and concentration differently compared to lorazepam. No withdrawal effects were seen with either drug. Buspirone was as effective as lorazepam with patients with diagnosed anxiety. Buspirone may have differed in effectiveness compared to lorazepam for treating certain physical symptoms common with anxiety disorder." +"Forty-four patients with DSM-III-R generalized anxiety disorder participated in this double-blind, randomized study. Patients were on a benzodiazepine before the study and were stabilized on 3 to 5 mg/day lorazepam for 5 weeks (weeks 0 to 5). Thereafter, they were randomized to 15 mg/day buspirone or placebo for the following 6 weeks (weeks 6 to 11). During the first 2 weeks of double-blind, randomized treatment (weeks 6 to 7), lorazepam was tapered off. During weeks 12 to 13, patients received single-blind placebo. Assessment included the Hamilton Rating Scale for Anxiety, the State-Trait Anxiety Inventory, the Zung and Eddy Self-Rating Scale of Anxiety Symptoms, the Hamilton Rating Scale for Depression, and the Rome Depression Inventory, completed at weeks 0, 5, 6, 7, 8, 9, 11, and 13. Side effects were assessed through the Dosage Treatment Emergent Symptoms at the same times. The benzodiazepine-withdrawal syndrome was evaluated through a 27-symptom checklist (Clinical-Rated Benzodiazepine Withdrawal Symptom Schedule) at weeks 0, 5, 6, 7, 11, and 13. The results showed that buspirone was more effective than placebo and comparable to lorazepam. Buspirone-treated patients showed no rebound anxiety or benzodiazepine-withdrawal syndrome compared with placebo. Buspirone caused fewer side effects than lorazepam and was not different from placebo in this respect. Finally, buspirone maintained its anxiolytic effect for at least 2 weeks after the discontinuation of treatment.","We studied 44 patients with generalized anxiety disorder based on the third edition of the Diagnostic and Statistical Manual of Mental Disorders. Patients were taking a benzodiazepine before the study and were stabilized on 3 to 5 mg/day lorazepam for 5 weeks (weeks 0-5), both anxiety-reducing drugs. We randomly assigned patients to take 15 mg/day buspirone - a possible anxiety-reducing drug - or sugar pills for the next 6 weeks (weeks 6-11). During weeks 6 to 7, patients gradually stopped taking lorazepam. During weeks 12 to 13, all patients took sugar pills. At the beginning of the study and weeks 5, 6, 7, 8, 9, 11, and 13, we measured severity of anxiety symptoms using common questionnaires. At the same times, we measured side effects using another questionnaire. At the beginning of the study and weeks 5, 6, 7, 11, and 13, we measured withdrawal symptoms using a common checklist. The results favored buspirone over sugar pills and were similar to lorazepam. Patients taking buspirone showed no signs of anxiety symptoms returning or withdrawal symptoms compared to sugar pills. Buspirone, similar to sugar pills, caused fewer side effects than lorazepam. Finally the anti-anxiety effects of buspirone lasted at least 2 weeks after patients stopped taking the studied drugs." +"The respiratory and behavioral effects of the benzodiazepine receptor (BZR) inverse agonist ethyl-beta-carboline-3-carboxylate (beta-CCE) were determined alone and in combination with buspirone, lorazepam, flumazenil, and SR 95195 in rhesus monkeys. For the respiratory studies, one group of monkeys inhaled either air or 5% CO2 mixed in air according to a fixed alternating schedule; respiratory frequency and minute volume were monitored. For the behavioral studies, another group of monkeys responded under a fixed-ratio (FR 30) schedule of food presentation. The respiratory stimulant effects of beta-CCE in both air and 5% CO2 were enhanced by prior treatment with the 5-hydroxytryptamine1A (5-HT1A) partial agonist buspirone (0.03 and 0.3 mg/kg) and a weak BZR inverse agonist, SR 95195 (10.0 mg/kg). Coadministration of buspirone (0.1 and 0.3 mg/kg) also potentiated the rate-decreasing effects of beta-CCE under the FR schedule. The BZR agonist lorazepam (3.0 mg/kg) and BZR antagonist flumazenil (1.0 mg/kg) attenuated the effects of beta-CCE on respiratory frequency and minute volume particularly under the 5% CO2 condition, and lorazepam (0.1 and 0.3 mg/kg) and flumazenil (0.1 and 0.3 mg/kg) attenuated the effects of beta-CCE on FR responding. These latter results show that the respiratory and behavioral effects of beta-CCE in rhesus monkeys are at least in part due to effects at BZRs. Moreover, the findings suggest either that coactivation of benzodiazepine and 5-HT1A sites lead to a greater than additive effect or that beta-CCE and buspirone share a common mechanism of action that is unrelated to the receptor at which BZR inverse agonists act.","We studied effects on breathing and behavior of the benzodiazepine receptor (BZR; a molecule that receives signals for a cell) inverse agonist (a drug that binds to the same receptor as an agonist or stimulating molecule but causes an opposite response) ethyl-beta-carboline-3-carboxylate (beta-CCE) alone and with the anxiety-reducing drugs of buspirone, lorazepam, flumazenil, and SR 95195 in monkeys. For the breathing-related studies, one group of monkeys breathed air or 5% CO2 mixed in air; breaths per minute and amount of gas breathed were measured. For the behavior studies, another group of monkeys responded to food given every thirty seconds. The increased breathing effects of beta-CCE in both air and 5% CO2 were increased by previously taking the drugs of 5-hydroxytryptamine1A (5-HT1A), partial agonist buspirone (0.03 and 0.3 mg/kg) and a weak BZR inverse agonist, SR 95195 (10.0 mg/kg). Taking buspirone (0.1 and 0.3 mg/kg) at the same time also increased effects of beta-CCE under the food schedule. The BZR agonist lorazepam (3.0 mg/kg) and BZR antagonist flumazenil (1.0 mg/kg) reduced the effects of beta-CCE on breaths per minute and amount of gas breathed especially under the 5% CO2 condition. Lorazepam (0.1 and 0.3 mg/kg) and flumazenil (0.1 and 0.3 mg/kg) reduced the effects of beta-CCE on behavior responding on the food schedule. These latter results shows that effects on breathing and behavior of beta-CCE in monkeys are at least due to effects at BZRs. The results also suggest that benzodiazepine and 5-HT1A sites activated at the same time cause an effect greater than their individual effects or that beta-CCE and buspirone work similarly independent of the receptor where BZR inverse antagonists work." +"Objective: To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). Design: Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. Data sources: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). Study selection: Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. Methods: After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ?100 patients randomised or ?20 events per treatment arm. Results: As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) -4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD -4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD -3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD -4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. Conclusion: In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit.","The objective of this paper is to evaluate the performance and safety of antiviral antibody therapies that help the body fight off or prevent a virus and blood products used to treat COVID-19. Published data from other studies is summarized on an ongoing basis and compares data from different medicines, including an analysis to fill in the gaps for studies that have limited data. The data sources for this summary are the World Health Organization (WHO) COVID-19 and six Chinese databases that store data up to July 21, 2021. In clinical trials, people with suspected COVID-19 (person has symptoms and/or exposure to covid but is not tested), probable COVID-19 (person who has tested positive with other tests but not confirmatory test), or confirmed COVID-19 are randomly put into different treatment groups or a placebo, where they receive something that looks like a drug but is not active. Two reviewers determine if the different clinical studies will be included in the summary. After data are collected from the clinical studies, the data are analyzed. The confidence that the results in the studies are accurate is graded using an established process. Clinical trials with 100 or more patients or 20 or more events per treatment type are analyzed. As of July 21st 2021, 47 trials that evaluated different blood products and medicines, including monoclonal antibodies, are found. Patients with non-severe disease who receive antiviral monoclonal antibodies (medicines that may block the virus from attaching to human cells) have lower risk of being hospitalized than those who received placebo. Antiviral monoclonal antibodies did not have an important impact on any other outcome. There is no major difference between monoclonal antibodies. No other treatment intervention is found to have any meaningful effect on any outcome in patients with non-severe COVID-19. No intervention, including antiviral antibodies, has an important impact on any outcome in patients with severe or critical COVID-19, except casirivimab-imdevimab, which may reduce death in patients who had a negative blood test. In conclusion, patients with non-severe COVID-19, the drug casirivimab-imdevimab probably reduces hospital stays; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalization. Other antibody and cell interventions may not provide any meaningful benefit." +"Objective: To evaluate the efficacy and safety of antiviral antibody therapies and blood products for the treatment of novel coronavirus disease 2019 (covid-19). Design: Living systematic review and network meta-analysis, with pairwise meta-analysis for outcomes with insufficient data. Data sources: WHO covid-19 database, a comprehensive multilingual source of global covid-19 literature, and six Chinese databases (up to 21 July 2021). Study selection: Trials randomising people with suspected, probable, or confirmed covid-19 to antiviral antibody therapies, blood products, or standard care or placebo. Paired reviewers determined eligibility of trials independently and in duplicate. Methods: After duplicate data abstraction, we performed random effects bayesian meta-analysis, including network meta-analysis for outcomes with sufficient data. We assessed risk of bias using a modification of the Cochrane risk of bias 2.0 tool. The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation (GRADE) approach. We meta-analysed interventions with ?100 patients randomised or ?20 events per treatment arm. Results: As of 21 July 2021, we identified 47 trials evaluating convalescent plasma (21 trials), intravenous immunoglobulin (IVIg) (5 trials), umbilical cord mesenchymal stem cells (5 trials), bamlanivimab (4 trials), casirivimab-imdevimab (4 trials), bamlanivimab-etesevimab (2 trials), control plasma (2 trials), peripheral blood non-haematopoietic enriched stem cells (2 trials), sotrovimab (1 trial), anti-SARS-CoV-2 IVIg (1 trial), therapeutic plasma exchange (1 trial), XAV-19 polyclonal antibody (1 trial), CT-P59 monoclonal antibody (1 trial) and INM005 polyclonal antibody (1 trial) for the treatment of covid-19. Patients with non-severe disease randomised to antiviral monoclonal antibodies had lower risk of hospitalisation than those who received placebo: casirivimab-imdevimab (odds ratio (OR) 0.29 (95% CI 0.17 to 0.47); risk difference (RD) -4.2%; moderate certainty), bamlanivimab (OR 0.24 (0.06 to 0.86); RD -4.1%; low certainty), bamlanivimab-etesevimab (OR 0.31 (0.11 to 0.81); RD -3.8%; low certainty), and sotrovimab (OR 0.17 (0.04 to 0.57); RD -4.8%; low certainty). They did not have an important impact on any other outcome. There was no notable difference between monoclonal antibodies. No other intervention had any meaningful effect on any outcome in patients with non-severe covid-19. No intervention, including antiviral antibodies, had an important impact on any outcome in patients with severe or critical covid-19, except casirivimab-imdevimab, which may reduce mortality in patients who are seronegative. Conclusion: In patients with non-severe covid-19, casirivimab-imdevimab probably reduces hospitalisation; bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Convalescent plasma, IVIg, and other antibody and cellular interventions may not confer any meaningful benefit.","Our objective is to measure the effectiveness and safety of antiviral antibody treatments and substances from blood for treating the new coronavirus disease 2019 (covid-19), a viral respiratory disease. People with suspected, probable, or confirmed covid-19 were randomized to antiviral antibody therapies, substances from blood, or standard care or an inactive placebo. As of 21 July 2021, we identified 47 trials evaluating a variety of substances from blood and antiviral antibody treatments for treating covid-19. Patients with non-severe disease given antiviral antibodies had lower risk of hospitalsation than those given the inactive placebo treatment. They did not have an important impact on any other outcome. There was no notable difference between antibodies. No other treatment had a meaningful effect on any outcome in patients with non-severe covid-19. No treatment, including antiviral antibodies, had an important effect on any outcome in patients with severe covid-19, except the antibodies casirivimab-imdevimab. These antibodies may reduce risk of death in those who do not make the antibodies naturally. In patients with non-severe covid-19, casirivimab-imdevimab likely reduces hospitalisation. Bamlanivimab-etesevimab, bamlanivimab, and sotrovimab may reduce hospitalisation. Substances from blood and other antibody treatments may not give any meaningful aid." +"Introduction: Treatments for subjects with Covid-19 are required. One approach is neutralising monoclonal antibodies. Bamlanivimab and etesevimab are monoclonal antibodies to SARS-CoV-2. Areas covered: This evaluation is of the phase 3 BLAZE-1 clinical trial, which was of bamlanivimab plus etesevimab in adult ambulatory participants with a risk factor for, and mild to moderate, Covid-19 illness. The primary outcome was Covid 19 related hospitalisation of ? 24 hours or death from any cause by day 29, and this occurred in 2.1% subjects in the bamlanivimab/etesevimab group, compared to 7.0% in the placebo group. Expert opinion: In the pandemic, the attempts by the FDA to shorten approval processes for medicines and by journals to make information available in a timely manner are admirable. However, these shortened processes made negotiating the details of BLAZE-1 and producing accurate and critical appraisals difficult. It seems to me, that if there are any benefits of bamlanivimab alone in Covid-19, they are not clear-cut. Bamlanivimab has limited effects against the beta and gamma variants and is not effective against the delta variant. Thus, the benefits of bamlanivimab/etesevimab in the phase 3 of the BLAZE-1 may be solely due to etesevimab, and this needs to be tested.","Treatments for people with COVID-19, a viral breathing-related disorder, are needed. One option is to use monoclonal antibodies, which are medicines that may block the virus that causes COVID-19 from attaching to human cells, making it more difficult for the virus to reproduce. Bamlanivimab and etesevimab are two types of monoclonal antibodies. This evaluation is of the 3rd phase of a clinical study called BLAZE that examines bamlanivimab plus etesevimab in adults. The main result researchers look for is COVID-19 related hospital stays that lasted at least 24 hours or death. This result occurred in 2.1% of patients in the bamlanivimab/etesevimab group, compared to 7.0% in the placebo group. Based on opinions of experts, the FDA's efforts to shorten the approval process for medicines and for medical journals to make information available is admirable. However, these shortened processes make the details of the BLAZE study and producing accurate reviews difficult. It seems that if there are any benefits for bamlanivimab alone in COVID-19, they are not clear-cut. Bamlanivimab has limited effects against the beta and gamma variants of COVID-19 and is not effective against the delta variant. Therefore, the benefits of the bamlanivimab/etesevimab in phase 3 of the BLAZE-1 trial may be solely due to the etesevimab medicine, and this needs to be tested." +"Over 80 mAbs have been shown to block the interaction between the SARS-CoV-2 S1 glycoprotein and its cellular receptor, thus neutralizing virus infectivity in vitro. Some of those mAbs demonstrate therapeutic efficacy to curtail viral burden and lung inflammation in animal models. The neutralization mechanisms of mAbs against SARS-CoV-2 in vivo are not fully understood, but optimal protection correlates with Fc effector functions. Approximately 30 SARS-CoV-2 neutralizing m Abs are undergoing clinical trials in COVID-19 patients. Some were granted emergency authorization since they reduced viral load, disease severity, and hospitalization in randomized, controlled phase II clinical trials. However, mAbs are unaffordable for healthcare systems in many developing countries due to their high cost (> USD 1,500/vial), meaning that most infected people would not have access to them. Another obstacle for COVID-19 therapy with mAbs is the emergence of viral variants harboring changes in the receptor-binding domain (RBD) of the S1 glycoprotein. The variants of concern (VoC) exhibit enhanced transmissibility or virulence, circulate worldwide, and include those designated as alpha, beta, epsilon, gamma, and delta, first detected in the UK, South Africa, Brazil, USA, and India, respectively. Therapeutic mAbs, and antibodies in the plasma of vaccinated or convalescent individuals, fail to neutralize VoC efficiently.","Over 80 monoclonal antibody medicines have been shown to block the interaction between the coronavirus glycoprotein (a molecule that has a carbohydrate and a protein) and its cell receptor that can send signals, resulting in making the virus ineffective. The coronavirus causes COVID-1, a viral breathing-related disorder, and monoclonal antibodies are medicines that may block the virus that causes COVID-19 from attaching to human cells. Some of those monoclonal antibodies show that they work well to reduce the effects of the virus and lung inflammation (redness and swelling in response to infection) in animal studies. The process used by monoclonal antibodies to make the virus ineffective in humans and animals is not fully understood, but the best protection is associated with the Fc effector functions, which are the part of the antibody that interacts with other cells. Approximately 30 monoclonal antibodies are currently being tested in clinical trials in COVID-19 patients. Some are granted emergency authorization (where unapproved medicines may be used) because they reduce the amount of virus in the body, lessen the seriousness of the disease, and reduce hospital stays in clinical trials. However, monoclonal antibodies are expensive for healthcare systems in many developing countries, meaning that most infected people would not have access to the medicine. Another challenge for COVID-19 medicines that use monoclonal antibodies is the new variants that change cell receptor activity for the glycoprotein. The variants of concern are more easily transmitted between people, are found worldwide, and include those designated as alpha, beta, epsilon, gamma, and delta. Monoclonal antibody medicines, and antibodies in plasma (the liquid portion of blood) of vaccinated or recovering people, fail to efficiently make the variants of interest ineffective." +"SARS-CoV-2 variants of concern show reduced neutralization by vaccine-induced and therapeutic monoclonal antibodies; therefore, treatment alternatives are needed. We tested therapeutic equine polyclonal antibodies (pAbs) that are being assessed in clinical trials in Costa Rica against five globally circulating variants of concern: alpha, beta, epsilon, gamma and delta, using plaque reduction neutralization assays. We show that equine pAbs efficiently neutralize the variants of concern, with inhibitory concentrations in the range of 0.146-1.078 ?g/mL, which correspond to extremely low concentrations when compared to pAbs doses used in clinical trials. Equine pAbs are an effective, broad coverage, low-cost and a scalable COVID-19 treatment.","Coronavirus variants of concern (variants that are easier to transmit and/or are more severe) show reduced effect from monoclonal antibodies which are drugs that may block the virus that causes COVID-19 (a viral breathing-related disorder) from attaching to human cells, making it more difficult for the virus to reproduce. Researchers tested equine or horse-derived polyclonal antibodies (antibody drugs that attack several parts of the COVID-19 virus) that are being tested in clinical trials in Costa Rica against five globally circulating variants of concern: alpha, beta, epsilon, gamma and delta. The results show that equine polyclonal antibodies efficiently make the variant of concern ineffective. Equine polyclonal antibodies are found to be an effective, low-cost, and accessible COVID-19 treatment for the variants of concern." +"SARS-CoV-2 variants of concern show reduced neutralization by vaccine-induced and therapeutic monoclonal antibodies; therefore, treatment alternatives are needed. We tested therapeutic equine polyclonal antibodies (pAbs) that are being assessed in clinical trials in Costa Rica against five globally circulating variants of concern: alpha, beta, epsilon, gamma and delta, using plaque reduction neutralization assays. We show that equine pAbs efficiently neutralize the variants of concern, with inhibitory concentrations in the range of 0.146-1.078 ?g/mL, which correspond to extremely low concentrations when compared to pAbs doses used in clinical trials. Equine pAbs are an effective, broad coverage, low-cost and a scalable COVID-19 treatment.","Alarming variants of SARS-CoV-2 (a viral respiratory disease) show reduced elimination by vaccine-induced and highly-specific antibodies. Thus, different treatments are needed. We tested horse-derived polyclonal antibodies (pAbs), a mixture of antibodies that bind to the same foreign organism. These pAbs are being measured in Costa Rica against five alarming, global variants: alpha, beta, epsilon, gamma, and delta. Horse-derived pAbs efficiently treat the concerning variants with much lower dosages than those used in clinical trials. Horse-derived pAbs are an effective, broad coverage, low-cost treatment for COVID-19 (a widespread viral respiratory disease)." +"Monoclonal antibodies (mAbs) with neutralizing activity against SARS-CoV-2 have demonstrated clinical benefit in cases of mild to moderate SARS-CoV-2 infection, substantially reducing the risk for hospitalization and severe disease 1-4. Treatment generally requires the administration of high doses of these mAbs with limited efficacy in preventing disease complications or mortality among hospitalized COVID-19 patients 5. Here we report the development and evaluation of Fc-optimized anti-SARS-CoV-2 mAbs with superior potency to prevent or treat COVID-19 disease. In several animal models of COVID-19 disease we demonstrate that selective engagement of activating Fc?Rs results in improved efficacy in both preventing and treating disease-induced weight loss and mortality, significantly reducing the dose required to confer full protection upon SARS-CoV-2 challenge and treatment of pre-infected animals. Our results highlight the importance of Fc?R pathways in driving antibody-mediated antiviral immunity, while excluding any pathogenic or disease-enhancing effects of Fc?R engagement of anti-SARS-CoV-2 antibodies upon infection. These findings have important implications for the development of Fc-engineered mAbs with optimal Fc effector function and improved clinical efficacy against COVID-19 disease.","Monoclonal antibodies are medicines that can make the coronavirus ineffective and have shown to be beneficial in cases of mild to moderate coronavirus infection, substantially reducing the risk for staying in the hospital and having severe symptoms of the disease. The coronavirus can cause COVID-19, the viral breathing-related infection. Treatment usually requires high doses of these monoclonal antibodies with limited ability in preventing complications or death among patients hospitalized with COVID-19. This study reports on the development and evaluation of monoclonal antibodies enhanced with the Fc (the part of the antibody that helps interactions with other cells) to prevent or treat COVID-19. In several animal studies of COVID-19, researchers show that activating certain parts of the Fc proteins results in improvements in both preventing and treating weight loss and death from the disease. This helps reduce the dose required to gain full protection in animals who are not infected with the coronavirus. Results highlight the importance of the Fc proteins in increasing immunity to the virus. These findings may influence the development of Fc monoclonal antibodies with improved functions to help strengthen immunity against COVID-19." +"The ongoing pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants has posed a serious global public health emergency. Therapeutic interventions or vaccines are urgently needed to treat and prevent the further dissemination of this contagious virus. This study described the identification of neutralizing receptor-binding domain (RBD)-specific antibodies from mice through vaccination with a recombinant SARS-CoV-2 RBD. RBD-targeted monoclonal antibodies (mAbs) with distinct function and epitope recognition were selected to understand SARS-CoV-2 neutralization. High-affinity RBD-specific antibodies exhibited high potency in neutralizing both live and pseudotype SARS-CoV-2 viruses and the SARS-CoV-2 pseudovirus particle containing the spike protein S-RBDV367F mutant (SARS-CoV-2(V367F)). These results demonstrated that these antibodies recognize four distinct groups (I-IV) of epitopes on the RBD and that mAbs targeting group I epitope can be used in combination with mAbs recognizing groups II and/or IV epitope to make mAb cocktails against SARS-CoV-2 and its mutants. Moreover, structural characterization reveals that groups I, III, and IV epitopes are closely located to an RBD hotspot. The identification of RBD-specific antibodies and cocktails may provide an effective therapeutic and prophylactic intervention against SARS-CoV-2 and its isolates.","The ongoing pandemic of the coronavirus (the virus that causes COVID-19 or the breathing-related infection) and its variants has created a global public health emergency. Medical drugs and vaccines are needed to treat and prevent the spread of this contagious virus. This study describes how antibodies that are linked to receptor-binding domains (parts of the cell that connect the virus and allow entry to the cell) are identified in mice using a vaccine that includes a small piece of DNA or genetic material to teach the body to fight the infection. Monoclonal antibodies are medicines that may block the virus that causes COVID-19 from attaching to human cells, making it more difficult for the virus to reproduce. Certain monoclonal antibodies are selected for the study to understand how the coronavirus can be made ineffective. Some antibodies with these receptor-binding domains have a high ability to make the coronavirus ineffective. These results show that monoclonal antibodies targeting certain parts of the virus can be used in combination with other monoclonal antibodies medicines against the coronavirus. The identification of these antibodies linked to receptor-binding domains and the mix of medicines may provide effective treatment and prevention against coronavirus." +"Objectives: We aimed to evaluate the impact of neutralizing monoclonal antibodies (mAbs) treatment and to determine whether the mAbs selective pressure could facilitate the proliferation of virus variants with spike protein mutations that might attenuate mAb effectiveness. Patients and methods: We therefore evaluated the impact of mAbs on the nasopharyngeal (NP) viral load and virus quasispecies of mAb-treated patients using single molecule real time sequencing (Pacific Biosciences). The mAbs used were: Bamlanivimab alone (4 patients), Bamlanivimab/Etesevimab (23 patients), and Casirivimab/Imdevimab (5 patients). Results: The NP SARS-CoV-2 viral load of mAb-treated patients decreased from 8.2 log10 copies/ml before administration to 4.3 log10 copies/ml 7 days after administration. Five immunocompromised patients given Bamlanivimab/Etesevimab were found to have mAbs activity-reducing spike mutations. Two patients harbored SARS-CoV-2 variants with a Q493R spike mutation 7 days after administration, as did a third patient 14 days after administration. The fourth patient harbored a variant with a Q493K spike mutation 7 days post-treatment, and the fifth patient had a variant with a E484K spike mutation on day 21. The emergence of the spike mutation was accompanied by stabilization or rebound of the NP viral load in 3/5 patients. Conclusion: Two-m Ab therapy can drive the selection of resistant SARS-CoV-2 variants in immunocompromised patients. Patients given mAbs should be closely monitored and measures to limit virus spread reinforced.","This study aims to evaluate the impact of monoclonal antibodies, medicines that may block the virus that causes COVID-19 (a viral lung infection) from attaching to human cells, making it more difficult for the virus to reproduce. The study also aims to determine if certain monoclonal antibodies can lead to spread of virus variants through mutations that may reduce the effectiveness of monoclonal antibodies. Researchers evaluate the impact of monoclonal antibodies on the viral load (quantity of the virus) found in the nose and the number of mutations in patients treated with monoclonal antibodies. The monoclonal antibodies used are bamlanivimab alone (in 4 patients), Bamlanivimab/Etesevimab (in 23 patients), and Casirivimab/Imdevimab (in5 patients). The viral load in the nose of monoclonal antibodies-treated patients decreased 7 days after the medicines were given. Five patients with a weak immune system who were given Bamlanivimab/Etesevimab are found to have reduced mutations that allow the virus to enter cells and cause infection. Two patients with coronavirus variants have a mutation that enabled the virus to enter cells 7 days after the medicines are given. The same occurred with a third patient 14 days after the medicines are given. The fourth patient with a variant has a mutation 7 days after the medicine is stopped, and the fifth patient has a variant with a mutation on day 21. The start of the mutation is connected with a stable or increased viral load in the nose in 3 out of 5 patients. In conclusion, two monoclonal antibody drugs can drive the targeting of coronavirus variants in patients with weak immune systems. Patients given monoclonal antibody should be closely monitored, and measures to limit virus spread should be strengthened." +"Objectives: We aimed to evaluate the impact of neutralizing monoclonal antibodies (mAbs) treatment and to determine whether the mAbs selective pressure could facilitate the proliferation of virus variants with spike protein mutations that might attenuate mAb effectiveness. Patients and methods: We therefore evaluated the impact of mAbs on the nasopharyngeal (NP) viral load and virus quasispecies of mAb-treated patients using single molecule real time sequencing (Pacific Biosciences). The mAbs used were: Bamlanivimab alone (4 patients), Bamlanivimab/Etesevimab (23 patients), and Casirivimab/Imdevimab (5 patients). Results: The NP SARS-CoV-2 viral load of mAb-treated patients decreased from 8.2 log10 copies/ml before administration to 4.3 log10 copies/ml 7 days after administration. Five immunocompromised patients given Bamlanivimab/Etesevimab were found to have mAbs activity-reducing spike mutations. Two patients harbored SARS-CoV-2 variants with a Q493R spike mutation 7 days after administration, as did a third patient 14 days after administration. The fourth patient harbored a variant with a Q493K spike mutation 7 days post-treatment, and the fifth patient had a variant with a E484K spike mutation on day 21. The emergence of the spike mutation was accompanied by stabilization or rebound of the NP viral load in 3/5 patients. Conclusion: Two-m Ab therapy can drive the selection of resistant SARS-CoV-2 variants in immunocompromised patients. Patients given mAbs should be closely monitored and measures to limit virus spread reinforced.","We aimed to test the effect of monoclonal antibodies (mAbs), antibodies that bind to only one site of a foreign organism. We determine if mAbs may help grow mutated virus variants that may weaken mAb effectiveness. We test the effect of mAbs on the virus species and amount in the upper throat of mAb-treated patients. The mAbs used were: Bamlanivimab alone (4 patients), Bamlanivimab/Etesevimab (23 patients), and Casirivimab/Imdevimab (5 patients). The amount of SARS-CoV-2 viruses, which cause a respiratory illness, in the upper throats of mAb-treated patients decreased 7 days after treatment. Five patients with an impaired immune system and given Bamlanivimab/Etesevimab had mutations that reduced the effect of mAbs. Two patients with SARS-CoV-2 variants had a mutations 7 days after treatment, along with a third patient 14 days after treatment. The fourth patient had a variant with a mutation 7 days after treatment, along with a fifth patient on day 21. The onset of the mutation came with a rebound or stabilization of virus amount in 3/5 patients. Two-mAb treatment can lead to resistant SARS-CoV-2 variants in patients with an impaired immune system. Patients given mAbs should be monitored and measures to limit virus spread reinforced." +"Importance: The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. Objective: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. Design, setting, and participants: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. Interventions: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. Main outcome and measures: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao2/Fio2 ratio less than 150 mm Hg, whichever came first. Results: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. Conclusions and relevance: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao2/Fio2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease.","The COVID-19 pandemic is threatening billions of people worldwide. COVID-19 is a viral, breathing-related disease. Tocilizumab, a type of drug called monoclonal antibodies, has shown promising results in recent studies in patients with COVID-19 pneumonia or lung infections. Monoclonal antibodies are medicines that may block the virus that causes COVID-19 from attaching to human cells, making it more difficult for the virus to reproduce. The objective of this study is to evaluate the effect of giving tocilizumab early, compared to the standard treatment, to prevent a hospitalized COVID-19 patient with pneumonia from getting worse. Patients who are in the hospital with COVID-19 pneumonia are randomly put in groups to receive either tocilizumab or the standard care. Cases of COVID-19 are confirmed by taking a swab from inside the back of the nose. To be included in the study, patients must have COVID-19 pneumonia confirmed by an x-ray, certain oxygen levels, a fever, and an increase in C-reactive proteins which are created in the liver in response to inflammation (redness and swelling from fighting an infection). Patients in the experimental group receive tocilizumab through an IV (medicine is delivered in a vein in the arm) within 8 hours of being randomly placed in the group. A second dose is given after 12 hours. Patients in the comparison group receive support care based on hospital standards until the patient's condition worsens, and then they receive tocilizumab. The main study observations of interest are 1) going into intensive care units with machines to help breathe, 2) death from all causes, or 3) a worsening of a condition measured by oxygen levels. A total of 126 patients are randomly put into the experimental group to receive tocilizumab (60 patients) or in the comparison group (66 patients). The average age is 60 years, and most patients (61.1%) are male. Three patients dropped out of the study, leaving 123 patients in the study. Within 14 days since they were randomly put into groups, 17 out of 60 patients in the tocilizumab (experimental) group and 17 out of 63 patients in the standard (comparison) group have worsening conditions. Two patients in the experimental group and 1 in the comparison group died before 30 days after being randomly assigned into groups. Six patients in the experimental group and 5 patients of the other group were intubated (a tube is inserted through the nose or throat to help a person breathe). The trial was stopped early after an analysis showed that the experimental group is not likely to show any added benefit than the comparison group. This clinical study of adult patients with COVID-19 pneumonia showed no benefit on lessening of the disease in patients receiving tocilizumab when compared to the standard care. Additional clinical studies are needed to confirm these results and to evaluate tocilizumab when given at different stages of the disease." +"Background: Monoclonal antibody therapy (MAT) is recommended in mild to moderate Coronavirus disease 2019 (COVID-19) patients who are at risk of progressing to severe disease. Due to limited data on its outcomes and the logistic challenges in administering the drug, MAT has not been widely used in the United States (US) despite of emergency use authorization (EUA) approval by the Food and Drug Administration (FDA). Aim: We aim to study the outcomes of MAT in patients predominantly from ethnic minority groups and the challenges we experienced in implementing the infusion therapy protocol in an inner-city safety-net-hospital in the South Bronx. Methods and results: We conducted a retrospective observational study of 49 patients who were offered MAT as per EUA protocol of FDA. Patient who met the criteria for MAT and received therapy were included in treatment group (n = 38) and the remaining (n = 11) who declined treatment were included in the control group. A majority of patients (76%) in the study group reported symptomatic improvement, the day after infusion. There was statistically significant reduction in COVID-19 related hospitalizations (7.8 vs 54.5%, P = < 0.001) mortality (0 vs 18.1%, P value = 0.008) in the treatment group. Conclusion: MAT reduced both hospitalization and mortality in this predominantly Hispanic patient population with mild to moderate COVID-19 with high risk factors for disease progression.","Monoclonal antibodies are medicines recommended in mild to moderate COVID-19 patients who are at risk of progressing to a severe stage of the disease. Monoclonal antibodies are medicines that may block the virus that causes COVID-19 (a breathing-related disease) from attaching to human cells, making it more difficult for the virus to reproduce. Monoclonal antibodies are not widely used in the United States because there is little data on the impact of these drugs, and it is difficult to give these drugs to patients. This study aimed to assess the outcomes of monoclonal antibodies in patients who were mostly from ethnic minority groups and to study the challenges in providing the treatment in an inner-city hospital in the South Bronx. Researchers looked at data previously collected from 49 patients who were offered monoclonal antibody medicines. The 38 patients who received the monoclonal antibody therapy were put in the treatment group. Eleven people did not want to receive the medicines, so they were made the comparison group. A majority of patients (76%) reported improvement in their symptoms the day after receiving the medicine. There was a big reduction in hospital stays due to COVID-19 and death in the group that received monoclonal antibody medicines. Monoclonal antibody medicines reduced both hospital stays and deaths in this predominantly Hispanic group of patients with mild or moderate COVID-19." +"Hyperinflammation and cytokine storm has been noted as a poor prognostic factor in patients with severe pneumonia related to coronavirus disease 2019 (COVID-19). In COVID-19, pathogenic myeloid cell overactivation is found to be a vital mediator of damage to tissues, hypercoagulability, and the cytokine storm. These cytokines unselectively infiltrate various tissues, such as the lungs and heart, and nervous system. This cytokine storm can hence cause multi-organ dysfunction and life-threatening complications. Mavrilimumab is a monoclonal antibody (mAb) that may be helpful in some cases with COVID-19. During an inflammation, Granulocyte-macrophage colony-stimulating factor (GM-CSF) release is crucial to driving both innate and adaptive immune responses. The GM-CSF immune response is triggered when an antigen attaches to the host cell and induces the signaling pathway. Mavrilimumab antagonizes the action of GM-CSF and decreases the hyperinflammation associated with pneumonia in COVID-19, therefore strengthening the rationale that mavrilimumab when added to the standard protocol of treatment could improve the clinical outcomes in COVID-19 patients, specifically those patients with pneumonia. With this review paper, we aim to demonstrate the inhibitory effect of mavrilimumab on cytokine storms in patients with COVID-19 by reviewing published clinical trials and emphasize the importance of extensive future trials.","Patients with severe pneumonia or lung infections related to COVID-19 (a viral breathing-related disease) may also have an overactive immune response and cytokine storm, which is when the immune system floods the body with proteins called cytokines. These events are associated with poor outcomes. In COVID-19, excessive activity of immune cells is linked to tissue damage, an increased risk of blood clots, and the cytokine storm. The cytokines enter different tissues, such as the lungs and heart, and the nervous system (the spinal cord, brain, and nerves). This cytokine storm can cause multiple organs to not work properly and cause life-threatening complications. Monoclonal antibodies are medicines that may block the virus that causes COVID-19 from attaching to human cells, making it more difficult for the virus to reproduce. One type of monoclonal antibody that may help some COVID-19 cases is mavrilimumab. During inflammation, the release of a GM-CSF, another type of protein that controls the body's immune responses, is necessary for proper immune responses. These proteins are triggered when a foreign substance attaches to a cell and creates a path for cells to communicate and pass information. Mavrilimumab disrupts the action of GM-CSF and decreases the severe inflammation associated with pneumonia in COVID-19. Therefore, adding mavrilimumab to the standard treatment may improve the condition of COVID-19 patients, especially those with pneumonia. This paper reviews data from published studies to show how mavrilimumab can block cytokine storms in patients with COVID-19, and to highlight the importance of future studies." +"Hyperinflammation and cytokine storm has been noted as a poor prognostic factor in patients with severe pneumonia related to coronavirus disease 2019 (COVID-19). In COVID-19, pathogenic myeloid cell overactivation is found to be a vital mediator of damage to tissues, hypercoagulability, and the cytokine storm. These cytokines unselectively infiltrate various tissues, such as the lungs and heart, and nervous system. This cytokine storm can hence cause multi-organ dysfunction and life-threatening complications. Mavrilimumab is a monoclonal antibody (mAb) that may be helpful in some cases with COVID-19. During an inflammation, Granulocyte-macrophage colony-stimulating factor (GM-CSF) release is crucial to driving both innate and adaptive immune responses. The GM-CSF immune response is triggered when an antigen attaches to the host cell and induces the signaling pathway. Mavrilimumab antagonizes the action of GM-CSF and decreases the hyperinflammation associated with pneumonia in COVID-19, therefore strengthening the rationale that mavrilimumab when added to the standard protocol of treatment could improve the clinical outcomes in COVID-19 patients, specifically those patients with pneumonia. With this review paper, we aim to demonstrate the inhibitory effect of mavrilimumab on cytokine storms in patients with COVID-19 by reviewing published clinical trials and emphasize the importance of extensive future trials.","Hyperinflammation and overproduction of inflammatory molecules is a poor predictor of recovery in patients with severe pneumonia (an infection that inflames air sacs in lungs) related to the viral respiratory disease, coronavirus disease 2019 (COVID-19). In COVID-19, disease-causing white blood cell overactivation is a key mediator of damage to tissues, increased blood clots, and inflammatory molecule overproduction. These inflammatory molecules invade many body parts like the lungs, heart, and nervous system. This overproduction of inflammatory molecules can cause multi-organ damage and life-threatening issues. Mavrilimumab is a monoclonal antibody (mAb), which binds to only one site of a foreign organism. It may aid some cases of COVID-19. During inflammation, granulocyte-macrophage colony-stimulating factor (GM-CSF) release, release of molecules that activate specific white blood cells, is crucial for an immune response. The GM-CSF immune response is triggered when a foreign organism attaches to a cell and activates a signal. Mavrilimumab combats the effect of GM-CSF and reduces hyperinflammation linked to pneumonia in COVID-19. This effect stregthens the idea that mavrilimumab, when added to standard treatment, may improve health outcomes in COVID-19 patients, specifically those with pneumonia. With this paper, we aim to show how mavrilimumab reduces overproduction of inflammatory molecules in patients with COVID-19." +"Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods: In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 ?g per dose). BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results: A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions: A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).","The coronavirus and the resulting Covid-19 disease (a viral, breathing-related disease) has impacted tens of millions of people around the world. Vaccines that are safe and work well are urgently needed. In a clinical study that is in progress, people who are at least 16 years old are randomly placed in a group to receive two doses of either a placebo (a shot that does not have medicine) or the BNT162b2 vaccine. The BNT162b2 vaccine works by increasing proteins that help the immune system. The main study outcomes are how well the vaccine works against Covid-19 and its safety. A total of 43,548 participants are randomly put into two groups. Among this group, 43,448 received shots: 21,720 with the BNT162b2 vaccine and 21,728 with the placebo. Among people who received the BNT162b2 vaccine, 8 got Covid-19 at least 7 days after they received the second dose. Among people who received the placebo, 162 got Covid-19. The BNT162b2 vaccine was 95% effective in preventing Covid-19. Similar results are observed across smaller groups of participants when looking at age, sex, race, ethnicity, weight, and the presence of other conditions. Among 10 cases of serious Covid-19 starting after the first dose, 9 cases happened in people who received the placebo and 1 in someone who received the BNT162b2 vaccine. The safety of the BNT162b2 vaccine is described as having short-term, mild-to-moderate pain on the arm where the shot was given, tiredness, and a headache. The number of serious side effects is low and is similar in the vaccine and placebo groups. In conclusion, receiving two doses of the BNT162b2 vaccine provided 95% protection against Covid-19 in people 16 years or older. Safety over an average of 2 months is similar to those of other vaccines. " +"Background: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 ?g) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).","Vaccines are needed to prevent Covid-19 (a viral respiratory disease) and to protect people who are at a high risk for complications or harm. The mRNA-1273 vaccine helps the body make proteins that will strengthen the immune system to fight the coronavirus that causes COVID-19. The 3rd phase of a clinical study is conducted in 99 centers across the United States. People who are at a high risk for the coronavirus or its complications are randomly placed in either the group to receive two shots of the mRNA-1273 vaccine or in the placebo group (people will be given a shot of an inactive substance). The main result researchers are interested in is the prevention of Covid-19 starting at least 14 days after the second shot in study participants who have not already been infected with coronavirus. The trial includes 30,420 volunteers who are randomly placed in a group to receive the vaccine or to receive the placebo. More than 96% of volunteer participants receive both shots, and 2.2% are positive for (or have) the coronavirus at the start of the study. Covid-19 is found in 185 participants in the placebo group and in 11 people in the mRNA-1273 vaccine group. The effectiveness of the vaccine is 94.1%. In additional analyses, the vaccine is found to be effective during the patient evaluation 14 days after the first dose, in participants who were positive for coronavirus at the start of the study, and in participants 65 years old or older. Serious Covid-19 occurs in 30 participants, with one death. All 30 are in the placebo group. Moderate, short-lasting side effects after vaccination occur more often in the mRNA-1273 vaccination group. Serious side effects are rare, and the number of times it occurred is similar in the two groups. In conclusion, the mRNA-1273 vaccine group shows 94.1% effectiveness at preventing Covid-19, including serious cases of Covid-19. Aside from short reactions to mRNA-1273, no safety concerns are found. " +"Background: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 ?g) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results: The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions: The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).","Vaccines are needed to prevent coronavirus disease 2019 (Covid-19), which is a breathing-related viral illness. Vaccines also protect those at high risk for issues. This randomized, controlled trial was performed at 99 centers across the United States. People at high risk for SARS-CoV-2, or Covid-19, infection or its effects were randomly split in a 1:1 ratio to get two injections of the new vaccine or inactive placebo 28 days apart. The key measure was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not been infected with SARS-CoV-2 prior. The trial had 30,420 volunteers randomly assigned in a 1:1 ratio to receive either the vaccine or inactive placebo (15,210 participants in each group). More than 96& of participants got both injections. 2.2% had evidence (antibody and/or molecular testing) of SARS-CoV-2 infection at the start. 185 participants in the inactive placebo group showed symptoms of Covid-19., while11 participants in the vaccine group showed symptoms of Covid-19. Effectiveness was similar for key secondary analyses like analysis 14 days after the first dose, analysis with participants who had evidence of SARS-CoV-2 infection at the start, and analysis in participants 65 years or older. Severe Covid-19 occured in 30 participants, with one death. All 30 were in the inactive placebo group. Moderate, temporary body reactions after vaccination occured more often in the vaccine group. Serious, harmful events were rare, and the frequency was similar in the two groups. The vaccine showed 94.1% success at preventing Covid-19, including severe disease. Aside from temporary local and full-body reactions, no safety concerns were found. " +"Objective: The ""Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)"" disease has caused a worldwide challenging and threatening pandemic (COVID-19), with huge health and economic losses. The US Food and Drug Administration, (FDA) has granted emergency use authorization for treatment with the Pfizer/BioNTech and Moderna COVID-19 vaccines. Many people have a history of a significant allergic reaction to a specific food, medicine, or vaccine; hence, people all over the world have great concerns about these two authorized vaccines. This article compares the pharmacology, indications, contraindications, and adverse effects of the Pfizer/BioNTech and Moderna vaccines. Materials and methods: The required documents and information were collected from the relevant databases, including Web of Science (Clarivate Analytics), PubMed, EMBASE, World Health Organization (WHO), Food and Drug Authorities (FDA) USA, Local Ministries, Health Institutes, and Google Scholar. The key terms used were: Coronavirus, SARS-COV-2, COVID-19 pandemic, vaccines, Pfizer/BioN Tech vaccine, Moderna vaccine, pharmacology, benefits, allergic responses, indications, contraindications, and adverse effects. The descriptive information was recorded, and we eventually included 12 documents including research articles, clinical trials, and websites to record the required information. Results: Based on the currently available literature, both vaccines are beneficial to provide immunity against SARS-CoV-2 infection. Pfizer/BioN Tech Vaccine has been recommended to people 16 years of age and older, with a dose of 30 ?g (0.3 m) at a cost of $19.50. It provides immunogenicity for at least 119 days after the first vaccination and is 95% effective in preventing the SARS-COV-2 infection. However, Moderna Vaccine has been recommended to people 18 years of age and older, with a dose of 50 ?g (0.5 mL) at a cost of $32-37. It provides immunogenicity for at least 119 days after the first vaccination and is 94.5% effective in preventing the SARS-CoV-2 infection. However, some associated allergic symptoms have been reported for both vaccines. The COVID-19 vaccines can cause mild adverse effects after the first or second doses, including pain, redness or swelling at the site of vaccine shot, fever, fatigue, headache, muscle pain, nausea, vomiting, itching, chills, and joint pain, and can also rarely cause anaphylactic shock. The occurrence of adverse effects is reported to be lower in the Pfizer/BioNTech vaccine compared to the Moderna vaccine; however, the Moderna vaccine compared to the Pfizer vaccine is easier to transport and store because it is less temperature sensitive. Conclusions: The FDA has granted emergency use authorization for the Pfizer/BioNTech and Moderna COVID-19 vaccines. These vaccines can protect recipients from a SARS-CoV- 2 infection by formation of antibodies and provide immunity against a SARS-CoV-2 infection. Both vaccines can cause various adverse effects, but these reactions are reported to be less frequent in the Pfizer/BioNTech vaccine compared to the Moderna COVID-19 vaccine; however, the Moderna vaccine compared to the Pfizer vaccine is easier to transport and store because it is less temperature sensitive.","The coronavirus disease has caused a global pandemic (Covid-19 - a viral breathing-related disease), with huge health and economic losses. The US Food and Drug Administration (FDA) has granted emergency use authorization, where unapproved medicines may be used, for treatment with the Pfizer/BioNTech and Moderna Covid-19 vaccines. Many people have a history of bad allergic reactions to specific foods, medicine, or vaccines, so people all over the world have great concerns about these two vaccines. This article compares the use, reasons to take, reasons to not get, and side effects of the Pfizer and Moderna vaccines. The documents and information are collected from multiple databases and sources, including the FDA and World Health Organization. Researchers used key search terms to collect information: Coronavirus, SARS-COV-2 (the coronavirus's name), Covid-19 pandemic, vaccines, Pfizer vaccine, Moderna vaccine, impact of drugs, benefits, allergic responses, reasons to take vaccines, reasons to not take the vaccine, and unexpected serious side effects. Twelve documents including research articles, clinical studies, and websites are used to record the required information. Based on available information, both vaccines are beneficial in providing immunity (resistance) against the coronavirus infection. The Pfizer vaccine is recommended to people 16 years of age and older. It triggers an immune response for at least 119 days after the first vaccination and is 95% effective in preventing the coronavirus infection. However, the Moderna vaccine is recommended to people 18 years of age and older. It triggers an immune response for at least 119 days after the first vaccination and is 94.5% effective in preventing the coronavirus infection. However, some allergic reactions have been reported for both vaccines. The Covid-19 vaccines can cause mild side effects after the first and second shot, including pain, redness or swelling at the site of the vaccine shot, fever, fatigue, headache, muscle pain, nausea, vomiting, itching, chills, and joint pain. Rarely, it can cause anaphylactic shock which is a severe allergic reaction that begins very quickly and can be life-threatening. Side effects are reported to be lower in the Pfizer vaccine compared to Moderna; however, the Moderna vaccine is easier to transport and store. In conclusion, the FDA has granted emergency use authorization for the Pfizer and Moderna Covid-19 vaccines. These vaccines can protect people from coronavirus infection by forming antibodies (protective proteins made by the immune system to fight infections) and provide immunity against a coronavirus infection. Both vaccines can cause different side effects, but these reactions are found to be less frequent in the Pfizer vaccine compared to the Moderna vaccine. However, the Moderna vaccine is easier to transport and store compared to the Pfizer vaccine." +"In December 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (EUAs) for Pfizer-BioNTech and Moderna COVID-19 vaccines, and in February 2021, FDA issued an EUA for the Janssen (Johnson & Johnson) COVID-19 vaccine. After each EUA, the Advisory Committee on Immunization Practices (ACIP) issued interim recommendations for vaccine use; currently Pfizer-BioNTech is authorized and recommended for persons aged ?12 years and Moderna and Janssen for persons aged ?18 years (1-3). Both Pfizer-BioNTech and Moderna vaccines, administered as 2-dose series, are mRNA-based COVID-19 vaccines, whereas the Janssen COVID-19 vaccine, administered as a single dose, is a recombinant replication-incompetent adenovirus-vector vaccine. As of July 22, 2021, 187 million persons in the United States had received at least 1 dose of COVID-19 vaccine (4); close monitoring of safety surveillance has demonstrated that serious adverse events after COVID-19 vaccination are rare (5,6). Three medical conditions have been reported in temporal association with receipt of COVID-19 vaccines. Two of these (thrombosis with thrombocytopenia syndrome [TTS], a rare syndrome characterized by venous or arterial thrombosis and thrombocytopenia, and Guillain-Barr� syndrome [GBS], a rare autoimmune neurologic disorder characterized by ascending weakness and paralysis) have been reported after Janssen COVID-19 vaccination. One (myocarditis, cardiac inflammation) has been reported after Pfizer-BioNTech COVID-19 vaccination or Moderna COVID-19 vaccination, particularly after the second dose; these were reviewed together and will hereafter be referred to as mRNA COVID-19 vaccination. ACIP has met three times to review the data associated with these reports of serious adverse events and has comprehensively assessed the benefits and risks associated with receipt of these vaccines. During the most recent meeting in July 2021, ACIP determined that, overall, the benefits of COVID-19 vaccination in preventing COVID-19 morbidity and mortality outweigh the risks for these rare serious adverse events in adults aged ?18 years; this balance of benefits and risks varied by age and sex. ACIP continues to recommend COVID-19 vaccination in all persons aged ?12 years. CDC and FDA continue to closely monitor reports of serious adverse events and will present any additional data to ACIP for consideration. Information regarding risks and how they vary by age and sex and type of vaccine should be disseminated to providers, vaccine recipients, and the public.","In December 2020, the Food and Drug Administration (FDA) issued Emergency Use Authorizations (when unapproved medicines may be used) for Pfizer-BioNTech and Moderna Covid-19 vaccines (vaccines for the viral, respiratory disease). In February 2021, the FDA issued an emergency authorization for the Janssen (Johnson & Johnson) Covid-19 vaccine. After each emergency authorization was issued, short-term recommendations for vaccine use were issued. Currently, Pfizer is authorized and recommended for persons aged 12 years or older and Moderna and Janssen for persons aged 18 years and older. The Pfizer and Moderna vaccines require two shots and use a strand of genetic code that the body uses to build a protein that�s found in the coronavirus. The Janssen vaccine requires one shot and delivers instructions by DNA that the virus cannot replicate. As of July 22, 2021, 187 million people in the United States received at least one shot of the Covid-19 vaccine, and it has been demonstrated that serious side effects are rare. Three medical conditions have been reported after getting the Covid-19 vaccine, but the association between these conditions and the vaccine is mainly based on timing, in which the condition and vaccine occur around the same time. Two of these conditions are reported after getting the Johnson & Johnson vaccine. They are 1) thrombosis with thrombocytopenia syndrome [TTS], a rare condition with blood clots in the veins and arteries and low blood platelet counts (platelets help the body form blood clots to stop bleeding from injury), and 2) Guillain-Barr� syndrome [GBS], a rare disorder characterized by muscle weakness and paralysis. One condition (myocarditis, cardiac inflammation or heart-related swelling from an infection) has been reported after the Pfizer or Moderna vaccine, usually after the second dose. These two vaccines will be referred to as mRNA Covid-19 vaccination. Data associated with these reports of serious side effects, in addition to the benefits and risks associated with vaccination, have been reviewed by the Advisory Committee on Immunization Practices (ACIP). During the most recent meeting in July 2021, ACIP determined that, overall, the benefits of Covid-19 vaccination in preventing Covid-19 illness and death outweigh the risks for these rare serious side effects in adults aged 18 years or older. This balance of benefits and risks was different by age and sex. ACIP continues to recommend Covid-19 vaccination in all people aged 12 years and older. CDC and FDA continue to closely monitor reports of serious side effects and will present any additional data to ACIP for review. Information on risks and how they vary by age, sex, and type of vaccine should be shared with providers, people who receive the vaccine, and the public." +"As of January 3, 2021, a total of 20,346,372 cases of coronavirus disease 2019 (COVID-19) and 349,246 associated deaths have been reported in the United States. Long-term sequalae of COVID-19 over the course of a lifetime currently are unknown; however, persistent symptoms and serious complications are being reported among COVID-19 survivors, including persons who initially experience a mild acute illness.* On December 11, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Pfizer-BioNTech COVID-19 vaccine to prevent COVID-19, administered as 2 doses separated by 21 days. On December 12, 2020, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine (1); initial doses were recommended for health care personnel and long-term care facility residents (2). As of December 23, 2020, a reported 1,893,360 first doses of Pfizer-BioNTech COVID-19 vaccine had been administered in the United States, and reports of 4,393 (0.2%) adverse events after receipt of Pfizer BioNTech COVID-19 vaccine had been submitted to the Vaccine Adverse Event Reporting System (VAERS). Among these, 175 case reports were identified for further review as possible cases of severe allergic reaction, including anaphylaxis. Anaphylaxis is a life-threatening allergic reaction that does occur rarely after vaccination, with onset typically within minutes to hours (3). Twenty-one cases were determined to be anaphylaxis (a rate of 11.1 per million doses administered), including 17 in persons with a documented history of allergies or allergic reactions, seven of whom had a history of anaphylaxis. The median interval from vaccine receipt to symptom onset was 13 minutes (range = 2-150 minutes). Among 20 persons with follow-up information available, all had recovered or been discharged home. Of the remaining case reports that were determined not to be anaphylaxis, 86 were judged to be nonanaphylaxis allergic reactions, and 61 were considered nonallergic adverse events. Seven case reports were still under investigation. This report summarizes the clinical and epidemiologic characteristics of case reports of allergic reactions, including anaphylaxis and nonanaphylaxis allergic reactions, after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine during December 14-23, 2020, in the United States. CDC has issued updated interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States (4) and interim considerations for preparing for the potential management of anaphylaxis (5). In addition to screening for contraindications and precautions before administering COVID-19 vaccines, vaccine locations should have the necessary supplies available to manage anaphylaxis, should implement postvaccination observation periods, and should immediately treat persons experiencing anaphylaxis signs and symptoms with intramuscular injection of epinephrine (4,5).","As of January 3, 2021, a total of 20,346,372 cases of Covid-19 (a viral, breathing-related disease) and 349,246 deaths associated with Covid-19 have been reported in the United States. Long-lasting effects of Covid-19 over the course of a lifetime are currently unknown; however, continuing symptoms and serious complications are being reported by some Covid-19 survivors, including people who first have a mild acute (sudden) case. On December 11, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA), which allows unapproved medicines to be used, for Pfizer-BioNTech Covid-19 vaccine to prevent Covid-19, administered as 2 doses separated by 21 days. A group of medical and public health experts called the Advisory Committee on Immunization Practices issued a temporary recommendation in December 2020 for using the Pfizer vaccine; the first available doses were to be used for health care staff and people who lived in long-term care facilities. As of December 23, 2020, a reported 1,893,360 first shots of the Pfizer vaccine had been administered in the United States, and reports of 4,393 (0.2%) unexpected side effects (adverse events) after receiving the Pfizer vaccine had been submitted to the Vaccine Adverse Event Reporting System (VAERS), a national vaccine safety tracking system that accepts reports of adverse events after vaccination. Among these reports of adverse events, 175 case reports were identified for further review as possible cases of severe allergic reaction, including anaphylaxis - a life-threatening allergic reaction. Anaphylaxis is a life-threatening allergic reaction that occurs rarely after vaccination and usually starts within minutes to hours of receiving the vaccine. There were 21 cases with anaphylaxis, including 17 in people with a documented history of allergies or allergic reactions, 7 of whom had a history of anaphylaxis. The average time between receiving the vaccine to the start of symptoms was 13 minutes, but the range of time for symptoms to start was between 2 minutes - 150 minutes. Among 20 people with follow-up information available, all had recovered or been sent home. Of the remaining case reports that were found not to have anaphylaxis, 86 cases were judged not to be anaphylaxis allergic reactions, and 61 were considered nonallergic adverse events. Seven case reports were still under investigation. This report summarizes the case reports of allergic reactions, including anaphylaxis and nonanaphylaxis allergic reactions, after receiving the first shot of the Pfizer vaccine during December 14-23, 2020, in the United States. CDC has issued updated temporary clinical guidance for use of Covid-19 vaccines currently allowed in the United States and temporary guidance for preparing for people who experience anaphylaxis. In addition to checking for reasons a person should not get the vaccine and precautions before giving the Covid-19 vaccines, the locations providing the vaccine should have necessary supplies if anaphylaxis occurs. Additionally, these locations should set aside time to observe people who receive the vaccine and should immediately treat people experiencing anaphylaxis signs and symptoms." +"As of January 3, 2021, a total of 20,346,372 cases of coronavirus disease 2019 (COVID-19) and 349,246 associated deaths have been reported in the United States. Long-term sequalae of COVID-19 over the course of a lifetime currently are unknown; however, persistent symptoms and serious complications are being reported among COVID-19 survivors, including persons who initially experience a mild acute illness.* On December 11, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Pfizer-BioNTech COVID-19 vaccine to prevent COVID-19, administered as 2 doses separated by 21 days. On December 12, 2020, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for use of Pfizer-BioNTech COVID-19 vaccine (1); initial doses were recommended for health care personnel and long-term care facility residents (2). As of December 23, 2020, a reported 1,893,360 first doses of Pfizer-BioNTech COVID-19 vaccine had been administered in the United States, and reports of 4,393 (0.2%) adverse events after receipt of Pfizer BioNTech COVID-19 vaccine had been submitted to the Vaccine Adverse Event Reporting System (VAERS). Among these, 175 case reports were identified for further review as possible cases of severe allergic reaction, including anaphylaxis. Anaphylaxis is a life-threatening allergic reaction that does occur rarely after vaccination, with onset typically within minutes to hours (3). Twenty-one cases were determined to be anaphylaxis (a rate of 11.1 per million doses administered), including 17 in persons with a documented history of allergies or allergic reactions, seven of whom had a history of anaphylaxis. The median interval from vaccine receipt to symptom onset was 13 minutes (range = 2-150 minutes). Among 20 persons with follow-up information available, all had recovered or been discharged home. Of the remaining case reports that were determined not to be anaphylaxis, 86 were judged to be nonanaphylaxis allergic reactions, and 61 were considered nonallergic adverse events. Seven case reports were still under investigation. This report summarizes the clinical and epidemiologic characteristics of case reports of allergic reactions, including anaphylaxis and nonanaphylaxis allergic reactions, after receipt of the first dose of Pfizer-BioNTech COVID-19 vaccine during December 14-23, 2020, in the United States. CDC has issued updated interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States (4) and interim considerations for preparing for the potential management of anaphylaxis (5). In addition to screening for contraindications and precautions before administering COVID-19 vaccines, vaccine locations should have the necessary supplies available to manage anaphylaxis, should implement postvaccination observation periods, and should immediately treat persons experiencing anaphylaxis signs and symptoms with intramuscular injection of epinephrine (4,5).","As of January 3, 2021, the United States has reported 20,346,372 cases of a breathing-related illness, coronavirus disease 2019 (COVID-19), and 349,246 related deaths. Long-term consequences of COVID-19 over a lifetime are unknown. However, COVID-19 survivors, including those who initially had a mild, sudden illness, report persistent symptoms and serious issues. On December 11, 20202, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) or approval for Pfizer-BioNTech COVID-19 vaccine to prevent COVID-19, given as 2 doses separated by 21 days. On December 12, 2020, the Advisory Committee on Immunization Practices (ACIP), a group of health experts, gave an temporary recommendation for the Pfizer-BioNTech COVID-19 vaccine (1). Initial doses were recommended for health care workers and long-term care residents (2). As of December 23, 2020, 1,893,360 first doses of Pfizer-BioNTech COVID-19 vaccine had been given in the United States. After people received the vaccine, reports of 4,393 (0.2%) unfortunate events were submitted to an official vaccine event tracking system. Among the unfortunate events, 175 individual patient reports were picked for further review as possible cases of severe allergic reaction, including life-threatening reactions. Anaplylaxis is a life-threatening allergic reaction that occurs rarely after vaccination, usually starting within minutes to hours (3). Twenty-one cases were identified as anaphylaxis (a rate of 11.1 per million doses given). These includ 17 in those with a noted history of allergies or allergic reactions, seven of whom had anaphylaxis before. The average interval from receiving the vaccine to experiencing symptoms was 13 minutes (ranging from 2 to 150 minutes). Among 20 people with follow-up information available, all had recovered or been sent home. Of the other case reports determined to not be anaphylaxis, 86 were noted to be nonanaphylaxis allergic reactions. 61 were considered nonallergic unfortunate events. Seven individual patient reports were still under investigation. This report summarizes the clinical and social characteristics of individual patient reports of alltergic reactions, including anaphylaxis and nonanaphylaxis reactions, after receiving the first dose of Pfizer-BioNTech COVID-19 vaccine during December 14-23, 2020 in the United States. The nation's health protection agency issued new clinical considerations for using mRNA COVID-19 vaccines currently allowed in the United States (4) and for preparaing for possibly managing analphylaxis (5). Along with testing for eligibility and safety measures before giving COVID-19 vaccines, vaccine locations should have the necessary supplies to manage anaphylaxis, enforce postvaccination observation periods, and immediately treat those experiencing anaphylaxis sign and symptoms with injections of epinephrine, first-aid medication for anaphylaxis (4, 5)." +"As of January 20, 2021, a total of 24,135,690 cases of coronavirus disease 2019 (COVID-19) and 400,306 associated deaths had been reported in the United States (https://covid.cdc.gov/covid-data-tracker/#cases_casesper100klast7days). On December 18, 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Moderna COVID-19 vaccine administered as 2 doses, 1 month apart to prevent COVID-19. On December 19, 2020, the Advisory Committee on Immunization Practices (ACIP) issued an interim recommendation for use of Moderna COVID-19 vaccine (1). As of January 10, 2021, a reported 4,041,396 first doses of Moderna COVID-19 vaccine had been administered in the United States, and reports of 1,266 (0.03%) adverse events after receipt of Moderna COVID-19 vaccine were submitted to the Vaccine Adverse Event Reporting System (VAERS). Among these, 108 case reports were identified for further review as possible cases of severe allergic reaction, including anaphylaxis. Anaphylaxis is a life-threatening allergic reaction that occurs rarely after vaccination, with onset typically within minutes to hours (2). Among these case reports, 10 cases were determined to be anaphylaxis (a rate of 2.5 anaphylaxis cases per million Moderna COVID-19 vaccine doses administered), including nine in persons with a documented history of allergies or allergic reactions, five of whom had a previous history of anaphylaxis. The median interval from vaccine receipt to symptom onset was 7.5 minutes (range = 1-45 minutes). Among eight persons with follow-up information available, all had recovered or been discharged home. Among the remaining case reports that were determined not to be anaphylaxis, 47 were assessed to be nonanaphylaxis allergic reactions, and 47 were considered nonallergic adverse events. For four case reports, investigators have been unable to obtain sufficient information to assess the likelihood of anaphylaxis. This report summarizes the clinical and epidemiologic characteristics of case reports of allergic reactions, including anaphylaxis and nonanaphylaxis allergic reactions, after receipt of the first dose of Moderna COVID-19 vaccine during December 21, 2020-January 10, 2021, in the United States. CDC has issued updated interim clinical considerations for use of mRNA COVID-19 vaccines currently authorized in the United States (3) and interim considerations for preparing for the potential management of anaphylaxis (4).","As of January 20, 2021, a total of 24,135,690 cases of Covid-19 (a viral, respiratory disease) and 400,306 associated deaths have been reported in the United States. In December 2020, the Food and Drug Administration (FDA) issued an Emergency Use Authorization, where unapproved medicines are allowed to be used, for the Moderna Covid-19 vaccine given as 2 doses, 1 month apart to prevent Covid-19. A group of medical and public health experts called the Advisory Committee on Immunization Practices made a temporary recommendation for using the Moderna vaccine. As of January 2021, a reported 4,041,396 first doses of the Moderna vaccine have been given in the United States. Additionally, reports of 1,266 (0.03%) unexpected serious side effects (adverse events) after receiving the Moderna vaccine are sent to the Vaccine Adverse Event Reporting System (VAERS), a national vaccine safety tracking system that accepts reports of adverse events after vaccination. Among these adverse events, 108 cases are identified for additional review for possible cases of severe allergic reaction, including anaphylaxis - a life-threatening allergic reaction. Anaphylaxis is a life-threatening allergic reaction that occurs rarely after vaccination and usually starts within minutes to hours of receiving the vaccine. Among these case reports, 10 cases are determined to be anaphylaxis, including 9 in people with a history of allergies or allergic reactions, 5 of whom had a previous history of anaphylaxis. The average time from receiving the vaccine to symptoms of anaphylaxis starting is 7.5 minutes, but the time ranges between 1 minute - 45 minutes. Among 8 people with follow-up information available, all have recovered or are sent home. Among the remaining reports that are not anaphylaxis, 47 are found to be allergic reactions that are not anaphylaxis, and 47 are considered nonallergic adverse events. For 4 case or individual's reports, investigators have been unable to obtain enough information to assess the possibility of anaphylaxis. This report summarizes the case reports of allergic reactions, including anaphylaxis and allergic reactions that are not anaphylaxis, after receiving the first dose of the Moderna vaccine during December 21, 2020-January 10, 2021, in the United States. CDC has issued updated temporary clinical guidance for use of Covid-19 vaccines currently allowed in the United States and temporary guidance for preparing for people who experience anaphylaxis." +"The coronavirus disease 2019 (COVID-19) pandemic is a global crisis, with devastating health, business and social impacts. Vaccination is a safe, simple, and effective way of protecting a person against COVID-19. By the end of August 2021, only 24.6% of the world population has received two doses of a COVID-19 vaccine. Since the emergence of COVID-19, several COVID-19 vaccines have been developed and approved for emergency use. Current vaccines have shown efficacy with low risk of adverse effects. However, COVID-19 vaccines have been related to a relatively small number of cases of heart inflammation, anaphylaxis (allergic reactions), and blood clots formation. On the other hand, COVID-19 vaccination is not recommended for children less than 12 years of age. Furthermore, It has been proposed that some new variants (e.g., Lambda and Delta) are proficient in escaping from the antiviral immunity elicited by vaccination. Herein we present current considerations regarding the COVID-19 vaccines including: efficacy against new variants, challenges in distribution, disparities in availability, dosage gender and race difference, COVID-19 vaccine transport and storage, limitations in children and pregnant women. Long-time monitoring is essential in order to find vaccine efficacy and to rule out related side effects.","The Covid-19 (a breathing-related, viral disease) pandemic is a global crisis, with devastating health, business and social impacts. Vaccination is a safe, simple, and effective way of protecting a person against Covid-19. By the end of August 2021, only 24.6% of the world population has received two doses of a Covid-19 vaccine. Several Covid-19 vaccines have been developed and approved for emergency use, which is when medicines not yet approved are allowed to be used. Current vaccines are shown to be effective with a low risk of unexpected serious side effects, also called adverse effects. However, Covid-19 vaccines are related to a relatively small number of cases of heart inflammation that can cause damage to the heart muscle via redness and swelling from an infection, anaphylaxis (severe allergic reactions that may be life-threatening), and blood clot formation. On the other hand, Covid-19 vaccination is not recommended for children less than 12 years of age. Also, it is proposed that some new variants (e.g., Lambda and Delta) are able to escape the immune response from vaccinations. This paper presents current considerations on the Covid-19 vaccines including: effectiveness against new variants, challenges in distribution of the vaccines, differences in availability to groups, differences in doses by gender and race, how to transport and store the vaccines, and limitations in children and pregnant women. Long-time monitoring is key in order to find vaccine effectiveness and to rule out related side effects." +"There have been reports of myocarditis following COVID-19 vaccination. We surveyed all hospitalized military personnel in the Isareli Defense Forces during the period of the COVID-19 vaccination operation (12/28/2021-3/7/2021) for diagnosed myocarditis. We identified 7 cases of myocarditis with symptoms starting in the first week after the second dose of COVID-19 Pfizer-BioNTech vaccine. One case of myocarditis diagnosed 10 days after the second dose of the vaccine was not included. These 8 cases comprise of all events of myocarditis diagnosed in military personnel during this time period. All patients were young and generally healthy. All had mild disease with no sequalae. The incidence of myocarditis in the week following a second dose of the vaccine was 5.07/100,000 people vaccinated. Due to the nature of this report no causality could be established. Clinicians should be aware of the possibility of myocarditis following Pfizer-BioNTech vaccination. True incidence rates should be further investigated.","There are reports of inflammation (redness and swelling from fighting and infection) of the heart muscle, also called myocarditis, after vaccination for Covid-19 (a viral lung infection). Researchers reviewed all hospitalized military personnel in the Isareli Defense Forces during the period of the Covid-19 vaccination (12/28/2021-3/7/2021) for confirmed cases of myocarditis. Researchers found 7 cases of myocarditis with symptoms starting in the first week after the second dose of Covid-19 Pfizer-BioNTech vaccine. One case of myocarditis diagnosed 10 days after the second dose of the vaccine is not included. These 8 cases are all events of myocarditis diagnosed in military personnel during this time period. All patients are young and generally healthy. All have a mild case of the disease with no long-lasting effects. The number of myocarditis in the week following a second dose of the vaccine is 5.07 out of 100,000 people vaccinated. Due to the nature of this report, no deaths can be established. Medical providers should be aware of the possibility of myocarditis following Pfizer vaccination. The true number of occurrence of myocarditis among people receiving the vaccine should be further investigated." +"There have been reports of myocarditis following COVID-19 vaccination. We surveyed all hospitalized military personnel in the Isareli Defense Forces during the period of the COVID-19 vaccination operation (12/28/2021-3/7/2021) for diagnosed myocarditis. We identified 7 cases of myocarditis with symptoms starting in the first week after the second dose of COVID-19 Pfizer-BioNTech vaccine. One case of myocarditis diagnosed 10 days after the second dose of the vaccine was not included. These 8 cases comprise of all events of myocarditis diagnosed in military personnel during this time period. All patients were young and generally healthy. All had mild disease with no sequalae. The incidence of myocarditis in the week following a second dose of the vaccine was 5.07/100,000 people vaccinated. Due to the nature of this report no causality could be established. Clinicians should be aware of the possibility of myocarditis following Pfizer-BioNTech vaccination. True incidence rates should be further investigated.","There have been reports of myocarditis (heart muscle inflammation) following vaccination of COVID-19 (a viral respiratory disease). We checked all hospitalized military people in the Isareli Defense Forces during the COVID-19 vaccination operation (12/28/2021-3/7/2021) for diagnosed myocarditis. We found 7 cases of myocarditis with symptoms starting in the first week after the second dose of COVID-19 Pfizer-BioNTech vaccine. One case of myocarditis identified 10 days after the second vaccine dose was not included. These 8 cases were all the events of myocarditis diagnosed in military people during this time period. All patients were young and generally healthy. All had mild disease with no consequences. The frequency of myocarditis in the week after a second vaccine dose was 5.07/100,000 people vaccinated. Due to the nature of this report, no causality could be identified. Clinicians should know about the possibility of myocarditis after Pfizer-BioNTech vaccination. True frequency rates should be further investigated." +"Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson). Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS. Design, setting, and participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination. Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria. Main outcomes and measures: Clinical characteristics and mortality rate. Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later. Conclusions and relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.","Thrombosis with thrombocytopenia syndrome (TTS) is a rare condition of blood clots in the veins and arteries and low blood platelet counts. TTS has been reported in some people after they receive the AstraZeneca and Janssen/Johnson & Johnson vaccines. These vaccines provide immunity or resistance to the coronavirus, which causes COVID-19 (a viral, respiratory disease). The objective of this study is to describe the clinical traits and outcomes of patients with cerebral venous sinus thrombosis (CVST) (blood clot in the brain) after receiving the coronavirus vaccine among people with and without TTS. This study uses data from patients who have CVST within 28 days of vaccination in March-June 2021. Data came from 81 hospitals in 19 countries. Existing data from patients with CVST between 2015 and 2018 are used to compare. Clinical traits and death are described for adults with (1) CVST in the case of coronavirus vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after coronavirus vaccination not meeting all parts for TTS, and (3) CVST unrelated to the coronavirus vaccination. Patients are classified as having TTS (thrombosis with thrombocytopenia syndrome) if they have new thrombocytopenia (low blood platelets) without recent exposure to heparin, a medicine that prevents blood clots. Clinical traits and deaths are the main measures in this study. Of the 116 patients with CVST after being vaccinated, 78 (67.2%) have TTS. Of those, 76 people had been vaccinated with AstraZeneca and 38 (32.8%) have no indication of TTS. The comparison group included 207 patients with CVST before the Covid-19 pandemic. A total of 63 out of 78 (81%) are female with an average age of 45, 30 out of of 38 (79%) are female with an average age of 55, and 145 of 207 (70.0%) patients are female and have an average age of 42 years. Thromboembolism, which is a blood clot in the vein that has been dislodged from another part of the body, occurred in 25 out of 70 patients (36%) in the TTS group, 2 out of 35 (6%) in the no TTS group, and 10 out of 206 (4.9%) in the comparison group. Deaths in the hospital are at 47% in the TTS group, 5% in the no TTS group, and 3.9% in the comparison group. The rate of deaths is 61% among patients with TTS diagnosed before the condition got the attention of scientists and 42% among patients diagnosed later. In this study of patients with cerebral venous sinus thrombosis, a detailed clinical description and high death rate is observed in patients who have thrombosis with thrombocytopenia syndrome after vaccination." +"Purpose: The COVID-19 pandemic has galvanized the development of new vaccines at an unprecedented pace. Since the widespread implementation of vaccination campaigns, reports of ocular adverse effects after COVID-19 vaccinations have emerged. This review summarizes ocular adverse effects possibly associated with COVID-19 vaccination, and discusses their clinical characteristics and management. Results: Ocular adverse effects of COVID-19 vaccinations include facial nerve palsy, abducens nerve palsy, acute macular neuroretinopathy, central serous retinopathy, thrombosis, uveitis, multiple evanescent white dot syndrome, Vogt-Koyanagi-Harada disease reactivation, and new-onset Graves' Disease. Studies in current literature are primarily retrospective case series or isolated case reports - these are inherently weak in establishing association or causality. Nevertheless, the described presentations resemble the reported ocular manifestations of the COVID-19 disease itself. Hence, we hypothesize that the human body's immune response to COVID-19 vaccinations may be involved in the pathogenesis of the ocular adverse effects post-COVID-19 vaccination. Conclusion: Ophthalmologists and generalists should be aware of the possible, albeit rare, ocular adverse effects after COVID-19 vaccination.","The pandemic of Covid-19 (a viral, breathing-related disease) has led to the development of new vaccines at an very fast pace. Since the start of major efforts to promote vaccination, reports of ocular adverse effects, which are side effects that impact the eyes or the face near the eyes, after Covid-19 vaccinations have emerged. This review summarizes these ocular adverse effects that are possibly associated with Covid-19 vaccines and discusses their medical traits and how to care for these effects. Ocular adverse effects of Covid-19 vaccinations include weakness or paralysis in the facial muscles, problems with eye movement, blind or blurry spots, distorted vision due to fluid build up in the eye, blood clots in the veins or arteries, inflammation (redness or swelling from fighting an infection) inside the eye, inflammation in the retina of the eye, rapid vision loss from previous diseases, and newly-contracted Graves' Disease, a condition that increases thyroid (metabolism-regulating) hormones and can impact the skin and eyes. Published studies mainly use existing information from previous cases or isolated reports; these are weak studies in establishing association or cause and effect. However, the described cases are similar, regarding the impact on the eyes or vision, to the Covid-19 disease itself. Researchers have a theory that the body's immune response to Covid-19 vaccinations may be involved in the development of the ocular adverse effects that occur after receiving the Covid-19 vaccine. Eye surgeons and doctors should be aware of the possible, although rare, ocular adverse effects that impact the eyes after a Covid-19 vaccine." +"The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its threat to humans have drawn worldwide attention. The acute and long-term effects of SARS-CoV-2 on the nervous system pose major public health challenges. Patients with SARS-CoV-2 present diverse symptoms of the central nervous system. Exploring the mechanism of coronavirus damage to the nervous system is essential for reducing the long-term neurological complications of COVID-19. Despite rapid progress in characterizing SARS-CoV-2, the long-term effects of COVID-19 on the brain remain unclear. The possible mechanisms of SARS-CoV-2 injury to the central nervous system include: 1) direct injury of nerve cells, 2) activation of the immune system and inflammatory cytokines caused by systemic infection, 3) a high affinity of the SARS-CoV-2 spike glycoprotein for the angiotensin-converting enzyme ACE2, 4) cerebrovascular disease caused by hypoxia and coagulation dysfunction, and 5) a systemic inflammatory response that promotes cognitive impairment and neurodegenerative diseases. Although we do not fully understand the mechanism by which SARS-CoV-2 causes nerve injury, we hope to provide a framework by reviewing the clinical manifestations, complications, and possible mechanisms of neurological damage caused by SARS-CoV-2. With hope, this will facilitate the early identification, diagnosis, and treatment of possible neurological sequelae, which could contribute toward improving patient prognosis and preventing transmission.","The ongoing global pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known COVID-19 (a viral, breathing-related disease). It has threatened public health and drawn worldwide attention. The short- and long-term effects of COVID-19 on the nervous system pose major public health challenges. Patients with COVID-19 present a wide range of symptoms of the central nervous system (the brain and spinal cord). It is essential to better understand how COVID-19 affects the nervous system. Increasing current understanding will reduce the long-term effects COVID-19 may cause within the brain. Despite rapid progress in better understanding how COVID-19 hurts the human body, the long-term effects of the virus on the brain are still unclear. There are several possible ways COVID-19 affects the central nervous system. One of these ways is by potentially hurting nerve cells. Second, the virus may cause body-wide inflammation (redness and swelling from fighting an infection) that may activate the immune system. Third, COVID-19 may be highly attracted to a specific pathway into cells and can then rapidly distribute throughout the body. Fourth, the virus may cause disease by decreasing oxygen and increase blood clotting within the body. And lastly, COVID-19 may cause body-wide inflammation that decreases brain function. Despite not fully understanding how COVID-19 causes nerve injury, the authors hoped to provide a review of clinical reports, documented human health effects, and potential pathways of COVID-19-caused brain damage. The aim of this paper was to assist in early detection, diagnosis, and treatment of COVID-19-caused brain damage. Additionally, the authors hope this can help predict COVID-19 related effects before they occur and decrease viral spread in general." +"The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its threat to humans have drawn worldwide attention. The acute and long-term effects of SARS-CoV-2 on the nervous system pose major public health challenges. Patients with SARS-CoV-2 present diverse symptoms of the central nervous system. Exploring the mechanism of coronavirus damage to the nervous system is essential for reducing the long-term neurological complications of COVID-19. Despite rapid progress in characterizing SARS-CoV-2, the long-term effects of COVID-19 on the brain remain unclear. The possible mechanisms of SARS-CoV-2 injury to the central nervous system include: 1) direct injury of nerve cells, 2) activation of the immune system and inflammatory cytokines caused by systemic infection, 3) a high affinity of the SARS-CoV-2 spike glycoprotein for the angiotensin-converting enzyme ACE2, 4) cerebrovascular disease caused by hypoxia and coagulation dysfunction, and 5) a systemic inflammatory response that promotes cognitive impairment and neurodegenerative diseases. Although we do not fully understand the mechanism by which SARS-CoV-2 causes nerve injury, we hope to provide a framework by reviewing the clinical manifestations, complications, and possible mechanisms of neurological damage caused by SARS-CoV-2. With hope, this will facilitate the early identification, diagnosis, and treatment of possible neurological sequelae, which could contribute toward improving patient prognosis and preventing transmission.","The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a breathing-related viral illness, and its threat to humans have drawn worldwide attention. The immediate and long-term effects of SARS-CoV-2 on the nervous system present major public health challenges. Patients with SARS-CoV-2 have diverse symptoms of the brain and spinal cord. Exploring how coronavirus damages the nervous system is essential to reduce the long-term damage from COVID-19, or SARS-CoV-2 illness, to the nervous system. Despite rapid progress in describing SARS-CoV-2, the long-term effects of COVID-19 on the brain is unclear. Some ways SARS-CoV-2 may injure the brain and spinal cord are: 1) directly harming nerve cells, 2) activating the immune system and inflammatory molecules from full-body infection, 3) binding of the virus to a specific molecule, 4) damaged blood flow in the brain due to reduced oxygen and blood clotting, and 5) full-body inflammation leading to cognitive damage and harmful nervous system diseases. While we do not fully know how SARS-CoV-2 causes nerve injury, we hope to lay the groundwork by reviewing clinical symptoms, issues, and possible methods for nerve damage caused by SARS-CoV-2. This review will hopefully aid early identification and treatment of possible nerve-related consequences, which may improve patient recovery and prevent transmission." +"Emerging evidence suggests that endothelial activation plays a central role in the pathogenesis of acute respiratory distress syndrome (ARDS) and multi-organ failure in patients with COVID-19. However, the molecular mechanisms underlying endothelial activation in COVID-19 patients remain unclear. In this study, the SARS-CoV-2 viral proteins that potently activate human endothelial cells were screened to elucidate the molecular mechanisms involved in endothelial activation. It was found that nucleocapsid protein (NP) of SARS-CoV-2 significantly activated human endothelial cells through TLR2/NF-?B and MAPK signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Remarkablely, though the protein sequences of N proteins from coronaviruses are highly conserved, only NP from SARS-CoV-2 induced endothelial activation. The NPs from other coronaviruses such as SARS-CoV, MERS-CoV, HUB1-CoV and influenza virus H1N1 did not activate endothelial cells. These findings are well consistent with the results from clinical investigations showing broad endotheliitis and organ injury in severe COVID-19 patients. In conclusion, the study provides insights on SARS-CoV-2-induced vasculopathy and coagulopathy, and suggests that simvastatin, an FDA-approved lipid-lowering drug, may benefit to prevent the pathogenesis and improve the outcome of COVID-19 patients. IMPORTANCE Coronavirus disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, is a worldwide challenge for health-care systems. The leading cause of mortality in patients with COVID-19 is hypoxic respiratory failure from acute respiratory distress syndrome (ARDS). To date, pulmonary endothelial cells (ECs) have been largely overlooked as a therapeutic target in COVID-19, yet emerging evidence suggests that these cells contribute to the initiation and propagation of ARDS by altering vessel barrier integrity, promoting a pro-coagulative state, inducing vascular inflammation and mediating inflammatory cell infiltration. Therefore, a better mechanistic understanding of the vasculature is of utmost importance. In this study, we screened the SARS-CoV-2 viral proteins that potently activate human endothelial cells and found that nucleocapsid protein (NP) significantly activated human endothelial cells through TLR2/NF-?B and MAPK signaling pathways. Moreover, by screening a natural microbial compound library containing 154 natural compounds, simvastatin was identified as a potent inhibitor of NP-induced endothelial activation. Our results provide insights on SARS-CoV-2-induced vasculopathy and coagulopathy, and suggests that simvastatin, an FDA-approved lipid-lowering drug, may benefit to prevent the pathogenesis and improve the outcome of COVID-19 patients.","Recent scientific reports suggest that increased endothelial activation plays a key role in the acute respiratory distress syndrome (ARDS) and multi-organ failure seen within patients of COVID-19 (a viral, breathing-related disease). Endothelial cells line our organs within our body, especially blood vessels. When these cells become activated, they encourage inflammation (redness and swelling from fighting an infection) and blood clotting or scabbing. However, how COVID-19 causes this endothelial cell activation is unclear. In this study, COVID-19 virus proteins (small molecules within the virus that help it function) were analyzed. The goal of analyzing the proteins was to determine how they might activate endothelial cells. This study found a specific protein of COVID-19 that highly activated endothelial cells through two specific bodily pathways. Secondly, the authors identified a prescription medication, known as Simvastatin, that can reduce the identified endothelial activation. The authors also noted that the identified protein only caused endothelial activation in COVID-19 illness. This protein in other illnesses, such as SARS-CoV, MERS-CoV, HUB1-CoV and influenza virus H1N1, did not activate endothelial cells. These scientific findings match with results from clinical research (research within patients). Clinical research has shown broad endothelial cell inflammation and organ injury within COVID-19 patients. The authors concluded this paper increases current knowledge surrounding how COVID-19 impacts blood vessels and blood flow within patients. Additionally, this paper suggested simvastatin may help prevent damage and improve overall health within COVID-19 patients. COVID-19, caused by a coronavirus, is a worldwide challenge for health-care. The leading cause of death in those with COVID-19 is lack of oxygen in the blood from a breathing-related illness. To date, cells that line the lungs and its blood vessels have been overlooked as a therapy target in COVID-19, yet new evidence suggests these cells contribute to the start and spread of breathing-related illnesses by changing blood vessel structures, promoting clotting, causing inflammation, and influencing inflammatory cell reactions. Therefore, a better understanding of the blood vessels Is of great importance. In this study, we tested COVID-19 virus proteins that activate these blood-vessel lining cells and found that viral proteins activate these cells through phosphate-related pathways. Also, by testing a natural microorganism library with 154 natural compounds, simvastatin was found to be a powerful blocker of the viral-caused lining cell activation. Our results give insights on the viral-caused blood- and blood vessel-related diseases, and suggests that simvastatin, an FDA-approved fat-lowering drug, may help prevent these diseases and improve outcomes for COVID-19 patients." +"Background: Inflammation-mediated lung injury is a major cause of health problems in many countries and has been the leading cause of morbidity/mortality in intensive care units. In the current COVID-19 pandemic, the majority of the patients experienced serious pneumonia resulting from inflammation (Acute respiratory distress syndrome/ARDS). Pathogenic infections cause cytokine release syndrome (CRS) by hyperactivation of immune cells, which in turn release excessive cytokines causing ARDS. Currently, there are no standard therapies for viral, bacterial or pathogen-mediated CRS. Purpose: This study aimed to investigate and validate the protective effects of Dehydrozingerone (DHZ) against LPS induced lung cell injury by in-vitro and in-vivo models and to gain insights into the molecular mechanisms that mediate these therapeutic effects. Methods:�The therapeutic activity of DHZ was determined in in-vitro models by pre-treating the cells with DHZ and exposed to LPS to stimulate the inflammatory cascade of events. We analysed the effect of DHZ on LPS induced inflammatory cytokines, chemokines and cell damage markers expression/levels using various cell lines. We performed gene expression, ELISA, and western blot analysis to elucidate the effect of DHZ on inflammation and its modulation of MAPK and NF-?B pathways. Further, the prophylactic and therapeutic effect of DHZ was evaluated against the LPS induced ARDS model in rats. Results: DHZ significantly (p < 0.01) attenuated the LPS induced ROS, inflammatory cytokine, chemokine gene expression and protein release in macrophages. Similarly, DHZ treatment protected the lung epithelial and endothelial cells by mitigating the LPS induced inflammatory events in a dose-dependent manner. In vivo analysis showed that DHZ treatment significantly (p < 0.001) mitigated the LPS induced ARDS pathophysiology of increase in the inflammatory cells in BALF, inflammatory cytokine and chemokines in lung tissues. LPS stimulated neutrophil-mediated events, apoptosis, alveolar wall thickening and alveolar inflammation were profoundly reduced by DHZ treatment in a rat model. Conclusion: This study demonstrates for the first time that DHZ has the potential to ameliorate LPS induced ARDS by inhibiting cytokine storm and oxidative through modulating the MAPK and NF-?B pathways. This data provides pre-clinical support to develop DHZ as a potential therapeutic agent against ARDS.","Lung injuries caused by inflammation (redness and swelling from fighting an infection) in the body is a major cause of health problems in several countries. Additionally, inflammation is a leading cause for disease and death within intensive care units (ICU) in hospitals. The majority of patients of COVID-19 (a viral, breathing-related or respiratory disease) have suffered from a condition known as acute respiratory distress syndrome (ARDS) that results from inflammation. It is similar to pneumonia (lung infection). Infections within the body can trigger the excess release of cytokines. Cytokines are proteins that can tell your immune system what to do. Sometimes, when we are sick, cytokines stimulate too many immune cells, causing hyperactivation, which in turn causes more cytokines to release more signals. This causes a biological loop known as cytokine release syndrome (CRS) that results in ARDS. Currently, there are no medical treatments to prevent CRS that is causes by viruses, bacteria, or germs. The goal of this paper was to better understand how a chemical, known as Dehydrozingerone (DHZ), can protect lung cells from damage caused by lipopolysaccharides (LPS). LPS are molecules that exist within the cell walls of bacteria and are extremely toxic. This study used two types of studies, in vitro (in cells) and in vivo (in animals), to fully comprehend how DHZ can prevent LPS-induced lung cell injury. For the in vitro study, cells were treated with DHZ before being exposed to LPS. This caused a series of inflammatory events to occur within the treated cells. The authors reviewed how DHZ protected against LPS damage within several different types of cells. They performed several lab tests looking at cells' internal health to better determine the effect DHZ had on inflammation and how it was protective. Additionally, the authors determined how DHZ could prevent disease and protect against LPS within rats already sick with ARDS. Within one type of cell, DHZ significantly decreased the negative effects caused by LPS exposure. Similarly, DHZ protected lung cells by reducing LPS-induced inflammation in a dose-dependent manner. Meaning as the amount of DHZ given was increased, the symptoms from LPS treatment decreased. In the rats treated with DHZ, the chemical significantly reduced LPS-caused ARDS. DHZ significantly reduced several harmful effects of LPS within the rat model, including cell injury and cell death. This study is the first to show that DHZ has the ability to protect against ARDS by decreasing harmful immune responses triggered by LPS. This data provides support to develop DHZ as a potential human pharmaceutical prescription or drug to protect against ARDS." +"Evidence is emerging that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect various organs of the body, including cardiomyocytes and cardiac endothelial cells in the heart. This review focuses on the effects of SARS-CoV-2 in the heart after direct infection that can lead to myocarditis and an outline of potential treatment options. The main points are: (1) Viral entry: SARS-CoV-2 uses specific receptors and proteases for docking and priming in cardiac cells. Thus, different receptors or protease inhibitors might be effective in SARS-CoV-2-infected cardiac cells. (2) Viral replication: SARS-CoV-2 uses RNA-dependent RNA polymerase for replication. Drugs acting against ssRNA(+) viral replication for cardiac cells can be effective. (3) Autophagy and double-membrane vesicles: SARS-CoV-2 manipulates autophagy to inhibit viral clearance and promote SARS-CoV-2 replication by creating double-membrane vesicles as replication sites. (4) Immune response: Host immune response is manipulated to evade host cell attacks against SARS-CoV-2 and increased inflammation by dysregulating immune cells. Efficiency of immunosuppressive therapy must be elucidated. (5) Programmed cell death: SARS-CoV-2 inhibits programmed cell death in early stages and induces apoptosis, necroptosis, and pyroptosis in later stages. (6) Energy metabolism: SARS-CoV-2 infection leads to disturbed energy metabolism that in turn leads to a decrease in ATP production and ROS production. (7) Viroporins: SARS-CoV-2 creates viroporins that lead to an imbalance of ion homeostasis. This causes apoptosis, altered action potential, and arrhythmia.","New scientific research has shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or COVID-19 (a viral, breathing-related disease), can infect various parts of the body, including cells within the heart. This paper reviews the effects COVID-19 has on the heart after direct infection, which can lead to myocarditis. Myocarditis is inflammation of the heart muscle. This paper will also outline potential treatment options for this illness. The authors proposed seven potential treatment options to help reduce heart injury in COVID-19 patients. First, the virus uses specific entry points to infect heart cells so that it can replicate and grow stronger. Therefore, specific drugs that target these entry points might be helpful. Second, COVID-19 uses a specific pathway to replicate itself. This pathway uses RNA, a chain of genetic material that helps form proteins. Drugs that prevent the creation of RNA for viral replication could be helpful. Third, COVID-19 decreases the body's ability to degrade infected cells. This prevents the body from decreasing the amount of virus within it. COVID-19 is able to replicate as it creates double-membrane vesicles, extra-strong chambers, as spaces safe from the body's natural defense system. Fourth, COVID-19 can cause the host immune response to be changed so that the virus is not targeted for removal. It can also increase inflammation (redness and swelling from fighting an infection) which alters the function of immune cells. Better understanding of drugs that suppress the immune system is needed. Fifth, COVID-19 prevents cells from dying in the early stages of infection but induces cell death later, once it has replicated and moved to other cells. Sixth, COVID-19 infection can disturb energy metabolism (the process in getting energy from food). This can reduce energy production and affect cell function and viability. Seventh, COVID-19 creates virus proteins to lead to an imbalance within the host body. This can cause cell death, abnormal heart function, and an abnormal heartbeat." +"Evidence is emerging that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can infect various organs of the body, including cardiomyocytes and cardiac endothelial cells in the heart. This review focuses on the effects of SARS-CoV-2 in the heart after direct infection that can lead to myocarditis and an outline of potential treatment options. The main points are: (1) Viral entry: SARS-CoV-2 uses specific receptors and proteases for docking and priming in cardiac cells. Thus, different receptors or protease inhibitors might be effective in SARS-CoV-2-infected cardiac cells. (2) Viral replication: SARS-CoV-2 uses RNA-dependent RNA polymerase for replication. Drugs acting against ssRNA(+) viral replication for cardiac cells can be effective. (3) Autophagy and double-membrane vesicles: SARS-CoV-2 manipulates autophagy to inhibit viral clearance and promote SARS-CoV-2 replication by creating double-membrane vesicles as replication sites. (4) Immune response: Host immune response is manipulated to evade host cell attacks against SARS-CoV-2 and increased inflammation by dysregulating immune cells. Efficiency of immunosuppressive therapy must be elucidated. (5) Programmed cell death: SARS-CoV-2 inhibits programmed cell death in early stages and induces apoptosis, necroptosis, and pyroptosis in later stages. (6) Energy metabolism: SARS-CoV-2 infection leads to disturbed energy metabolism that in turn leads to a decrease in ATP production and ROS production. (7) Viroporins: SARS-CoV-2 creates viroporins that lead to an imbalance of ion homeostasis. This causes apoptosis, altered action potential, and arrhythmia.","There is evidence that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a severe breathing-related virus, can infect various body organs, like heart cells. This review focuses on the effects of SARS-CoV-2 in the heart after direct infection that can cause myocarditis (heart muscle inflammation) and possible treatments. The main points are: (1) Viral entry: SARS-CoV-2 uses specific cell parts to attach to heart cells. Thus, different blockers of specific cell parts may help with SARS-CoV-2-infected heart cells. (2) Viral replication: SARS-CoV-2 uses a specific molecule for replication. Drugs acting against a specific form of viral replication for heart cells can be effective. (3) Cell degradation and transport molecules: SARS-COV-2 alters cell degradation to block virus removal and promote virus replication by making transport molecules as replication sites. (4) Immune response: Patient immune response is altered to evade paitent cell attacks against SARS-CoV-2 and increased inflammation by impairing immune cells. Efficiency of immune-system-suppressing therapy must be explained. (5) Intentional cell death: SARS-CoV-2 blocks intentional cell death in early stages and causes cell death in later stages. (6) Energy metabolism: SARS-CoV-2 infection leads to damaged energy metabolism that leads to a decrease in energy and reactive chemical production. (7) Virus channels: SARS-CoV-2 pokes openings in the cell that leads to leaking of important cell molecules. This leaking causes cell death, altered cell signals, and an irregular heart beat." +"SARS-CoV-2 infection has caused a global pandemic that has severely damaged both public health and the economy. The nucleocapsid protein of SARS-CoV-2 is multifunctional and plays an important role in ribonucleocapsid formation and viral genome replication. In order to elucidate its functions, interaction partners of the SARS-CoV-2 N protein in human cells were identified via affinity purification and mass spectrometry. We identified 160 cellular proteins as interaction partners of the SARS-CoV-2 N protein in HEK293T and/or Calu-3 cells. Functional analysis revealed strong enrichment for ribosome biogenesis and RNA-associated processes, including ribonucleoprotein complex biogenesis, ribosomal large and small subunits biogenesis, RNA binding, catalysis, translation and transcription. Proteins related to virus defence responses, including MOV10, EIF2AK2, TRIM25, G3BP1, ZC3HAV1 and ZCCHC3 were also identified in the N protein interactome. This study comprehensively profiled the viral-host interactome of the SARS-CoV-2 N protein in human cells, and the findings provide the basis for further studies on the pathogenesis and antiviral strategies for this emerging infection.","SARS-CoV-2 infection, also known as COVID-19 (a viral, breathing-related disease), has caused a global pandemic that has hurt both public health and the economy. A protein of the virus has several purposes and plays an important role in creating the protective outer shell of the virus and helping the virus replicate itself. In order to better understand how the virus protein works, proteins within human cells that interact with the COVID-19 protein were identified. The authors identified 160 proteins within two different human cell types that interact in some way with the COVID-19 protein. The human proteins found to interact with the virus protein are responsible for several cell functions, all of which impact the creation of more proteins. Additionally, some human proteins identified to interact with the virus protein have roles in defending the body from viruses. This study thoroughly characterized how the viral protein and the host (or human) protein interact when a person is infected. These findings can provide a foundation for future studies on the development and treatment options for COVID-19." +"Background and Objectives. The importance of mitochondria in inflammatory pathologies, besides providing energy, is associated with the release of mitochondrial damage products, such as mitochondrial DNA (mt-DNA), which may perpetuate inflammation. In this review, we aimed to show the importance of mitochondria, as organelles that produce energy and intervene in multiple pathologies, focusing mainly in COVID-19 and using multiple molecular mechanisms that allow for the replication and maintenance of the viral genome, leading to the exacerbation and spread of the inflammatory response. The evidence suggests that mitochondria are implicated in the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which forms double-membrane vesicles and evades detection by the cell defense system. These mitochondrion-hijacking vesicles damage the integrity of the mitochondrion's membrane, releasing mt-DNA into circulation and triggering the activation of innate immunity, which may contribute to an exacerbation of the pro-inflammatory state. Conclusions. While mitochondrial dysfunction in COVID-19 continues to be studied, the use of mt-DNA as an indicator of prognosis and severity is a potential area yet to be explored.","Mitochondria (the powerhouse of a cell) play several important roles in the body. These roles include providing energy and participating in pathways of inflammation (redness and swelling from fighting an infection). The event of mitochondria increasing inflammation is associated with the release of products from mitochondrial damage. One of these products is mitochondrial DNA which can increase inflammation within the body. This review aimed to show the importance of the mitochondria in energy production and in the intervention in the development of several diseases, mainly COVID-19 (a viral, respiratory disease). Additionally the paper aimed to show how the mitochondria organelle uses several different ways to allow the replication and maintenance of a virus. This can lead to the worsening and spread of inflammation. The reviewed scientific evidence suggested that mitochondria are involved in the replication of COVID-19. The virus forms double-walled vesicles, a small chamber outside or within a cell, that evades detection by the host's immune system. These vesicles can then damage mitochondria within cells, releasing mitochondrial DNA into the body. This can trigger the innate immune system, the defense system you were born with, which increase inflammation within the body. This review concluded that while the role of the mitochondria in COVID-19 is still being studied, the use of mitochondrial DNA as an indicator of illness is a potential area yet to be researched." +"Some COVID-19 patients suffer complications from anti-viral immune responses which can lead to both a dangerous cytokine storm and development of blood-borne factors that render severe thrombotic events more likely. The precise immune response profile is likely, therefore, to determine and predict patient outcomes and also represents a target for intervention. Anti-viral T cell exhaustion in the early stages is associated with disease progression. Dysregulation of T cell functions, which precedes cytokine storm development and neutrophil expansion in alveolar tissues heralds damaging pathology. T cell function, cytokine production and factors that attract neutrophils to the lung can be modified through targeting molecules that can modulate T cell responses. Manipulating T cell responses by targeting the PI3K/Akt/mTOR pathway could provide the means to control the immune response in COVID-19 patients. During the initial anti-viral response, T cell effector function can be enhanced by delaying anti-viral exhaustion through inhibiting PI3K and Akt. Additionally, immune dysregulation can be addressed by enhancing immune suppressor functions by targeting downstream mTOR, an important intracellular modulator of cellular metabolism. Targeting this signalling pathway also has potential to prevent formation of thrombi due to its role in platelet activation. Furthermore, this signalling pathway is essential for SARS-cov-2 virus replication in host cells and its inhibition could, therefore, reduce viral load. The ultimate goal is to identify targets that can quickly control the immune response in COVID-19 patients to improve patient outcome. Targeting different levels of the PI3K/Akt/mTOR signalling pathway could potentially achieve this during each stage of the disease.","Some patients suffer complications from anti-viral immune responses, or the response their body creates when infected with a virus. These complications can lead to both a dangerous cytokine storm (proteins that control activity of immune and blood cells that flood the body) and development of blood-borne factors that increase the likelihood of blood clots or scabs. Each person's unique immune response will likely determine and predict how a patient will react to infection. Therefore, each person's immune system represents a target for intervention to prevent harmful side effects. In the early stages of infection, exhausted or overworked T cells (an immune system cell) can lead to disease progression. Alteration of T cell functions often comes before a cytokine storm and neutrophil expansion, or the suppression of immune system. When these events occur in lung tissues, diseases are often even more damaging. T cell function, cytokine production, and events that attract neutrophils (cells that sweep humans for signs of infection) to the lung can be changed by specifically targeting molecules that trigger T cell responses. Manipulating T cell responses could provide the means to control the immune response in patients with COVID-19 (a viral, breathing-related disorder). During the initial anti-viral response, T cell function can be enhanced by delaying anti-viral exhaustion by suppressing certain biological pathways. Additionally, immune dysregulation or errors can be addressed by enhancing immune suppressor functions by targeting molecules that control cell metabolism. Targeting cell metabolism pathways may also prevent formation of blood clots. Furthermore, the cell metabolism pathway is needed for COVID-19 replication in host cells. Suppressing the pathway could potentially decrease the amount of virus within the host. The overall goal is to identify biological targets than can control the immune response in COVID-19 patients to improve patient well-being. Targeting specific pathways in the body could achieve this goal during each stage of the disease." +"Some COVID-19 patients suffer complications from anti-viral immune responses which can lead to both a dangerous cytokine storm and development of blood-borne factors that render severe thrombotic events more likely. The precise immune response profile is likely, therefore, to determine and predict patient outcomes and also represents a target for intervention. Anti-viral T cell exhaustion in the early stages is associated with disease progression. Dysregulation of T cell functions, which precedes cytokine storm development and neutrophil expansion in alveolar tissues heralds damaging pathology. T cell function, cytokine production and factors that attract neutrophils to the lung can be modified through targeting molecules that can modulate T cell responses. Manipulating T cell responses by targeting the PI3K/Akt/mTOR pathway could provide the means to control the immune response in COVID-19 patients. During the initial anti-viral response, T cell effector function can be enhanced by delaying anti-viral exhaustion through inhibiting PI3K and Akt. Additionally, immune dysregulation can be addressed by enhancing immune suppressor functions by targeting downstream mTOR, an important intracellular modulator of cellular metabolism. Targeting this signalling pathway also has potential to prevent formation of thrombi due to its role in platelet activation. Furthermore, this signalling pathway is essential for SARS-cov-2 virus replication in host cells and its inhibition could, therefore, reduce viral load. The ultimate goal is to identify targets that can quickly control the immune response in COVID-19 patients to improve patient outcome. Targeting different levels of the PI3K/Akt/mTOR signalling pathway could potentially achieve this during each stage of the disease.","Some patients of COVID-19 (a respiratory viral illness) suffer issues from anti-viral immune responses. These can lead to a dangerous inflammatory molecule overproduction and blood-borne substances that increase blood clotting risk. The exact immune response type may determine and predict patient outcomes. It may also be a target for treatment. Elimination of specific anti-viral immune cells called T cells in the early stages is linked with disease progression. Damaged T cell function, which is before inflammatory molecule overproduction and expansion in lungs, signals harmful disease effects. T cell function, inflammatory molecule production and attraction to the lung can be changed by targeting molecules that can alter responses of specific immune cells. Changing T cell responses by targeting a specific pathway may help control the immune response in COVID-19 patients. During initial anti-viral response, specific T cell function can be improved by delaying anti-viral elimination by blocking a specific cell pathway. Also, immune system impairment can be addressed by improving functions to suppress the immune response. This can be done by targeting a specific molecule that influences cellular metabolism. Targeting this specific cell signaling pathway may prevent blood clotting. Also, this cellular pathway is needed for the replication of the SARS-CoV-2 virus that causes COVID-19. Blocking the pathway could reduce virus amount. The end goal is to identify targets that can quickly control the immune response in COVID-19 patients to improve patient outcome. Targeting different parts of a specific cellular pathway could achieve this immune response control at each stage of the disease." +"Senescent cells, which arise due to damage-associated signals, are apoptosis-resistant and can express a pro-inflammatory, tissue-destructive senescence-associated secretory phenotype (SASP). We recently reported that a component of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface protein, S1, can amplify the SASP of senescent cultured human cells and that a related mouse ?-coronavirus, mouse hepatitis virus (MHV), increases SASP factors and senescent cell burden in infected mice. Here, we show that SARS-CoV-2 induces senescence in human non-senescent cells and exacerbates the SASP in human senescent cells through Toll-like receptor-3 (TLR-3). TLR-3, which senses viral RNA, was increased in human senescent compared to non-senescent cells. Notably, genetically or pharmacologically inhibiting TLR-3 prevented senescence induction and SASP amplification by SARS-CoV-2 or Spike pseudotyped virus. While an artificial TLR-3 agonist alone was not sufficient to induce senescence, it amplified the SASP in senescent human cells. Consistent with these findings, lung p16INK4a+ senescent cell burden was higher in patients who died from acute SARS-CoV-2 infection than other causes. Our results suggest that induction of cellular senescence and SASP amplification through TLR-3 contribute to SARS-CoV-2 morbidity, indicating that clinical trials of senolytics and/or SASP/TLR-3 inhibitors for alleviating acute and long-term SARS-CoV-2 sequelae are warranted.","Senescent cells are cells that are no longer able to divide but are still active. Senescent cells become active when damage-associated signals are triggered. These cells are resistant to cell death. They can also release tissue damaging, senescence-associated secretory phenotype (SASP). This means these cells release high levels of inflammatory (infection-fighting) cells. The authors of this report recently reported that a protein associated with the coronavirus or virus for COVID-19 (a viral, breathing-related disease) can increase SASP within cultured (grown within a lab) human cells. Additionally, the authors reported that a specific strain of mouse coronavirus increases SASP and the amount of senescent cells within sickened mice. In this study, the authors demonstrate that COVID-19 causes cells to become senescent and overactive SASP in human senescent cells through a specific immune system receptor known as Toll-like receptor-3 (TLR-3). Immune receptors are structures that bind to the surface of a cell and causes a response. TLR-3 can detect virus RNA or genetic material. TLR-3 was increased in human senescent cells compared to those not in a state of senescence. The blocking of TLR-3 prevented senescence causation and SASP amplification from occurring following COVID-19 or Spike pseudo-typed virus (a virus manipulated to not replicate). An artificial TLR-3 agonist, a substance that induces a specific response similar to the original, was not strong enough to induce or cause senescence. However, it did amplify SASP in senescent human cells. Consistent with these findings, the amount of senescent cells within lungs was increased in patients who died from acute COVID-19 infection when compared to patients who passed away for other reasons. These results suggest increased cell senescence and SASP through TLR-3 contributed to COVID-19 death. This indicates that clinical trials of senolytics (drugs that only kill senescent cells) or SASP/TLR-3 inhibitors or blockers are needed. These trials may help reduce short- and long-term effects of COVID-19." +"Some studies reported that genomic RNA of SARS-CoV-2 can absorb a few host miRNAs that regulate immune-related genes and then deprive their function. In this perspective, we conjecture that the absorption of the SARS-CoV-2 genome to host miRNAs is not a coincidence, which may be an indispensable approach leading to viral survival and development in host. In our study, we collected five datasets of miRNAs that were predicted to interact with the genome of SARS-CoV-2. The targets of these miRNAs in the five groups were consistently enriched immune-related pathways and virus-infectious diseases. Interestingly, the five datasets shared no one miRNA but their targets shared 168 genes. The signaling pathway enrichment of 168 shared targets implied an unbalanced immune response that the most of interleukin signaling pathways and none of the interferon signaling pathways were significantly different. Protein-protein interaction (PPI) network using the shared targets showed that PPI pairs, including IL6-IL6R, were related to the process of SARS-CoV-2 infection and pathogenesis. In addition, we found that SARS-CoV-2 absorption to host miRNA could benefit two popular mutant strains for more infectivity and pathogenicity. Conclusively, our results suggest that genomic RNA absorption to host miRNAs may be a vital approach by which SARS-CoV-2 disturbs the host immune system and infects host cells.","Some scientific reports have stated that RNA, or genetic material, from COVID-19 virus (a virus leading to lung infection) can absorb microRNA (small chains of RNA that cannot be coded into proteins) from the host. MiRNA can regulate immune system-related genes. When the virus absorbs this miRNA, it can deprive the genes of their ability to function. Using this knowledge, the authors hypothesized or theorized that the absorption of COVID-19 genetic material to host miRNA is not a coincidence. Therefore, this may be a pathway in which the virus survives and replicates within a host. In this study, the authors collected five datasets of miRNAs that were predicted to interact with the COVID-19 genetic material. The targets of the selected miRNA were pathways related to immune response and virus-infectious diseases. Interestingly, the five datasets had no repeated miRNA, but their targets shared 168 genes. A test analyzing the 168 shared targets implied an unbalanced immune response where most of the interleukin (a messenger protein) signaling pathways and none of the interferon (another messenger protein) signaling pathways were significantly different. A second test using the shared targets show protein-protein interaction pairs, including IL6 to IL6R. The test showed the pairs are related to the process of COVID-19 infection and development. Additionally, the authors found that COVID-19 absorption to host miRNA could help two popular viral strains to infect more and cause more damage in hosts. These results suggest that the absorption of viral RNA to host miRNAs may be a way that COVID-19 disturbs the host immune system and infects host cells." +"The coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the detrimental effects of antibodies. Antibody-dependent enhancement (ADE) of infection is one of the biggest concerns in terms of not only the antibody reaction to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon reinfection with the virus but also the reaction to COVID-19 vaccines. In this study, we evaluated ADE of infection by using COVID-19 convalescent-phase plasma and BHK cells expressing human Fc? receptors (Fc?Rs). We found that Fc?RIIA and Fc?RIIIA mediated modest ADE of infection against SARS-CoV-2. Although ADE of infection was observed in monocyte-derived macrophages infected with SARS-CoV-2, including its variants, proinflammatory cytokine/chemokine expression was not upregulated in macrophages. SARS-CoV-2 infection thus produces antibodies that elicit ADE of infection, but these antibodies do not contribute to excess cytokine production by macrophages. IMPORTANCE Viruses infect cells mainly via specific receptors at the cell surface. Antibody-dependent enhancement (ADE) of infection is an alternative mechanism of infection for viruses to infect immune cells that is mediated by antibodies and IgG receptors (Fc?Rs). Because ADE of infection contributes to the pathogenesis of some viruses, such as dengue virus and feline coronavirus, it is important to evaluate the precise mechanism of ADE and its contribution to the pathogenesis of SARS-CoV-2. Here, using convalescent-phase plasma from COVID-19 patients, we found that two types of Fc?Rs, Fc?RIIA and Fc?RIIIA, mediate ADE of SARS-CoV-2 infection. Although ADE of infection was observed for SARS-CoV-2 and its recent variants, proinflammatory cytokine production in monocyte-derived macrophages was not upregulated. These observations suggest that SARS-CoV-2 infection produces antibodies that elicit ADE of infection, but these antibodies may not be involved in aberrant cytokine release by macrophages during SARS-CoV-2 infection.","The pandemic of COVID-19 (a viral, breathing-related disease) has raised concerns about the harmful effects antibodies can have. Antibodies are proteins used by the immune system to identify and neutralize viruses. Antibody-dependent enhancement (ADE) is a unique occurrence in which virus-specific antibodies actually increase entrance of the virus into the host. ADE is a big concern for both people who are exposed to COVID-19 and those who receive the vaccine. In this study, the authors evaluated ADE of infection by using COVID-19 convalescent-phase plasma (a specific of plasma often used to treat infections) and human cells expressing Fc? receptors (Fc?Rs), special receptors on infection-fighting cells. The authors found two Fc? receptors mediated or controlled most ADE of infection against COVID-19. Although ADE of infection was found in macrophages (a white blood cell) infected with COVID-19, and its variants, proteins that increase inflammation were not upregulated or increased. COVID-19 creates antibodies that cause ADE of infection. However, these antibodies do not increase inflammatory or infection-fighting responses by macrophages. Viruses infect cells mainly through specific receptors (pathways) on the cell surface. ADE of infection is an alternative way that viruses can infect immune cells. ADE is mediated by antibodies and Fc?Rs. Because ADE of infection contributes to the development of some viruses, it is import to better understand the exact way ADE contributes to COVID-19 progression. In this study, using plasma or blood from COVID-19 patients, we found that two types of Fc? receptors mediate ADE of COVID-19 infection. Although ADE of infection was seen for COVID-19, and its variants, increased inflammatory responses in macrophages was not found. These findings suggest that COVID-19 infection produces antibodies that produce ADE of infection. However, these antibodies may not be involved in pro-inflammatory pathways by macrophages." +"The coronavirus disease 2019 (COVID-19) pandemic has raised concerns about the detrimental effects of antibodies. Antibody-dependent enhancement (ADE) of infection is one of the biggest concerns in terms of not only the antibody reaction to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) upon reinfection with the virus but also the reaction to COVID-19 vaccines. In this study, we evaluated ADE of infection by using COVID-19 convalescent-phase plasma and BHK cells expressing human Fc? receptors (Fc?Rs). We found that Fc?RIIA and Fc?RIIIA mediated modest ADE of infection against SARS-CoV-2. Although ADE of infection was observed in monocyte-derived macrophages infected with SARS-CoV-2, including its variants, proinflammatory cytokine/chemokine expression was not upregulated in macrophages. SARS-CoV-2 infection thus produces antibodies that elicit ADE of infection, but these antibodies do not contribute to excess cytokine production by macrophages. IMPORTANCE Viruses infect cells mainly via specific receptors at the cell surface. Antibody-dependent enhancement (ADE) of infection is an alternative mechanism of infection for viruses to infect immune cells that is mediated by antibodies and IgG receptors (Fc?Rs). Because ADE of infection contributes to the pathogenesis of some viruses, such as dengue virus and feline coronavirus, it is important to evaluate the precise mechanism of ADE and its contribution to the pathogenesis of SARS-CoV-2. Here, using convalescent-phase plasma from COVID-19 patients, we found that two types of Fc?Rs, Fc?RIIA and Fc?RIIIA, mediate ADE of SARS-CoV-2 infection. Although ADE of infection was observed for SARS-CoV-2 and its recent variants, proinflammatory cytokine production in monocyte-derived macrophages was not upregulated. These observations suggest that SARS-CoV-2 infection produces antibodies that elicit ADE of infection, but these antibodies may not be involved in aberrant cytokine release by macrophages during SARS-CoV-2 infection.","The pandemic of coronavirus disease 2019 (COVID-19), a viral respiratory disease, highlights harmful effects of antibodies, body molecules that combat foreign organisms. Antibody-dependent enhancement (ADE) of infection is a big concern because of the antibody reaction to severe acute respiratory syndrome coronavirus (SARS-CoV-2), which causes COVID-19, upon reinfection and the reaction to COVID-19 vaccines. We found that certain cell molecules affect mild ADE of infection against SARS-CoV-2. Although certain immune cells infected with SARS-CoV-2 and its variants had infection enhancement, proinflammatory molecules were not increased in these cells. SARS-CoV-2 infection thus creates antibodies that cause ADE of infection, but these antibodies do not lead to increased inflammatory molecule production by certain cells. Viruses infect cells via certain cell parts. ADE of infection or improvement of infection is another method of infection for viruses to infect immune cells influenced by antibodies and certain cellular molecules. Because ADE of infection leads to disease symptoms of some viruses, understanding how ADE works and leads to these symptoms of SARS-CoV-2 is important. Using blood from COVID-19 patients, we found two cellular molecules that influence ADE of SARS-CoV-2 infection. While ADE of infection was seen for SARS-CoV-2 and its variants, proinflammatory molecule production in certain immune cells was not increased. Thus, SARS-CoV-2 infection may create antibodies that cause ADE of infection, but these antibodies may not lead to increased inflammatory production by certain cells during infection." +"COVID-19 virus is a causative agent of viral pandemic in human beings which specifically targets respiratory system of humans and causes viral pneumonia. This unusual viral pneumonia is rapidly spreading to all parts of the world, currently affecting about 105 million people with 2.3 million deaths. Current review described history, genomic characteristics, replication, and pathogenesis of COVID-19 with special emphasis on Nigella sativum (N. sativum) as a treatment option. N. sativum seeds are historically and religiously used over the centuries, both for prevention and treatment of different diseases. This review summarizes the potential role of N. sativum seeds against COVID-19 infection at levels of in silico, cell lines and animal models.","The Covid-19 virus has caused a pandemic in humans and targets the organs and tissues that help people breathe. It also causes viral pneumonia which is an infection in the lungs. This unusual viral pneumonia is quickly spreading to all parts of the world and is currently impacting about 105 million people with 2.3 million deaths. Reviews describe the history of the Covid-19 virus, its genetic make-up, how it replicates, and how it develops with attention to Nigella sativum (N. sativum), a black seed from a plant that may be a possible treatment. N. sativum seeds have been used for centuries, both for prevention and treatment of different diseases. This review summarizes the potential role of N. sativum seeds against Covid-19 infection using computers and lab and animal experiments." +"SARS-CoV-2 infection is associated with diverse clinical manifestations, immune dysfunction, and gut microbiota alterations. The nutritional and biochemical quality of one's diet can influence the intestinal microbiota, which may play a role in the defense mechanisms against potential pathogens, by promoting a wide variety of immune-host interactions. In the COVID-19 pandemic, besides the development of pharmacological therapies, a healthy balanced diet, rich with food-derived antioxidants, may be a useful strategy. Many studies demonstrated that vitamins and probiotic therapies have positive effects on the treatment and prevention of oxidative stress and inflammation in COVID-19. The ecology of the gut microbiota in the digestive tract has been linked to the transport function of the host receptor known as angiotensin converting enzyme 2 (ACE2), suggesting that COVID-19 may be related to the gut microbiota. The angiotensin converting enzyme (ACE), and its receptor (ACE2), play central roles in modulating the renin-angiotensin system (RAS). In addition, ACE2 has functions that act independently of the RAS. ACE2 is the receptor for the SARS coronavirus, and ACE2 is essential for the expression of neutral amino acid transporters in the gut. In this context, ACE2 modulates innate immunity and influences the composition of the gut microbiota. Malnutrition is one of the leading underlying causes of morbidity and mortality worldwide and, including comorbidities, may be a major cause of worse outcomes and higher mortality among COVID-19 patients. This paper reviews the research on dietary components, with particular emphasis on vitamins, antioxidants, and probiotic therapies, and their impacts on the intestinal microbiota's diversity during the SARS-CoV-2 pandemic.","Coronavirus infection (a viral, respiratory disease) is associated with different types of symptoms, as well as damage to the immune system and changes in gut microbiota, which are important microorganisms in the digestive system that process food and help the body use nutrients. The nutrition and chemical processes of one's diet can alter the microbiota in the stomach, which may play a role in the body's ability to fight possible infections. In the Covid-19 pandemic, besides developing medicines and vaccines, a healthy diet with antioxidants (vitamins, minerals, and other nutrients that protect and repair cells) may be a useful option. Many studies show that vitamins and probiotic (good bacteria) therapies have positive effects on the treatment and prevention of oxidative stress (a condition that happens when antioxidant levels are low leading to cell and tissue damage) and inflammation (redness and swelling from fighting an infection) in Covid-19. Research on the relationship between the gut microbiota in the digestive system and its environment is linked to the protein receptor of the cell surface that allows the virus to enter, called ACE2, suggesting that Covid-19 may be linked to the gut microbiota. The protein and its ACE2 receptor that allows viruses to attach to cells play central roles in controlling the renin-angiotensin system (RAS), which is the system that regulates blood pressure and fluids in the body. In addition, ACE2 has functions that act without influence by the RAS. ACE2 is the receptor for the SARS coronavirus that causes COVID-19, and ACE2 is essential for the production of amino acids (molecules that form proteins) in the gut. In this instance, ACE2 controls natural immunity or infection prevention and influences what substances make up the gut microbiota. Malnutrition is one of the leading underlying causes of illness and death across the world and, including other health problems, may be a major cause of worse outcomes and higher deaths among Covid-19 patients. This paper reviews the existing research on food and diets, with a focus on vitamins, antioxidants, and probiotics, and their impact on the gut bacteria during the coronavirus pandemic." +"Dietary strategies aimed at preventing COVID-19 and dangerous pneumonia are continually being considered. Unfortunately, as in the case of drugs, studies in humans have not confirmed any specific food components to be effective in the case of COVID-19. We know that the immune system is the key to reducing the severity of COVID-19, and perhaps by modulating it in the right way we can save human lives with preventive measures. Numerous clinical studies have shown that nutraceuticals can beneficially stimulate the immune response in patients with various diseases, such as cancer or AIDS, and in healthy people at risk of viral infections. Natural compounds are commonly recognized as valuable agents in the fight against viruses due to their structural diversity and safety. Many products consumed by people and used in traditional medicine have been shown to contain substances with anti-inflammatory, antibacterial, and antiviral properties, e.g., vitamin C in the fruit or juice of raspberries or elderberries, hesperidin in St. John�s wort, kaempferol and methylglyoxal in honey, allicin in garlic and onion, gingerols in ginger, curcumin in turmeric, and piperine in black pepper. However, there is no strong scientific evidence, nor are there any systematic literature reviews with meta-analyses indicating that herbs, spices, health-promoting food ingredients, or dietary supplements prevent infection with SARS-CoV-2, mitigate COVID-19 symptoms, or can even be used to treat infections, including severe COVID pneumonia, acute lung failure, a cytokine storm, clotting disorders, or multiple organ failure.","Different types of diets aimed at preventing Covid-19 (a viral, breathing-related disease) and a dangerous lung infection called pneumonia are continually being considered. Unfortunately, studies in humans have not confirmed any specific foods to be effective in the case of Covid-19. The body's immune system is the key to reducing the seriousness of Covid-19, and perhaps by modifying the immune system in the right way, we can save human lives with prevention efforts. Many clinical studies show that certain parts of food can help stimulate the immune response in patients with various diseases, such as cancer or AIDS, and in healthy people who are at risk of a viral infection. Natural substances found in nature are often seen as important parts in the fight against viruses. Many products consumed by people and used in traditional medicine are shown to contain substances with properties described as anti-inflammatories that can relieve pain or swelling, antibacterial to prevent the spread of bacteria, and antiviral to fight viruses. Examples include vitamin C from fruits and substances in honey, garlic, onions, ginger, turmeric, and black pepper. However, there is no strong scientific evidence or analyses with a lot data suggesting that herbs, spices, health-promoting food ingredients, or dietary supplements prevent infection of coronavirus. Additionally, there is little data that they minimize Covid-19 symptoms or can even be used to treat infections, including severe COVID pneumonia, sudden lung failure, a cytokine storm (when the body's immune system floods the blood stream with proteins called cytokines), clotting or scabbing disorders, or multiple organ failure." +"Dietary strategies aimed at preventing COVID-19 and dangerous pneumonia are continually being considered. Unfortunately, as in the case of drugs, studies in humans have not confirmed any specific food components to be effective in the case of COVID-19. We know that the immune system is the key to reducing the severity of COVID-19, and perhaps by modulating it in the right way we can save human lives with preventive measures. Numerous clinical studies have shown that nutraceuticals can beneficially stimulate the immune response in patients with various diseases, such as cancer or AIDS, and in healthy people at risk of viral infections. Natural compounds are commonly recognized as valuable agents in the fight against viruses due to their structural diversity and safety. Many products consumed by people and used in traditional medicine have been shown to contain substances with anti-inflammatory, antibacterial, and antiviral properties, e.g., vitamin C in the fruit or juice of raspberries or elderberries, hesperidin in St. John�s wort, kaempferol and methylglyoxal in honey, allicin in garlic and onion, gingerols in ginger, curcumin in turmeric, and piperine in black pepper. However, there is no strong scientific evidence, nor are there any systematic literature reviews with meta-analyses indicating that herbs, spices, health-promoting food ingredients, or dietary supplements prevent infection with SARS-CoV-2, mitigate COVID-19 symptoms, or can even be used to treat infections, including severe COVID pneumonia, acute lung failure, a cytokine storm, clotting disorders, or multiple organ failure.","Diet strategies for preventing COVID-19 (a breathing-related viral disorder) and pneumonia (an infection the inflames the lung air sacs) are being considered. Unfortunately, as with drugs, human studies have not confirmed specific foods to be effective with COVID-19. We know the immune system is key to reducing the severity of COVID-19. Perhaps by influencing it the right way, we can save humans with preventative steps. Many studies show that certain foods used as medicine can beneficially activate the immune response in patients with many diseases, like cancer or AIDS (a disease from an immunodeficiency virus), and healthy people at risk of viral infections. Natural substances are usually seen as valuable tools in the fight against viruses due to the structural diversity and safety of the substances. Many products consumed by people and used in traditional medicine have substances with anti-inflammatory, antibacterial, and antiviral properties like vitamins and other plant chemicals. However, there is no evidence that herbs, spices, health-promoting food ingredients, or dietary supplements can prevent, reduce, or treat COVID-19 or other infections, including severe COVID-19 pneymonia, immediate lung failure, inflammatory molecule overproduction, blood clotting disorders, or multiple organ failure." +"Previously, we reported that immunomodulatory lactobacilli, nasally administered, beneficially regulated the lung antiviral innate immune response induced by Toll-like receptor 3 (TLR3) activation and improved protection against the respiratory pathogens, influenza virus and respiratory syncytial virus in mice. Here, we assessed the immunomodulatory effects of viable and non-viable Lactiplantibacillus plantarum strains in human respiratory epithelial cells (Calu-3 cells) and the capacity of these immunobiotic lactobacilli to reduce their susceptibility to the acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Immunobiotic L. plantarum MPL16 and CRL1506 differentially modulated IFN-?, IL-6, CXCL8, CCL5 and CXCL10 production and IFNAR2, DDX58, Mx1 and OAS1 expression in Calu-3 cells stimulated with the TLR3 agonist poly(I:C). Furthermore, the MPL16 and CRL1506 strains increased the resistance of Calu-3 cells to the challenge with SARS-CoV-2. L. plantarum MPL16 induced these beneficial effects more efficiently than the CRL1506 strain. Of note, neither non-viable MPL16 and CRL1506 strains nor the non-immunomodulatory strains L. plantarum CRL1905 and MPL18 could modify the resistance of Calu-3 cells to SARS-CoV-2 infection or the immune response to poly(I:C) challenge. To date, the potential beneficial effects of immunomodulatory probiotics on SARS-CoV-2 infection and COVID-19 outcome have been extrapolated from studies carried out in the context of other viral pathogens. To the best of our knowledge, this is the first demonstration of the ability of immunomodulatory lactobacilli to positively influence the replication of the new coronavirus. Further mechanistic studies and in vivo experiments in animal models of SARS-CoV-2 infection are necessary to identify specific strains of beneficial immunobiotic lactobacilli like L. plantarum MPL16 or CRL1506 for the prevention or treatment of the COVID-19.","Lactobacilli is a type of probiotic (good bacteria) found in the digestive system and can be consumed to improve gut health. When lactobacilli is given through a spray in the nose in mice, it can help regulate the natural immune or infection-fighting response in the lungs and fight lung infections. Lactobacilli bacteria that comes from plants is tested to see how it impacts the immune systems of the cells in the lungs and if it can reduce the ability of the coronavirus (a virus causing COVID-19 - a lung infection) from entering the cells. Two types of lactobacilli bacteria that come from plants, called MPL16 and CRL506, are tested to understand their influence on the production of cells that are part of the immune response and the development of proteins. Additionally, these two types of bacteria increase the resistance of certain cells in the lungs called Calu-3 against the coronavirus. The lactobacilli MPL16 bacteria started these beneficial effects more efficiently than the CRL1506. No lactobacilli bacteria from the tested plants can change the resistance of Calu-3 cells to coronavirus infection. As of now, the possible benefits of good bacteria (probiotics) on the immune system against the coronavirus and Covid-19 have been pulled from studies of other viruses. It is believed that this study is the first to show the ability of lactobacilli to positively influence the replication of the new coronavirus. Further studies and experiments with animals with the coronavirus are necessary to identify specific types of lactobacilli from plants for the prevention or treatment of Covid-19." +"Objectives: The novel coronavirus infection (COVID-19) conveys a serious threat globally to health and economy because of a lack of vaccines and specific treatments. A common factor for conditions that predispose for serious progress is a low-grade inflammation, e.g., as seen in metabolic syndrome, diabetes, and heart failure, to which micronutrient deficiencies may contribute. The aim of the present article was to explore the usefulness of early micronutrient intervention, with focus on zinc, selenium, and vitamin D, to relieve escalation of COVID-19. Methods: We conducted an online search for articles published in the period 2010-2020 on zinc, selenium, and vitamin D, and corona and related virus infections. Results: There were a few studies providing direct evidence on associations between zinc, selenium, and vitamin D, and COVID-19. Adequate supply of zinc, selenium, and vitamin D is essential for resistance to other viral infections, immune function, and reduced inflammation. Hence, it is suggested that nutrition intervention securing an adequate status might protect against the novel coronavirus SARS-CoV-2 (Severe Acute Respiratory Syndrome - coronavirus-2) and mitigate the course of COVID-19. Conclusion: We recommended initiation of adequate supplementation in high-risk areas and/or soon after the time of suspected infection with SARS-CoV-2. Subjects in high-risk groups should have high priority as regards this nutritive adjuvant therapy, which should be started prior to administration of specific and supportive medical measures.","The new Covid-19 (a viral, respiratory disease) is a serious threat to health and financial stability because of a lack of vaccines and treatments. Low-grade inflammation (how the body responds to infection) is a common factor in cases that become more serious, and low levels of vitamins and minerals may contribute to this inflammation. The aim of this paper is to explore the usefulness of starting certain vitamins and minerals early, especially zinc, selenium (a mineral found in water and foods), and vitamin D, to keep Covid-19 infections from becoming more serious. Researchers did an online search for scientific articles published from 2010 to 2020 on zinc, selenium, and vitamin D, in addition to corona and similar virus infections. There are a few studies that show direct evidence on associations between zinc, selenium, and vitamin D, and Covid-19. Getting enough zinc, selenium, and vitamin D is important for the body to resist other viral infections, as well as for immune function and to reduce inflammation, which is the body's response to infections. Therefore, it is suggested that changing nutrition to get enough of these vitamins and minerals might provide protection against the coronavirus and keep Covid-19 infection from becoming serious. Researchers of this paper recommend giving supplements to high-risk areas and/or soon after suspected infection with coronavirus. People in high-risk groups should have a high priority to receive nutrition supplements and therapies, which should be started before specific and supportive medical measures." +"Viral infections are a leading cause of morbidity and mortality worldwide, and the importance of public health practices including handwashing and vaccinations in reducing their spread is well established. Furthermore, it is well known that proper nutrition can help support optimal immune function, reducing the impact of infections. Several vitamins and trace elements play an important role in supporting the cells of the immune system, thus increasing the resistance to infections. Other nutrients, such as omega-3 fatty acids, help sustain optimal function of the immune system. The main aim of this manuscript is to discuss of the potential role of micronutrients supplementation in supporting immunity, particularly against respiratory virus infections. Literature analysis showed that in vitro and observational studies, and clinical trials, highlight the important role of vitamins A, C, and D, omega-3 fatty acids, and zinc in modulating the immune response. Supplementation with vitamins, omega 3 fatty acids and zinc appears to be a safe and low-cost way to support optimal function of the immune system, with the potential to reduce the risk and consequences of infection, including viral respiratory infections. Supplementation should be in addition to a healthy diet and fall within recommended upper safety limits set by scientific expert bodies. Therefore, implementing an optimal nutrition, with micronutrients and omega-3 fatty acids supplementation, might be a cost-effective, underestimated strategy to help reduce the burden of infectious diseases worldwide, including coronavirus disease 2019 (COVID-19).","Virus infections are a leading cause of illness and death across the world, and the importance of practices such as handwashing and vaccination in reducing the spread of viruses is well known. It is also well known that proper nutrition can help support a healthy immune system, which reduces the impact of infections. Several vitamins and minerals in small amounts play an important role in supporting the cells of the immune system, which can help the body resist infections. Other nutrients, such as omega-3 fatty acids, help keep the function of the immune system running well. The aim of this paper is to discuss how adding vitamins and minerals (also called micronutrients) to the body might support immunity, especially immunity against viruses that impact the lungs. A review of existing studies shows the important role of vitamins A, C, and D, omega-3 fatty acids, and zinc in influencing the immune response. Using vitamin, omega-3 fatty acid, and zinc supplements appears to be a safe and low-cost way to support immune system function. These supplements also have the possibility of reducing the risk and effects of infections, including viruses that cause lung infection. Supplements should be an addition to healthy diets and should be taken at the safe amounts recommended by experts. Developing a good nutrition plan, with micronutrients and omega-3 fatty acids supplements, might be a cost-effective way to help reduce the effects of infectious diseases around the world, including Covid-19 (a viral, respiratory disease)." +"Viral infections are a leading cause of morbidity and mortality worldwide, and the importance of public health practices including handwashing and vaccinations in reducing their spread is well established. Furthermore, it is well known that proper nutrition can help support optimal immune function, reducing the impact of infections. Several vitamins and trace elements play an important role in supporting the cells of the immune system, thus increasing the resistance to infections. Other nutrients, such as omega-3 fatty acids, help sustain optimal function of the immune system. The main aim of this manuscript is to discuss of the potential role of micronutrients supplementation in supporting immunity, particularly against respiratory virus infections. Literature analysis showed that in vitro and observational studies, and clinical trials, highlight the important role of vitamins A, C, and D, omega-3 fatty acids, and zinc in modulating the immune response. Supplementation with vitamins, omega 3 fatty acids and zinc appears to be a safe and low-cost way to support optimal function of the immune system, with the potential to reduce the risk and consequences of infection, including viral respiratory infections. Supplementation should be in addition to a healthy diet and fall within recommended upper safety limits set by scientific expert bodies. Therefore, implementing an optimal nutrition, with micronutrients and omega-3 fatty acids supplementation, might be a cost-effective, underestimated strategy to help reduce the burden of infectious diseases worldwide, including coronavirus disease 2019 (COVID-19).","Viral infections are a leading cause of illness and death worldwide. The importance of public health practices like handwashing and vaccinations in reducing their spread is well supported. Also, proper nutrition can help support ideal immune function, reducing the effect of infections. Many vitamins and trace elements or minerals help support immune cells, thus increasing resistance to infections. Other nutrients, like omega-3 fatty acids, help maintain ideal immune system function. This manuscript discusses the possible role of micronutrients supplementation to support immunity, especially against breathing-related virus infections. Some trials highlight the important role of vitamins A, C, and D, omega-3 fatty acids, and zinc in influencing the immune response. Taking vitamins, omega 3 fatty acids and zinc may be a safe and low-cost way to support idea immune system function. It may also reduce the risk and effects of infection, including viral respiratory infections. Supplementation should be an addition to a healthy diet and used within recommended safety limits. Thus, having ideal nutrition, with micronutrients and omega-3 fatty acids supplementation, may be a cost-effective, underrated strategy to help reduce the effects of infectious diseases worldwide, including the viral respiratory coronavirus disease 2019 (COVID-19)." +"Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, were responsible for approximately 2.38 million deaths worldwide in 2016. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: (1) supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; (2) supplementation above the Recommended Dietary Allowance (RDA), but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and (3) public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.","Public health practices, including handwashing and vaccinations, help reduce the spread and impact of infections. However, the global impact of infection is high, and additional measures are necessary. Sudden infections in the lung, also called acute respiratory tract or breathing-related infections, for example, were responsible for about 2.38 million deaths worldwide in 2016. The role nutrition plays in supporting the immune or infection-fighting system is well-documented. A lot of data from existing studies show that vitamins and natural acids play important roles in supporting the immune system. These include vitamins A, B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids and other acids. Not eating or maintaining enough of these nutrients is common, leading to a decrease in the body's ability to resist infections which may result in higher illness, loss, and death because of disease. Based on this available information, the following conclusions are made: 1) using supplements to add vitamins, minerals, and omega-3 fatty acids is a safe, effective, and inexpensive way to help support immune system functions; 2) supplements above the recommended amount, but still within safety limits, for certain nutrients may be allowed; and 3) public health officials are encouraged to include nutrition plans in their recommendations to improve public health." +"The pandemic caused by the new coronavirus has caused shock waves in many countries, producing a global health crisis worldwide. Lack of knowledge of the biological mechanisms of viruses, plus the absence of effective treatments against the disease (COVID-19) and/or vaccines have pulled factors that can compromise the proper functioning of the immune system to fight against infectious diseases into the spotlight. The optimal status of specific nutrients is considered crucial to keeping immune components within their normal activity, helping to avoid and overcome infections. Specifically, the European Food Safety Authority (EFSA) evaluated and deems six vitamins (D, A, C, Folate, B6, B12) and four minerals (zinc, iron, copper and selenium) to be essential for the normal functioning of the immune system, due to the scientific evidence collected so far. In this report, an update on the evidence of the contribution of nutritional factors as immune-enhancing aspects, factors that could reduce their bioavailability, and the role of the optimal status of these nutrients within the COVID-19 pandemic context was carried out. First, a non-systematic review of the current state of knowledge regarding the impact of an optimal nutritional status of these nutrients on the proper functioning of the immune system as well as their potential role in COVID-19 prevention/treatment was carried out by searching for available scientific evidence in PubMed and LitCovid databases. Second, a compilation from published sources and an analysis of nutritional data from 10 European countries was performed, and the relationship between country nutritional status and epidemiological COVID-19 data (available in the Worldometers database) was evaluated following an ecological study design. Furthermore, the potential effect of genetics was considered through the selection of genetic variants previously identified in Genome-Wide Association studies (GWAs) as influencing the nutritional status of these 10 considered nutrients. Therefore, access to genetic information in accessible databases (1000genomes, by Ensembl) of individuals from European populations enabled an approximation that countries might present a greater risk of suboptimal status of the nutrients studied. Results from the review approach show the importance of maintaining a correct nutritional status of these 10 nutrients analyzed for the health of the immune system, highlighting the importance of Vitamin D and iron in the context of COVID-19. Besides, the ecological study demonstrates that intake levels of relevant micronutrients-especially Vitamins D, C, B12, and iron-are inversely associated with higher COVID-19 incidence and/or mortality, particularly in populations genetically predisposed to show lower micronutrient status. In conclusion, nutrigenetic data provided by joint assessment of 10 essential nutrients for the functioning of the immune system and of the genetic factors that can limit their bioavailability can be a fundamental tool to help strengthen the immune system of individuals and prepare populations to fight against infectious diseases such as COVID-19.","The pandemic caused by the new coronavirus (which causes COVID-19 - a viral, breathing-related illness) has caused shock waves in many countries, producing a global health crisis. Lack of knowledge of how the virus works, plus the absence of effective treatments against Covid-19 and/or vaccines have put the immune system and its ability to fight disease in the spotlight. Having a healthy balance of specific nutrients is key to keeping parts of the immune system working in order to avoid and fight infections. There are 6 vitamins (D, A, C, Folate, B6, B12) and 4 minerals (zinc, iron, copper and selenium) that the European Food Safety Authority sees as important for the immune system to function well. In this report is an update on the evidence of 1) how nutrition impacts the immune system, 2) what things might reduce how long nutrients stay in the body, and 3) the role of the healthy balance of these nutrients during the Covid-19 pandemic. First, researchers review available scientific data on the impact of a healthy balance of these nutrients on the immune system, as well as their role in Covid-19 prevention and treatment. Second, nutrition data from 10 European countries are compiled and analyzed, and the relationship between country nutrition and Covid-19 data is evaluated. Additionally, the possible effect of genes on nutrient balance is considered for these 10 nutrients. Using genetic information from available databases, researchers estimated that countries may be at a greater risk of low nutritional balance. Results from the review show the importance of keeping a correct nutritional balance of these 10 nutrients for the health of the immune system and highlights the importance of Vitamin D and iron in the context of Covid-19. The study of these nutrients and their environment shows that the amount consumed of certain vitamins and minerals-especially Vitamins D, C, B12, and iron-are inversely or oppositely associated with higher Covid-19 numbers and/or death (i.e., the higher the nutrition, the lower the risk of Covid-19 illness and vice versa). This finding is very important for groups with genes shown to lower micronutrient status. In conclusion, using nutritional and genetic data and how they influence the immune system and how long nutrients stay in the body can be key tools to help strengthen the immune system of individuals and prepare people to fight viruses such as Covid-19." +"The World Health Organization declared the novel coronavirus, named as SARS-CoV-2, as a global pandemic in early 2020 after the disease spread to more than 180 countries leading to tens of thousands of cases and many deaths within a couple of months. Consequently, this paper aims to summarize the evidence for the relationships between nutrition and the boosting of the immune system in the fight against the disease caused by SARS-CoV-2. This review, in particular, assesses the impact of vitamin and mineral supplements on the body's defence mechanisms against SARS-CoV-2. The results revealed that there is a strong relationship between the ingestion of biological ingredients like vitamins C-E, and minerals such as zinc, and a reduction in the effects of coronavirus infection. These can be received from either nutrition rich food sources or from vitamin supplements. Furthermore, these macromolecules might have roles to play in boosting the immune response, in the healing process and the recovery time. Hence, we recommend that eating healthy foods rich in vitamins C-E with zinc and flavonoids could boost the immune system and consequently protect the body from serious infections.","The World Health Organization called the new coronavirus (which causes COVID-19 - a viral lung infection) a pandemic in early 2020 after the disease spread to over 180 countries. This paper aims to summarize the evidence for the relationships between nutrition and boosting the immune system in the fight against Covid-19 caused by the coronavirus. This review discusses the impact of vitamin and mineral supplements (an additional amount of vitamins or minerals often in the form of a pill) on the body's defense system against coronavirus. The results show that there is a strong connection between taking ingredients like vitamin C-E and minerals such as zinc, and a reduction in the effects of coronavirus infection. These can be received from either foods that have a lot of healthy nutrients or from vitamin supplements. Also, these tiny molecules might have roles to play in boosting the immune response as well as the healing process and recovery time. Researchers of this study recommend that eating healthy foods with a lot of vitamins C-E with zinc and other vitamins from plants called flavonoids found in many fruits and vegetables could boost the immune system and help protect the body from serious infections." +"The World Health Organization declared the novel coronavirus, named as SARS-CoV-2, as a global pandemic in early 2020 after the disease spread to more than 180 countries leading to tens of thousands of cases and many deaths within a couple of months. Consequently, this paper aims to summarize the evidence for the relationships between nutrition and the boosting of the immune system in the fight against the disease caused by SARS-CoV-2. This review, in particular, assesses the impact of vitamin and mineral supplements on the body's defence mechanisms against SARS-CoV-2. The results revealed that there is a strong relationship between the ingestion of biological ingredients like vitamins C-E, and minerals such as zinc, and a reduction in the effects of coronavirus infection. These can be received from either nutrition rich food sources or from vitamin supplements. Furthermore, these macromolecules might have roles to play in boosting the immune response, in the healing process and the recovery time. Hence, we recommend that eating healthy foods rich in vitamins C-E with zinc and flavonoids could boost the immune system and consequently protect the body from serious infections.","The World Health Organization declared the new coronavirus, named as SARS-CoV-2, as a global pandemic in early 2020 after the respiratory viral disease spread to over 180 countries, leading to tens of thousands of cases and many deaths in a few months. Thus, this paper aims to summarize the evidence for links between nutrition and boosting the immune system in the fight against the disease caused by SARS-CoV-2. This review measures the impact of vitamin and mineral supplements on the body's defense mechanisms against SARS-CoV-2. There is a strong link between consuming biological ingredients like vitamins C-E and minerals like zinc, and a reduction in the effects of coronavirus infection. These biological ingredients can come from nutrient-rich foods or vitamin supplements. Also, these biological molecules may help boost the immune response, healing response, and recovery time. Thus, eating healthy foods rich in vitamins C-E with zinc and other helpful molecules could boost the immune system and protect the body from serious infections." +"This review focused on the use of plant based foods for enhancing the immunity of all aged groups against COVID-19. In humans, coronaviruses are included in the spectrum of viruses that cause the common cold and, recently, severe acute respiratory syndrome (SARS). Emerging infectious diseases, such as SARS present a major threat to public health. The novel coronavirus has spread rapidly to multiple countries and has been declared a pandemic by the World Health Organization. COVID-19 is usually caused a virus to which most probably the people with low immunity response are being effected. Plant based foods increased the intestinal beneficial bacteria which are helpful and makes up of 85% of the immune system. By the use of plenty of water, minerals like magnesium and Zinc, micronutrients, herbs, food rich in vitamins C, D & E and better life style one can promote the health and can overcome this infection. Various studies investigated that a powerful antioxidant Glutathione and a bioflavonoid Quercetin may prevent various infections including COVID-19. In conclusion, the plant based foods play a vital role to enhance the immunity of people to control of COVID-19.","This review focuses on the use of plant based foods for increasing the immunity of all age groups against Covid-19 (a viral, breathing-related illness). In humans, coronaviruses, which cause COVID-19, are included in the type of viruses that cause the common cold and, recently, severe acute respiratory syndrome (SARS), which can cause fever, cough, and breathing problems. New infectious diseases, such as SARS, present a major threat to public health. The new coronavirus has quickly spread to many countries and has been declared a pandemic by the World Health Organization. People with a low or weakened immune response are probably most effected by Covid-19. Plant based foods increase the good bacteria in the stomach which are helpful and make up of 85% of the immune system. Drinking plenty of water, consuming minerals like magnesium and Zinc, vitamins, herbs, food with a lot of vitamins C, D & E, and a healthy life style can promote health and can fight this infection. Different research studies find that a powerful antioxidant (a vitamin or mineral that can repair cells) called Glutathione and a plant-based vitamin called Quercetin may prevent infections, including Covid-19. In conclusion, plant based foods play a key role in strengthening the immunity of people to control Covid-19." +"Purpose of review: Tardive dyskinesia (TD) is caused by exposure to medications with dopamine antagonism, mainly antipsychotics. It often distresses individuals, physically and emotionally and affects their quality of life. We evaluated peer-reviewed recently published articles with a goal of providing a critically appraised update on the latest advancements in this field. Recent findings: In 2017, FDA approved VMAT2 inhibitors, deutetrabenazine and valbenazine. They have demonstrated efficacy in several class 1 studies. Also there have been update in the evidence-based guidelines for treatment for tardive dyskinesia. Various medication classes are being used for treatment of TD with VMAT2 inhibitors to be first FDA-approved medications. Their use should be tailored to the individual patient. Long-term studies will further guide us in how to optimize treatment, especially in the real-world setting. As clinicians, we need to take into consideration all aspects of symptomatology, etiology, potential side effects of the medications, to find the best possible ""match"" for our patients.","Taking medications, mainly antipsychotics, that reduce activity of dopamine (a chemical messenger released when your brain is expecting a reward) causes tardive dyskinesia (TD) - a movement disorder. TD often causes physical and emotional pain or suffering and affects the quality of life of patients. We rated scientific studies to summarize the latest advancements in the area of TD. We found that FDA approved vesicular monoamine transporter type 2 (VMAT2) inhibitors, drugs that reduce dopamine (a chemical messenger released when your brain is expecting a reward), deutetrabenazine and valbenazine, in 2017. These drugs work in several clinical trials. Best practice guidelines for doctors for treating tardive dyskinesia have also been updated. Different drugs are being used to treat TD with VMAT2 inhibitors to be the first drug approved by the FDA. Drugs used to treat TD should be specific to the individual patient. Long-term studies will determine how best to treat patients, especially in the real world. As doctors, we need to consider all symptoms, causes, and possible drug side effects to find the best possible ""match"" for our patients." +"Tardive dyskinesia (TD) is an iatrogenic condition that encompasses a wide phenomenological spectrum of movement disorders caused by exposure to dopamine receptor blocking agents (DRBAs). TD may cause troublesome or disabling symptoms that impair quality of life. Due to frequent, often inappropriate, use of DRBAs, TD prevalence rates among patients exposed to DRBAs continue to be high. The judicious use of DRBAs is key to the prevention of TD, reduction of disease burden, and achieving lasting remission. Dopamine-depleting vesicular monoamine transporter type 2 inhibitors are considered the treatment of choice of TD.","Tardive dyskinesia (TD) is a condition that includes a wide range of uncontrollable movement disorders caused by taking antipsychotics. TD may cause physical and emotional pain or suffering that negatively affects quality of life. The total number of TD cases in patients who have taken antipsychotics at a given time continues to be high due to frequent, often unnecessary, antipsychotic use. Sensible use of antipsychotics is needed to prevent, reduce disability and death associated with, and end TD for good. Vesicular monoamine transporter type 2 (VMAT2) inhibitors, drugs that reduce dopamine (a chemical messenger released when your brain is expecting a reward), are the best treatment for TD." +"Background: Tardive dyskinesia is a movement disorder characterised by irregular, stereotyped, and choreiform movements associated with the use of antipsychotic medication. We aim to provide recommendations on the treatment of tardive dyskinesia. Results: Preventing tardive dyskinesia is of primary importance, and clinicians should follow best practice for prescribing antipsychotic medication, including limiting the prescription for specific indications, using the minimum effective dose, and minimising the duration of therapy. The first-line management of tardive dyskinesia is the withdrawal of antipsychotic medication if clinically feasible. Yet, for many patients with serious mental illness, the discontinuation of antipsychotics is not possible due to disease relapse. Switching from a first-generation to a second-generation antipsychotic with a lower D2 affinity, such as clozapine or quetiapine, may be effective in reducing tardive dyskinesia symptoms. The strongest evidence for a suitable co-intervention to treat tardive dyskinesia comes from tests with the new VMAT inhibitors, deutetrabenazine and valbenazine. These medications have not been approved for use in Canada. Conclusion: Data on tardive dyskinesia treatment are limited, and the best management strategy remains prevention. More long-term safety and efficacy data are needed for deutetrabenazine and valbenazine, and their routine availability to patients outside of the USA remains in question.","Tardive dyskinesia is characterized by possibly irreversible, abnormal, uncontrolled movements related to the use of antipsychotics. We try to suggest ways to treat tardive dyskinesia. Preventing tardive dyskinesia is very important, and doctors should prescribe antipsychotics as recommended, including only prescribing them for certain conditions, using the lowest working dose, and limiting how long patients take them. The first recommended treatment of tardive dyskinesia is to have the patient stop taking antipsychotics if possible. Stopping antipsychotics is not possible for many patients with serious mental illness due to the disease returning. Switching from a first-generation (older) to a second-generation (newer) antipsychotic, such as clozapine or quetiapine, may help reduce tardive dyskinesia symptoms. Studies show tests with new vesicular monoamine transporter (VMAT) inhibitors, drugs that reduce dopamine (a chemical messenger released when your brain is expecting a reward), deutetrabenazine and valbenazine, to be the best additional treatment for tardive dyskinesia. Canada has not approved these drugs for use. We conclude that information on tardive dyskinesia treatment is limited, and preventing TD is the best way to manage it. More studies that look at safety and how well deutetrabenazine and valbenazine work are needed, and it is uncertain how reliably available these drugs are to patients outside of the United States." +"Background: Tardive dyskinesia is a movement disorder characterised by irregular, stereotyped, and choreiform movements associated with the use of antipsychotic medication. We aim to provide recommendations on the treatment of tardive dyskinesia. Results: Preventing tardive dyskinesia is of primary importance, and clinicians should follow best practice for prescribing antipsychotic medication, including limiting the prescription for specific indications, using the minimum effective dose, and minimising the duration of therapy. The first-line management of tardive dyskinesia is the withdrawal of antipsychotic medication if clinically feasible. Yet, for many patients with serious mental illness, the discontinuation of antipsychotics is not possible due to disease relapse. Switching from a first-generation to a second-generation antipsychotic with a lower D2 affinity, such as clozapine or quetiapine, may be effective in reducing tardive dyskinesia symptoms. The strongest evidence for a suitable co-intervention to treat tardive dyskinesia comes from tests with the new VMAT inhibitors, deutetrabenazine and valbenazine. These medications have not been approved for use in Canada. Conclusion: Data on tardive dyskinesia treatment are limited, and the best management strategy remains prevention. More long-term safety and efficacy data are needed for deutetrabenazine and valbenazine, and their routine availability to patients outside of the USA remains in question.","Tardive duskinesia is a movement disorder of irregular, repetitive, and jerking movements linked with using antipsychotic medication for treating mental illnesses. We aim to provide recommendation on treating tardive dyskinesia. Preventing tardive dyskinesia is very important. Clinicians should follow the best policies for prescribing antipsychotic medication. These include limiting the amount for specific symptoms, using the minimum effective dose, and minimising the duration of treatment. The first-to-try treatment of tardive dyskinesia is removing antipsychotic medication if clinically possible. Yet, for many patients with serious mental illness, removing antipsychotics is not possible due to disease reappearance. Switching from one class to another class of antipsychotics, like clozapine or quetiapine, may help reduce tardive dyskinesia symptoms. The strongest evidence for a suitable co-treatment for tardive dyskinesia comes from tests with new VMAT inhibitors, deutetrabenazine and valbenazine, which treat movement disorders. These drugs have not been approved for use in Canada. Data on tardive dyskinesia treatment is limited. The best treatment remains prevention. We need more long-term safety and effectiveness data for deutetrabenazine and valbenazine. Their regular availability to patients outside the USA is unknown." +"Tardive dyskinesia (TD), a condition of potentially irreversible abnormal involuntary movements that is associated with dopamine receptor blocking agents (DRBAs), produces significant impairment of functioning and quality of life for patients. Contrary to expectations, TD has not vanished despite the introduction of SGAs. Instead, changing prescription practices and increased off-label prescription of DRBAs have placed more patients than ever at risk of this potentially dangerous and disabling condition. This activity provides an overview of treatment strategies for TD as part of an individualized management plan, including DRBA medication adjustment and antidyskinetic treatment.","Tardive dyskinesia (TD), characterized by possibly irreversible, abnormal, uncontrolled movements related to the use of antipsychotics, negatively affects functioning and quality of life for patients. Although many believed it would be different, TD has not gone away even with the use of second-generation antipsychotics (SGAs), which are less likely to cause movement side effects. Instead, changes in how antipsychotics are prescribed and antipsychotics prescribed for unapproved use have increased the patients at risk of TD. We describe treatment options for TD as part of an individual-specific plan, including changing antipsychotic dosing and treating dyskinesia." +"Tardive dyskinesia (TD) is a common, iatrogenic movement disorder affecting many individuals treated with dopamine-receptor blocking agents (DRBAs). Studying treatment of TD can be complex, as the symptoms can be affected by changes in either dosage or type of DRBA, as well as by the variable natural course of the disease. Historically many pharmacological therapies have been studied in TD, finding varying degrees of treatment success. Most recently, the VMAT2 inhibitors valbenazine and deutetrabenazine were rigorously studied in TD in large, phase III clinical trials, and were shown to be beneficial in this population. In this article, we will review various treatments of TD, including manipulation of the offending agent, VMAT2 inhibitors, other non-VMAT2-inhibiting medications, and non-pharmacological approaches.","Tardive dyskinesia (TD) is a common movement disorder in many people taking antipsychotics. Studying treatment of TD can be difficult, because the symptoms can change based on changes to how much or what kind of antipsychotics are used, and by the range of normal disease progression. Many drugs made to treat TD have been studied with different levels of success. Most recently, the vesicular monoamine transporter type 2 (VMAT2) inhibitors, drugs that reduce dopamine (a chemical messenger released when your brain is expecting a reward), valbenazine and deutetrabenazine, were studied in TD in large human trials, and were shown to work in this group. In this article, we will look at different treatments of TD, including changing the drug causing TD, VMAT2 inhibitors, other non-VMAT2-inhibiting drugs, and non-drug options." +"Tardive dyskinesia (TD) is a disorder characterized by involuntary movements, typically of the orofacial muscles and also of the extremities and other muscle groups. The condition is associated with exposure to dopamine receptor blocking agents, including antipsychotics. Because the indications and off-label uses for these agents have expanded over the last 2 decades, a larger number of patients are receiving antipsychotic medications than in the past. While evidence suggests that patients being treated with second-generation antipsychotics have less risk for developing TD than those treated with first-generation antipsychotics, the decreased risk is not as great as was originally expected. In addition, patients with chronic psychiatric conditions often require long-term use of antipsychotics, putting them at risk for TD. This article addresses the prevalence, risk factors, and prevention of TD; assessment strategies including diagnostic criteria and rating scales; and evidence for TD treatments, including 2 newly approved medications: deutetrabenazine and valbenazine.","Tardive dyskinesia (TD) is characterized by uncontrolled movements, usually of the face muscles and also of the arms, legs, and other muscles. TD is related to antipsychotic use. Because reasons to prescribe and unapproved uses for antipsychotics have increased, more patients are taking antipsychotic drugs than in the past. Although data suggest that patients taking second-generation (newer) antipsychotics are less likely to develop TD than those taking first-generation (older) antipsychotics, the decreased risk is not as great as originally thought. In addition, patients with long-term mental conditions often need long-term antipsychotics use, putting them at risk for TD. This article looks at the total number of TD cases at a given time, risk factors, and prevention of TD; ways to measure TD including signs and symptoms and questionnaires; and TD treatments, including 2 newly approved drugs: deutetrabenazine and valbenazine." +"Tardive dyskinesia (TD) is a disorder characterized by involuntary movements, typically of the orofacial muscles and also of the extremities and other muscle groups. The condition is associated with exposure to dopamine receptor blocking agents, including antipsychotics. Because the indications and off-label uses for these agents have expanded over the last 2 decades, a larger number of patients are receiving antipsychotic medications than in the past. While evidence suggests that patients being treated with second-generation antipsychotics have less risk for developing TD than those treated with first-generation antipsychotics, the decreased risk is not as great as was originally expected. In addition, patients with chronic psychiatric conditions often require long-term use of antipsychotics, putting them at risk for TD. This article addresses the prevalence, risk factors, and prevention of TD; assessment strategies including diagnostic criteria and rating scales; and evidence for TD treatments, including 2 newly approved medications: deutetrabenazine and valbenazine.","Tardive dyskinesia (TD) is a disorder of involuntary movements, typlically of the lower face muscles, limbs, and other muscle groups. The condition is linked to exposure with blocking agents, like antipsychotics used to treat mental illnesses, of the chemical messenger dopamine. Since the allowed and off-label uses for these agents has increased over the last 20 years, more patients are receiving antipsychotics than before. While patients treated with one class of antipsychotics may have less risk for developing TD than those treated with another class, the decreased risk is not as big as expected. Also, patients with long-lasting mental illnesses often need long-term use of antipsychotics, pytting them at risk for TD. This article describes the widespreadness of TD, its risk factors, its prevention, its identification strategies like medical criteria and ratings, and evidence for its treatments, including deutetrabenazine and valbenzaine used for treating movement disorders." +"Objective: To examine the efficacy of pharmacologic treatments for tardive dyskinesia (TD). Data sources: PubMed was searched on December 12, 2017, for randomized, placebo-controlled trials examining the treatment of TD using the search terms (drug-induced dyskinesia OR tardive dyskinesia) AND (psychotic disorders OR schizophrenia). Study selection: Studies were included if they examined tardive dyskinesia treatment as the primary outcome and were randomized and placebo-controlled trials. Data extraction: The effect size (standard mean difference) of improvement (compared to placebo) stratified by medication class is reported for each of the trials included in this systematic review. A meta-analysis was conducted utilizing a fixed-effects model. Results: Vitamin E was associated with significantly greater reduction in TD symptoms compared to placebo (standardized mean difference [SMD] = 0.31 � 0.08; 95% CI, 0.16 to 0.46; z = 4.1; P < .001). There was significant evidence of publication bias in vitamin E studies (Egger test: P = .02). Shorter duration of treatment and lower dose of vitamin E were significantly associated with greater measured treatment benefit. Vitamin B? was associated with significantly greater reduction in TD symptoms compared to placebo (SMD = 1.41 � 0.22; 95% CI, 0.98 to 1.85; z = 6.4; P < .001) in 2 trials conducted by the same research group. Vesicular monoamine transporter 2 (VMAT2) inhibitors demonstrated significant benefit on tardive dyskinesia symptoms compared to placebo (SMD = 0.63 � 0.11; 95% CI, 0.41 to 0.85; z = 5.58; P < .005). Amantadine was associated with significantly greater score reduction compared to placebo (SMD = 0.46 � 0.21; 95% CI, 0.05 to 0.87; z = 2.20; P < .05). Calcium channel blockers were not associated with significantly greater score reduction compared to placebo (SMD = 0.31 � 0.33; 95% CI, -0.34 to 0.96; z = 0.93; P = .35). Conclusions: Data from multiple trials suggests that VMAT2 inhibitors, vitamin E, vitamin B?, and amantadine may be effective for the treatment of TD. Evidence of publication bias and a significant negative association of dose and duration of treatment with measured efficacy suggest that the benefits of vitamin E in TD may be overstated. Head-to-head trials are needed to compare the efficacy and cost-effectiveness of pharmacologic agents for TD.","We aim to understand how well different drugs work to treat tardive dyskinesia (TD) - a movement disorder. On December 12, 2017, we searched for published scientific studies looking at the treatment of TD versus sugar pills. We included studies if they looked at treatment of TD as the main result and randomly assigned participants to groups receiving TD treatment or sugar pills. We used statistical methods to combine the results of multiple studies. Results favored vitamin E over sugar pills in TD symptom reduction. The results of the published vitamin E studies were different from results of unpublished studies. Taking vitamin E for a shorter amount of time and at a lower dose was associated with greater TD symptom reduction. Results favored vitamin B6 over sugar pills in TD symptom reduction. Results favored vesicular monoamine transporter type 2 (VMAT2) inhibitors, drugs that reduce dopamine (a chemical messenger released when your brain is expecting a reward), over sugar pills in TD symptom reduction. Results favored amantadine - a dopamine promoter - over sugar pills. Results did not favor calcium channel blockers, which block transport of calcium in the body, over sugar pills. We conclude that many studies show that VMAT2 inhibitors, vitamin E, vitamin B?, and amantadine may work to treat TD. Because results of the published vitamin E studies were different from results of unpublished studies and taking vitamin E for a shorter amount of time and at a lower dose was associated with greater TD symptom reduction, the benefits of vitamin E in TD might not be as great as studies suggest. Studies comparing TD treatments to each other are needed to compare how well they work and how cost-effective they are." +"Tardive dyskinesias (TDs) are still common long-term sequelae of antipsychotic treatment. They are generally irreversible and associated with cognitive deficits, a decrease in quality of life and increased mortality. Furthermore, they potentially contribute to further stigmatization of the affected patients. However due to limited treatment options, antipsychotic drugs are still one of the cornerstones in treatment of most severe mental illnesses. Therefore, knowledge about risk factors and prevention of TDs is crucial. If TDs occur, the immediate optimization of the antipsychotic drug regimen is required. Targeted medical treatments such as VMAT - 2 inhibitors can be considered. The novel VMAT-2 inhibitors are not yet approved in Germany. Other drugs that are currently used to treat TDs include clonazepam and gingko biloba. This review summarizes the current evidence of treatment options of TDs and seeks to formulate clinical recommendations for the prevention and management of TDs.","Tardive dyskinesias (TDs) - movement disorders - are still common long-term consequences of antipsychotic drugs. TDs generally cannot be reversed and are linked with intellectual disabilities, decreased quality of life and increased death. Furthermore, TDs possibly cause patients to be viewed more negatively by society. Because of a lack of treatment options, antipsychotic drugs are still one of the main treatments for serious mental illness. Therefore, knowing about TD risk factors and prevention is very important. IF TDs happen, the amount of antipsychotic drugs prescribed must be changed quickly to an appropriate amount. Specialized drugs such as vesicular monoamine transporter type 2 (VMAT - 2) inhibitors, drugs that reduce dopamine (a chemical messenger released when your brain is expecting a reward), can be used. Germany has not yet approved the new VMAT-2 inhibitors. Clonazepam and gingko biloba, used for seizures and memory problems, respectively, are other drugs that can be used to treat TDs. We summarize the current data on TD treatment options and try to come up with recommendations for doctors to prevent and treat TDs." +"Aim: The aim of this study was to summarize the characteristics, efficacy, and safety of vesicular monoamine transporter-2 (VMAT-2) inhibitors for treating tardive dyskinesia (TD). Materials and methods: We conducted a literature search in PubMed, Cochrane Database, and ClinicalTrials.gov, screening for systematic reviews, meta-analyses or double-blind, randomized, placebo-controlled trials (DBRPCTs) reporting efficacy or safety data of VMAT-2 inhibitors (tetrabenazine, deutetrabenazine, and valbenazine) in patients with TD. A random effects meta-analysis of efficacy and safety data from DBRPCTs was performed. Results: Two acute, 12-week DBRPCTs with deutetrabenazine 12-48 mg/day (n=413) and 4 acute, 4-6-week double-blind trials with valbenazine 12.5-100 mg/day (n=488) were meta-analyzable, without meta-analyzable, high-quality data for tetrabenazine. Regarding reduction in total Abnormal Involuntary Movement Scale (AIMS) scores (primary outcome), both deutetrabenazine (k=2, n=413, standardized mean difference [SMD] =-0.40, 95% confidence interval [CI] =-0.19, -0.62, p<0.001; weighted mean difference (WMD) =-1.44, 95% CI =-0.67, -2.19, p<0.001) and valbenazine (k=4, n=421, SMD =-0.58, 95% CI =-0.26, -0.91, p<0.001; WMD =-2.07, 95% CI =-1.08, -3.05, p<0.001) significantly outperformed placebo. Results were confirmed regarding responder rates (?50% AIMS total score reduction; deutetrabenazine: risk ratio [RR] =2.13, 95% CI =1.10, 4.12, p=0.024, number-needed-to-treat [NNT] =7, 95% CI =3, 333, p=0.046; valbenazine: RR =3.05, 95% CI =1.81, 5.11, p<0.001, NNT =4, 95% CI =3, 6, p<0.001). Less consistent results emerged from patient-rated global impression-based response (p=0.15) and clinical global impression for deutetrabenazine (p=0.088), and for clinical global impression change for valbenazine (p=0.67). In an open-label extension (OLE) study of deutetrabenazine (?54 weeks) and a dose-blinded valbenazine study (?48 weeks), responder rates increased over time. With valbenazine, discontinuation effects were studied, showing TD symptom recurrence towards baseline severity levels within 4 weeks after valbenazine withdrawal. No increased cumulative or specific adverse (AEs) events versus placebo (acute trials) in extension versus acute trial data were observed. Conclusion: The 2 VMAT-2 inhibitors, valbenazine and deutetrabenazine, are effective in treating TD, both acutely and long-term, without concerns about increased risk of depression or suicide in the TD population. No head-to-head comparison among VMAT-2 inhibitors and no high-quality, meta-analyzable data are available for tetrabenazine in patients with TD.","We aimed to summarize the characteristics, how well it works, and safety of vesicular monoamine transporter type 2 (VMAT-2) inhibitors, drugs that reduce dopamine (a chemical messenger released when your brain is expecting a reward), for treating tardive dyskinesia (TD) - a movement disorder. We searched for published scientific studies, including studies that summarized other studies, used statistics to combine results from other studies, or randomly assigned participants to groups receiving TD treatment or sugar pills that looked at how well treatments worked and safety of VMAT-2 inhibitors (tetrabenazine, deutetrabenazine, and valbenazine) in patients with TD. We used statistical methods to determine how well treatments work and safety results across multiple studies. We used statistical methods to combine results from two 12-week studies with deutetrabenazine 12-48 mg/day (413 patients) and four 4-6 week studies with valbenazine 12.5-100 mg/day (488 patients). No high-quality data were available for tetrabenazine for a similar analysis. Results favored deutetrabenazine and valbenazine over sugar pills in scores on a rating scale that measures involuntary movements (AIMS). The percentage of patients who had 50% reduction in scores on the same rating scale (AIMS) favored deutetrabenazine and valbenazine over sugar pills. Results were less consistent using another rating scale done by patients and doctors for deutetrabenazine and by doctors for valbenazine. In one study of deutetrabenazine and one study of valbenazine, the percentage of patients who had a 50% reduction in scores on the AIMS rating scale went up over time. Effects of stopping valbenazine were studied, showing TD symptoms returning to levels before stopping valbenazine within 4 weeks of stopping the drug. No increased unfavorable and unintended effects were observed in studies where participants continued to take the studied drug compared to sugar pills. We conclude that the 2 VMAT-2 inhibitors, valbenazine and deutetrabenazine, work to treat TD, both in the short- and long-term, without causing increased risk of depression or suicide in people with TD. No studies comparing VMAT-2 inhibitors or high-quality tetrabenazine data that could be compared across studies were available." +"Aim: The aim of this study was to summarize the characteristics, efficacy, and safety of vesicular monoamine transporter-2 (VMAT-2) inhibitors for treating tardive dyskinesia (TD). Materials and methods: We conducted a literature search in PubMed, Cochrane Database, and ClinicalTrials.gov, screening for systematic reviews, meta-analyses or double-blind, randomized, placebo-controlled trials (DBRPCTs) reporting efficacy or safety data of VMAT-2 inhibitors (tetrabenazine, deutetrabenazine, and valbenazine) in patients with TD. A random effects meta-analysis of efficacy and safety data from DBRPCTs was performed. Results: Two acute, 12-week DBRPCTs with deutetrabenazine 12-48 mg/day (n=413) and 4 acute, 4-6-week double-blind trials with valbenazine 12.5-100 mg/day (n=488) were meta-analyzable, without meta-analyzable, high-quality data for tetrabenazine. Regarding reduction in total Abnormal Involuntary Movement Scale (AIMS) scores (primary outcome), both deutetrabenazine (k=2, n=413, standardized mean difference [SMD] =-0.40, 95% confidence interval [CI] =-0.19, -0.62, p<0.001; weighted mean difference (WMD) =-1.44, 95% CI =-0.67, -2.19, p<0.001) and valbenazine (k=4, n=421, SMD =-0.58, 95% CI =-0.26, -0.91, p<0.001; WMD =-2.07, 95% CI =-1.08, -3.05, p<0.001) significantly outperformed placebo. Results were confirmed regarding responder rates (?50% AIMS total score reduction; deutetrabenazine: risk ratio [RR] =2.13, 95% CI =1.10, 4.12, p=0.024, number-needed-to-treat [NNT] =7, 95% CI =3, 333, p=0.046; valbenazine: RR =3.05, 95% CI =1.81, 5.11, p<0.001, NNT =4, 95% CI =3, 6, p<0.001). Less consistent results emerged from patient-rated global impression-based response (p=0.15) and clinical global impression for deutetrabenazine (p=0.088), and for clinical global impression change for valbenazine (p=0.67). In an open-label extension (OLE) study of deutetrabenazine (?54 weeks) and a dose-blinded valbenazine study (?48 weeks), responder rates increased over time. With valbenazine, discontinuation effects were studied, showing TD symptom recurrence towards baseline severity levels within 4 weeks after valbenazine withdrawal. No increased cumulative or specific adverse (AEs) events versus placebo (acute trials) in extension versus acute trial data were observed. Conclusion: The 2 VMAT-2 inhibitors, valbenazine and deutetrabenazine, are effective in treating TD, both acutely and long-term, without concerns about increased risk of depression or suicide in the TD population. No head-to-head comparison among VMAT-2 inhibitors and no high-quality, meta-analyzable data are available for tetrabenazine in patients with TD.","This study's aim was to summarize the characteristics, effect, and safety of vesicular monoamine transporter-2 (VMAT-2) inhibitors, drugs that treat movement disorders, for treating tardive dyskinesia (TD), a movement disorder of irregular, jerking movements. We searched online for studies reporting the effect and safety of VMAT-2 inhibitors like tetrabenazine, deutetrabenazine, and valbenazine in patients with TD. Two short, 12-week studies with deutetrabenazine12-48 mg/day (with 413 patients) and 4 short, 4-6-week studies with valbenazine 12.5-100 mg/day (with 488 patients) were analyzed. There was no high-quality data for tetrabenazine. Regarding reducing irregular, involuntary movements (the primary symptom), both deutetrabenazine and valbenazine outperformed placebo or a dummy treatment. Results were confirmed regarding responder rates, or the proportion of patients with a reduction in symptoms in a define period of time. Patient-rated global impressions for deutetrabenazine and clinical global impressions for deutetrabenazine and valbenazine were less strong. In a long-term study of deutetrabenazine (?54 weeks) and a valbenazine study (?48 weeks), responder rates increased. With valbenazine, drug use stoppage effects were studied, showing TD symptom reappearance of initial severity 4 weeks after valbenazine stoppage. No increased or specific, serious or adverse events (AEs) versus dummy treatment (acute trials) in long-term versus short-term trials were seen. The 2 VMAT-2 inhibitors, valbenazine and deutetrabenazine, can treat TD, both short- and long-term, without concerns about increased risk of depression or suicide in the TD population. No direct comparison between the VMAT-2 inhibitors and no high-quality data are available for tetrabenazine in patients with TD." +"Tardive dyskinesia (TD) is a condition of potentially irreversible abnormal involuntary movements associated with dopamine receptor blocking agents, such as antipsychotics. While prevention is the best strategy, it is not always possible. This report outlines strategies to reduce TD symptoms, including the use of the FDA-approved treatment options (valbenazine and deutetrabenazine).","Tardive dyskinesia (TD) is characterized by possibly irreversible, abnormal, uncontrolled movements related to the use of antipsychotics. While prevention is the best approach, it is not always possible. This report lists approaches to reduce TD symptoms, including the use of treatments options approved by the FDA (such as the drugs valbenazine and deutetrabenazine)." +"Recent studies have shown that antihypertensive drugs like diuretics increase plasma homocysteine (Hcy) levels. However, the effect of other antihypertensive drugs on plasma Hcy levels has not been tested extensively. The aim of present study was to investigate the effect of antihypertensive therapy (AHT) on Hcy levels in essential hypertensive subjects. A case-control study of 273 patients with essential hypertension (EH) and 103 normotensive controls was undertaken. Plasma Hcy levels were measured before and after 6 weeks of AHT. The genotyping of MTHFR C677T polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism. Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers significantly decreased and hydrochlorothiazides significantly increased the plasma Hcy levels in hypertensive patients (P<0.05). No significant association between MTHFR C677T genotypes and changes in Hcy levels in response to antihypertensive was observed in EH patients. The decrease in Hcy induced by beta-blockers and ACE inhibitors observed in our study may be due to the improvement of endothelial function along with improved renal function. Thus, our results suggest that ACE inhibitors and beta-blockers may provide additional beneficial therapeutic effects to the EH patients by decreasing Hcy levels.","Recent studies have shown that antihypertensive drugs (that treat high blood pressure), like diuretics, increase plasma or blood homocysteine (Hcy) levels. Hcy is am amino acid that creates other chemicals your body needs. However, the effect of other antihypertensive drugs on plasma Hcy levels has not been tested extensively. The goal of this study was to investigate the effect of antihypertensive therapy (AHT) on Hcy levels in essential hypertensive subjects. Essential hypertensive patients have high blood pressure that is not the result of a medical condition. A study of 273 patients with essential hypertension (EH) and 103 patients with normal blood pressure was begun. Plasma Hcy levels were measured before and after 6 weeks of AHT. Patients were genotyped to analyze a specific genetic variation or gene material. Angiotensin-converting enzyme (ACE) inhibitors are drugs that lower blood pressure by relaxing veins and arteries. Beta-blockers are drugs that lower blood pressure by blocking the effects of adrenaline. ACE inhibitors and beta-blockers significantly decrease plasms Hcy levels in hypertensive patients. Hydrochlorothiazides, or ""water pills"", significantly increase plasms Hcy levels in hypertensive patients. There was no association between the identified genetic variation and changes in Hcy levels in response to antihypertensive within EH patients. The observed decrease in Hcy caused by ACE inhibitors and beta-blockers may be due to the improvement of endothelial (tissue lining various organs and cavities in the body) and kidney function. Therefore, this study suggests that ACE inhibitors and beta-blockers may provide additional, beneficial or therapeutic effects to the EH patients by decreasing Hcy levels." +"Objectives: Elevated plasma homocysteine has been implicated as a risk factor for hypertension. C677T polymorphism in methylenetetrahydrofolate reductase gene (MTHFR) is a major determinant of hyperhomocysteinemia, which results in endothelial dysfunction. Angiotensin-converting enzyme (ACE) inhibitors appear to remedy the endothelial dysfunction and restore endothelium-dependent vasodilatation. The co-existence of genetic polymorphisms in drug metabolizing enzymes, targets, receptors, and transporters may influence the drug efficacy. The purpose of this study was to investigate whether short-term blood pressure control by benazepril, an ACE inhibitor, was modulated by C677T MTHFR gene polymorphism. Methods and results: A total of 444 hypertensive patients, aged 27 to 65 years, without any anti hypertensive therapy within 2 weeks were included. All of them were treated orally with benazepril at a single daily fixed dosage of 10 mg for 15 consecutive days. Blood pressures were measured at baseline and on the 16th day of treatment. Among them, the frequency of MTHFR C677T genotype CC, CT and TT was 24.3%, 51.8%, and 23.9%, respectively. In a recessive model (CC+CT versus TT genotype), both baseline diastolic blood pressure (DBP) and diastolic blood pressure response (DeltaDBP) were significantly higher in patients with the TT genotype than in those with the CT or CC genotype (P value=0.0076 for DBP, and P value=0.0005 for DeltaDBP). We further divided all patients into three groups based on the tertiles of the DeltaBP distribution. Compared to subjects in the lowest tertile of DeltaDBP, the adjusted relative odds of having the TT genotype among subjects in the highest tertile was 2.6 (95% CI, 1.4 to 4.9). However, baseline systolic blood pressure (SBP) and SBP response did not significantly associate with MTHFR C677T polymorphism. Conclusions: Our finding suggests that MTHFR C667T polymorphism modulated baseline DBP and DBP responsiveness by short-term treatment of ACE inhibitor in Chinese essential hypertensive patients.","Increase plasma, or blood, homocysteine has been identified as a risk factor for hypertension (high blood pressure). Homocysteine is a chemical your body produces to help make proteins. An identified genetic variation or gene type within the human population is a major determinant of hyperhomocysteinemia. Hyperhomocysteinemia is a condition with excess homocysteine in the blood. The condition can result in endothelial dysfunction, or a heart disease where the blood vessels narrow instead of opening. Angiotensin-converting enzyme (ACE) inhibitors are a type of drug commonly used to treat high blood pressure. ACE Inhibitors appear to fix the endothelial (or blood vessel lining) dysfunction and allow blood vessels to open. The presence of the genetic variation in specific bodily locations that metabolize or digest drugs, such as enzymes and receptors, may influence how well a drug works. The goal of this study was to investigate if short-term blood pressure control by an ACE inhibitor (Benazepril) is effected by the identified genetic variation. A total of 444 hypertensive patients, aged 27 to 65 years, without any anti hypertensive therapy within 2 weeks were included. All patients were treated with Benazepril with a single, daily dose of 10 mg for 15 consecutive days. Blood pressures were measured prior to the study beginning (baseline) and on the 16th day of treatment. The unique genetic variation has three unique ""versions"" or genotypes, known as CC, CT, or TT. Among the patients, the frequency of the genetic variation genotype CC, CT, and TT was 24.3%, 51.8%, and 23.9%, respectively. In a statistical analysis, several blood pressure measurements were higher in patients with the TT genotype than those with the CT or CC genotype. The authors further divided all patients into three groups based on where their diastolic blood pressure response (DeltaDBP) fell within a population scale. Diastolic blood pressure is the lowest pressure when the heart is relaxed. Patients with the highest DeltaDBP had the highest chance of having the TT genotype. However, baseline systolic blood pressure (when the heart is contracting) was not significantly associated with the unique genetic variation. This study suggests that the unique genetic variation altered baseline DBP by short-term treatment of ACE inhibitor in hypertensive patients." +"Objectives: Elevated plasma homocysteine has been implicated as a risk factor for hypertension. C677T polymorphism in methylenetetrahydrofolate reductase gene (MTHFR) is a major determinant of hyperhomocysteinemia, which results in endothelial dysfunction. Angiotensin-converting enzyme (ACE) inhibitors appear to remedy the endothelial dysfunction and restore endothelium-dependent vasodilatation. The co-existence of genetic polymorphisms in drug metabolizing enzymes, targets, receptors, and transporters may influence the drug efficacy. The purpose of this study was to investigate whether short-term blood pressure control by benazepril, an ACE inhibitor, was modulated by C677T MTHFR gene polymorphism. Methods and results: A total of 444 hypertensive patients, aged 27 to 65 years, without any anti hypertensive therapy within 2 weeks were included. All of them were treated orally with benazepril at a single daily fixed dosage of 10 mg for 15 consecutive days. Blood pressures were measured at baseline and on the 16th day of treatment. Among them, the frequency of MTHFR C677T genotype CC, CT and TT was 24.3%, 51.8%, and 23.9%, respectively. In a recessive model (CC+CT versus TT genotype), both baseline diastolic blood pressure (DBP) and diastolic blood pressure response (DeltaDBP) were significantly higher in patients with the TT genotype than in those with the CT or CC genotype (P value=0.0076 for DBP, and P value=0.0005 for DeltaDBP). We further divided all patients into three groups based on the tertiles of the DeltaBP distribution. Compared to subjects in the lowest tertile of DeltaDBP, the adjusted relative odds of having the TT genotype among subjects in the highest tertile was 2.6 (95% CI, 1.4 to 4.9). However, baseline systolic blood pressure (SBP) and SBP response did not significantly associate with MTHFR C677T polymorphism. Conclusions: Our finding suggests that MTHFR C667T polymorphism modulated baseline DBP and DBP responsiveness by short-term treatment of ACE inhibitor in Chinese essential hypertensive patients.","Increased blood levels of homocysteine, a specific chemical, may be a risk factor for high blood pressure. A specific mutation in DNA (C677T) encoding methylenetetrahydrofolate reductase (MTHFR), a protein that transforms homocysteine, greatly influences hyperhomocysteinemia, or high blood levels of homocysteine. This condition results in damage to cells that line the heart and blood vessels. Blood pressure medication called angiotensin-converting enzyme (ACE) inhibitors seem to repair damage to cells lining the heart and blood vessels and restore blood vessel widening. The co-existence of varied DNA for drug-digesting enzymes, targets, target sites, and transporters may affect drug effect. This study investigates if short-term blood pressure control by benazepril, an ACE inhibitor, was affected by variation in the DNA sequence for the C667T MTHFR gene. 444 patients with high blood pressure, aged 27 to 65 years, without any high blood pressure therapy within 2 weeks were included. All of them swallowed benazepril at a single daily fixed dose of 10 mg for 15 consecutive days. Blood pressures were measured at start and on the 16th day of treatment. Among them, the gene sequence for MTHFR C677T varied. Diastolic blood pressure at the start and end were much higher for patients with a certain DNA sequence for the MTHFR C677T gene than patients with two other DNA sequences. We then divided all patients into 3 groups based on the distribution of blood pressure readings at the study's end. Compared to those with the lowest blood pressure measurements, the chances of having a certain DNA sequence for the MTHFR C667T gene among those with the highest blood pressure readings was 2.6 times higher. However, systolic blood pressure at the start and end was not linked to DNA sequences. DNA sequence variation for the MTHFR C667T gene affects diastolic blood pressure at the study's start and end in Chinese essential patients with high blood pressure." +"Objective: In a subgroup analysis of the China Stroke Primary Prevention Trial, we aimed to explore the impact of folic acid supplementation on arterial stiffness and assess the modifying effect of the methylenetetrahydrofolate reductase (MTHFR) gene in Chinese patients with hypertension. Methods: This prospective study enrolled 2529 hypertensive Chinese patients. Participants were randomized to receive treatment with either a combination of enalapril and folic acid or enalapril. Brachial-ankle pulse wave velocity (PWV) was measured by trained medical staff using PWV instruments at both baseline and exit visits, approximately 5 years after enrollment. This trial was registered with clinicaltrials.gov (NCT00794885). Results: During the follow-up, change in folate was significantly and independently correlated with change in ba-PWV in study patients (? = -1.31, P < 0.001). Individuals with CC genotype had a significantly greater PWV response to folic acid supplementation than did carriers of the T allele (? = -2.79, P < 0.001 for CC homozygotes compared with ? = -0.56, P = 0.464 for TT homozygotes). The positive effect of folic acid on improved PWV was modified by the MTHFR genotype (P for interaction = 0.034). Conclusion: In a subgroup of Chinese hypertensive patients who had received 5-year antihypertensive therapy, increases in folate status were associated with higher reductions in PWV, and individuals with the CC genotype showed greatest PWV response to folic acid supplementation.","This study conducted an analysis using patients from the China Stroke Primary Prevention Trial. The goal of this study was to explore the impact of folic acid (a specific vitamin) on arterial stiffness (hardness of arteries or specific blood vessels). Additionally, this study aimed to measure the modifying or influencing effect of a specific gene (methylenetetrahydrofolate reductase-MTHFR) in Chinese patients with hypertension (high blood pressure). This study enrolled 2,529 hypertensive (high blood pressure) Chinese patients. Participants were randomized to receive treatment with either a combination of enalapril (common blood pressure medication) and folic acid or enalapril. Brachial-ankle pulse wave velocity (PWV) is a measurement of arterial stiffness. It is measured by looking at the brachial and tibial arteries, located within the upper arm. PWV was taken by trained medical staff using appropriate equipment during both baseline (before treatment) and exit (end of treatment) visits, approximately 5 years after enrollment. This trial was registered with clinicaltrials.gov (NCT00794885). During the follow-up, change in folate (vitamin in the body) was significantly and independently linked with change in PWV in patients. Patients with CC genotype (a person's collection of specific genes) had a significantly greater PWV response to folic acid than those with genotype CT or TT. The positive effect of folic acid on improved PWV was modified by what genotype the patient had. The study concluded that within the analyzed subgroup of Chinese hypertensive patients who had received a 5-year antihypertensive therapy, increase in folate status were correlated or linked with decreased PWV. Additionally, individuals with CC genotype showed greatest PWV response to folic acid treatment." +"Objective: This post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial) assessed the individual variation in total homocysteine (tHcy)-lowering response after an average 4.5 years of 0.8 mg daily folic acid therapy in Chinese hypertensive adults and evaluated effect modification by methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and serum folate levels. Approach and results: This analysis included 16 413 participants from the CSPPT, who were randomly assigned to 2 double-blind treatment groups: either 10-mg enalapril+0.8-mg folic acid or 10-mg enalapril, daily and had individual measurements of serum folate and tHcy levels at baseline and exit visits and MTHFR C677T genotypes. Mean baseline tHcy levels were comparable between the 2 treatment groups (14.5�8.5 versus 14.4�8.1 ?mol/L; P=0.561). After 4.5 years of treatment, mean tHcy levels were reduced to 12.7�6.1 ?mol/L in the enalapril+folic acid group, but almost stayed the same in the enalapril group (14.4�7.9 ?mol/L, group difference: 1.61 ?mol/L; 11% reduction). More importantly, tHcy lowering varied by MTHFR genotypes and serum folate levels. Compared with CC and CT genotypes, participants with the TT genotype had a more prominent L-shaped curve between tHcy and serum folate levels and required higher folate levels (at least 15 ng/mL) to eliminate the differences in tHcy by genotypes. Conclusions: Compared with CC or CT, tHcy in the TT group manifested a heightened L-shaped curve from low to high folate levels, but this difference in tHcy by genotype was eliminated when plasma folate levels reach ?15 ng/mL or higher. Our data raised the prospect to tailor folic acid therapy according to individual MTHFR C677T genotype and folate status.","This study represents an analysis on the China Stroke Primary Prevention Trial (CSPPT). Individual variation in total homocysteine (tHcy)-lowering response was measured after an average of 4.5 years of 0.8 mg daily folic acid (or specific vitamin) therapy. Homocysteine is a chemical your body produces to help make proteins. This study was completed in Chinese hypertensive (high blood pressure) adults. This study evaluated effect modification by methylenetetrahydrofolate reductase (MTHFR) C677T genotypes (a person's specific gene type for a specific protein) and serum or blood folate (derivative of folic acid) levels. The study included 16,413 participants from the CSPPT study. The participants were randomly assigned to 2 double-blind treatment groups. Double-blind indicates the study participants were not told which treatment group they were apart of. The participants received either 10-mg enalapril (common blood pressure medication) +0.8-mg folic acid or 10-mg enalapril daily. The participants had individual measurements of serum folate and tHcy levels at baseline (before study) and exit (end of study) visits and MTHFR C677T genotypes. Average baseline tHcy levels were similar between the 2 treatment groups. After 4.5 years of treatment, mean or average tHcy levels were reduced in the enalapril+folic acid group, but almost stayed the same in the enalapril group. However, tHcy lowering varied by MTHFR genotypes and serum folate levels. Participants with a specific MTHFR genotype (TT) required higher folate levels to eliminate the differences in tHcy between them and the other two genotypes (CC and CT). The study concluded that the TT genotype group showed that as folate levels increased, tHcy levels decreased. However, this difference in tHcy between the genotype groups was removed when plasma or blood folate levels reached ?15 ng/mL or higher. This study suggests to tailor folic acid therapy by MTHFR genotype and folate status." +"Background: Genome-wide and clinical studies have linked the 677C?T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with hypertension, whilst limited evidence shows that intervention with riboflavin (i.e. the MTHFR co-factor) can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. We investigated the impact of this common polymorphism on BP throughout adulthood and hypothesised that riboflavin status would modulate the genetic risk of hypertension. Methods: Observational data on 6076 adults of 18-102 years were drawn from the Joint Irish Nutrigenomics Organisation project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008-2012 using standardised methods. Results: The variant MTHFR 677TT genotype was identified in 12% of adults. From 18 to 70 years, this genotype was associated with an increased risk of hypertension (i.e. systolic BP ? 140 and/or a diastolic BP ? 90 mmHg): odds ratio (OR) 1.42, 95% confidence interval (CI) 1.07 to 1.90; P = 0.016, after adjustment for antihypertensive drug use and other significant factors, namely, age, male sex, BMI, alcohol and total cholesterol. Low or deficient biomarker status of riboflavin (observed in 30.2% and 30.0% of participants, respectively) exacerbated the genetic risk of hypertension, with a 3-fold increased risk for the TT genotype in combination with deficient riboflavin status (OR 3.00, 95% CI, 1.34-6.68; P = 0.007) relative to the CC genotype combined with normal riboflavin status. Up to 65 years, we observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype (30%) compared to those without this variant, CT (37%) and CC (45%) genotypes (P < 0.027). Conclusions: The MTHFR 677TT genotype is associated with higher BP independently of homocysteine and predisposes adults to an increased risk of hypertension and poorer BP control with antihypertensive treatment, whilst better riboflavin status is associated with a reduced genetic risk. Riboflavin intervention may thus offer a personalised approach to prevent the onset of hypertension in adults with the TT genotype; however, this requires confirmation in a randomised trial in non-hypertensive adults.","Research has linked a specific a genetic variation or gene change, known as 677C?T, within the gene encoding methylenetetrahydrofolate reductase (MTHFR - a blood-pressure-related protein) with hypertension (high blood pressure). Limited evidence has shown that taking riboflavin, which is a co-factor or helper of MTHFR, can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. This study investigated the impact of the common genetic variation on BP throughout adulthood. They hypothesized that riboflavin status would alter the genetic risk of hypertension. Observational data on 6076 adults of 18-102 years were drawn from the Joint Irish Nutrigenomics Organization project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts or groups. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008-2012 using standard methods. The genetic variant MTHFR 677TT genotype was identified in 12% of recruited adults. In patients 18 to 70 years old, this genotype was associated with an increased risk of hypertension. Low or deficient levels of riboflavin increased the genetic risk of hypertension. Participants with 677TT genotype and a riboflavin deficiency have a 3-fold higher risk of developing hypertension. In participants up to 65 years, the authors observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype compared to participants with other genotypes (CC or CT). The study concluded the MTHFR 677TT genotype is associated with higher BP independently of homocysteine levels. Homocysteine is a chemical your body produces to help make proteins. Additionally, the MTHFR 677TT genotype makes people more likely to have an increased risk of hypertension and poorer BP control with antihypertensive treatment. Better riboflavin status was associated with a reduced genetic risk for hypertension. Riboflavin administration or use may offer a personalized or unique approach to prevent the onset or start of hypertension in adults with the TT genotype. However, this requires more researched in non-hypertensive adults." +"Background: Genome-wide and clinical studies have linked the 677C?T polymorphism in the gene encoding methylenetetrahydrofolate reductase (MTHFR) with hypertension, whilst limited evidence shows that intervention with riboflavin (i.e. the MTHFR co-factor) can lower blood pressure (BP) in hypertensive patients with the variant MTHFR 677TT genotype. We investigated the impact of this common polymorphism on BP throughout adulthood and hypothesised that riboflavin status would modulate the genetic risk of hypertension. Methods: Observational data on 6076 adults of 18-102 years were drawn from the Joint Irish Nutrigenomics Organisation project, comprising the Trinity-Ulster Department of Agriculture (TUDA; volunteer sample) and the National Adult Nutrition Survey (NANS; population-based sample) cohorts. Participants were recruited from the Republic of Ireland and Northern Ireland (UK) in 2008-2012 using standardised methods. Results: The variant MTHFR 677TT genotype was identified in 12% of adults. From 18 to 70 years, this genotype was associated with an increased risk of hypertension (i.e. systolic BP ? 140 and/or a diastolic BP ? 90 mmHg): odds ratio (OR) 1.42, 95% confidence interval (CI) 1.07 to 1.90; P = 0.016, after adjustment for antihypertensive drug use and other significant factors, namely, age, male sex, BMI, alcohol and total cholesterol. Low or deficient biomarker status of riboflavin (observed in 30.2% and 30.0% of participants, respectively) exacerbated the genetic risk of hypertension, with a 3-fold increased risk for the TT genotype in combination with deficient riboflavin status (OR 3.00, 95% CI, 1.34-6.68; P = 0.007) relative to the CC genotype combined with normal riboflavin status. Up to 65 years, we observed poorer BP control rates on antihypertensive treatment in participants with the TT genotype (30%) compared to those without this variant, CT (37%) and CC (45%) genotypes (P < 0.027). Conclusions: The MTHFR 677TT genotype is associated with higher BP independently of homocysteine and predisposes adults to an increased risk of hypertension and poorer BP control with antihypertensive treatment, whilst better riboflavin status is associated with a reduced genetic risk. Riboflavin intervention may thus offer a personalised approach to prevent the onset of hypertension in adults with the TT genotype; however, this requires confirmation in a randomised trial in non-hypertensive adults.","Genetic and clinical studies have linked variation in a specific DNA sequence for methylenetetrahydrofolate reductase (MTHFR), a certain protein, with high blood pressure. Some evidence shows that treatment with riboflavin (a molecule that attaches to MTHFR) can lower blood pressure (BP) in patients with high blood pressure and an altered DNA sequence for MTHFR called 677TT. We tested the impact of this altered DNA sequence on BP through adulthood. We believed that riboflavin would affect the genetic risk of high blood pressure. Patients were recruited from the Republic of Ireland and Northern Ireland in 2008-2012. The altered DNA sequence of MTHFR 677TT was found in 12% of adults. From 18 to 70 years, this altered DNA sequence, or genotype, was linked with increased risk of high blood pressure after adjusting for blood pressure medication use, age, sex, body mass, alcohol, total cholesterol, and other factors. Low or no riboflavin (seen in 30.2% and 30.0% of participants, respectively) worsened the genetic risk of high blood pressure. Patients with a certain genotype along with no riboflavin had a 3-fold increased risk compared to patients with the standard genotype along with normal riboflavin. Up to 65 years, we saw poorer BP control rates on anti-high-BP treatment in participants with a certain DNA sequence for MTHFR compared to those without this altered DNA sequence. A specific gentoype for MTHFR is linked with higher BP regardless of homocysteine, a molecule that MTHFR acts on, and biases adults to increased risk of high BP and poorer BP control with anti-high-BP treatment. Better riboflavin amount is linked with reduced genetic risk. Riboflavin treatment may thus give an individualized approach to prevent high BP in adults with a certain genotype for MTHFR. Still, this needs confirmation in a trial in adults without high BP." +"Methylenetetrahydrofolate reductase (MTHFR) is a critical folate-metabolising enzyme which requires riboflavin as its co-factor. A common polymorphism (677C?T) in the MTHFR gene results in reduced MTHFR activity in vivo which in turn leads to impaired folate metabolism and elevated homocysteine concentrations. Homozygosity for this polymorphism (TT genotype) is associated with an increased risk of a number of conditions including heart disease and stroke, but there is considerable variability in the extent of excess risk in various reports. The present review will explore the evidence which supports a role for this polymorphism as a risk factor for a number of adverse health outcomes, and the potential modulating roles for B-vitamins in alleviating disease risk. The evidence is convincing in the case which links this polymorphism with hypertension and hypertensive disorders of pregnancy, particularly preeclampsia. Furthermore, elevated blood pressure was found to be highly responsive to riboflavin intervention specifically in individuals with the MTHFR 677TT genotype. Future intervention studies targeted at these genetically predisposed individuals are required to further investigate this novel gene-nutrient interaction. This polymorphism has also been associated with an increased risk of neural tube defects (NTD) and other adverse pregnancy outcomes; however, the evidence in this area has been inconsistent. Preliminary evidence has suggested that there may be a much greater need for women with the MTHFR 677TT genotype to adhere to the specific recommendation of commencing folic acid prior to conception for the prevention of NTD, but this requires further investigation.","Methylenetetrahydrofolate reductase (MTHFR) is a critical folate (specific vitamin)-metabolizing enzyme which requires riboflavin as its co-factor. Co-factors are needed for enzymes, catalysts for chemical reactions in the body, to complete their roles. A common variation (677C?T) in the MTHFR gene results in reduced MTHFR activity. This can caused impaired folate metabolism and increased homocysteine concentrations. Homocysteine is a chemical your body produces to help make proteins. Individuals can inherit the same form of a gene from both parents. When this occurs, a person has homozygosity. Homozygosity for this genetic variation (TT genotype) is associated with an increased risk of a number of conditions. These conditions include heart disease and stroke. However, there is a large amount of variability or differences in the extent of excess risk in various reports. The study aimed to explore the evidence available that supports this genetic variation increasing the risk for several adverse or bad health outcomes. Additionally, the study aimed to explore the evidence of how B-vitamins can help alleviate or lessen disease risk. There is strong evidence that links the genetic variation (TT genotype) with hypertension (hig blood pressure) and hypertensive disorders of pregnancy, particularly preeclampsia. Furthermore, high blood pressure was found to be highly responsive to or affected by riboflavin intervention or treatment specifically in individuals with the MTHFR 677TT genotype. Future intervention studies aimed at genetically predisposed or genetically risky individuals are required to further understand this gene-nutrient interaction. This genetic variation has also been associated with an increased risk of neural tube defects (NTD), brain-related damage, and other adverse pregnancy outcomes. However, the evidence on this subject has been inconsistent. Initial evidence has suggested there may be a greater need for women with MTHFR 677TT genotype to take folic acid prior to conception (or having a baby) for the prevention of NTD. However, this idea requires further investigation." +"Background: Hyperhomocysteinemia (HHCY) is a risk factor for cardiovascular and cerebrovascular diseases. The C677T 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism increases homocysteine (HCY) levels. This study analyzed the relationship between C677T MTHFR polymorphism and the therapeutic effect of lowering HCY in stroke patients with HHCY. Methods: Baseline data were collected from stroke patients with HHCY for this prospective cohort study. The C677T MTHFR genotype was detected by polymerase chain reaction-restriction fragment length polymorphism and the therapeutic effect to reduce HCY was compared. Results: Of 200 stroke patients 162 (81.0%) completed follow-up and were evaluated. Most of them responded well to treatment (103 cases, 63.5%), but 59 (36.4%) patients were in the poor efficacy group. There was a significant difference in terms of age (P < 0.001), hypertension (P = 0.041), hyperuricemia (P = 0.042), HCY after treatment (P < 0.001), and MTHFR genotype (P < 0.001) between the poor efficacy and effective groups, with increased frequency of the TT genotype in the poor efficacy group. Logistic regression showed that the T allele was associated with poor efficacy (OR = 0.733, 95%CI: 0.693, 0.862, P < 0.001). In the codominant model the TT genotype was associated with poor outcome (OR = 0.862, 95%CI: 0.767, 0.970, P = 0.017) and this was also the case in the recessive model (OR = 0.585, 95%CI: 0.462, 0.741, P < 0.001) but there was no association between CT and TT in the dominant model. Conclusions: The T allele and TT genotype of the MTHFR C677T polymorphism was associated with poor HCY reduction treatment efficacy in stroke patients with HHCY.","Hyperhomocysteinemia (HHCY), when there is excess homocysteine in the blood, is a risk factor for cardiovascular, or blood- and heart-related, and cerebrovascular, or blood- and brain-related, diseases. Homocysteine is an intermediate amino acid (molecule that form proteins). A specific genetic variation or gene change, known as C677T 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphism, which alters the MTHFR protein involved in blood pressure, increases homocysteine (HCY) levels. This study analyzed the relationship between C677T MTHFR variation and the therapeutic, beneficial effect (response after a treatment) of lowering HCY in stroke patients with HHCY. Baseline data, meaning prior to treatment, was collected from stroke patients with HHCY for this study. The C677T MTHFR genotype was detected, and the therapeutic effect to reduce HCY was compared. Of 200 stroke patients, 162 completed follow-up and were evaluated. Most of them responded well to treatment, but 59 patients were in the poor efficacy or poor effect group. There was a significant difference in terms of age, hypertension (high blood pressure), hyperuricemia (high uric acid or waste), HCY after treatment, and MTHFR genotype between the poor efficacy and effective groups. The poor efficacy group had more participated with TT genotype of the genetic variant. Statistical analysis showed that the T allele (an alternative form of a gene) was associated with poor efficacy. The TT genotype was associated with poor outcomes. The study concluded the T allele and TT genotype of the MTHFR C677T genetic variation was associated with poor HCY reduction treatment efficacy in stroke patients with HHCY." +"Objective: We evaluated the interaction of serum folate and vitamin B12 with methylenetetrahydrofolate reductase (MTHFR) C677T genotypes on the risk of first ischemic stroke and on the efficacy of folic acid treatment in prevention of first ischemic stroke. Methods: A total of 20,702 hypertensive adults were randomized to a double-blind treatment of daily enalapril 10 mg and folic acid 0.8 mg or enalapril 10 mg alone. Participants were followed up every 3 months. Results: Median values of folate and B12 concentrations at baseline were 8.1 ng/mL and 280.2 pmol/L, respectively. Over a median of 4.5 years, among those not receiving folic acid, participants with baseline serum B12 or serum folate above the median had a significantly lower risk of first ischemic stroke (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57-0.96), especially in those with MTHFR 677 CC genotype (wild-type) (HR, 0.49; 95% CI, 0.31-0.78). Folic acid treatment significantly reduced the risk of first ischemic stroke in participants with both folate and B12 below the median (2.3% in enalapril-folic acid group vs 3.6% in enalapril-only group; HR, 0.62; 95% CI, 0.46-0.86), particularly in MTHFR 677 CC carriers (1.6% vs 4.9%; HR, 0.24; 95% CI, 0.11-0.55). However, TT homozygotes responded better with both folate and B12 levels above the median (HR, 0.28; 95% CI, 0.10-0.75). Conclusions: The risk of first ischemic stroke was significantly higher in hypertensive patients with low levels of both folate and B12. Effect of folic acid treatment was greatest in patients with low folate and B12 with the CC genotype, and with high folate and B12 with the TT genotype.","The aim of this study was to evaluate the interaction of serumor blood folate (a specific vitamin) and vitamin B12 with methylenetetrahydrofolate reductase (MTHFR- a gene) C677T genotypes, or inherited gene types for a protein involved in blood pressure, on the risk of first ischemic or brain-related stroke. Genotypes are variations of a gene. These variations are often referred to as TT, CC, or CT. Additionally, the study aimed to review the efficacy or success of folic acid treatment in prevention of first ischemic stroke. A total of 20,702 hypertensive (high blood pressure) adults were randomly placed into one of two treatment groups: daily enalapril (common blood pressure medication) 10 mg and folic acid 0.8 mg or enalapril 10 mg alone. Participants were followed up every 3 months. Average values of folate and B12 concentrations before treatment were 8.1 ng/mL and 280.2 pmol/L, respectively. Over an average of 4.5 years, participants not receiving folic acid with baseline (starting) serum or blood B12 or serum folate above the median (average) had a significantly lower risk of first ischemic stroke. This decreased risk was found especially in those with MTHFR 677 CC genotype (wild-type or normal). Folic acid treatment significantly reduced the risk of first ischemic stroke in participants with both folate and B12 below the median, particularly in patients with CC genotype. However, participants with TT genotype responded better with both folate and B12 levels above the median of participants. The study concluded the risk of first ischemic stroke was significantly higher in hypertensive patients with low levels of both folate and B12. Folic acid treatment helped the most in patients with low folate and B12 with the CC genotype, and with high folate and B12 with the TT genotype." +"Objective: We evaluated the interaction of serum folate and vitamin B12 with methylenetetrahydrofolate reductase (MTHFR) C677T genotypes on the risk of first ischemic stroke and on the efficacy of folic acid treatment in prevention of first ischemic stroke. Methods: A total of 20,702 hypertensive adults were randomized to a double-blind treatment of daily enalapril 10 mg and folic acid 0.8 mg or enalapril 10 mg alone. Participants were followed up every 3 months. Results: Median values of folate and B12 concentrations at baseline were 8.1 ng/mL and 280.2 pmol/L, respectively. Over a median of 4.5 years, among those not receiving folic acid, participants with baseline serum B12 or serum folate above the median had a significantly lower risk of first ischemic stroke (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57-0.96), especially in those with MTHFR 677 CC genotype (wild-type) (HR, 0.49; 95% CI, 0.31-0.78). Folic acid treatment significantly reduced the risk of first ischemic stroke in participants with both folate and B12 below the median (2.3% in enalapril-folic acid group vs 3.6% in enalapril-only group; HR, 0.62; 95% CI, 0.46-0.86), particularly in MTHFR 677 CC carriers (1.6% vs 4.9%; HR, 0.24; 95% CI, 0.11-0.55). However, TT homozygotes responded better with both folate and B12 levels above the median (HR, 0.28; 95% CI, 0.10-0.75). Conclusions: The risk of first ischemic stroke was significantly higher in hypertensive patients with low levels of both folate and B12. Effect of folic acid treatment was greatest in patients with low folate and B12 with the CC genotype, and with high folate and B12 with the TT genotype.","We checked the interaction of blood folate, a B-vitamin, and vitamin B12 with methylenetetrahydrofolate reductase (MTHFR) C6677T genotypes, or specific DNA sequences in humans encoding the same protein. This was done to measure the risk of first ischemic stroke, or blood clotting that would block brain blood flow, and success of folic acid treatment to prevent this stroke. 20,702 adults with high blood pressure randomly received either 10 mg of daily blood pressure medication and 0.8 mg of folic acid or 10 mg of blood pressure alone. Participants were checked every 3 months. Average folate and B12 levels at start were 8.1 ng/mL and 280.2 pmol/L, respectively. Over around 4.5 years, among those not receiving folid acid, participants with starting blood B12 or blood folate above the average had much lower risk of first ischemic stroke, especially those with the standard MTHFR C6677T genotype. Folic acid treatment reduced the risk of first ischemic stroke in participants with both folate and B12 below the average, especially in those with the altered MTHFR genotype. However, those with certain MTHFR genotypes responded with both folate and B12 levels above the average. The risk of first ischemic stroke was higher in patients with high blood pressure and low levels of folate and B12. Folic acid treatment had the most effect in patients with low folate and B12 with a certain MTHFR genotype, and with high folate and B12 with another genotype." +"Hypertension, a major risk factor for heart disease and stroke, is the world's leading cause of preventable, premature death. A common polymorphism (677C?T) in the gene encoding the folate metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) is associated with increased blood pressure, and there is accumulating evidence demonstrating that this phenotype can be modulated, specifically in individuals with the MTHFR 677TT genotype, by the B-vitamin riboflavin, an essential co-factor for MTHFR. The underlying mechanism that links this polymorphism, and the related gene-nutrient interaction, with hypertension is currently unknown. Previous research has shown that 5-methyltetrahydrofolate, the product of the reaction catalysed by MTHFR, appears to be a positive allosteric modulator of endothelial nitric oxide synthase (eNOS) and may thus increase the production of nitric oxide, a potent vasodilator. Blood pressure follows a circadian pattern, peaking shortly after wakening and falling during the night, a phenomenon known as 'dipping'. Any deviation from this pattern, which can only be identified using ambulatory blood pressure monitoring (ABPM), has been associated with increased cardiovascular disease (CVD) risk. This review will consider the evidence linking this polymorphism and novel gene-nutrient interaction with hypertension and the potential mechanisms that might be involved. The role of ABPM in B-vitamin research and in nutrition research generally will also be reviewed.","Hypertension, also known as high blood pressure, is a major risk factor for heart disease and stroke. Hypertension is the world's leading cause of preventable, premature death. A common genetic variation or gene change (677C?T) is found in the gene that codes the folate (specific vitamin) metabolizing (digesting) enzyme methylenetetrahydrofolate reductase (MTHFR). 677C?T is associated with increased blood pressure. There is accumulating evidence that shows this event can be altered, especially in people with MTHFR 677TT genotype, by the B-vitamin riboflavin. Riboflavin is an essential co-factor, meaning it is needed for a biological process to be completed, for MTHFR. The underlying mechanism that links this genetic variation or gene differences, and the related gene-nutrient interaction, with hypertension is currently unknown. Previous research has shown that the product produced by the biological reaction caused by MTHFR is a positive modulator (increases activity) of a specific enzyme. The enzyme is known as endothelial nitric oxide synthase (eNOS), which helps fight blood vessel disease. The product of MTHFR, known as 5-methyltetrahydrofolate, may increase the production of nitric oxide, a potent vasodilator. Vasodilators widen blood vessels, which decreases blood pressure. Blood pressure follows a circadian rhythm (a 24 hour cycle), peaking shortly after wakening and falling during the night. This process is known as 'dipping'. Any change in this pattern, which can only be identified using ambulatory blood pressure monitoring (ABPM), has been associated with increased cardiovascular (or heart-related) disease (CVD) risk. This review will consider the evidence linking this genetic variation and new gene-nutrient interaction with hypertension. This paper will also investigate the potential mechanisms that might be involved. The role of ABPM in B-vitamin research and in nutrition research generally will also be reviewed." +"Intervention with riboflavin was recently shown to produce genotype-specific lowering of blood pressure (BP) in patients with premature cardiovascular disease homozygous for the 677C? T polymorphism (TT genotype) in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). Whether this effect is confined to patients with high-risk cardiovascular disease is unknown. The aim of this randomized trial, therefore, was to investigate the responsiveness of BP to riboflavin supplementation in hypertensive individuals with the TT genotype but without overt cardiovascular disease. From an available sample of 1427 patients with hypertension, we identified 157 with the MTHFR 677TT genotype, 91 of whom agreed to participate in the trial. Participants were stratified by systolic BP and randomized to receive placebo or riboflavin (1.6 mg/d) for 16 weeks. At baseline, despite being prescribed multiple classes of antihypertensive drugs, >60% of participants with this genotype had failed to reach goal BP (?140/90 mm Hg). A significant improvement in the biomarker status of riboflavin was observed in response to intervention (P<0.001). Correspondingly, an overall treatment effect of 5.6�2.6 mm Hg (P=0.033) in systolic BP was observed, with pre- and postintervention values of 141.8�2.9 and 137.1�3.0 mm Hg (treatment group) and 143.5�3.0 and 144.3�3.1 mm Hg (placebo group), whereas the treatment effect in diastolic BP was not significant (P=0.291). In conclusion, these results show that riboflavin supplementation targeted at hypertensive individuals with the MTHFR 677TT genotype can decrease BP more effectively than treatment with current antihypertensive drugs only and indicate the potential for a personalized approach to the management of hypertension in this genetically at-risk group.","Use of riboflavin (a B vitamin) was recently shown to have genotype-specific effects on lowering blood pressure (BP). This means a person's response was different depending on their genetic makeup. This process was shown within patients of premature (or early) cardiovascular (or heart-related) disease with a TT genotype of a specific genetic variation or gene change. This genetic variation, known as 677C, is found within the gene that encodes the enzyme methylenetetrahydrofolate reductase (MTHFR). MTHFR is involved in the processing of amino acids, the building blocks of proteins. It is unknown if this effect is confined to patients with high-risk cardiovascular disease. The goal of this study was to investigate the responsiveness of BP in hypertensive (high blood pressure) patients taking riboflavin. Specifically, these patients would have the TT genotype but no obvious cardiovascular disease. Of 1427 hypertensive patients, the authors identified 157 with the MTHFR 677TT genotype. Ninety-one agreed to participate in the study. Participants were ordered by systolic BP (when the heart contracts and the higher blood pressure number) and randomized to receive a placebo (harmless pill) or riboflavin (1.6 mg/d) for 16 weeks. Before treatment, despite being prescribed multiple classes of antihypertensive drugs, the majority of participants with this genotype had failed to reach the goal BP. A significant improvement in the level of bodily riboflavin was observed in response to intervention or treatment. A significant treatment effect in systolic BP was observed. However, no significant treatment was found in diastolic (when the heart relaxes and the lower blood pressure number) BP. The study concluded riboflavin supplementation within hypertensive individuals with the MTHFR 677TT genotype decreases BP more efficiently than current antihypertensive drugs only. Furthermore, this study indicates the potential for a personalized, or individualized, approach to the way high blood pressure is managed in this genetically at-risk group." +"Aims: Gabapentin (GBP) is widely used to treat neuropathic pain, including diabetic neuropathic pain. Our objective was to evaluate the role of diabetes and glycaemic control on GBP population pharmacokinetics. Methods: A clinical trial was conducted in patients with neuropathic pain (n = 29) due to type 2 diabetes (n = 19) or lumbar/cervical disc herniation (n = 10). All participants were treated with a single oral dose GBP. Blood was sampled up to 24 hours after GBP administration. Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm. Weight, body mass index, sex, biomarkers of renal function and diabetes, and genotypes for the main genetic polymorphisms of SLC22A2 (rs316019) and SLC22A4 (rs1050152), the genes encoding the transporters for organic cations OCT2 and OCTN1, were tested as potential covariates. Results: GBP drug disposition was described by a 1-compartment model with lag-time, first-order absorption and linear elimination. The total clearance was dependent on estimated glomerular filtration rate. Population estimates (between-subject variability in percentage) for lag time, first-order absorption rate, apparent volume of distribution and total clearance were 0.316 h (10.6%), 1.12 h-1 (10.7%), 140 L (7.7%) and 14.7 L/h (6.97%), respectively. No significant association was observed with hyperglycaemia, glycated haemoglobin, diabetes diagnosis, age, sex, weight, body mass index, SLC22A2 or SLC22 A4 genotypes. Conclusion: This population pharmacokinetics model accurately estimated GBP concentrations in patients with neuropathic pain, using estimated glomerular filtrationrate as a covariate for total clearance. The distribution and excretion processes of GBP were not affected by hyperglycaemia or diabetes.","Neuropathic pain is caused by damage to the nervous system (like brain and spinal cord) and is often described as a shooting pain, burning sensation, or numbness. Gabapentin is a common medication used to treat neuropathic pain, including neuropathic pain caused by diabetes. The objective of this study is to evaluate the role of diabetes and controlling blood sugar on people taking gabapentin. A clinical trial is conducted in patients with neuropathic pain due to type 2 diabetes (19 people) or a slipped disc in the neck or spine (10 people). All participants are treated with a single dose of gabapentin by mouth. Blood is sampled up to 24 hours after gabapentin is given. Data are analyzed using computer models. Other information are included in the model including weight, sex, kidney functions and other changes in genes that impact how the medication works. The total clearance of gabapentin from the body depends on how well the kidneys are able to process and filter the drug. The estimated total clearance of the drug (completely removed) in the population is 14.7 liters per hour. No major association is found with having high blood sugar levels, a diabetes diagnosis, or with age, sex, weight or other factors evaluated. This model studying how the drug is processed in the body estimates gabapentin concentrations in patients with neuropathic pain. The distribution and clearance processes of gabapentin are not affected by having high blood sugar levels or diabetes." +"Aims: Gabapentin (GBP) is widely used to treat neuropathic pain, including diabetic neuropathic pain. Our objective was to evaluate the role of diabetes and glycaemic control on GBP population pharmacokinetics. Methods: A clinical trial was conducted in patients with neuropathic pain (n = 29) due to type 2 diabetes (n = 19) or lumbar/cervical disc herniation (n = 10). All participants were treated with a single oral dose GBP. Blood was sampled up to 24 hours after GBP administration. Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm. Weight, body mass index, sex, biomarkers of renal function and diabetes, and genotypes for the main genetic polymorphisms of SLC22A2 (rs316019) and SLC22A4 (rs1050152), the genes encoding the transporters for organic cations OCT2 and OCTN1, were tested as potential covariates. Results: GBP drug disposition was described by a 1-compartment model with lag-time, first-order absorption and linear elimination. The total clearance was dependent on estimated glomerular filtration rate. Population estimates (between-subject variability in percentage) for lag time, first-order absorption rate, apparent volume of distribution and total clearance were 0.316 h (10.6%), 1.12 h-1 (10.7%), 140 L (7.7%) and 14.7 L/h (6.97%), respectively. No significant association was observed with hyperglycaemia, glycated haemoglobin, diabetes diagnosis, age, sex, weight, body mass index, SLC22A2 or SLC22 A4 genotypes. Conclusion: This population pharmacokinetics model accurately estimated GBP concentrations in patients with neuropathic pain, using estimated glomerular filtrationrate as a covariate for total clearance. The distribution and excretion processes of GBP were not affected by hyperglycaemia or diabetes.","Gabapentin (GBP), an antiseizure drug, can treat neuropathic or nerve-related pain, including diabetic neuropathic pain. We evaluate the role of diabetes and blood sugar control on drug activity in the GBP population. A trial was done in 29 patients with neuropathic pain, 19 from type 2 diabetes and 10 from lower back/neck disc herniation or bulging. All participants swallowed a single dose of GBP. Blood was taken up to 24 hours after GBP treatment. Measurements for lag time, absorption rate, volume of distribution, and clearance rate were 0.316 h (10.6%), 1.12 h-1 (10.7%), 140 L (7.7%) and 14.7 L/h (6.97%), respectively. No link was seen with high blood sugar, blood sugar levels, diabetes diagnosis, age, sex, weight, body mass index, or certain DNA sequences. This model measuring drug activity accurately estimated GBP concentrations in those with neuropathic pain, using kidney drug filtration rate for total drug clearance. The distribution and removal processes of GBP were not affected by high blood sugar or diabetes." +"Gabapentin (GBP) is an organic cation mainly eliminated unchanged in urine, and active drug secretion has been suggested to contribute to its renal excretion. Our objective was to evaluate the potential drug-drug interaction between GBP and cetirizine (CTZ), an inhibitor of transporters for organic cations. An open-label, 2-period, crossover, nonrandomized clinical trial was conducted in patients with neuropathic pain to evaluate the effect of CTZ on GBP pharmacokinetics. Twelve participants were treated with a single dose of 300 mg GBP (treatment A) or with 20 mg/d of CTZ for 5 days and 300 mg GBP on the last day of CTZ treatment (treatment B). Blood sampling and pain intensity evaluation were performed up to 36 hours after GBP administration. The interaction of GBP and CTZ with transporters for organic cations was studied in human embryonic kidney (HEK) cells expressing the organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATEs), and OCTN1. CTZ treatment resulted in reduced area under the concentration-time curve and peak concentration compared with treatment A. In treatment B, the lower plasma concentrations of GBP resulted in reduced pain attenuation. GBP renal clearance was similar between treatments. GBP has low apparent affinity for OCT2 (concentration of an inhibitor where the response [or binding] is reduced by half [IC50 ] 237 �mol/L) and a high apparent affinity for hMATE1 (IC50 1.1 nmol/L), hMATE2-K (IC50 39 nmol/L), and hOCTN1 (IC50 2.1 nmol/L) in HEK cells. At therapeutic concentrations, CTZ interacts with hMATE1 and OCTN1. In summary, CTZ reduced the systemic exposure to GBP and its effect on neuropathic pain attenuation. However, CTZ � GBP interaction is not mediated by the renal transporters.","Gabapentin (GBP) is a nerve-related pain medication that is mainly removed from the body in urine, and is also processed by the kidneys. The objective of this study is to evaluate how gabapentin may interact with another medicine called cetirizine (CTZ) that is used to temporarily relieve allergies. A clinical trial in patients with a shooting or burning pain caused by damage to the nervous system called neuropathic pain is conducted to understand the effect of cetirizine on how gabapentin is processed in the body. In this study, 12 patients are treated with either one dose of gabapentin (called Treatment A) or with cetirizine for 5 days and gabapentin given on the last day of cetirizine (Treatment B). Blood samples are taken and the level of pain is measured up to 36 hours after gabapentin is taken. The interaction of gabapentin and cetirizine is analyzed. Cetirizine treatment resulted a reduced time the body is exposed to the medication and reduced peak amount when compared with Treatment A (one dose of gabapentin). In treatment B, the lower concentrations of gabapentin or GBP in the blood results in reduced pain. GBP clearance from the kidneys is similar between treatments A and B. GBP appears to bind less to some receptors or kidney target sites such as OCT2 and attach more towards others such as hMATE1 in certain human kidney cells. At certain concentrations, CTZ interacts with transporters in the body that move materials across cells. In summary, cetirizine (CTZ) reduces the exposure to gabapentin (GBP) and its effect on neuropathic pain. However, CTZ � GBP interaction is not influenced by the transporters in the kidney." +"The objective of this study was to perform population pharmacokinetic (PK) analysis of gabapentin in healthy Korean subjects and to investigate the possible effect of genetic polymorphisms (1236C > T, 2677G > T/A, and 3435C > T) of ABCB1 gene on PK parameters of gabapentin. Data were collected from bioequivalence studies, in which 173 subjects orally received three different doses of gabapentin (300, 400, and 800 mg). Only data from reference formulation were used. Population pharmacokinetics (PKs) of gabapentin was estimated using a nonlinear mixed-effects model (NONMEM). Gabapentin showed considerable inter-individual variability (from 5.2- to 8.7-fold) in PK parameters. Serum concentration of gabapentin was well fitted by a one-compartment model with first-order absorption and lag time. An inhibitory Emax model was applied to describe the effect of dose on bioavailability. The oral clearance was estimated to be 11.1 L/h. The volume of distribution was characterized as 81.0 L. The absorption rate constant was estimated at 0.860 h-1, and the lag time was predicted at 0.311 h. Oral bioavailability was estimated to be 68.8% at dose of 300 mg, 62.7% at dose of 400 mg, and 47.1% at dose of 800 mg. The creatinine clearance significantly influenced on the oral clearance (P < 0.005) and ABCB1 2677G > T/A genotypes significantly influenced on the absorption rate constant (P < 0.05) of gabapentin. However, ABCB1 1236C > T and 3435C > T genotypes showed no significant effect on gabapentin PK parameters. The results of the present study indicate that the oral bioavailability of gabapentin is decreased when its dosage is increased. In addition, ABCB1 2677G > T/A polymorphism can explain the substantial inter-individual variability in the absorption of gabapentin.","The objective of this study is to perform an analysis on how the nerve-related pain medication gabapentin performs in healthy Korean participants and to investigate the possible effect of genetic changes in the drug-resistant ABCB1 gene on how gabapentin is absorbed and distributed in the body. Data are collected from other studies where 173 people received three different doses by mouth (orally) of gabapentin. Only data on the drug design and performance are used. How the body handles and uses gabapentin is measured. Gabapentin shows a lot of variation or differences between people in how it is absorbed, distributed and released from the body. Blood concentration of gabapentin is used to understand the process of distributing and eliminating the medication from the body. How the dose amount impacts availability in the body is measured. The oral clearance is estimated to be 11.1 liters per hour. The volume of distribution was characterized as 81.0 L. How quickly the medication enters the body remains steady. Availability of the drug from the oral dose is estimated to be 68.8% at a dose of 300 mg, 62.7% at a dose of 400 mg, and 47.1% at a dose of 800 mg. Clearing creatinine (a waste product that comes from wear and tear of the muscles) influences the oral clearance, and ABCB1 genes influence how quickly gabapentin is absorbed by the body. However, genes showed no significant effect on gabapentin drug activity parameters. The results of this study suggest that the availability of gabapentin to the body when taken by mouth is decreased when the dosage is increased. In addition, changes in the ABCB1 gene can explain the major differences in how gabapentin is absorbed by the body between people." +"Pharmacokinetic data of gabapentin (GBP) in community-dwelling elderly patients show a significant effect of advanced age on GBP pharmacokinetics due to altered renal function. However, there are no data in elderly nursing home (NH) patients to evaluate gabapentin absorption and elimination. Our objective was to characterize the pharmacokinetics of GBP in elderly nursing home patients maintained on GBP therapy. This was a prospective pharmacokinetic study in elderly nursing home patients (?60 years) receiving GBP for the management of chronic pain or epilepsy from seven nursing homes. Pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. A one-compartment model described the data and clearance (CL) was associated with estimated glomerular filtration rate (eGFR) (p < 0.0001). The GBP CL in elderly nursing home patients was 2.93 L/h. After adjusting for the effect of GFR, GBP CL was not affected by age, sex, body weight, or comorbidity scores. No significant effects of body size measures, age, and sex were detected on volume of distribution. Dose-dependent bioavailability of GBP was demonstrated, and the saturable absorption profile was described by a nonlinear hyperbolic function. Prediction-corrected visual predictive check (pc-VPC) suggests adequate fixed- and random-effects models that successfully simulated the mean trend and variability in gabapentin concentration-time profiles. In this analysis, the parameters of the hyperbolic nonlinearity appear to be similar between elderly and younger adults.","Data on how gabapentin (GBP -a nerve-related pain medication) is used in the body in elderly patients show a major effect of older age on how the drug works due to changes in kidney function. However, there are no data in elderly nursing home patients to evaluate how the body absorbs and removes gabapentin. The objective of this study is to describe how the body uses and processes gabapentin in elderly nursing home patients who are on gabapentin. This study observed elderly nursing home patients (?60 years) receiving gabapentin for chronic (ongoing) pain or epilepsy (seizure disorders) from 7 nursing homes. Data on gabapentin and the clearance of the drug are associated with the rate that measures how well the kidneys are working. The gabapentin clearance in elderly nursing home patients was 2.93 liters per hour. After accounting for the rate that measures how well the kidneys are working, GBP clearance is not affected by age, sex, body weight, or other illnesses and their medications. No significant effects of body size measures, age, and sex are detected on volume of distribution, the ability of various drugs to distribute through the body fluids. The availability of the drug being dependent on dosage is shown, and how it is absorbed is calculated. Additional calculations are done on the entire group to evaluate the performance of the drug and identify other individual factors that may impact the effect. In this analysis, the patterns of the drug appear to be similar between elderly and younger adults." +"Pharmacokinetic data of gabapentin (GBP) in community-dwelling elderly patients show a significant effect of advanced age on GBP pharmacokinetics due to altered renal function. However, there are no data in elderly nursing home (NH) patients to evaluate gabapentin absorption and elimination. Our objective was to characterize the pharmacokinetics of GBP in elderly nursing home patients maintained on GBP therapy. This was a prospective pharmacokinetic study in elderly nursing home patients (?60 years) receiving GBP for the management of chronic pain or epilepsy from seven nursing homes. Pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling. A one-compartment model described the data and clearance (CL) was associated with estimated glomerular filtration rate (eGFR) (p < 0.0001). The GBP CL in elderly nursing home patients was 2.93 L/h. After adjusting for the effect of GFR, GBP CL was not affected by age, sex, body weight, or comorbidity scores. No significant effects of body size measures, age, and sex were detected on volume of distribution. Dose-dependent bioavailability of GBP was demonstrated, and the saturable absorption profile was described by a nonlinear hyperbolic function. Prediction-corrected visual predictive check (pc-VPC) suggests adequate fixed- and random-effects models that successfully simulated the mean trend and variability in gabapentin concentration-time profiles. In this analysis, the parameters of the hyperbolic nonlinearity appear to be similar between elderly and younger adults.","Drug activity data of gabapentin (GBP) in community-dwelling elderly patients show a great effect of advanced age on GVP drug activity due to altered kidney function. However, there are no data in elderly nursing home (NH) patients to measure gabapentin absorption and elimination. We characterize the drug activity of GBP in elderly nursing home patients that are on GBP therapy. This is a drug actvity study in elderly nursing home patients (?60 years) given GBP for long-term pain or epilepsy (brain disorder causing seizures) from seven nursing homes. A mathematical model showed the data and clearance (CL) was linked with estimated kidney filtration rate. The GBP clearance in elderly nursing home patients was 2.93 liters/hour. After adjusting for kidney filtration, GBP clearance was not affected by age, sex, body weight, or associated diseases. No effects of body size, age, and sex were detected on amount of distribution. Functional or active GBP amount is linked to dose amount. Analysis suggests certain mathematical models successfully tracked the trend and variation in gabapentin amount over time. In this analysis, certain measures seem similar between elderly and young adults." +"Purpose: The pharmacokinetics of gabapentin in paediatric patients with uncontrolled seizures was studied. Methods: Thirteen paediatric patients (mean age: 9.4 years) with uncontrolled partial seizures were included. Patients received gabapentin orally until doses were individualized to 9.6-39.8 mg/kg/day. Blood samples were obtained just prior to the dose and over 8 h after gabapentin was administered in the fasting state. The plasma concentration of gabapentin was measured by a high-performance liquid chromatography assay. Pharmacokinetic parameters for gabapentin were determined by non-compartment methods using multivariate regression analysis. Results: Data from nine patients were suitable for pharmacokinetic analysis. The C(max) from 0.9 to 5.8 microg/mL (mean: 2.6 +/- 1.7 microg/mL) and T(max) from 0.5 to 2.0 h (mean: 1.6 +/- 1.0 h). The apparent clearance (Cl/F) ranged from 0.12 to 1.12 L/h/kg (mean: 0.50 +/- 0.29 L/h/kg), and the elimination half-life from 3.2 to 12.2 h (mean: 5.5 +/- 0.8 h). Five patients experienced moderate (n = 4) to severe (n = 1) aggressive behaviour and another gained weight on gabapentin. Conclusions: Our data suggests that gabapentin pharmacokinetics can vary substantially among paediatric patients. Gabapentin was well tolerated in patients with uncontrolled partial seizures up to 6 months of therapy.","How the pediatric or child patients with uncontrolled seizures are able to handle gabapentin (a nerve-related pain medication) and the processes of absorbing, distributing, using, and removing it is studied. In this study, 13 pediatric patients (less the 21 years old) with an average age of about 9 years with uncontrolled partial seizures are included. Patients received gabapentin orally (by mouth) until doses are changed for each patient. Blood samples are obtained just before the dose and over 8 hours after gabapentin is given during fasting, when all foods have been completely digested. Blood concentrations of gabapentin is measured by blood tests. Absorption, distribution, use, and removal of gabapentin in the body is analyzed. Data from 9 patients are able to be used for analysis. The maximum concentration of the drug and the time it takes to reach maximum concentration are estimated. Five patients experience moderate (4 patients) to severe (1 patient) aggressive behavior, and another gained weight on gabapentin. In conclusion, the data in this study suggests that how the body processes gabapentin can vary a lot among pediatric patients. In this study, patients with uncontrolled partial seizures were able to handle gabapentin well up to 6 months of therapy." +"Purpose: This study was conducted to evaluate the effect of age, age-related changes in renal function, and gender on the single-dose pharmacokinetics of orally administered gabapentin (GBP). Methods: The pharmacokinetics of a single 400-mg oral dose of GBP were studied in 36 healthy subjects (18 men and 18 women) aged 20-78 years. Serial blood samples and total urine output were collected for 48 h after the dose. GBP concentrations in plasma and urine were measured by high-performance liquid chromatography, and pharmacokinetic parameters were calculated by noncompartmental methods. Results: All subjects tolerated the drug well, with only mild symptoms reported. No change in maximal GBP plasma concentration (Cmax), time at which Cmax occurred (tmax), or apparent volume of distribution (V/F) with age was noted. A significant linear decline in apparent oral clearance (CL/F), elimination-rate constant (lambda z), and renal clearance (CLR) with increasing age was observed (p < 0.005). Because total urinary recovery of unchanged drug (an estimate of F for GBP) did not change with age, the decline in CL/F and lambda z can be explained by the decline in CLR. The only pharmacokinetic parameter that was significantly different between genders was Cmax, which was approximately 25% higher for women than for men (p = 0.016), consistent with gender differences in body size. Conclusions: The results of this study suggest that changes in renal function are responsible for age-related changes in GBP pharmacokinetics. Reduction of GBP dosage may be required in elderly patients with reduced renal function. The pharmacokinetics of GBP are similar in men and women.","This study is conducted to evaluate the effect of age, age-related changes in renal or kidney function, and gender on the single-dose pharmacokinetics (or drug activity) of orally (by mouth) administered gabapentin (GBP). The body's process of absorbing, distributing, using, and removing a single oral dose (by mouth) of gabapentin is studied in 36 healthy patients (18 men and 18 women) aged 20-78 years. Blood and urine samples are continuously collected for 48 hours after the dose of gabapentin. The amount of Gabapentin in plasma (or blood) and urine samples are measured, and other tests are done to understand how the body processes gabapentin. All patients are able to handle the drug well, with only mild symptoms reported. No change in the highest (peak) gabapentin amount, the time at which the highest gabapentin amount occurred, or apparent volume of distribution (the ability of various drugs to distribute through the body fluids) with age was noted. A major decline in clearance of gabapentin that is taken orally, the rate of removal from the body, and clearing it through the kidneys with increasing age is observed. The decline of oral clearance and rate of removal of gabapentin from the body can be explained by the decline in clearance by the kidneys. The only measure that is very different between genders is the highest (peak) gabapentin amount, which is approximately 25% higher for women than for men, consistent with gender differences in body size. In conclusion, the results of this study suggest that changes in kidney function are responsible for age-related changes in how the body processes gabapentin. Giving a lesser dose of gabapentin may be required in elderly patients who have weaker kidney functions. How the body processes gabapentin is similar in men and women." +"Gabapentin is an anticonvulsant drug, which in man is cleared solely by renal excretion and is not bound to plasma proteins. Because the clearance of gabapentin is dependent on renal function, the pharmacokinetics of gabapentin were investigated in anuric subjects maintained on hemodialysis. Plasma samples were obtained over an 8-day period after administration of single oral 400-mg doses of gabapentin. Pre- and post-dialyzer plasma samples and dialysate samples from quantitative collection of dialyzer effluent were obtained during hemodialysis sessions performed 2, 4, and 7 days after dosing. A mean (SD) maximum gabapentin plasma concentration of 6.0 (2.4) micrograms/mL was achieved at 4.7 (2.1) hours post-dose. The elimination half-life of gabapentin on non-hemodialysis days averaged 132 hours. Approximately 35% of the gabapentin dose was recovered in dialysate, and mean hemodialysis clearance of gabapentin was 142 (26) mL/min; approximately 93% of the dialyzer creatinine clearance. Gabapentin elimination half-life during hemodialysis was approximately 4 hours. Systemic plasma gabapentin concentrations increased approximately 30% during the first 2 hours after hemodialysis as a result of drug redistribution in the body. It is recommended that patients with end-stage renal disease maintained on hemodialysis receive an initial 300-mg to 400-mg gabapentin loading dose. Plasma gabapentin concentrations can be maintained by giving 200 to 300 mg of gabapentin after every 4 hours of hemodialysis.","Gabapentin is a nerve-related pain drug, which in humans is cleared from the body solely by the kidneys and is not attached to proteins in plasma (the liquid part of blood). Because the clearance of gabapentin depends on the kidneys, how the body processes gabapentin is investigated in patients who do not make enough urine and who are on dialysis, a process of cleaning the blood of a person whose kidneys are not working normally. Plasma samples are collected over an 8-day period after a single oral (by mouth) dose of gabapentin is given. Plasma samples before and after being filtered, as well as dialysis fluid, are collected during dialysis sessions performed 2, 4, and 7 days after receiving the gabapentin dose. An average maximum amount of gabapentin in plasma is achieved at 4.7 hours after the dose. The time it takes for the concentration of the gabapentin in the plasma to be reduced by half on non-dialysis days averages 132 hours. About 35% of gabapentin dose is recovered in dialysis fluid, and the average clearance of gabapentin in dialysis was 142 milliliters per minute. The time it takes for the concentration of the gabapentin in the plasma to be reduced by half during dialysis is about 4 hours. Gabapentin concentrations in the plasma increased about 30% during the first 2 hours after dialysis as a result of the drug being sent to other parts of the body. It is recommended that patients with end-stage kidney disease who are on dialysis receive a starting 300-mg to 400-mg gabapentin dose. Plasma gabapentin concentrations can remain stable by giving 200 to 300 mg of gabapentin after every 4 hours of dialysis." +"Gabapentin is an anticonvulsant drug, which in man is cleared solely by renal excretion and is not bound to plasma proteins. Because the clearance of gabapentin is dependent on renal function, the pharmacokinetics of gabapentin were investigated in anuric subjects maintained on hemodialysis. Plasma samples were obtained over an 8-day period after administration of single oral 400-mg doses of gabapentin. Pre- and post-dialyzer plasma samples and dialysate samples from quantitative collection of dialyzer effluent were obtained during hemodialysis sessions performed 2, 4, and 7 days after dosing. A mean (SD) maximum gabapentin plasma concentration of 6.0 (2.4) micrograms/mL was achieved at 4.7 (2.1) hours post-dose. The elimination half-life of gabapentin on non-hemodialysis days averaged 132 hours. Approximately 35% of the gabapentin dose was recovered in dialysate, and mean hemodialysis clearance of gabapentin was 142 (26) mL/min; approximately 93% of the dialyzer creatinine clearance. Gabapentin elimination half-life during hemodialysis was approximately 4 hours. Systemic plasma gabapentin concentrations increased approximately 30% during the first 2 hours after hemodialysis as a result of drug redistribution in the body. It is recommended that patients with end-stage renal disease maintained on hemodialysis receive an initial 300-mg to 400-mg gabapentin loading dose. Plasma gabapentin concentrations can be maintained by giving 200 to 300 mg of gabapentin after every 4 hours of hemodialysis.","Gabapentin is an antiseizure drug, which in man is cleared just by kidney removal and is not bound to blood proteins. Because gabapentin clearance is dependent on kidney function, the drug activity of gabapentin was investigated in patients unable to make urine and maintained on artifical kidney machines or hemodialysis. We took blood samples over an 8-day period after treatment of single 400-mg swallowed doses of gabapentin. Blood and kidney solution samples were obtained during treatment sessions performed 2, 4, and 7 days after dosing. An average maximum gabapentin blood level of 6.0 micrograms/mL was measured at 4.7 hours after the dose. The time for half of gabapentin to clear on non-hemodialysis days was 132 hours. Around 35% of the gabapentin dose was recovered in the fluid of the artificial kidney machine. The average hemodialysis clearance of gabapentin was 142 mL/min; around 93% of the standard dialyzer clearance. The time for half of gabapentin to clear during hemodialysis was around 4 hours. Blood gabapentin levels increased around 30% during the first 2 hours after hemodialysis due to drug redistribution in the body. It is recommended that patients with kidney failure and on hemodialysis get an initial 300-mg to 400-mg gabapentin starting dose. Blood gabapentin levels can be maintained by giving 200 to 300 mg of gabapentin after every 4 hours of hemodialysis." +"The amino acid antiepileptic drug (AED) gabapentin (GBP) is indicated for adjunctive use in the treatment of partial seizures with or without becoming secondarily generalized in individuals older than 12 years. GBP was about as potent as phenytoin in the maximal electroshock test, but had a different profile of efficacy than standard antiepileptics in a range of animal models. Possible mechanisms of action include biochemical effects enhancing the ratio of gamma-aminobutyric acid (GABA) to glutamate, ion-channel actions (direct or indirect), and/ or enhancement of nonsynaptic GABA release. The anticonvulsant effect appears to depend on concentration of gabapentin in neurons, presumably by the L-system amino acid transporter that has been implicated in absorption from the gut. Data from studies for U.S. Food and Drug Administration (FDA) approval suggested a direct relationship of clinical response to dose and efficacy did not plateau at the doses used. The maximally effective dose, relationship of efficacy to blood level, and maximum tolerable dose are not yet known conclusively. Lack of significant binding to plasma proteins and lack of liver metabolism contribute to the absence of known limiting drug-drug interactions, particularly with other AEDs. Excretion intact in the urine affords dose adjustment on the basis of creatinine clearance. A half-life of approximately 7 h necessitates multiple doses daily for many individuals. The medication is well tolerated, in general. Side effects tend to be mild to moderate in intensity, most frequently affect the central nervous system, and resolve with time in many individuals. GBP has been prescribed for approximately 70,000 individuals worldwide without untoward incidence of severe systemic toxicity to date. Safety data continue to accumulate. GBP has been labeled category C on the basis of effects on rodent fetuses. Experience with use in pregnant women is limited and human teratogenic effects have not been reported. Data from ongoing monotherapy trials will help to clarify the range of clinical utility of gabapentin.","The drug gabapentin (GBP) is an addition to the regular treatment of partial seizures with or without becoming generalized seizures in the entire brain in people older than 12 years. Gabapentin has performed differently than other standard drugs that are used to prevent seizures in a number of animal experiments. Possible processes that lead the drug to have an effect include the response of increasing the development of neurotransmitters (signaling molecules in the brain) and other cell functions. The act of stopping or slowing the excessive rapid firing of neurons (brain cells) during seizures seems to depend on the concentration of gabapentin in neurons. Data from studies for U.S. Food and Drug Administration (FDA) approval suggest a direct relationship of medical response to the dose and success did not level-off at the doses used. The maximally effective dose (the dose at which any higher dose would not lead to improvement), the relationship of its performance to blood level, and the maximum tolerable dose (the highest dose most people can handle) are not completely known. Lack of attachment to plasma (or blood) proteins and lack of liver energy contribute to the absence of known interactions between drugs, particularly with other drugs that are used to prevent seizures. Doses can be adjusted based on the amount of the drug found in the urine. The time it takes for the concentration of the gabapentin in the plasma or in the body to be reduced by half is about 7 hours, requiring multiple doses daily for many people. In general, people are able to handle the medication and its side effects. Side effects tend to be mild to moderate in intensity, most frequently affect the central nervous system (spinal cord and brain), and resolve with time in many individuals. Gabapentin (GBP) is prescribed for about 70,000 people around the world without unexpected incidence of severe toxic effects so far. Safety data continues to be collected. Gabapentin has shown to have adverse effects on rodent fetuses. Experience with use in pregnant women is limited, and adverse (or bad) effects or abnormalities in human fetuses have not been reported. Data from ongoing single drug trials will help to clarify the range of the clinical use of gabapentin." +"Gabapentin is almost exclusively cleared by the kidney and thus presents challenges in patients with kidney failure. Gabapentin is known to be effectively cleared by hemodialysis, but the efficiency of clearance by peritoneal dialysis (PD) has not been previously described. We report a case of gabapentin toxicity in a patient on long-term PD who was treated with continuous automated cycling PD. We find that continuous PD provides significant clearance of gabapentin. With 2-L exchanges every 2 hours, we document an apparent elimination half-life of 41.33 hours, which is substantially shorter than the reported elimination half-life of 132 hours in the absence of kidney function. Further, our patient's symptoms of gabapentin toxicity gradually improved and had fully resolved after about 36 hours of dialysis. Gabapentin clearance by PD was estimated at 94% of urea clearance. We conclude that intensive PD provides gabapentin clearance that approximates that of urea and is an effective but slow method to treat gabapentin overdose and toxicity.","The nerve-related pain medication gabapentin is cleared from the body almost entirely by the kidney. Because of this, patients with kidney failure face a challenge. Gabapentin is known to be effectively cleared by hemodialysis, a process of using machines to clean the blood of a person whose kidneys are not working normally, but how well peritoneal dialysis (PD), a process that filters blood using the inside lining of the stomach, clears the drug has not been previously described. Researchers describe a case of too much gabapentin in a patient with long-term peritoneal dialysis who is treated with continuous automated cycling peritoneal dialysis, which is when a mechanical device filters the blood at night while sleeping. Researchers find that continuous peritoneal dialysis provides significant clearance of gabapentin. The documented elimination half-life (the time it takes for the concentration of the gabapentin in the plasma or body to be reduced by half) is 41.33 hours, which is much shorter than the 132 hours reported in other studies in the absence of kidney function. In addition, the patient's symptoms of gabapentin toxicity (often muscle weakness, drowsiness, and drooping eyelids) improved and fully resolved after about 36 hours of dialysis. Gabapentin clearance in the body by peritoneal dialysis is estimated at 94% of urea (or waste protein) clearance. In conclusion, intensive peritoneal dialysis provides gabapentin clearance and is an effective but slow method to treat gabapentin overdose and toxicity." +"Gabapentin is a new antiepileptic drug (AED) with an attractive pharmacokinetic profile. It is absorbed by an active and saturable transport system, and has a high volume of distribution. Gabapentin is not bound to plasma proteins, does not induce hepatic enzymes and is not metabolized. At steady state, it has a half-life of 6-8 h, and is eliminated unchanged by renal route with a plasma clearance proportional to the creatinine clearance. It is devoid of significant drug-drug interactions when administered with the established AEDs or with oral contraceptives. Gabapentin used as an add-on AED significantly reduced the frequency of partial seizures and secondarily generalized tonic-clonic seizures in three large double-blind, placebo-controlled, parallel-group clinical trails. It is well tolerated, with transient somnolence and dizziness being the most frequent adverse effects. Although the mechanism of action of gabapentin is not fully established, there is strong evidence to suggest a novel mechanism of action. Gabapentin is a unique and promising drug that could improve the quality of life of patients with epilepsy and is a welcome addition to the armamentarium of currently available AEDs for the treatment of patients with seizures of partial onset.","Gabapentin is a new drug to treat seizures that appears to work well for patients. It is absorbed into the body by an active and fluid-filled transport system, and is able to be distributed to tissues in the body. Gabapentin is not attached to proteins in the blood, does not create liver enzymes that can speed up chemical reactions in the body, and is not broken down. When the amount of the drug in the body is the same amount that is being cleared, the time it takes for the concentration of the gabapentin in the plasma or body to be reduced by half is 6-8 hours and is eliminated through the kidneys. Gabapentin does not have any major interactions with other drugs when given with other standard drugs that treat seizures or with oral (by mouth) birth control. In 3 clinical studies, gabapentin used as an add-on anti-seizure drug to assist the main treatment reduces the frequency of partial seizures (impacting half the brain) and seizures (impacting both halves of the brain). The medicine is handled well by patients, with drowsiness and dizziness being the most common side effects. Although the exact process of how gabapentin can lead to an effect is not fully understood, there is strong evidence that suggests a new process in the body. Gabapentin is a unique and promising drug that could improve the quality of life of patients with epilepsy (seizure disorders) and is a welcome addition to currently available drugs for the treatment of patients with seizures that start in one part of the brain." +"Gabapentin is a new antiepileptic drug (AED) with an attractive pharmacokinetic profile. It is absorbed by an active and saturable transport system, and has a high volume of distribution. Gabapentin is not bound to plasma proteins, does not induce hepatic enzymes and is not metabolized. At steady state, it has a half-life of 6-8 h, and is eliminated unchanged by renal route with a plasma clearance proportional to the creatinine clearance. It is devoid of significant drug-drug interactions when administered with the established AEDs or with oral contraceptives. Gabapentin used as an add-on AED significantly reduced the frequency of partial seizures and secondarily generalized tonic-clonic seizures in three large double-blind, placebo-controlled, parallel-group clinical trails. It is well tolerated, with transient somnolence and dizziness being the most frequent adverse effects. Although the mechanism of action of gabapentin is not fully established, there is strong evidence to suggest a novel mechanism of action. Gabapentin is a unique and promising drug that could improve the quality of life of patients with epilepsy and is a welcome addition to the armamentarium of currently available AEDs for the treatment of patients with seizures of partial onset.","Gabapentin is a new antiseizure or antiepileptic drug (AED) with attractive drug activity. Gabapentin is absorbed by an active transport system. The drug has a large distribution. Gabapentin is not bound to blood proteins, does not activate liver enzymes and is not broken down. Normally, half of the drug is eliminated in 6-8 hours. It is cleared unchanged by the kidney with a blood clearance similar to standard kidney substance clearance. The drug does not have major drug-drug interactions when used with other AEDs or swallowed birth control drugs. Gabapentin used as an add-on AED greatly reduces the amount of partial seizures and partial seizures developing into standard serizures in three clinical trials. The drug is well tolerated, with temporary drowsiness and dizziness as the most common side effects. Although how gabapentin works is unknown, there is evidence for a new mechanism of its biological action. Gabapentin is a unique and promising drug that could improve life for patients with epilepsy (a brain disorder causing seizures). The drug is a welcome addition to current AEDs for treating patients with seizures of partial onset." +"BACKGROUND: Although bone mineral density (BMD) testing to screen for osteoporosis (BMD T score, ?2.50 or lower) is recommended for women 65 years of age or older, there are few data to guide decisions about the interval between BMD tests. METHODS: We studied 4957 women, 67 years of age or older, with normal BMD (T score at the femoral neck and total hip, ?1.00 or higher) or osteopenia (T score, ?1.01 to ?2.49) and with no history of hip or clinical vertebral fracture or of treatment for osteoporosis, followed prospectively for up to 15 years. The BMD testing interval was defined as the estimated time for 10% of women to make the transition to osteoporosis before having a hip or clinical vertebral fracture, with adjustment for estrogen use and clinical risk factors. Transitions from normal BMD and from three subgroups of osteopenia (mild, moderate, and advanced) were analyzed with the use of parametric cumulative incidence models. Incident hip and clinical vertebral fractures and initiation of treatment with bisphosphonates, calcitonin, or raloxifene were treated as competing risks. RESULTS: The estimated BMD testing interval was 16.8 years (95% confidence interval [CI], 11.5 to 24.6) for women with normal BMD, 17.3 years (95% CI, 13.9 to 21.5) for women with mild osteopenia, 4.7 years (95% CI, 4.2 to 5.2) for women with moderate osteopenia, and 1.1 years (95% CI, 1.0 to 1.3) for women with advanced osteopenia. CONCLUSIONS: Our data indicate that osteoporosis would develop in less than 10% of older, post-menopausal women during rescreening intervals of approximately 15 years for women with normal bone density or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia.","Although bone mineral density (BMD) testing to measure how much calcium and other minerals are in bones to look for osteoporosis (a condition in which bones become weak and brittle) is suggested for women 65 years old or older, few studies look at how long to wait between tests. We studied 4957 women, 67 years old and older, with normal BMD or weaker than normal bones who had never broken a hip or spine or received treatment for osteoporosis, followed for up to 15 years. The time between BMD testing was the estimated time for 10% of women to develop osteoporosis before breaking a hip or spine, considering estrogen (female-specific hormone) use and risk factors. We used mathematical models to look at changes from normal BMD and from mild, moderate, and advanced osteopenia. We considered hip and spine breaks and people taking drugs to strengthen bones. We found the estimated time between BMD testing was 16.8 years for women with normal BMD and 17.3, 4.7. and 1.1 years for women with mild, moderate, and advanced osteopenia, respectively. Our results suggest that less than 10% of older women who had gone through menopause (a point in time 12 months after the last period) would develop osteoporosis if tested about every 15 years for women with normal BMD or mild osteopenia, 5 years for women with moderate osteopenia, and 1 year for women with advanced osteopenia." +"The US Preventive Services Task Force (USPSTF) guideline for osteoporosis screening concludes that there is a lack of evidence about optimal rescreening intervals and states that intervals >2 years may be necessary to better predict fracture risk. In addition, the USPSTF cites a prospective study showing that repeat measurement of BMD after 8 years added little predictive value compared with baseline DEXA scan results. Reconsider the intervals at which you recommend rescreening for osteoporosis; for post-menopausal women with a baseline of normal bone mineral density (BMD) or mild osteopenia, a 15-year interval is probably sufficient.","Current expert panel guidance for osteoporosis (a condition in which bones become weak and brittle) testing states that not enough data exist on the best period of time in between tests and that periods of over 2 years may be needed to better predict the risk of breaking bones. In addition, the guidance mentions a study showing that measuring BMD after 8 years only helped a small amount to predict osteoporosis compared with initial BMD scan results. Re-think the period of time between osteoporosis checks; for women who have gone through menopause (a point in time 12 months after the last period) with an initial normal bone mineral density (BMD) or slightly weaker than normal bones, 15 years between checks is likely enough." +"The US Preventive Services Task Force (USPSTF) guideline for osteoporosis screening concludes that there is a lack of evidence about optimal rescreening intervals and states that intervals >2 years may be necessary to better predict fracture risk. In addition, the USPSTF cites a prospective study showing that repeat measurement of BMD after 8 years added little predictive value compared with baseline DEXA scan results. Reconsider the intervals at which you recommend rescreening for osteoporosis; for post-menopausal women with a baseline of normal bone mineral density (BMD) or mild osteopenia, a 15-year interval is probably sufficient.","The US Preventative Services Task Force (USPSTF) guideline for screening osteoporosis, a bone-weakening disease, states that there is a lack of evidence about best rescreening intervals. The guideline states that intervals >2 years may be needed to better preduct fracture risk. Also, the USPSTF mentions a study in which repeat measurement of bone mineral density (BMD) or hardness after 8 years adds litte value relative to inital bone scans. Reconsider the intervals at which you recommend rescreening for osteoporosis. For post-menopausal or older women with normal BMD or mild bone weakening, a 15-year interval is likely enough." +"Importance: By 2020, approximately 12.3 million individuals in the United States older than 50 years are expected to have osteoporosis. Osteoporotic fractures, particularly hip fractures, are associated with limitations in ambulation, chronic pain and disability, loss of independence, and decreased quality of life, and 21% to 30% of patients who experience a hip fracture die within 1 year. The prevalence of primary osteoporosis (ie, osteoporosis without underlying disease) increases with age and differs by race/ethnicity. With the aging of the US population, the potential preventable burden is likely to increase in future years. Objective: To update the 2011 US Preventive Services Task Force (USPSTF) recommendation on screening for osteoporosis. Evidence review: The USPSTF reviewed the evidence on screening for and treatment of osteoporotic fractures in men and women, as well as risk assessment tools, screening intervals, and efficacy of screening and treatment in subgroups. The screening population was postmenopausal women and older men with no known previous osteoporotic fractures and no known comorbid conditions or medication use associated with secondary osteoporosis. Findings: The USPSTF found convincing evidence that bone measurement tests are accurate for detecting osteoporosis and predicting osteoporotic fractures in women and men. The USPSTF found adequate evidence that clinical risk assessment tools are moderately accurate in identifying risk of osteoporosis and osteoporotic fractures. The USPSTF found convincing evidence that drug therapies reduce subsequent fracture rates in postmenopausal women. The USPSTF found that the evidence is inadequate to assess the effectiveness of drug therapies in reducing subsequent fracture rates in men without previous fractures. Conclusions and recommendation: The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in women 65 years and older. (B recommendation) The USPSTF recommends screening for osteoporosis with bone measurement testing to prevent osteoporotic fractures in postmenopausal women younger than 65 years at increased risk of osteoporosis, as determined by a formal clinical risk assessment tool. (B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis to prevent osteoporotic fractures in men. (I statement).","By 2020, about 12.3 million people in the United States older than 50 years are expected to have osteoporosis, a condition in which bones become weak and brittle. Broken bones from osteoporosis, especially hip breaks, are related to a limited ability to walk, long-term pain and disability, loss of independence, and reduced quality of life. 21% to 30% of people who break a hip die within 1 year. The number of people during a specific period with primary osteoporosis (i.e., osteoporosis not resulting from other disease), goes up with age and changes depending on race/ethnicity. With the U.S. population getting older, the possible cost of preventable disease is expected to go up in the future. We aim to update a 2011 expert panel suggestion on checking for osteoporosis. The expert panel looked at scientific studies on checking for and treatment of bone breaks due to osteoporosis in men and women, and tools to measure risk, periods between checks, and how well checks and treatment work in smaller groups. The group that was checked for osteoporosis was women who had gone through menopause (a point in time 12 months after the last period) and older men who had never had a known bone break due to osteoporosis and no known conditions or drug use known to cause osteoporosis. The expert panel found strong proof that bone measurement tests are correct for finding osteoporosis and predicting bone breaks due to osteoporosis in women and men. The expert panel found some proof that tools to measure risk are somewhat correct in finding risk of osteoporosis and bone breaks due to osteoporosis. The expert panel found strong proof that drugs decrease later bone break rates in women who have gone through menopause. The expert panel found there is not enough proof to measure how well drugs work to decrease later bone break rates in men without previous bone breaks. The expert panel suggests checking for osteoporosis with bone measurement testing to prevent bone breaks from osteoporosis in women 65 years and older. The expert panel suggests checking for osteoporosis with bone measurement testing to prevent bone breaks from osteoporosis in women younger than 65 years who have gone through menopause who have a greater risk of osteoporosis, as decided by a tool used by doctors to measure risk. The expert panel concludes there is not enough data to measure the pros versus cons of checking for osteoporosis to prevent bone breaks from osteoporosis in men. " +"Background: Existing guidelines for repeat screening and treatment monitoring intervals regarding the use of dual-energy x-ray absorptiometry (DXA) scans are conflicting or lacking. The Choosing Wisely campaign recommends against repeating DXA scans within 2 years of initial screening. It is unclear how frequently physicians order repeat scans and what clinical factors contribute to their use. Objective: To estimate cumulative incidence and predictors of repeat DXA for screening or treatment monitoring in a regional health system. Design: Retrospective longitudinal cohort study PARTICIPANTS: A total of 5992 women aged 40-84 years who received initial DXA screening from 2006 to 2011 within a regional health system in Sacramento, CA. Main measures: Two- and five-year cumulative incidence and hazard rations (HR) of repeat DXA by initial screening result (classified into three groups: low or high risk of progression to osteoporosis, or osteoporosis) and whether women were prescribed osteoporosis drugs after initial DXA. Key results: Among women not treated after initial DXA, 2-year cumulative incidence for low-risk, high-risk, and osteoporotic women was 8.0%, 13.8%, and 19.6%, respectively, increasing to 42.9%, 60.4%, and 57.4% by 5 years after initial screening. For treated women, median time to repeat DXA was over 3 years for all groups. Relative to women with low-risk initial DXA, high-risk initial DXA significantly predicted repeat screening for untreated women [adjusted HR 1.67 (95% CI 1.40-2.00)] but not within the treated group [HR 1.09 (95% CI 0.91-1.30)]. Conclusions: Repeat DXA screening was common in women both at low and high risk of progression to osteoporosis, with a substantial proportion of women receiving repeat scans within 2 years of initial screening. Conversely, only 60% of those at high-risk of progression to osteoporosis were re-screened within 5 years. Interventions are needed to help clinicians make higher-value decisions regarding repeat use of DXA scans.","Current guidelines disagree or do not exist for how long to wait between checks and treatment check-ins involving the use of dual-energy x-ray absorptiometry (DXA) scans, a technique used by doctors to measure a patient's risk of osteoporosis (a condition in which bones become weak and brittle). A campaign to avoid unnecessary medical tests, treatments and procedures does not suggest DXA scans within 2 years of the first test. How often and for which patient characteristics doctors order repeat scans is unclear. We aim to estimate the number of people at risk who develop osteoporosis over a period and predictors of repeat DXA for checks and treatment check-ins in a healthcare facility. We studied 5992 women aged 40-84 years who underwent DXA scans to check for osteoporosis from 2006 to 2011 at a healthcare facility in Sacramento, CA. Main test scores included two- and five-year amounts and risks of repeat DXA by initial test results (classified into three groups: low or high risk of worsening to osteoporosis, or osteoporosis) and whether women were given osteoporosis drugs after the first DXA. For women not treated after a first DXA, 2-year amounts for low-risk, high-risk, and osteoporotic women were 8.0%, 13.8%, and 19.6%, respectively, increasing to 42.9%, 60.4%, and 57.4% by 5 years after the first screening. For treated women, average time to repeat DXA was over 3 years for all groups. Compared to women with low-risk initial DXA, high-risk initial DXA significantly led to repeat screening for untreated women but not within the treated group. Conclusions: Repeat DXA screening was common in women both at low and high risk of worsening to osteoporosis, with a large amount of women receiving repeat scans within 2 years of initial screening. On the other hand, only 60% of those at high-risk of worsening or progression to osteoporosis were re-screened within 5 years. Treatments are needed to help clinicians make better decisions regarding repeat use of DXA scans." +"Background: Clinical practice guidelines recommend use of fracture risk scores for screening and pharmacologic treatment decisions. The timing of occurrence of treatment-level (according to 2014 National Osteoporosis Foundation guidelines) or screening-level (according to 2011 US Preventive Services Task Force guidelines) fracture risk scores has not been estimated in postmenopausal women. Methods: We conducted a retrospective competing risk analysis of new occurrence of treatment-level and screening-level fracture risk scores in postmenopausal women aged 50 years and older, prior to receipt of pharmacologic treatment and prior to first hip or clinical vertebral fracture. Results: In 54,280 postmenopausal women aged 50 to 64 years without a bone mineral density test, the time for 10% to develop a treatment-level FRAX score could not be estimated accurately because of rare incidence of treatment-level scores. In 6096 women who had FRAX scores calculated with bone mineral density, the estimated unadjusted time to treatment-level FRAX ranged from 7.6 years (95% confidence interval [CI], 6.6-8.7) for those aged 65 to 69, to 5.1 years (95% CI, 3.5-7.5) for those aged 75 to 79 at baseline. Of 17,967 women aged 50 to 64 with a screening-level FRAX at baseline, 100 (0.6%) experienced a hip or clinical vertebral fracture by age 65 years. Conclusions: Postmenopausal women with sub-threshold fracture risk scores at baseline were unlikely to develop a treatment-level FRAX score between ages 50 and 64 years. After age 65, the increased incidence of treatment-level fracture risk scores, osteoporosis, and major osteoporotic fracture supports more frequent consideration of FRAX and bone mineral density testing.","Guidelines for patient care recommend use of fracture risk scores, or the likelihood of having a major bone break, for checks and drug treatment decisions. The timing of treatment-level or screening-level fracture risk scores based on guidelines has not been estimated in women who have gone through menopause (a point in time 12 months after the last period). We measured new occurences of teratment-level and testing-level fracture risk scores in postmenopausal women aged 50 years and older, before receiving drug treatment and the first hip or clinical vertebral fracture. In 54,280 women who had gone through menopause aged 50 to 64 years without a bone mineral density test, we could not estimate the time for 10% to need treatment based on a common osteoporosis questionnaire due to too few scores suggesting treatment. In 6096 women who had scores from a common osteoporosis questionnaire, the estimated time to need treatment was 7.6 years and 5.1 years for those aged 65 to 69 and aged 75 to 79, respectively. Of 17,967 women aged 50 to 64 with an initial screening-level FRAX (or fracture-risk score), 100 (0.6%) broke their hip or spine by age 65 years. We conclude that women who have gone through menopause with questionnaire scores that did not suggest treatment were unlikely to have a score suggesting treatment between ages 50 and 64 years. After age 65, questionnaire scores suggesting treatment, osteoporosis, and serious bone breaks due to osteoporosis suggest doing more questionnaires and bone mineral density testing more often." +"Background: Clinical practice guidelines recommend use of fracture risk scores for screening and pharmacologic treatment decisions. The timing of occurrence of treatment-level (according to 2014 National Osteoporosis Foundation guidelines) or screening-level (according to 2011 US Preventive Services Task Force guidelines) fracture risk scores has not been estimated in postmenopausal women. Methods: We conducted a retrospective competing risk analysis of new occurrence of treatment-level and screening-level fracture risk scores in postmenopausal women aged 50 years and older, prior to receipt of pharmacologic treatment and prior to first hip or clinical vertebral fracture. Results: In 54,280 postmenopausal women aged 50 to 64 years without a bone mineral density test, the time for 10% to develop a treatment-level FRAX score could not be estimated accurately because of rare incidence of treatment-level scores. In 6096 women who had FRAX scores calculated with bone mineral density, the estimated unadjusted time to treatment-level FRAX ranged from 7.6 years (95% confidence interval [CI], 6.6-8.7) for those aged 65 to 69, to 5.1 years (95% CI, 3.5-7.5) for those aged 75 to 79 at baseline. Of 17,967 women aged 50 to 64 with a screening-level FRAX at baseline, 100 (0.6%) experienced a hip or clinical vertebral fracture by age 65 years. Conclusions: Postmenopausal women with sub-threshold fracture risk scores at baseline were unlikely to develop a treatment-level FRAX score between ages 50 and 64 years. After age 65, the increased incidence of treatment-level fracture risk scores, osteoporosis, and major osteoporotic fracture supports more frequent consideration of FRAX and bone mineral density testing.","Healtchare guidelines recommend using fracture risk scores for screening and drug treatment decisions. The timing of occurence of treatment-level (according to 2014 guidelines by an expert goup) or screening-level (according to 2011 guidelines by national experts) fracture risk scores has not been estimated in postmenopausal women who finished their last menstrual cycle. We conducted a risk analysis of new occurence of treatment- and screening-level fracture risk scores in postmenopausal women aged 50 years and older, before receiving drug treatment and hip or spine fracture. In 54, 280 postmenopausal women aged 50 to 64 years without a bone hardness test, the time for 10% to get a treatment-level fracture risk score could not be estimated correctly due to rare amount of treatment-level scores. In 6096 women who had fracture risk scores calculated with bone hardness, the estimated unadjusted time to treatment-level fracture risk ranged from 7.6 years for those aged 65 to 69, to 5.1 years, for those aged 75 to 79 at the start. Of 17,967 women aged 50 to 64 with a screening-level fracture risk score at the start, 100 (0.6%) had a hip or back fracture by age 65 years. Postmenopausal women with sub-threshold fracture risk scores at the start were unlikely to get a treatment-level fracture risk score between 50 and 64 years. After age 65, the increased amount of treatment-level fracture risk scores, bone weakening, and major fractures from bone weakening support more frequent consideration of fracture risk and bone hardness testing." +"We investigated the value of routine laboratory testing for identifying underlying causes in older men diagnosed with osteoporosis. Most osteoporotic and nonosteoporotic men had ?1 laboratory abnormality. Few individual laboratory abnormalities were more common in osteoporotic men. The benefit of routine laboratory testing in older osteoporotic men may be low. Introduction: To evaluate the utility of recommended laboratory testing to identify secondary causes in older men with osteoporosis, we examined prevalence of laboratory abnormalities in older men with and without osteoporosis. Methods: One thousand five hundred seventy-two men aged ?65 years in the Osteoporotic Fractures in Men study completed bone mineral density (BMD) testing and a battery of laboratory measures, including serum calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), 25-OH vitamin D, total testosterone, spot urine calcium/creatinine ratio, spot urine albumin/creatinine ratio, creatinine-derived estimated glomerular filtration rate, 24-h urine calcium, and 24-h urine free cortisol. Using cross-sectional analyses, we calculated prevalence ratios (PRs) and 95 % confidence intervals (CI) for the association of any and specific laboratory abnormalities with osteoporosis and the number of men with osteoporosis needed to test to identify one additional laboratory abnormality compared to testing men without osteoporosis. Results: Approximately 60 % of men had ?1 laboratory abnormality in both men with and without osteoporosis. Among individual tests, only vitamin D insufficiency (PR, 1.13; 95 % CI, 1.05-1.22) and high alkaline phosphatase (PR, 3.05; 95 % CI, 1.52-6.11) were more likely in men with osteoporosis. Hypercortisolism and hyperthyroidism were uncommon and not significantly more frequent in men with osteoporosis. No osteoporotic men had hypercalciuria. Conclusions: Though most of these older men had ?1 laboratory abnormality, few routinely recommended individual tests were more common in men with osteoporosis than in those without osteoporosis. Possibly excepting vitamin D and alkaline phosphatase, benefit of routine laboratory testing to identify possible secondary causes in older osteoporotic men appears low. Results may not be generalizable to younger men or to older men in whom history and exam findings raise clinical suspicion for a secondary cause of osteoporosis.","We looked at how helpful routine lab testing is for finding underlying causes in older men diagnosed with osteoporosis (a condition in which bones become weak and brittle). Most men with and without osteoporosis had one or more abnormal lab measurement. Few single lab abnormalities were more common in men with osteoporosis. Routine lab testing in older men with osteoporosis may not be helpful. We aim to rate how useful recommended lab testing is to find underlying causes of osteoporosis in older men by looking at the number of older men with lab abnormalities with and without osteoporosis during a specific period. We studied 1,572 men 65 years old and older who has bone mineral density (BMD) testing and many other lab measurements. We checked for links of any lab abnormalities with osteoporosis and the number of men with osteoporosis needed to test to find one more lab abnormality compared to testing men without osteoporosis. We found that about 60% of men with and without osteoporosis had one or more lab abnormality. Among lab tests, only not enough vitamin D and high alkaline phosphatase (suggesting damage to liver or bone disorder) were more likely in men with osteoporosis. Too much cortisol (stress hormone) and overactive thyroid (metabolism-regulating hormone) were rare and not meaningfully more common in men with osteoporosis. No men with osteoporosis had high levels of calcium in the urine. Though most of these older men had one or more lab abnormality, few often-recommended tests were more common in men with osteoporosis than in those without. Except for possibly vitamin D and alkaline phosphatase, usefulness of routine lab testing to find possible underlying causes in older men with osteoporosis seems low. Results may not apply to younger men or to older men thought to have osteoporosis from underlying causes." +"Osteoporosis-related fractures affect approximately one in two white women and one in five white men in their lifetime. The impact of fractures includes loss of function, significant costs, and increased mortality. The U.S. Preventive Services Task Force recommends using dual energy x-ray absorptiometry to screen all women 65 years and older, and younger women who have an increased fracture risk as determined by the World Health Organization's FRAX Fracture Risk Assessment Tool. Although guidelines are lacking for rescreening women who have normal bone mineral density on initial screening, intervals of at least four years appear safe. The U.S. Preventive Services Task Force found insufficient evidence to recommend screening for osteoporosis in men; other organizations recommend screening all men 70 years and older. In patients with newly diagnosed osteoporosis, suggested laboratory tests to identify secondary causes include serum 25-hydroxyvitamin D, calcium, creatinine, and thyroid-stimulating hormone. First-line treatment to prevent fractures consists of fall prevention, smoking cessation, moderation of alcohol intake, and bisphosphonate therapy. Clinicians should consider discontinuing bisphosphonate therapy after five years in women without a personal history of vertebral fractures. Raloxifene, teriparatide, and denosumab are alternative effective treatments for certain subsets of patients and for those who are unable to take or whose condition does not respond to bisphosphonates. The need for follow-up bone mineral density testing in patients receiving treatment for osteoporosis is uncertain.","Bone breaks due to osteoporosis (a condition in which bones become weak and brittle) happen in about 50% of white women and 20% of white men in their lifetime. Bone breaks cause loss of physical function, high costs, and increased death. An expert panel recommends using dual energy x-ray absorptiometry, or bone density scanning, to check all women 65 year and older, and younger women who are more likely to have bone breaks based on a popular measurement tool to measure fracture risk. Although there are not guidelines for rechecking women who have initial normal bone mineral density, four years between checks looks safe. The expert panel did not find enough proof to recommend checking for osteoporosis in men; other groups recommend checking all men 70 years and older. In people with newly found osteoporosis, lab tests to find underlying causes include measuring blood levels of different substances. The best treatment to prevent breaks includes preventing falls, stopping smoking, reducing alcohol consumption, and a group of drugs that help prevent or slow down bone thinning. Doctors should think about stopping a group of drugs that help prevent or slow down bone thinning after five years in women without a history of spine breaks. Other types of drugs for osteoporosis exist for certain groups of patients and for those who are unable to take or whose condition is not helped by one group of drugs that help prevent or slow down bone thinning. The need to recheck bone mineral density in people taking drugs for osteoporosis is unknown." +"Background: To develop an OSTAi tool and compare this with the National Osteoporosis Foundation recommendations in 2013 (NOF 2013) for bone mineral density (BMD) testing among Taiwan postmenopausal women. Methods: Taiwan Osteoporosis Association (TOA) conducted a nationwide BMD survey by a bus installed with a dual energy X-ray absorptiometry (DXA) between 2008 and 2011. All of the participants completed questionnaire, which included demographics and risk factors of osteoporotic fracture in FRAX tool. We used the database to analyze potential risk factors for osteoporosis and followed the model by Koh et al. to develop a risk index via multiple variable regression analysis and item reduction. We used the index values to set up a simple algorithm (namely OSTAi) to identify those who need BMD measurement. Receiver operating characteristic (ROC) curve and the area under the curve (AUC) was used to compare the sensitivity/specificity analysis of this model with that of recommendations by NOF 2013. Results: A total of 12,175 Taiwan postmenopausal women enrolled in this survey. The index value was derived by age and body weight of the participants according to weighted odds of each risk factor and the selected cutoff value was set at ""-1"". There are 6393 (52.5%) participants whose index value is below ""-1"" and whose risk of osteoporosis was 57.5% (3674/6393). The AUC for OSTAi and NOF 2013 were 0.739 (95% confidence interval (CI), 0.728-0.749, P<0.001) and 0.618 (95% CI, 0.606-0.630, P<0.001), respectively. The sensitivity and specificity of OSTAi, at the selected cutoff value of -1, and NOF 2013 to identify osteoporosis were 73.1%, 62.0% and 78.3%, 45.7%, respectively. Conclusions: As OSTA for Asian populations, OSTAi is an useful tool to identify Taiwan postmenopausal women with osteoporosis, In comparison with NOF 2013, OSTAi may be an easier and better tool for referral to BMD measurement by DXA in this area.","We aimed to make an Osteoporosis (a condition in which bones become weak and brittle) Self-Assessment Tool for Taiwan (OSTAi) and compare this with existing 2013 guidelines for bone mineral density (BMD) testing among Taiwan women who had gone through menopause (a point in time 12 months after the last period). We tested women nationwide using a dual energy X-ray absorptiometry (DXA; a common text to measure bone density) between 2008 and 2011. All women filled out a questionnaire, which included individual information and risk factors of bone breaks caused by osteoporosis. We used this information to look at possible risk factors for osteoporosis. We set up OSTAi to find those who needed BMD measurement. We compared accuracy for disease detection and no detection between OSTAi and the 2013 guidelines. We studied 12,175 Taiwan women who had gone through menopause. There are 6393 (52.5%) participants whose risk of osteoporosis was 57.5% (3674/6393). OSTAi showed slightly lower accuracy for disease detection and higher accuracy for no detection than 2013 guidelines. OSTAi is useful to find Taiwan women who have gone through menopause with osteoporosis. Compared to current guidelines, OSTAi may be an easier and better tool to determine who should have DXA in Taiwan." +"Background: To develop an OSTAi tool and compare this with the National Osteoporosis Foundation recommendations in 2013 (NOF 2013) for bone mineral density (BMD) testing among Taiwan postmenopausal women. Methods: Taiwan Osteoporosis Association (TOA) conducted a nationwide BMD survey by a bus installed with a dual energy X-ray absorptiometry (DXA) between 2008 and 2011. All of the participants completed questionnaire, which included demographics and risk factors of osteoporotic fracture in FRAX tool. We used the database to analyze potential risk factors for osteoporosis and followed the model by Koh et al. to develop a risk index via multiple variable regression analysis and item reduction. We used the index values to set up a simple algorithm (namely OSTAi) to identify those who need BMD measurement. Receiver operating characteristic (ROC) curve and the area under the curve (AUC) was used to compare the sensitivity/specificity analysis of this model with that of recommendations by NOF 2013. Results: A total of 12,175 Taiwan postmenopausal women enrolled in this survey. The index value was derived by age and body weight of the participants according to weighted odds of each risk factor and the selected cutoff value was set at ""-1"". There are 6393 (52.5%) participants whose index value is below ""-1"" and whose risk of osteoporosis was 57.5% (3674/6393). The AUC for OSTAi and NOF 2013 were 0.739 (95% confidence interval (CI), 0.728-0.749, P<0.001) and 0.618 (95% CI, 0.606-0.630, P<0.001), respectively. The sensitivity and specificity of OSTAi, at the selected cutoff value of -1, and NOF 2013 to identify osteoporosis were 73.1%, 62.0% and 78.3%, 45.7%, respectively. Conclusions: As OSTA for Asian populations, OSTAi is an useful tool to identify Taiwan postmenopausal women with osteoporosis, In comparison with NOF 2013, OSTAi may be an easier and better tool for referral to BMD measurement by DXA in this area.","The study aims to create an osteoporosis (or bone weakening) self assessment (OSTAi) tool and compare it with the National Osteoporosis Foundation 2013 recommendations (NOF 2013) or bone mineral density (BMD) or hardness testing among Taiwan postmenopausal women who completed their final menstrual or sexual cycle. Taiwan Osteoporosis Associated (TOA) had a nationwide BMD survey by a bus installed with an X-ray machine between 2008 and 2011. All participants completed a questionnaire, which had socioeconomic and risk factors of osteoporotic fracture in fracture risk tool. 12,175 Taiwan postmenopausal women participated in this survey. There are 6393 (52.5%) participants below the cutoff and whose risk of osteoporosis was 57.5% (3647/6393). The measurements for OSTAi and NOF were noteworthy. The sensitivity (accuracy of detecting people with the disease) and specificity (accuracy of detecting people without the disease) of OSTAi at the cutoff and NOF 2013 to detect osteoporosis were 73.1%, 62.0% and 78.3%, 45.7%, respectively. Known as OSTA for Asian populations, OSTAi is useful to identify Taiwan postmenopausal women with osteoporosis. Compared to NOF 2013, OSTAi may be an easier, better tool to suggest BMD measurement by bone scans in this area." +"We evaluated the prevalence and geographic variation of short-interval (repeated in under 2 years) dual-energy X-ray absorptiometry tests (DXAs) among Medicare beneficiaries. Short-interval DXA use varied across regions (coefficient of variation = 0.64), and unlike other DXAs, rates decreased with payment cuts. Introduction: The American College of Rheumatology, through the Choosing Wisely initiative, identified measuring bone density more often than every 2 years as care ""physicians and patients should question."" We measured the prevalence and described the geographic variation of short-interval (repeated in under 2 years) DXAs among Medicare beneficiaries and estimated the cost of this testing and its responsiveness to payment change. Methods: Using 100 % Medicare claims data, 2006-2011, we identified DXAs and short-interval DXAs for female Medicare beneficiaries over age 66. We determined the population rate of DXAs and short-interval DXAs, as well as Medicare spending on short-interval DXAs, nationally and by hospital referral region (HRR). Results: DXA use was stable 2008-2011 (12.4 to 11.5 DXAs per 100 women). DXA use varied across HRRs: in 2011, overall DXA use ranged from 6.3 to 23.0 per 100 women (coefficient of variation = 0.18), and short-interval DXAs ranged from 0.3 to 8.0 per 100 women (coefficient of variation = 0.64). Short-interval DXA use fluctuated substantially with payment changes; other DXAs did not. Short-interval DXAs, which represented 10.1 % of all DXAs, cost Medicare approximately US$16 million in 2011. Conclusions: One out of ten DXAs was administered in a time frame shorter than recommended and at a substantial cost to Medicare. DXA use varied across regions. Short-interval DXA use was responsive to reimbursement changes, suggesting carefully designed policy and payment reform may reduce this care identified by rheumatologists as low value.","We rated the number and variation (or differences) across the country of dual-energy x-ray absorptiometry tests (DXAs - useful tests for measuring bone density) repeated in under 2 years (short-interval) in people on Medicare during a specific period. Use of short-interval DXAs varied across the country and unlike other DXAs, use went down with Medicare payment cuts. A campaign to avoid unnecessary medical tests, treatments and procedures found measuring bone density more often than every 2 years as care ""physicians and patients should question."" We rated the number and variation across the country of short-interval DXAs in people on Medicare during a specific period and estimated the testing cost and how much is changed based on payment. We used only information from Medicare claims in 2006-2011 to find DXAs and short-term DXAs for females over age 66 on Medicare. We found out how many DXAs and short-term DXAs were done, and how many Medicare dollars were spent on short-interval DXAs, across the country and by healthcare markets. From 2008-2011, DXA use was steady (12.4 to 11.5 DXAs per 100 women). DXA use varied across healthcare markets. Short-interval DXA use changed a lot based on payment; other DXAs did not. In 2011, Medicare spent about $16 million USD on short-interval DXAs, which made up 10.1% of all DXAs. We conclude that one out of 10 DXAs was done sooner than recommended, costing Medicare considerably. DXA use varied across the country. Short-interval DXA use changed based on payment, suggesting policy and payment changes may decrease this low-value care." +"Osteoporosis and its consequent increase in fracture risk is a major health concern for postmenopausal women and older men and has the potential to reach epidemic proportions. The ""gold standard"" for osteoporosis diagnosis is bone densitometry. However, economic issues or availability of the technology may prevent the possibility of mass screening. The goal of this study was to develop and validate a clinical scoring index designed as a prescreening tool to help clinicians identify which women are at increased risk of osteoporosis [bone mineral density (BMD) T-score -2.5 or less] and should therefore undergo further testing with bone densitometry. Records were analyzed for 1522 postmenopausal females over 50 years of age who had undergone testing with dual-energy X-ray absorptiometry (DXA). Osteoporosis risk index scores were compared to bone density T-scores. Hologic QDR 4500 technology was used to measure BMD at the femoral neck and lumbar spine (L1-L4). Participants who had a previous diagnosis of osteoporosis or were taking bone-active medication were excluded. Receiver-operating characteristic (ROC) analysis was used to identify the specific cutpoint value that would identify women at increased risk of low BMD. A simple algorithm based on age, weight, history of previous low impact fracture, early menopause, and corticosteroid therapy was developed. Validation of this five-item osteoporosis prescreening risk assessment (OPERA) index showed that the tool, at the recommended threshold (or cutoff value) of two, had a sensitivity that ranged from 88.1 [95% confidence interval (CI) for the mean: 86.2-91.9%] at the femoral neck to 90% (95% CI for the mean: 86.1-93.1%) at the lumbar spine area. Corresponding specificity values were 60.6 (95% CI for the mean: 57.9-63.3%) and 64.2% (95% CI for the mean: 61.4-66.9%), respectively. The positive predictive value (PPV) ranged from 29 at the femoral neck to 39.2% at the lumbar spine, while the corresponding negative predictive values (NPVs) reached 96.5 and 96.2%, respectively. Based on this cutoff value, the area under the ROC curve was 0.866 (95% CI for the mean: 0.847-0.882) for the lumbar spine and 0.814 (95% CI for the mean: 0.793-0.833) for the femoral neck. We conclude that the OPERA is a free and effective method for identifying Italian postmenopausal women at increased risk of osteoporosis. Its use could facilitate the appropriate and more cost-effective use of bone densitometry in developing countries.","Osteoporosis, a condition in which bones become weak and brittle, and the increase in the risk of bone breaks it causes has worried women who have gone through menopause (a point in time 12 months after the last period) and older men and could become a huge problem. The best way to diagnose osteoporosis is bone densitometry, a common test to measure bone density. Large-scale checks may not be possible due to economic issues or availability of densitometry. We aimed to make and test a scoring system to help doctors find which women are more likely to develop osteoporosis and should have more testing with bone densitometry. We looked at records for 1522 women who have gone through menopause over 50 years old who had dual-energy X-ray absorptiometry (DXA - a common test for bone density). We compared risk scores to bone density tests. We measured BMD at the hip and lower spine. We excluded people who were previously diagnosed with osteoporosis or were taking drugs affecting bones. We came up with a simple calculation based on age, weight, history of previous falls from a standing height or lower, early menopause, and use of a certain kind of steroid. Testing of this five-item osteoporosis prescreening risk assessment (OPERA) shows high accuracy for osteoporosis detection. OPERA shows high accuracy for no detection. The accuracy for results detecting osteoporosis ranged from 29 at the femoral neck to 39.2% at the lumbar spine, while the corresponding accuracy for results not detecting osteoporosis reached 96.5 and 96.2%, respectively. We conclude that the OPERA is a free and effective way to identify Italian women who have gone through menopause at higher risk of osteoporosis. Use of OPERA could help the appropriate and more cost-effective use of bone densitometry in developing countries." +"Background: Pregabalin has shown opioid sparing and analgesic effects in the early postoperative period; however, perioperative effects on cognition have not been studied. A randomized, parallel group, placebo-controlled investigation in 80 donor nephrectomy patients was previously performed that evaluated the analgesic, opioid-sparing, and antihyperalgesic effects of pregabalin. This article describes a secondary exploratory analysis that tested the hypothesis that pregabalin would impair cognitive function compared to placebo. Methods: Eighty patients scheduled for donor nephrectomy participated in this randomized, placebo-controlled study. Pregabalin (150 mg twice daily, n = 40) or placebo (n = 40) was administered on the day of surgery and the first postoperative day, in addition to a pain regimen consisting of opioids, steroids, local anesthetics, and acetaminophen. Specific cognitive tests measuring inhibition, sustained attention, psychomotor speed, visual memory, and strategy were performed at baseline, 24 h, and 3 to 5 days after surgery, using tests from the Cambridge Neuropsychological Test Automated Battery. Results: In the spatial working memory within errors test, the number of errors increased with pregabalin compared to placebo 24 h after surgery; median (25th, 75th percentile) values were 1 (0, 6) versus 0 (0, 1; rate ratio [95% CI], 3.20 [1.55 to 6.62]; P = 0.002). Furthermore, pregabalin significantly increased the number of errors in the stop-signal task stop-go test compared with placebo; median (25th, 75th percentile) values were 3 (1, 6) versus 1 (0, 2; rate ratio, 2.14 [1.13 to 4.07]; P = 0.020). There were no significant differences between groups in the paired associated learning, reaction time, rapid visual processing, or spatial working memory strategy tests. Conclusions: Perioperative pregabalin significantly negatively affected subdomains of executive functioning, including inhibition, and working memory compared to placebo, whereas psychomotor speed was not changed.","Pregabalin is a nerve pain medication. The drug has been shown to help reduce opioid use (opioid-sparing) and have pain relieving (analgesic) effects in the early period following a surgery. However, effects before, during, and after surgery on cognition (thinking ability) have not been studied. A study in 80 patients that had one or both of their kidneys removed was previously conducted to evaluate the opioid-sparing, analgesic, and antihyperalgesic (reduction of pain sensitivity) effects of pregabalin. This paper describes a secondary investigation that tested if pregabalin would impair cognitive function when compared to a control (no treatment) group. Eighty patients scheduled for donor nephrectomy (removal of one or both kidneys) participated in this study. Pregabalin (150 mg twice daily) or placebo (a harmless pill) was administered (given) on the day of surgery and the first post-operation day. This was given in addition to a pain regimen consisting of opioids, steroids, local anesthetics, and acetaminophen (pain medication). Cognitive tests measuring inhibition (restraint), sustained attention, psychomotor (movement) speed, visual memory, and strategy were performed before, 24 h, and 3 to 5 days after surgery. The spatial working memory test is used to determine if a participant can recall the configuration of a series of images. During the test, the number of errors increased with pregabalin treatment compared to placebo 24 h after surgery. Furthermore, pregabalin significantly increased the number of errors in the stop-signal task stop-go test compared with placebo. There were no significant differences between treatment groups in the paired associated learning, reaction time, rapid visual processing, or spatial working memory strategy tests. Perioperative (around surgery time) pregabalin significantly negatively affected several aspects of cognitive function when compared to placebo. However, psychomotor speed or movement was not changed." +"Objective: Long-term benzodiazepine (BDZ) use and dependence affect cognitive functioning adversely and partly irreversibly. Emerging evidence suggests that pregabalin (PGB) might be a safe and efficacious treatment of long-term BDZ use. The aim of the present study was to investigate the changes in several core cognitive functions after successful treatment of long-term BDZ use and dependence with PGB. Methods: Fourteen patients with long-term BDZ use (mean duration >15 years) underwent neuropsychological assessment with the mini-mental state examination and four tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) battery before the initiation of PGB treatment and at a two months follow-up after the cessation of BDZs. Patients' CANTAB percentile score distributions were compared with normative CANTAB data. Results: Patients improved on cognitive measures of global cognitive functioning, time orientation, psychomotor speed, and visuospatial memory and learning with strong effect sizes. By contrast, they failed to improve on measures of attentional flexibility. Despite their significant improvement, patients' scores on most tests remained still at the lower percentiles of CANTAB normative scores. Conclusions: Although preliminary, our findings suggest that successful treatment of long-term BDZ use with PGB is associated with a substantial, though only partial, recovery of BDZ-compromised neuropsychological functioning, at least at a 2-month follow-up.","Benzodiazepines (BDZ) are drugs that are often used to treat anxiety, muscle spasms, and seixures. Long-term BDZ use and dependence negatively affect cognitive functioning (thinking ability). These effects can be partially irreversible. New evidence suggests that pregabalin (PGB) might be a safe and effective treatment of long-term BDZ use. The goal of the study was investigate the changes in cognitive function after successful treatment of long-term BDZ use and dependence with PGB. Fourteen patients with long-term BDZ use underwent several neurological (brain-related) and cognititive function tests. These evaluations were conducted before the initiation of PGB treatment and at a two months follow-up after the cessation (stopping) of BDZs. Patients' scores from the tests were compared with control data. Patients improved on several cognitive measures with strong effect sizes. By contrast, they failed to improve on measures of attentional flexibility (the ability to shift focus). Despite their significant improvement, patients' scores on most tests were low when compared to control scores. The study findings suggest that successful treatment of long-term BDZ use with PGB is associated (linked) with a substantial, though only partial, recovery of BDZ-compromised brain function, at least at a 2-month follow-up." +"Central nervous system adverse effects are commonly reported with pregabalin (PGB). On the other hand, movement disorders (MDs) associated with this drug were rarely described. However, their occurrence could significantly affect the quality of life of PGB users. This literature review aims to evaluate the clinical epidemiological profile, pathological mechanisms, and management of PGB-associated MDs. Relevant reports in six databases were identified and assessed by two reviewers without language restriction. A total of 46 reports containing 305 cases from 17 countries were assessed. The MDs encountered were as follows: 184 individuals with ataxia, 61 with tremors, 39 with myoclonus, 8 with parkinsonism, 1 with restless legs syndrome, 1 with dystonia, 1 with dyskinesia, and 1 with akathisia. The mean age was 62 years (range: 23-94). The male sex was slightly predominant with 54.34%. The mean PGB dose when the MD occurred was 238 mg, and neuropathic pain was the most common indication of PGB. The time from PGB start to MD was < 1 month at 75%. The time from PGB withdrawal to recovery was < 1 week at 77%. All the individuals where the follow-up was reported had a full recovery. The most common management was PGB withdrawal. In the literature, the majority of the cases did not report information about timeline events, neurological examination details, or electrodiagnostic studies. The best management for all MDs is probably PGB withdrawal. If the patient is on dialysis program, perhaps an increased number of sessions will decrease recovery time. Furthermore, the addition of a benzodiazepine could accelerate recovery.","Central nervous system (brain and spinal cord) adverse effects (side effects) are commonly reported with pregabalin (PGB), a drug commonly given for nerve pain. However, movement disorders (MDs) associated with pregabalin were rarely described. However, their occurrence could significantly affect the quality of life of PGB users. This literature review aims to evaluate the clinical incidence, distribution, and control; underlying causative mechanisms; and management of PGB-associated MDs. Relevant scientific papers in six databases were identified and assessed (evaluated) by two reviewers without language restriction. A total of 46 reports containing 305 cases from 17 countries were assessed. The MDs reported were as follows: 184 individuals with ataxia (loss of full control of body movement), 61 with tremors (shaking), 39 with myoclonus (jerky movement), 8 with Parkinson's disease, 1 with restless legs syndrome, 1 with dystonia (involuntary muscle contraction), 1 with dyskinesia (uncontrolled muscle movement), and 1 with akathisia (feeling of restlessness). The average age was 62 years. The age range was 23 to 94 years old. The male sex was slightly predominant at 54.34% of all cases. The average PGB dose when the MD occurred was 238 mg. Nerve pain was the most common indication of PGB. The time between PGB start and onset of a MD was less than one month for a majority of cases. The time from PGB withdrawal to recovery was less than 1 week for a majority of cases. All the individuals where the follow-up was reported had a full recovery. The most common management was PGB withdrawal. In the literature, the majority of the cases did not report information about timeline events, neurological (brain-related) examination details, or electrodiagnostic studies (using electrical activity to gauge health). The best management for all MDs is probably PGB withdrawal. If the patient is on dialysis (blood filtering and purification) program, perhaps an increased number of sessions will decrease recovery time. Furthermore, the addition of a benzodiazepine (anti-anxiety drug) could speed up recovery." +"Central nervous system adverse effects are commonly reported with pregabalin (PGB). On the other hand, movement disorders (MDs) associated with this drug were rarely described. However, their occurrence could significantly affect the quality of life of PGB users. This literature review aims to evaluate the clinical epidemiological profile, pathological mechanisms, and management of PGB-associated MDs. Relevant reports in six databases were identified and assessed by two reviewers without language restriction. A total of 46 reports containing 305 cases from 17 countries were assessed. The MDs encountered were as follows: 184 individuals with ataxia, 61 with tremors, 39 with myoclonus, 8 with parkinsonism, 1 with restless legs syndrome, 1 with dystonia, 1 with dyskinesia, and 1 with akathisia. The mean age was 62 years (range: 23-94). The male sex was slightly predominant with 54.34%. The mean PGB dose when the MD occurred was 238 mg, and neuropathic pain was the most common indication of PGB. The time from PGB start to MD was < 1 month at 75%. The time from PGB withdrawal to recovery was < 1 week at 77%. All the individuals where the follow-up was reported had a full recovery. The most common management was PGB withdrawal. In the literature, the majority of the cases did not report information about timeline events, neurological examination details, or electrodiagnostic studies. The best management for all MDs is probably PGB withdrawal. If the patient is on dialysis program, perhaps an increased number of sessions will decrease recovery time. Furthermore, the addition of a benzodiazepine could accelerate recovery.","Side effects of the brain and spine are commonly reported with pregabalin (PGB), a common nerve pain medication. However, movement disorders (MDs) linked with this drug were rarely described. Still, their occurence could affect the quality of life of PGB users. This review evaluates the distribution, disease-causing mechanisms, and treatment of PGB-associated MDs. Two reviewers without language issues identified and checked relevant reports in six databases. 46 reports with 305 cases from 17 countries were assessed. The reported MDs include: 184 people with ataxia (impaired coordination), 61 with tremors (shaking movements), 39 with myoclonus (muscle jerks), 8 with parkinsonism (movement abnormalities from a brain disorder), 1 with restless legs syndrome (uncontrollable urge to move legs), 1 with dystonia (repetitive, twisting movements), 1 with dyskinesia (erratic movements), and 1 with akathisia (muscle quivering). Average age was 62 years. Proportion of male sex was 54.34%. Average PGB medication dose when MD occured was 238 mg. Nerve-related pain was the most common effect of PGB. Time from PGB start to MD was <1 month at 75%. Time from PGD drug use withdrawal to recovery was < 1 week at 77%. All individuals with a reported follow-up or later examination had a full recovery. Most common management was PGB drug withdrawal. In the text, many cases did not report information about timeline events, brain-related exam details, or details about the electrical activity of the body. The best treatment for all MDs is likely PGB drug use stoppage. If the patient is on an artificial kidney machine, perhaps more sessions will decrease recovery time. Also, adding a benzodiazepine, an anti-anxiety and anti-seizure drug, could quicken recovery." +"Pregabalin (PGB) is an analog of the inhibitory neurotransmitter gamma-aminobutyric acid. The currently available evidence favors the misuse and abuse potential of PGB. However, its neurotoxicity remains unclear. Therefore, this study assessed the toxic effects of chronic pregabalin dependence as well as withdrawal on the cortical neurons of the frontal lobe. This study included eighty adult male albino rats which were divided into three groups. Group I (Control) included 40 rats and was further subdivided into two equal subgroups (IA and IB) as negative and positive controls. Group II (PGB-dependent) included 20 rats which received PGB starting with the therapeutic dose (300 mg/day), then the doses were gradually increased until they reached the dependent dose (3400 mg/day) by the end of the first month. Further, the dependent dose was given daily for another 2 months. Group III (PGB withdrawal) included 20 rats which received PGB as described in group II. After that, administration of PGB was stopped and the rats were kept for another one month. By the end of the experiment, all animals were sacrificed by cervical decapitation. The specimens were taken from the frontal cortex for histologic and immunohistochemical staining as well as morphometric analysis. Sections of the frontal cortex of group II showed changes in the form of disturbed architectural pattern of cortical layers, apoptotic cells, weak immunoexpression of Bcl-2 and VEGF as well as moderate-strong immunoexpression of iNOS and nestin. These expressions were significantly different from the control groups, but they were non-significant in comparison with group III. These findings indicate that chronic PGB dependence induces neurotoxic effects mainly in the form of neuronal apoptosis, gliosis, and oxidative stress injury of the frontal cortex. The PGB- induced neurotoxic effects persisted after withdrawal. The influence of these neurotoxic effects and their relevance to the cognitive or neurologic disorders in PGB-dependent individuals warrants further research. Furthermore, it is recommended to quantify the behavioral changes related to PGB dependence as well as withdrawal in future studies.","Pregabalin (PGB) - a nerve pain medication - is an analog of the inhibitory (silencing) neurotransmitter, (chemical messenger in the brain) gamma-aminobutyric acid. Analogs are compounds that have similar structure to other compounds but are not identical. The currently available evidence favors the misuse and abuse potential of PGB. However, its neurotoxicity (poison to the brain) remains unclear. The aim of this study was to assess (measure) the toxic effects of long term dependence on pregabalin. Additionally, the study aimed to assess how withdrawal from (removal of) PGB affects cortical neurons (brain cells) in the front lobe of the brain. This study included eighty adult male albino rats which were divided into three groups. Group I (Control) included 40 rats and was further subdivided into two equal subgroups (IA and IB) as negative and positive controls - groups to compare the treatment group to. Group II (PGB-dependent) included 20 rats. Each rat received PGB starting with the therapeutic (beneficial) dose (300 mg/day). The doses were gradually increased until they reached the dependent (full) dose (3400 mg/day) by the end of the first month. Further, the dependent dose was given daily for another 2 months. Group III (PGB withdrawal) included 20 rats which received PGB as described in Group II. After that, administration (use) of PGB was stopped, and the rats were kept for another one month. By the end of the experiment, all animals were sacrificed by cervical decapitation. Samples were taken from the frontal cortex, a section of the brain, for further analysis. Brain samples showed changes in cortical layer (brain) structure, dying cells, and decreased expression of several critical factors needed for cell function. These expression level changes were significantly different from the Control groups. However, they were non-significant in comparison with Group III. These results indicate that long-term PGB dependence causes neurotoxic effects. These effects include brain cell death, scarring of the central nervous system (brain and spinal cord), and increased reactive oxidative species (harmful chemicals from oxygen) in the frontal cortex. The PGB- induced neurotoxic effects continued after withdrawal. Further research is needed to understand the impact of these neurotoxic effects and their relevance to the cognitive (memory-related) or neurologic (brain-related) disorders in PGB-dependent individuals. Furthermore, it is recommended to measure the behavioral changes related to PGB dependence and withdrawal in future studies." +"A 74-year-old man with peripheral neuropathy due to diabetes presented with deliberate ingestion of 450 mg of pregabalin (PBG) over a period of 8 hours followed by altered mental status. A bedside electroencephalogram was performed to rule out nonconvulsive status epilepticus, which showed continuous triphasic waves (TWs) with slow background activity. He recovered after 48 hours of stopping PBG, and his repeat electroencephalogram after 72 hours did not show any TWs. We present a rare case of PBG-induced TWs thereby highlighting the extent of the etiologic spectrum of TWs and discussing the literature related to this association.","A 74-year-old man showed nerve damage due to diabetes (a disease involving high blood sugar). The patient had ingested 450 mg of pregabalin (PBG - a nerve pain medication) over a period of 8 hours which was followed by altered mental status. A bedside test for brain activity was performed to rule out nonconvulsive status epilepticus, or a prolonged seizure. The test showed continuous triphasic waves (TWs), which is abnormal body activity, with slow background activity. The patient recovered after 48 hours of stopping PBG. A repeated brain acitivty test after 72 hours did not show any TWs. This study presents a rare case of PBG-induced TWs. This paper highlighting the extent of the etiologic spectrum of TWs, or how TWs promote disease. Additionally, the paper discusses the literature related to this association (or link)." +"Herpes zoster is an acute, painful, herpes skin disease caused by varicella-zoster virus, which may cause viral meningitis. Pregabalin has been shown to be efficacious in the treatment of pain in patients with herpes zoster. However, it has the side effects of neurotoxicity. We describe a 68-year-old female patient with herpes zoster, and she was treated with pregabalin. The patient presented with stuttering and frequent blepharospasm after 3 days of pregabalin treatment. Pregabalin was discontinued, the symptoms of stuttering and frequent blepharospasm completely resolved without any special treatment after one week. In this case, the etiology of stuttering and frequent blepharospasm may be related to pregabalin. Clinicians should be alert to the rare symptoms associated with the use of pregabalin.","Herpes zoster is an acute, painful, herpes skin disease. It is caused by the varicella-zoster virus. The virus may cause viral meningitis or inflammation of the brain and spinal cord. Pregabalin, a nerve pain medication, has been shown to be effecive in the treatment of pain in patients with herpes zoster. However, it can cause neurotoxicity or alteration of the normal acitivty of the nervous system (brain and spinal cord). This study describes a 68-year-old female patient with herpes zoster, and she was treated with pregabalin. The patient presented with stuttering and frequent, uncontrollable movement of the eyelids after 3 days of pregabalin treatment. Pregabalin was no longer given to the patient. The symptoms of stuttering and frequent eyelid movement completely resolved without any special treatment after one week. In this case, the onset of stuttering and frequent eyelid movement may be related to pregabalin. Clinicians should be alert to the rare symptoms associated with the use of pregabalin." +"Herpes zoster is an acute, painful, herpes skin disease caused by varicella-zoster virus, which may cause viral meningitis. Pregabalin has been shown to be efficacious in the treatment of pain in patients with herpes zoster. However, it has the side effects of neurotoxicity. We describe a 68-year-old female patient with herpes zoster, and she was treated with pregabalin. The patient presented with stuttering and frequent blepharospasm after 3 days of pregabalin treatment. Pregabalin was discontinued, the symptoms of stuttering and frequent blepharospasm completely resolved without any special treatment after one week. In this case, the etiology of stuttering and frequent blepharospasm may be related to pregabalin. Clinicians should be alert to the rare symptoms associated with the use of pregabalin.","Herpes zoster (shingles) is an immediate, painful, skin disease involved with reactivating the chickenpox virus. It may cause viral meningitis (inflamation of the brain and spine). Pregabalin, common nerve pain medication, helps treat pain from herpes zoster. However, pregabalin can be toxic to the nervous system. We describe a 68-year-old female with herpes zoster and treated with pregabalin. The patient had stuttering and frequent eye twitching after 3 days of using pregabalin. Pregabalin use was stopped. The symptoms of stuttering and eye twitching completely stopped without any special treatment after one week. In this case, the cause of stuttering and eye twitching may be linked to pregabalin. Clinicians should be alert to the rare symptoms linked with pregabalin use." +"Pregabalin abuse has become an emerging concern; thus, the current study has been designed to study the neurotoxic hazards of prolonged high-dose of pregabalin (akin to that abused by addicts) and to evaluate the effect of alpha tocopherol as a possible ameliorating agent. The current study evaluated the brain neurotransmitters; dopamine, glutamate, and norepinephrine. The study also assessed the expression of the apoptosis-related markers Bax, Bcl2, and caspase 3. Western-blotted analysis of the three major mitogen-activated protein kinases (MAPKs), the c-JUN N-terminal kinase (JNK), the p38 MAPK, and the extracellular signal-regulated kinase (ERK), has also been performed. The study also evaluated oxidative stress via assessment of the cortical tissue levels of reduced glutathione and malondialdehyde and the activity of superoxide dismutase. Histopathological examination and histomorphometric evaluation of the darkly degenerated cortical neurons have also been performed. Pregabalin in high doses (150 mg/kg/day and 300 mg/kg/day) disrupted the ERK/JNK/p38-MAPK signaling, reversed the bax/bcl2 ratio, and induced oxidative stress. It also diminished the release of dopamine, glutamate, and norepinephrine and increased the count of degenerated neurons. Alpha tocopherol treatment significantly attenuated the deleterious effects induced by pregabalin. The role of alpha tocopherol in ameliorating the oxidative stress injury, and apoptosis induced by pregabalin, along with its role in normalizing neurotransmitters, modulating the ERK/JNK/p38-MAPK signaling pathways and improving the histopathological cortical changes, offers alpha tocopherol as a promising adjunctive therapy in patients undergoing prolonged pregabalin therapy as those suffering from prolonged seizures and neuropathies.","Pregabalin, a drug often used to treat nerve damage, abuse has become an emerging concern. The current study aimed to investigate nervous system (brain and spinal cord) damage caused by prolonged high-dose of pregabalin. This dose is similar to that used by addicts. Additionally, the study aimed to evaluate the effect of alpha tocopherol, a type of Vitamin E, as a possible agent to help side effects. The study evaluated the brain neurotransmitters; dopamine, glutamate, and norepinephrine. Neurotransmitters are chemical messengers in the body. The study also assessed (measured) the expression of the cell death-related markers Bax, Bcl2, and caspase 3. Additional tests evaluating three mitogen-activated protein kinases (MAPKs) was completed. MAPKs are involved in biological pathways that direct cell response to mitogens, or things that induce cell division. The study also evaluated oxidative stress which is an imbalance between production and accumulation of harmful oxygen reactive species. Evaluations of the degenerated cortical neurons, nerve cells within the brain, were also preformed. Pregabalin in high doses (150 mg/kg/day and 300 mg/kg/day) disrupted the signaling for cellular processes, reversed ratios of proteins needed for cell cycles, and induced oxidative stress. It also diminished the release of neurotransmitters and increased the count of degenerated neurons. Alpha tocopherol treatment significantly reduced the harmful effects induced by pregabalin. Alpha tocopherol plays a role in reducing negative side effects induced by pregabalin. It also normalizes neurotransmitter levels, positively effects signaling pathways for cell function, and improves cortical (brain) structure changes. These reasons make alpha tocopherol a promising therapeutic option in patients undergoing prolonged pregabalin therapy." +"Background: Antiepileptic drugs (AEDs) can be associated with neurotoxic side effects including cognitive dysfunction, a problem of considerable importance given the usual long-term course of treatment. Pregabalin is a relatively new AED widely used for the treatment of seizures and some types of chronic pain including fibromyalgia. We measured the cognitive effects of 12 weeks of pregabalin in healthy volunteers. Methods: Thirty-two healthy volunteers were randomized in a double-blind parallel study to receive pregabalin or placebo (1:1). Pregabalin was titrated over 8 weeks to 600 mg/d. At baseline, and after 12 weeks of treatment, all subjects underwent cognitive testing. Test-retest changes in all cognitive and subjective measures were Z scored against test-retest regressions previously developed from 90 healthy volunteers. Z scores from the placebo and pregabalin groups were compared using Wilcoxon tests. Results: Thirty subjects completed the study (94%). Three of 6 target cognitive measures (Digit Symbol, Stroop, Controlled Oral Word Association) revealed significant test-retest differences between the pregabalin and placebo groups, all showing negative effects with pregabalin (p < 0.05). These cognitive effects were paralleled by complaints on the Portland Neurotoxicity Scale, a subjective measure of neurotoxicity (p < 0.01). Conclusion: At conventional doses and titration, pregabalin induced mild negative cognitive effects and neurotoxicity complaints in healthy volunteers. These effects are one factor to be considered in the selection and monitoring of chronic AED therapy. Class of Evidence: This study provides Class I evidence that pregabalin 300 mg BID negatively impacts cognition on some tasks in healthy volunteers.","Antiepileptic - or antiseizure - drugs (AEDs) can be associated with neurotoxic (brain damaging) side effects including cognitive dysfunction. Cognitive dysfunction or inability to think properly is a problem of considerable importance given the usual long-term course of treatment. Pregabalin is a relatively new AED widely used for the treatment of seizures and some types of chronic pain, including fibromyalgia - full-body pain. We measured the cognitive effects of 12 weeks of pregabalin administration (use) in healthy volunteers. Thirty-two healthy volunteers were randomly assigned to one of two groups: pregabalin or sham treatment/placebo (1:1). Pregabalin dose was continuously increased over 8 weeks to 600 mg/d. Before treatment and after 12 weeks of treatment, all subjects underwent cognitive testing. Test-retest changes in all cognitive and subjective measures were Z scored against test-retest scores taken from 90 healthy volunteers. Z scores determine how far a data point is away from a dataset average. Z scores from the placebo and pregabalin groups were compared. Thirty subjects completed the study (94%). Three of 6 cognitive measures revealed significant test-retest differences between the pregabalin and placebo groups, all showing negative effects with pregabalin. These cognitive effects were paralleled by complaints on the Portland Neurotoxicity Scale, a subjective measure of neurotoxicity. At standard doses and titration, pregabalin led to mild negative cognitive effects and neurotoxicity complaints in healthy volunteers. These effects are one factor to be considered in the selection and monitoring of chronic AED therapy. This study provides evidence that pregabalin 300 mg negatively impacts cognition on some tasks in healthy volunteers." +"We aimed to investigate the terms used to refer to cognitive and fatigue related side effects and their prevalence in phase III add-on clinical trials of anti-epileptic drugs (AEDs). We extracted data from publicly available FDA documents as well as the published literature. Target drug doses were then calculated as drug loads and divided into three categories (low, average, high). The odds ratio of developing the side effects was calculated for each drug load, and the presence of a dose-response effect was also assessed. We found that the cognitive terms used across trials were very variable, and data on discontinuation rates were limited. Placebo rates for cognitive side effects ranged from 0 to 10.6% while those for fatigue ranged from 2.5 to 37.7%. Keeping in mind the variable placebo rates and terminology, the majority of AEDs exhibited a clear dose response effect and significant odds ratios at high doses except brivaracetam and zonisamide for the cognitive side effects and tiagabine, topiramate, and zonisamide for the fatigue side effects. Due to their clinical relevance and impact on quality of life, new trials should make data related to the prevalence and discontinuation rates of these side effects publicly available. Given the clear dose response effect, physicians should consider aiming for lower drug loads and adjusting doses to improve tolerability.","The aim of this study was to investigate the terms used to refer to cognitive (memory-related) and fatigue related side effects. Additionally, the study aimed to understand the terms' prevalence or frequency in phase III add-on clinical trials of anti-epileptic - or antiseizure - drugs (AEDs). The authors extracted data from publicly available Food and Drug Administration of the United States (FDA) documents as well as the published literature. Target drug doses were then calculated as drug loads and divided into three categories (low, average, high). Odds ratio, or the measure of association between drug intake and side effect development, were calculated for each drug load. The presence of a dose-response effect, or when side effects increase when drug dose increases, was also assessed (measured). The authors found that the cognitive terms used across trials were very variable (all over the place). Data on discontinuation rates (stoppings in side effects) were limited. Placebo (harmless pills) rates for cognitive side effects ranged from 0 to 10.6% while those for fatigue ranged from 2.5 to 37.7%. Most of the AEDs exhibited a clear dose-response effect and significant odds ratios for developing side effects at high doses. Due to their clinical (medical) relevance and impact on quality of life, new trials should make data related to the prevalence and discontinuation rates of these side effects publicly available. Due to the clear dose response effect, doctors should consider using lower drug loads and adjusting doses to improve tolerability (or ability to take the drug)." +"We aimed to investigate the terms used to refer to cognitive and fatigue related side effects and their prevalence in phase III add-on clinical trials of anti-epileptic drugs (AEDs). We extracted data from publicly available FDA documents as well as the published literature. Target drug doses were then calculated as drug loads and divided into three categories (low, average, high). The odds ratio of developing the side effects was calculated for each drug load, and the presence of a dose-response effect was also assessed. We found that the cognitive terms used across trials were very variable, and data on discontinuation rates were limited. Placebo rates for cognitive side effects ranged from 0 to 10.6% while those for fatigue ranged from 2.5 to 37.7%. Keeping in mind the variable placebo rates and terminology, the majority of AEDs exhibited a clear dose response effect and significant odds ratios at high doses except brivaracetam and zonisamide for the cognitive side effects and tiagabine, topiramate, and zonisamide for the fatigue side effects. Due to their clinical relevance and impact on quality of life, new trials should make data related to the prevalence and discontinuation rates of these side effects publicly available. Given the clear dose response effect, physicians should consider aiming for lower drug loads and adjusting doses to improve tolerability.","We explored the terms used to refer to the mental and tiredness related side effects and their frequency in clinical trials of anti-seizure or anti-epileptic drugs (AEDs). We took data from publicly available government documents and from public literature. Target drug doses were calculated as drug amounts and divided into low, average, and high. We calculated the chances of developing side effects for each drug amount and if there was a link between the amount of dose and the bodily response. We found that mental terms used across trials varied. Data on drug stoppage rates were limited. Dummy treatment rates for mental side effects ranged from 0 to 10.6%. The same rates for fatigue ranged from 2.5 to 37.7%. With the inconsistent dummy treatment rates and terminology in mind, the majority of AEDs showed a link between dose amount and bodily response. Except for the drugs brivaracetam and zonisamide, they also showed increased chance of mental side effects at high doses. Except for the drugs tiagabine, topiramate, and zonisamide, they also showed increased chance of fatigue side effects at high doses. Due to their health-related relevance and impact on life, new trials should make data about the amount and stoppage rates of these side effects publicly available. Given the clear link between dose amount and bodily response, physicians should consider lower drug amount to improve tolerability." +"Aim: Randomized Phase I study examining the effects of gabapentinoids gabapentin, pregabalin and gastroretentive gabapentin on simulated driving performance, sedation and cognitive function in healthy volunteers (n = 32). Methods: Driving attentiveness, sleepiness and cognition were evaluated prior to subjects receiving study doses. Blood samples were collected during each treatment. Results: Subjects receiving gastroretentive gabapentin showed less change in variation in lateral lane position (p = 0.0275), less tremor (p = 0.0304) and fewer vision disturbances compared with gabapentin (p = 0.0177). Statistically significant decrease in One Card Learning Test performance was observed after treatment with gastroretentive gabapentin. Conclusion: Gastroretentive gabapentin demonstrated reduced driving impairment and lower scores on key neurotoxicity measures. Further studies in patients with postherpetic neuralgia are needed.","A study investigated the effects of gabapentinoids, drugs often used to prevent and control seizures. The tested drugs include gabapentin, pregabalin and gastroretentive gabapentin. The study evaluated the effects of the drugs on simulated driving performance, sedation (relaxation) and cognitive function (thinking ability). The study was conducted in 32 healthy volunteers. Driving attentiveness, sleepiness, and cognition were evaluated prior to treatment within participants. Blood samples were collected during each treatment. Subjects receiving gastroretentive gabapentin showed less change in variation (differences) in lateral (side) lane position, less tremors (shaking), and fewer vision disturbances compared with gabapentin. Statistically significant decreases in One Card Learning Test (a test used to test short term memory) performance was observed after treatment with gastroretentive gabapentin. The study concluded gastroretentive gabapentin reduced driving impairment and showed lower scores on key neurotoxicity (abnormal nervous system function) measures. Further studies in patients with postherpetic neuralgia (nerve-related pain from shingles) are needed." +"Mask wearing is now ubiquitous because of the COVID-19 pandemic and has given rise to medical device-related pressure injuries in persons at risk of skin breakdown. The ear has unique anatomy that is particularly susceptible to injury from pressure. In this time of mandatory personal protective equipment requirements in healthcare facilities, protection and assessment of skin in the vulnerable postauricular area are needed. This article presents a case report of a pressure injury on the ear, reviews the anatomy of the ear, and provides strategies for assessment and treatment of pressure injuries in this often overlooked anatomic region. Treating Mask-Related Pressure Injury: Begin by removing the offending device. If the patient continues to require a mask, provide a mask or �ear saver� mask strap that secures around the head or back of the neck rather than the ear, although again, this does not remove the need for continued skin assessment to areas subjected to pressure and friction. Infection should be considered and ruled out. Local cellulitis is characterized by warmth, redness, pain, and swelling. Presence of purulent discharge might indicate deeper infection and/or abscess. If infection is present, treatment should be initiated with topical and/or systemic antibiotics, depending on culture and severity. Removing hair in the area may be helpful, because it eliminates foreign body intrusion into the wound base, as well as a source of contamination, consistent with the principles of wound bed preparation. It is important to note that a healed wound may not have the same physical strength as normal tissue and may be prone to recurrence, also known as recidivism.","Mark wearing is now present everywhere. This is because of the COVID-19 pandemic (a global, viral, respiratory illness). Mask wearing has increased medical device-related pressure injuries, or skin sores, in persons that have higher chances of their skin breaking down. The ear has a unique structure that is more vulnerable to injury from pressure. Right now is a time of mandatory personal protective equipment requirements in healthcare facilities. Continual wear of personal protective equipment requires care for and assessment (evaluation) of the skin of the ear. This study presents a case of a pressure injury on the ear. This study will also review the anatomy of the ear and provide strategies for assessment and treatment of pressure injuries of the ear. When treating a mask-related pressure injury, you first begin by removing the mask. If the patient continues to require a mask, provide a mask or �ear saver� mask strap that secures around the head or back of the neck rather than the ear. However, providing an ""ear saver"" does not remove the need for continued monitoring of the skin areas that undergo continued pressure. Infection should be considered and ruled out. Local cellulitis (bacterial skin infection) is characterized by warmth, redness, pain, and swelling. Presence of pus might indicate a deeper infection and/or abscess (swollen area with pus). If there is signs of infection, treatment should be initiated with topical treatment (applied directly to the skin) and/or systemic antibiotics (drugs that affect the whole body). Treatment method chosen will depend on the skin health and severity of infection. Removing hair in the area may be helpful. This may be helpful as it eliminates things that may stray into the wound. Additionally, hair is a source of contamination. It is important to understand that a healed wound may not have the same physical strength as normal tissue. Additionally, healed skin may be vulnerable to reoccurring injuries, also known as recidivism." +"Background: The biodegradable and biocompatible nature of pectin-based films is of particular interest in wound dressing applications, due to its non-toxicity, pH-sensitivity and gelling activity. An approach to improve the mechanical properties, the release profile of bioactive compounds as well as the performance in wet environments of pectin-based films is mixing with other biopolymers. Objective: To prepare hydrocolloid films based on crosslinked pectin / starch blend loaded with bioactive extracts from leaves of G. tinctoria and U. molinae with controlled release of bioactive compounds and healing property. Methods: The hydrocolloid films were characterized by FTIR, SEM, and TGA-FTIR techniques and their tensile properties, water uptake, and polyphenolic release profile in aqueous media were evaluated. The dermal anti inflammatory activity of the hydrocolloid films was assessed by the mouse ear inflammation test. The wound healing property of the loaded hydrocolloid films was explored in a rat model and in a clinical trial (sacrum pressure ulcer). Results: The films showed an adequate water-uptake capacity between 100-160%. The release of active compounds from the hydrocolloid films followed the Korsmeyer-Peppas equation. The mechanical properties of hydrocolloid films were not affected by the plant extracts within the concentration range used. The incorporation of the bioactive extracts in the polysaccharide films inhibited the topical edematous response by about 50%. The topical application of the loaded hydrocolloid film on the pressure ulcer is completely closed after 17 days without showing any adverse reaction. Conclusion: A novel hydrocolloid matrix was produced from crosslinked starch-pectin, which exhibited suitable chemical-physical properties to be used as a carrier of plant extracts with wound healing properties.","Pectin-based films are wrapping that is made from pectin, a substance extracted from ripe fruits. Pectin-based films are biodegradable and biocompatible. Additionally, the films are non-toxic, are pH (acid-base) sensitive, and have gelling activity. These qualities make the films of interest in wound dressing. In order to improve how the films responsd to stress and strain, specifically how the material holds up when wet, other biopolymers could be mixed with the pectin-based films. Biopolymers are substances that are found within living organisms, just like pectin is found in fruit. The aim of this study was the prepare hydrocolloid (gel-forming) films using a pectin and starch blend with extracts from two different leaves. The film was made to have a controlled release of bioactive compounds and healing properties. Bioactive compounds are components of food that influence biological or cellular activity within humans or animals that eat them. The hydrocolloid films were tested for their tensile strength (resistance to tension breakage), water uptake, and polyphenolic release profile in wet environments. Polyphenols are compounds with various biological properties, including anti-inflammatory (anti-swelling and -redness from an infection) and antioxidant. The skin anti-inflammatory activity of the hydrocolloid films was assessed (measured) by a test evaluating inflammation on a mouse ear. The wound healing property of the hydrocolloid films was explored in a rat model. The wound healing property was also explored in a human clinical trial looking at lower back pressure ulcers (skin sores). The films showed an adequate water-uptake capacity between 100-160%. The release of active compounds from the hydrocolloid films followed the Korsmeyer-Peppas equation, which implies that release of healing properties was controlled over time. The mechanical properties of the hydrocolloid films, or how they respond to stress, were not affected by the plant extracts. Addition of the same bioactive extracts in a carbohydrate-based film significantly decreased the topical edematous response or the accumulation of watery fluid. Applying the loaded hydrocolloid film on the pressure ulcer completely closed the wound after 17 days without any negative side effects. The study concluded that a novel (new) hydrocolloid mixture was produced from starch and pectin. This mixture showed suitable chemical-physical properties to act as a carrier of plant extracts with wound healing properties." +"Background: The biodegradable and biocompatible nature of pectin-based films is of particular interest in wound dressing applications, due to its non-toxicity, pH-sensitivity and gelling activity. An approach to improve the mechanical properties, the release profile of bioactive compounds as well as the performance in wet environments of pectin-based films is mixing with other biopolymers. Objective: To prepare hydrocolloid films based on crosslinked pectin / starch blend loaded with bioactive extracts from leaves of G. tinctoria and U. molinae with controlled release of bioactive compounds and healing property. Methods: The hydrocolloid films were characterized by FTIR, SEM, and TGA-FTIR techniques and their tensile properties, water uptake, and polyphenolic release profile in aqueous media were evaluated. The dermal anti inflammatory activity of the hydrocolloid films was assessed by the mouse ear inflammation test. The wound healing property of the loaded hydrocolloid films was explored in a rat model and in a clinical trial (sacrum pressure ulcer). Results: The films showed an adequate water-uptake capacity between 100-160%. The release of active compounds from the hydrocolloid films followed the Korsmeyer-Peppas equation. The mechanical properties of hydrocolloid films were not affected by the plant extracts within the concentration range used. The incorporation of the bioactive extracts in the polysaccharide films inhibited the topical edematous response by about 50%. The topical application of the loaded hydrocolloid film on the pressure ulcer is completely closed after 17 days without showing any adverse reaction. Conclusion: A novel hydrocolloid matrix was produced from crosslinked starch-pectin, which exhibited suitable chemical-physical properties to be used as a carrier of plant extracts with wound healing properties.","The recycability of pectin-based films (thin strips of plant-based fiber) is of interest in wound bandaging, due to its non-toxicity, acid-sensitivity, and gel-like nature. One idea to improve the function, bioactive composition, and performance when wet of pectin-based films is mixing it with other biological molecules. Our objective is to create waterproof films based on a pectin/starch blend with specific plant extracts that have controlled release of bioactive and healing substances. The molecular composition of the waterproof films were measured with specific tools. We also measured the tension strength, water uptake, and bioactive molecules released in water. The skin-related anti-inflammatory activity of the waterproof films was measured by testing its anti-inflammatory eactivity on an inflammed mouse ear. We tested the healing effects of the active waterproof films with rats and human bedsores. The films showed an acceptable water-uptake capacity between 100-160%. The release of biological compounds from the waterproof films followed a standard drug-release trend. The function of the waterproof films was not affected by the plant extracts within the amounts used. Adding plant extracts into the films blocked the skin swelling by around 50%. The application of the active waterproof film on the surface of the bedsore is closed after 17 days without any side effects. A new waterproof film was created from a starch-pectin blend, with suitable chemical-physical properties to carry plant extracts with wound healing effects." +"The use of wound dressings that are based on the principles of moist wound healing has recently changed the management of pressure ulcers. These products may improve healing rates but also offer improved comfort to the patient, reduced dressing time and improved cosmesis. However, healing is unlikely to be achieved unless the factors that contribute to ulcer formation are addressed. Principles of management include the elimination or reduction of pressure and other contributing factors, treatment of infection, appropriate wound management, involvement and education of the patient and caregivers, and maintenance of healed tissue. It is estimated that 95 percent of all pressure ulcers are preventable. Prevention rather than mere treatment of established ulcers remains a top priority in the effort to reduce the incidence of this common, complex and difficult problem. Use of assessment tools that quantify the primary risk factors for the development of pressure ulcers is helpful in predicting and preventing compromise of tissue.","The use of wound dressings based on moist wound healing principles has recently changed how pressure ulcers (skin sores) are treated. Moist wound healing is when an injury is kept damp to prevent drying out. These products may improve healing rates. They may also offer improved comfort to the patient, reduced dressing time, and improved wound appearance. However, healing is unlikely to occur unless the reasons the ulcer was formed are addressed. There are several principles of ulcer management or healing. These principles include: eliminating or reducing pressure and other contributing factors, treating infection, appropriate wound management, involvement and education of the patient and caregivers, and maintenance of healed tissue. It is estimated that 95% of all pressure ulcers are preventable. Preventing ulcers rather than treating ulcers is a priority in the effort to reduce the incidence (frequency) of this common, complex, and difficult problem. Use of assessment (measurement) tools that identify the main reasons pressure ulcers are caused is helpful to predict and prevent injuries to the skin." +"Pressure ulcers are a common and serious problem predominately among elderly persons who are confined to bed or chair. Additional factors associated with pressure ulcer development include cerebrovascular accident, impaired nutritional intake, urinary or fecal incontinence, hypoalbuminemia, and previous fracture. Implementation of preventive measures, such as an in-depth assessment for mobility, a pressure-relieving device combined with adequate repositioning, and thorough evaluation for nutritional status and urinary incontinence, significantly reduce pressure ulcer incidence. If the pressure ulcer is a partial thickness (stage II) wound, the causative factors are probably friction or moisture. If the ulcer is full thickness (stage III and IV), it is secondary to pressure or shearing forces. The development of wound infection is the most common complication in the management approach. Osteomyelitis is not an uncommon occurrence and must be initially ruled out in all full thickness pressure ulcers. Surgical debridement of necrotic tissue is necessary prior to further treatment and assessments. Antibiotic therapy is indicated only upon evidence of infection (cellulitis, osteomyelitis, leukocytosis, bandemia, or fever). Topical pharmacologic agents may be used to prevent or treat infection but must be carefully controlled to avoid such adverse effects as toxicity to the wound, allergic reaction, and development of resistant pathogens. Proper use of occlusive dressings increase patient comfort, enhance healing, decrease the possibility of infection, save time, and reduce costs. A patient presenting an ulcer that fails to improve or, because of its size, will take a great deal of time to heal should be evaluated for surgical closure.","Pressure ulcers (skin sores) are a common and serious problem. Pressure ulcers mainly occur among elderly persons who are confined to bed or chair. Additional reasons pressure ulcers develop include cerebrovascular accident (damage to the brain and its blood vessels) or impaired nutritional intake (poor diet). Additionally, reasons include urinary or fecal incontinence (lack of control on bladder or bowels), hypoalbuminemia (low blood albumin - a protein in the blood), and previous fracture. Implementation of preventive measures significantly reduce pressure ulcer incidence (frequency). The measures include in-depth assessment of mobility, relieving pressure on the injured area, and evaluating nutritional status and urinary incontinence. If the pressure ulcer is a partial thickness (stage II) wound, the factors causing the injury are probably friction or moisture. If the ulcer is full thickness (stage III and IV), it is secondary to (caused by) pressure or shearing forces. The wound becoming infected is the most common complication in the management approach. Osteomyelitis, or a bone infection, is not an uncommon occurrence. It must be ruled out in all full thickness pressure ulcers. Removal of dead tissue by surgery is necessary prior to further treatment and assessments (measurements). Taking antibiotics (which fight bacteria) is used if there is evidence of infection. Topical (applied on skin) medicines may be used to prevent or treat infection. However, these medicines must be used carefully to avoid adverse effects (bad side effects) like wound toxicity, allergic reaction, and development of resistant pathogens, or harmful foreign organisms. Proper use of air- and water-tight medical wrappings increase patient comfort, enhance healing, decrease the possibility of infection, save time, and reduce costs. A patient presenting an ulcer that does not improve or, because of its size, will take a great deal of time to heal should be evaluated for surgical closure." +"A pressure ulcer is a localized injury to the skin or underlying tissue, usually over a bony prominence, as a result of unrelieved pressure. Predisposing factors are classified as intrinsic (e.g., limited mobility, poor nutrition, comorbidities, aging skin) or extrinsic (e.g., pressure, friction, shear, moisture). Prevention includes identifying at-risk persons and implementing specific prevention measures, such as following a patient repositioning schedule; keeping the head of the bed at the lowest safe elevation to prevent shear; using pressure-reducing surfaces; and assessing nutrition and providing supplementation, if needed. When an ulcer occurs, documentation of each ulcer (i.e., size, location, eschar and granulation tissue, exudate, odor, sinus tracts, undermining, and infection) and appropriate staging (I through IV) are essential to the wound assessment. Treatment involves management of local and distant infections, removal of necrotic tissue, maintenance of a moist environment for wound healing, and possibly surgery. Debridement is indicated when necrotic tissue is present. Urgent sharp debridement should be performed if advancing cellulitis or sepsis occurs. Mechanical, enzymatic, and autolytic debridement methods are nonurgent treatments. Wound cleansing, preferably with normal saline and appropriate dressings, is a mainstay of treatment for clean ulcers and after debridement. Bacterial load can be managed with cleansing. Topical antibiotics should be considered if there is no improvement in healing after 14 days. Systemic antibiotics are used in patients with advancing cellulitis, osteomyelitis, or systemic infection.","A pressure ulcer is an injury to the skin or underlying tissue, usually over a bony portion of the body, caused by unrelieved pressure. Factors that make someone more likely to have a pressure ulcer are classified as intrinsic (internal factors) or extrinsic (external factors). Intrinsic factors include limited mobility, poor nutrition, comorbidities, or aging skin. Extrinsic factors include pressure, friction, shear (vertical force), or moisture. There are several preventative protocols for pressure ulcers that can be used. These protocols include identifying at-risk persons and implementing specific prevention measures. Preventative measures include repositioning patients on a schedule, keeping hospital beds at a low and safe elevation to prevent shear, using pressure-reducing surfaces, and assessing (measuring) nutrition and providing supplementation. When an ulcer occurs, wound assessment is needed. When assessing each ulcer, there are several factors that need to be identified. These include ulcer size, location, dead or irregular tissue, discharge, odor, sinus tracts (channels in the skin), wound edge erosion or edge removal, infection, and appropriate staging (I through IV). Treatment involves managing local and spreading infections, removal of dead tissue, maintenance of a moist environment for wound healing, and possibly surgery. Debridement, or removal of damaged tissue from a wound, is indicated when necrotic or dead tissue is present. Urgent sharp debridement should be performed if advancing skin or bleed infection occurs. Mechanical (surgery), enzymatic (chemical agents), and autolytic debridement (body's natural defense system) methods are nonurgent treatments. Wound cleansing, preferably with normal saline (salt water) and appropriate dressings, is common for treatment for clean ulcers and after removal of damaged skin. Bacterial load, or the amount of bacteria within the body, can be managed with cleansing. Topical antibiotics are bacterial-fighting medicines applied to the skin. They should be considered if there is no improvement in healing after 14 days. Systemic antibiotics are medicines normally taken in pill form that effects the whole body. These are used in patients with advancing deep skin infection, bone infection, or whole body infection." +"A pressure ulcer is a localized injury to the skin or underlying tissue, usually over a bony prominence, as a result of unrelieved pressure. Predisposing factors are classified as intrinsic (e.g., limited mobility, poor nutrition, comorbidities, aging skin) or extrinsic (e.g., pressure, friction, shear, moisture). Prevention includes identifying at-risk persons and implementing specific prevention measures, such as following a patient repositioning schedule; keeping the head of the bed at the lowest safe elevation to prevent shear; using pressure-reducing surfaces; and assessing nutrition and providing supplementation, if needed. When an ulcer occurs, documentation of each ulcer (i.e., size, location, eschar and granulation tissue, exudate, odor, sinus tracts, undermining, and infection) and appropriate staging (I through IV) are essential to the wound assessment. Treatment involves management of local and distant infections, removal of necrotic tissue, maintenance of a moist environment for wound healing, and possibly surgery. Debridement is indicated when necrotic tissue is present. Urgent sharp debridement should be performed if advancing cellulitis or sepsis occurs. Mechanical, enzymatic, and autolytic debridement methods are nonurgent treatments. Wound cleansing, preferably with normal saline and appropriate dressings, is a mainstay of treatment for clean ulcers and after debridement. Bacterial load can be managed with cleansing. Topical antibiotics should be considered if there is no improvement in healing after 14 days. Systemic antibiotics are used in patients with advancing cellulitis, osteomyelitis, or systemic infection.","A pressure ulcer (bedsore) is a area-limited injury to the skin and neaby body parts, usually over a bone, due to unrelieved pressure. Risk factors can be intrinsic (e.g., limited movement, poor diet, other diseases, aging skin) or extrinsic (e.g, pressure, friction, strain, moisure). Prevention includes identifying at-risk people and applying preventative measures, like regularly moving the patient's position, keeping the bed head low to prevent strain, using pressure-reducing surfaces, evaluating diet and giving diet supplemets, if needed. When an ulcer occurs, examining it (i.e., size, location, type of affected tissue, leaking fluid, odor, wound openings, wear and tea, and infection) and the severity of the ulcer are essential to wound assessment. Treatment includes managing nearby and far-away infetions, removing dead body tissue, maintaining a moist environment for wound healing, and even surgery. Removing damaged body tissue (debridement) is needed when dead tissue is present. Urgent debridement should be done if bacterial skin infections develop. Physical removal, use of a chemical topical, and natural forms of debridement are nonurgent treatments. Wound cleaning, preferably with salt water and appropriate bandages, are common treatment for clean bedsores and after removing damaged body tissue. Bacteria can be managed with cleaning. Antibiotics applied skin-level should be considered if there is no healing after 14 days. Full-body antibiotics are used in those with developing skin infections, inflammation, or full-body infection." +"Pressure ulcers represent complex wounds that are difficult to prevent or manage. Guidelines for prevention include identifying patients at risk, reducing the effect of pressure, friction, shear forces, and assessing co-morbidities such as nutritional status. Management should follow eight treatment strategies including accurately assessing the ulcer, relieving pressure, assessing pain and nutritional status, maintaining a moist wound environment, encouraging granulation and epithelial tissue formation, evaluating the need for debridement, and controlling infection.","Pressure ulcers, or bedsores, are injuries to the skin and underlying tissues caused by long periods of pressure on the skin. These wounds are complex and are difficult to prevent or manage. Advice on how to prevent getting pressure ulcers include identifying patients at risk, reducing pressure, friction, shear forces, and assessing (measuring) compounding factors such as nutritional status. Management should follow eight treatment strategies. These include accurately assessing the ulcer, relieving pressure, assessing pain and nutritional status, maintaining a damp wound environment, encouraging skin healing, evaluating the need for damaged tissue removal, and controlling infection." +"Pressure injury (PI) corresponds to a skin damage of ischemic aetiology that affects the integrity of the skin and is produced by prolonged pressure or friction between a hard internal and external surface. Treatment can be challenging when there is no resolution with usual care. The use of autologous platelet-rich plasma (APRP) gel arises as a therapeutic possibility in the presence of chronic pressure injuries. The case of a patient with chronic PI who has been treated with APRP is presented, achieving resolution of the lesion.","Pressure injury (PI) is used to describe skin damage not caused by underlying diseases. PI affects strength of the skin. PI is produced by prolonged pressure or friction between a hard internal and external surface. Treatment can be challenging when there is no solution with usual clinical care. The use of autologous platelet-rich plasma (APRP) gel is a possible therapeutic (medical) option for chronic pressure injuries. APRP uses injections of the patient's own platelets (blood cells) to increase healing rates. The case of a patient with chronic PI who has been treated with APRP is presented, achieving resolution (healing) of the lesion (wound)." +"Wound pressure injuries have been given various names over the last several years. In the past, they were referred to as pressure ulcers, decubitus ulcers, or bed sores; and now they are most commonly termed ""pressure injuries."" Pressure injuries are defined as the breakdown of skin integrity due to some types of unrelieved pressure. This can be from a bony area on the body coming into contact with an external surface which leads to pressure injury. These wounds represent the destruction of normal structure and function of the skin and soft tissue through a variety of mechanisms and etiologies. The wound healing process is affected by various factors including infection, the presence of chronic diseases like diabetes, aging, nutritional deficiency like vitamin C, medications like steroids, and low perfusion of oxygen and blood flow to the wound in cases of hypoxia and cold temperature. Pressure ulcers result from long periods of repeated pressure applied to the skin, soft tissue, muscle, and bone. In pressure ulcers, the external pressure exceeds capillary closing pressure.","Wound pressure injuries (skin sores) have been given various names over the last several years. In the past, they were referred to as pressure ulcers, decubitus ulcers, or bed sores. Now, they are most commonly referred to as ""pressure injuries."" Pressure injuries are the breakdown of skin integrity due to some types of unrelieved pressure. Pressure injuries can come from a bony area on the body coming into contact with an external surface. Pressure injuries represent the breakdown of normal structure and function of the skin and soft tissue. Soft tissue includes muscles, fat, blood vessels, nerves, tendons, and tissues surrounding bones and joints. Pressure injuries are formed through several different mechanisms and causes. The wound healing process is affected by various factors. These factors include infection, the presence of chronic diseases like diabetes, aging, nutritional deficiency like vitamin C, medications like steroids. Additionally, the would healing process can be affected by low rates of oxygen and blood flow to the wound in cases of hypoxia (low oxygen in tissues) and cold temperature. Pressure ulcers result from long periods of repeated pressure applied to the skin, soft tissue, muscle, and bone. In pressure ulcers, the external pressure exceeds capillary closing pressure. Capillary closing pressure is the minimal amount of pressure needed to collapse a blood vessel. When external pressure is greater than the capillary closing pressure, blood flow is impaired for an extended period of time." +"Wound pressure injuries have been given various names over the last several years. In the past, they were referred to as pressure ulcers, decubitus ulcers, or bed sores; and now they are most commonly termed ""pressure injuries."" Pressure injuries are defined as the breakdown of skin integrity due to some types of unrelieved pressure. This can be from a bony area on the body coming into contact with an external surface which leads to pressure injury. These wounds represent the destruction of normal structure and function of the skin and soft tissue through a variety of mechanisms and etiologies. The wound healing process is affected by various factors including infection, the presence of chronic diseases like diabetes, aging, nutritional deficiency like vitamin C, medications like steroids, and low perfusion of oxygen and blood flow to the wound in cases of hypoxia and cold temperature. Pressure ulcers result from long periods of repeated pressure applied to the skin, soft tissue, muscle, and bone. In pressure ulcers, the external pressure exceeds capillary closing pressure.","Wound pressure injuries have various names over the last few years. In the past, they were known as pressure ulvers, decubitus ulcers, or bed sores. Now, they are known as ""pressure injuries"". Pressure injuries are the breakdown of skin due to some forms of constant pressure. This can be from a bone coming in contact with an external surface like skin which leads to pressure injury. These wounds are the destriction of normal structure and function of skin and nearby tissue through various physical processes and causes. Healing the wound is affected by factors like infection, other long-lasting diseases like diabetes, aging, nutrient shortages like Vitamin C, medications like steroids, and low blood flow to the wound during periods of reduced oxygen and cold temperature. Pressure ulcers come from extended, repeated pressure to the skin, nearby tissue, muscle, and bone. In pressure ulcers, the outside pressure is greater than blood vessel closing pressure." +"Background: Pressure ulcers, also known as bed sores, pressure sores or decubitus ulcers develop as a result of a localised injury to the skin or underlying tissue, or both. The ulcers usually arise over a bony prominence, and are recognised as a common medical problem affecting people confined to a bed or wheelchair for long periods of time. Anabolic steroids are used as off-label drugs (drugs which are used without regulatory approval) and have been used as adjuvants to usual treatment with dressings, debridement, nutritional supplements, systemic antibiotics and antiseptics, which are considered to be supportive in healing of pressure ulcers. Anabolic steroids are considered because of their ability to stimulate protein synthesis and build muscle mass. Comprehensive evidence is required to facilitate decision making, regarding the benefits and harms of using anabolic steroids. Objectives: To assess the effects of anabolic steroids for treating pressure ulcers. Main results: The review contains only one trial with a total of 212 participants, all with spinal cord injury and open pressure ulcers classed as stage III and IV. The participants were mainly male (98.2%, 106/108) with a mean age of 58.4 (standard deviation 10.4) years in the oxandrolone group and were all male (100%, 104/104) with a mean age of 57.3 (standard deviation 11.6) years in the placebo group. This trial compared oxandrolone (20 mg/day, administered orally) with a dose of placebo (an inactive substance consisting of 98% starch and 2% magnesium stearate) and reported data on complete healing of ulcers and adverse events. There was very low-certainty evidence on the relative effect of oxandrolone on complete ulcer healing at the end of a 24-week treatment period (risk ratio RR) 0.81, 95% confidence interval (CI) 0.52 to 1.26) (downgraded twice for imprecision due to an extremely wide 95% CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients). Thus, we are uncertain whether oxandrolone improves or reduces the complete healing of pressure ulcers, as we assessed the certainty of the evidence as very low. There was low-certainty evidence on the risk of non-serious adverse events reported in participants treated with oxandrolone compared with placebo (RR 3.85, 95% CI 1.12 to 13.26) (downgraded once for imprecision and once for indirectness, as the participants were mostly male spinal cord injury patients). Thus, the treatment with oxandrolone may increase the risk of non-serious adverse events reported in participants. There was very low-certainty evidence on the risk of serious adverse events reported in participants treated with oxandrolone compared with placebo (RR 0.54, 95% CI 0.25 to 1.17) (downgraded twice for imprecision due to an extremely wide 95% CI, which spanned both benefit and harm, and once for indirectness, as the participants were mostly male spinal cord injury patients). Of the five serious adverse events reported in the oxandrolone-treated group, none were classed by the trial teams as being related to treatment. We are uncertain whether oxandrolone increases or decreases the risk of serious adverse events as we assessed the certainty of the evidence as very low. Secondary outcomes such as pain, length of hospital stay, change in wound size or wound surface area, incidence of different type of infection, cost of treatment and quality of life were not reported in the included trial. Overall the evidence in this study was of very low quality (downgraded for imprecision and indirectness). This trial stopped early when the futility analysis (interim analysis) in the opinion of the study authors showed that oxandrolone had no benefit over placebo for improving ulcer healing. Authors' conclusions: There is no high quality evidence to support the use of anabolic steroids in treating pressure ulcers. Further well-designed, multicenter trials, at low risk of bias, are necessary to assess the effect of anabolic steroids on treating pressure ulcers, but careful consideration of the current trial and its early termination are required when planning future research.","Pressure ulcers, also known as bed sores, pressure sores, or decubitus ulcers develop because of a localized (regionalized) injury to the skin or underlying tissue, or both. The ulcers usually occur in a bony area of the body. Ulcers are recognized as a common medical problem affecting people confined to a bed or wheelchair for long periods of time. Anabolic (muscle building) steroids are used as off-label drugs. This means they are often used without doctor approval. They have been used to increase healing alongside usual treatment with dressings, debridement (removal of damaged tissue from a wound), nutritional supplements, systemic antibiotics (full-body medicines that fight infection) and antiseptics (antimicrobial skin medication). All of these measures are considered to be supportive in pressure ulcer healing. Anabolic steroids are considered because of their ability to encourage protein synthesis and build muscle mass. Thorough evidence is required to encourage decision making in regards to the benefits and harms of using anabolic steroids. The goal of this study is to evaluate the effects of anabolic steroids for treating pressure ulcers. The review contains a medical trial of 212 participants, all with spinal cord injury and open pressure ulcers classed as stage III and IV. The participants were mainly male with an average age of 58.4 years in the group receiving oxandrolone (synthetic steroid) treatment. Participants were all male with an average age of 57.3 years in the placebo group. Placebos are harmless pills used as control treatments. This trial compared oxandrolone (20 mg/day, administered orally) with placebo treatment. This study reported data on complete healing of ulcers and adverse side effects. There was very low-certainty evidence on the relative effect of oxandrolone on complete ulcer healing at the end of a 24-week treatment period. Therefore, it is unclear if oxandrolone improves or reduces the complete healing of pressure ulcers. There was low-certainty evidence on the risk of non-serious adverse events reported in participants treated with oxandrolone compared with placebo. Treatment with oxandrolone may increase the risk of non-serious negative side events reported in participants. There was very low-certainty evidence on the risk of serious adverse events reported in participants treated with oxandrolone compared with placebo. Five serious adverse events were reported in the oxandrolone-treated group. However, none were classed by the trial teams as being related to treatment. It is unclear if oxandrolone increases or decreases the risk of serious adverse events. Secondary outcomes were not reported in the included trial. Secondary outcomes include pain, length of hospital stay, change in wound size or wound surface area, incidence of different type of infection, cost of treatment, and quality of life. Overall the evidence in this study was of very low quality. This is due to lack of precision (low confidence in results) and indirectness (only males were evaluated) in data. The trial was stopped early when deeper investigation showed that oxandrolone had no benefit over the placebo for improving ulcer healing. The authors concluded there is no high quality evidence to support the use of anabolic steroids in treating pressure ulcers. Further well-designed, low-bias trials in several different facilities are needed to assess (measure) the effect of anabolic steroids on treating pressure ulcers. However, careful consideration of the current trial and its early termination are required when planning future research." +"Background: Pressure ulcers, also known as pressure injuries and bed sores, are localised areas of injury to the skin or underlying tissues, or both. Dressings made from a variety of materials, including foam, are used to treat pressure ulcers. An evidence-based overview of dressings for pressure ulcers is needed to enable informed decision-making on dressing use. This review is part of a suite of Cochrane Reviews investigating the use of dressings in the treatment of pressure ulcers. Each review will focus on a particular dressing type. Objectives: To assess the clinical and cost effectiveness of foam wound dressings for healing pressure ulcers in people with an existing pressure ulcer in any care setting. Main results: We included nine trials with a total of 483 participants, all of whom were adults (59 years or older) with an existing pressure ulcer Category/Stage II or above. All trials had two arms, which compared foam dressings with other dressings for treating pressure ulcers. The certainty of evidence ranged from low to very low due to various combinations of selection, performance, attrition, detection and reporting bias, and imprecision due to small sample sizes and wide confidence intervals. We had very little confidence in the estimate of effect of included studies. Where a foam dressing was compared with another foam dressing, we established that the true effect was likely to be substantially less than the study's estimated effect. We present data for four comparisons. One trial compared a silicone foam dressing with another (hydropolymer) foam dressing (38 participants), with an eight-week (short-term) follow-up. It was uncertain whether alternate types of foam dressing affected the incidence of healed pressure ulcers (RR 0.89, 95% CI 0.45 to 1.75) or adverse events (RR 0.37, 95% CI 0.04 to 3.25), as the certainty of evidence was very low, downgraded for serious limitations in study design and very serious imprecision. Four trials with a median sample size of 20 participants (230 participants), compared foam dressings with hydrocolloid dressings for eight weeks or less (short-term). It was uncertain whether foam dressings affected the probability of healing in comparison to hydrocolloid dressings over a short follow-up period in three trials (RR 0.85, 95% CI 0.54 to 1.34), very low-certainty evidence, downgraded for very serious study limitations and serious imprecision. It was uncertain if there was a difference in risk of adverse events between groups (RR 0.88, 95% CI 0.37 to 2.11), very low-certainty evidence, downgraded for serious study limitations and very serious imprecision. Reduction in ulcer size, patient satisfaction/acceptability, pain and cost effectiveness data were also reported but we assessed the evidence as being of very low certainty. One trial (34 participants), compared foam and hydrogel dressings over an eight-week (short-term) follow-up. It was uncertain if the foam dressing affected the probability of healing (RR 1.00, 95% CI 0.78 to 1.28), time to complete healing (MD 5.67 days 95% CI -4.03 to 15.37), adverse events (RR 0.33, 95% CI 0.01 to 7.65) or reduction in ulcer size (MD 0.30 cm2 per day, 95% CI -0.15 to 0.75), as the certainty of the evidence was very low, downgraded for serious study limitations and very serious imprecision. The remaining three trials (181 participants) compared foam with basic wound contact dressings. Follow-up times ranged from short-term (8 weeks or less) to medium-term (8 to 24 weeks). It was uncertain whether foam dressings affected the probability of healing compared with basic wound contact dressings, in the short term (RR 1.33, 95% CI 0.62 to 2.88) or medium term (RR 1.17, 95% CI 0.79 to 1.72), or affected time to complete healing in the medium term (MD -35.80 days, 95% CI -56.77 to -14.83), or adverse events in the medium term (RR 0.58, 95% CI 0.33 to 1.05). This was due to the very low-certainty evidence, downgraded for serious to very serious study limitations and imprecision. Reduction in ulcer size, patient satisfaction/acceptability, pain and cost effectiveness data were also reported but again, we assessed the evidence as being of very low certainty. None of the included trials reported quality of life or pressure ulcer recurrence. Authors' conclusions: It is uncertain whether foam dressings are more clinically effective, more acceptable to users, or more cost effective compared to alternative dressings in treating pressure ulcers. It was difficult to make accurate comparisons between foam dressings and other dressings due to the lack of data on reduction of wound size, complete wound healing, treatment costs, or insufficient time-frames. Quality of life and patient (or carer) acceptability/satisfaction associated with foam dressings were not systematically measured in any of the included studies. We assessed the certainty of the evidence in the included trials as low to very low. Clinicians need to carefully consider the lack of robust evidence in relation to the clinical and cost-effectiveness of foam dressings for treating pressure ulcers when making treatment decisions, particularly when considering the wound management properties that may be offered by each dressing type and the care context.","Pressure ulcers, also known as pressure injuries and bed sores, are localized areas of injury to the skin or underlying tissues, or both. Dressings made from a variety of materials, including foam, are used to treat pressure ulcers. An evidence-based evaluation of dressings for pressure ulcers is needed to promote informed decision-making on dressing use. This review is part of a suite (group) of Cochrane Reviews (scientific articles) investigating the use of dressings in the treatment of pressure ulcers. Each review will focus on a particular dressing type. The aim of this paper is to assess (measure) the clinical and cost effectiveness of foam wound dressings for healing pressure ulcers in people with an existing pressure ulcer in any care setting. This review included nine trials with a total of 483 participants. All participants were adults (59 years or older) with an existing pressure ulcer Category/Stage II or above - each category increasing in severity. All trials had two treatment groups, comparing foam dressings with other dressings for treating pressure ulcers. The certainty of evidence ranged from low to very low. This is because of various negative aspects of the collected data, including bias and imprecision (low confidence in results) due to small sample sizes (small participant groups) and wide confidence intervals. The authors had very little confidence in the estimate of effect of included studies. The authors present data for four comparisons. One trial compared a silicone foam dressing with another (hydropolymer) foam dressing. The study evaluated the treatments in 38 participants with an eight-week (short-term) follow-up. It was unclear whether alternate types of foam dressing affected the incidence (frequency) of healed pressure ulcers or negative side effects. It is unclear as there was low certainty of evidence with serious study limitations and imprecision. Four trials with an average sample size of 20 participants compared foam dressings with hydrocolloid (gel-forming) dressings for eight weeks or less (short-term). It was unclear whether foam dressing affected healing in comparison to hydrocolloid dressings over a short follow-up period in three trials. It is unclear as there was low certainty of evidence with serious study limitations and imprecision. It was uncertain if there was a difference in risk of negative side effects between groups. It is unclear as there was low certainty of evidence with serious study limitations and imprecision. Reduction in ulcer size, patient satisfaction/acceptability, pain and cost effectiveness data were also reported. However, the authors determined the evidence was of very low certainty. One trial with 34 participants compared foam and hydrogel dressings over an eight-week (short-term) follow-up. It was uncertain if the foam dressing affected the probability (likelihood) of healing, negative side effects, or reduction in ulcer size. It is unclear as there was low certainty of evidence with serious study limitations and imprecision. The remaining three trials with a total of 181 participants compared foam with basic wound contact dressings. Follow-up times ranged from short-term (8 weeks or less) to medium-term (8 to 24 weeks). It was uncertain whether foam dressings affected the probability of healing compared with basic wound contact dressings in either the short term or medium term groups. It was uncertain whether foam dressings affected time to complete healing or negative side effects in the medium term groups. This is because it is unclear as there was low certainty of evidence with serious study limitations and imprecision. Reduction in ulcer size, patient satisfaction/acceptability, pain and cost effectiveness data were reported again. However, the authors determined the evidence was of very low certainty. None of the included trials reported quality of life or pressure ulcer recurrence (reappearing). The authors conclude that it is unclear if foam dressings are more clinically effective, more acceptable to users, or more cost effective compared to alternative dressings in treating pressure ulcers. It was difficult to make accurate comparisons between foam dressings and other dressings. This is due to the lack of data on the reduction of wound size, complete wound healing, treatment costs, or insufficient time-frames. Quality of life and patient acceptability/satisfaction associated with foam dressings were not measured in any of the included studies. The authors determined the certainty of the evidence in the included trials as low to very low. Clinicians need to carefully consider the lack of strong evidence concerning clinical and cost-effectiveness of foam dressings for treating pressure ulcers when making treatment decisions. Special consideration needs to be given when investigating wound management properties available by each dressing type and the care context." +"This literature review focuses on the role of disease biomarkers in the management of patients with diabetic retinopathy (DR) investigating in detail the problem of retinal neurodegeneration in such patients. Identification and assessment of the significance of qualitative and quantitative biomarkers of DR and neurodegeneration can complement screening examination, as well as help predict the course of the disease and the response to therapy. A comprehensive analysis of these factors allows for effective treatment and prevention of complications in patients with DR based on prognostic models and dynamic monitoring of these indicators.","This literature review investigates the role of disease biomarkers in the management of patients with diabetic retinopathy (DR). DR refers to damaged blood vessels in the eye. Biomarkers are measurable substances in the body that are indicators of illness. Additionally, this review investigates the problem of retinal neurodegeneration, or nerve damage, in such patients. Evaluating the significance of various biomarkers of DR and neurodegeneration can complement screening examinations. Additionally, evaluating significant biomarkers can help predict the course of the disease and what type of therapy is appropriate. Analysis of these factors allows for effective treatment and prevention of complications in patients with DR." +"This literature review focuses on the role of disease biomarkers in the management of patients with diabetic retinopathy (DR) investigating in detail the problem of retinal neurodegeneration in such patients. Identification and assessment of the significance of qualitative and quantitative biomarkers of DR and neurodegeneration can complement screening examination, as well as help predict the course of the disease and the response to therapy. A comprehensive analysis of these factors allows for effective treatment and prevention of complications in patients with DR based on prognostic models and dynamic monitoring of these indicators.","This review article focuses on the role of biological disease markers in treating patients with diabetic retinopathy (DR), or eye diseases from diabetes. The article also investigates how nerve cells in the eye die in these patients. Evaluating the importance of non-measurable and measurable disease markers of DR and nerve cell degeneration can help disease detection, prediction, and treatment. An analysis of these markers allows for effective treatment and prevention of health hazards in patients with DR based on measuring and monitoring these markers." +"Among the many complications associated with pregnancy, hypertensive disorders of pregnancy (HDP) constitute one of the most important. Since the pathophysiology of HDP is complex, new disease biomarkers (DBMs) are needed to serve as indicators of disease activity. However, in the current status of laboratory medicine, despite the fact that blood pressure measurement has been used for a long time, not many DBMs contribute adequately to the subsequent diagnosis and treatment. In this article, we discuss studies focusing on peptide fragments in blood identified by comprehensive quantitative methods, among the currently proposed DBM candidates. Furthermore, we describe the basic techniques of peptidomics, especially quantitative proteomics, and outline the current status and challenges of measuring peptides in blood as DBM for HDP.","There are several complications associated with pregnancy. Hypertensive (high blood pressure) disorders of pregnancy (HDP) are one of the most important. Since the underlying mechanism of HDP is complex, new disease biomarkers (DBMs) are needed. Biomarkers are measurable substances in the body that are indicators of illness. However, despite current advanced medicine and the fact that blood pressure measurement has been used extensively, not many DBMs contribute adequately to the diagnosis and treatment of HDP. Herein, the authors review studies focusing on peptide fragments in blood as one of the currently proposed DBM candidates. Peptide fragments are portions of proteins. Furthermore, the authors describe the basic techniques of peptidomics, the study of peptides in an organism. Additionally, the authors outline the current status and challenges of measuring peptides in blood as DBM for HDP." +"Extracellular vesicles (EVs) are found in all biological fluids, providing potential for the identification of disease biomarkers such as colorectal cancer (CRC). EVs are heavily glycosylated with specific glycoconjugates such as tetraspanins, integrins, and mucins, reflecting the characteristics of the original cell offering valuable targets for detection of CRC. We report here on europium-nanoparticle (EuNP)-based assay to detect and characterize different surface glycoconjugates of EVs without extensive purification steps from five different CRC and the HEK 293 cell lines. The promising EVs candidates from cell culture were clinically evaluated on small panel of serum samples including early-stage (n = 11) and late-stage (n = 11) CRC patients, benign condition (n = 11), and healthy control (n = 10). The majority of CRC cell lines expressed tetraspanin sub-population and glycovariants of integrins and conventional tumor markers. The subpopulation of CD151 having CD63 expression (CD151CD63) was significantly (p = 0.001) elevated in early-stage CRC (8 out of 11) without detecting any benign and late-stage samples, while conventional CEA detected mostly late-stage CRC (p = 0.045) and with only four early-stage cases. The other glycovariant assays such as CEACon-A, CA125WGA, CA 19.9Ma696, and CA 19.9Con-A further provided some complementation to the CD151CD63 assay. These results indicate the potential application of CD151CD63 assay for early detection of CRC patients in human serum.","Extracellular vesicles (EVs) are found in all biological fluids. EVs are released by cells and are used as carriers of biomarkers. Biomarkers are measurable substances that can indicate illness. Because of this, EVs can potentially help identify diseases, such as colorectal cancer (CRC) or cancer of the colon. EVs are heavily modified with carbohydrates or sugar-carrying molecules, such as tetraspanins, integrins, and mucins. This modification allows EVs to reflect the characteristics of the original cell. Because EVs reflect the original cells, they can offer valuable targets for detection of CRC. This study reports on a testing assay (device) to detect and characterize different surface carbohydrates of EVs. The assay no longer requires extensive purification (filtration) steps. The assay is tested in five different CRC and the HEK 293 cell lines. HEK 293 cells are human kidney cells. The EVs candidates from cell culture (growing in a lab) were evaluated on a panel of serum (blood) samples. The panel included early-stage and late-stage CRC patients, benign (normal) condition, and healthy control samples. Most of the CRC cell lines expressed proteins associated with abnormal cell function and conventional tumor markers. A unique assay was used to detect CD151CD63, a specific combination of foreign substances associated with cancer induction (causation). The CD151CD63 assay showed significantly elevated levels in early-stage CRC without detecting any benign and late-stage samples. Conventional CEA assay detected mostly late-stage CRC and with only four early-stage cases. Other assays provided similar results to the CD151CD63 assay. These results indicate the potential use of CD151CD63 assay for early detection of CRC patients in human serum." +"Elevated expression of ?-amyloid (A?1-42) and tau are considered risk-factors for Alzheimer's disease in healthy older adults. We investigated the effect of aging and cerebrospinal fluid levels of A?1-42 and tau on 1) frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) and 2) cognition in cognitively normal older adults (n = 144; age range 50-85). Levels of frontal gamma aminobutyric acid (GABA+) and myo-inositol relative to creatine (mI/tCr) were predicted by age. Levels of GABA+ predicted cognitive performance better than mI/tCr. Additionally, we found that frontal levels of n-acetylaspartate relative to creatine (tNAA/tCr) were predicted by levels of t-tau. In cognitively normal older adults, levels of frontal GABA+ and mI/t Cr are predicted by aging, with levels of GABA+ decreasing with age and the opposite for mI/tCr. These results suggest that age- and biomarker-related changes in brain metabolites are not only located in the posterior cortex as suggested by previous studies and further demonstrate that MRS is a viable tool in the study of aging and biomarkers associated with pathological aging and Alzheimer's disease.","Increased expression of ?-amyloid (A?1-42) and tau proteins are considered risk-factors for Alzheimer's disease in healthy older adults. A?1-42 is a protein deposited in organs, clumps referred to as plaques, during certain diseases. Tau proteins are proteins that stabilizes microtubules or structures within cells. This paper investigated the effect of aging and cerebrospinal (brain and spine) fluid levels of A?1-42 and tau on two health endpoints. These endpoints include evaluating frontal metabolites with a proton magnetic resonance spectroscopy (MRS) and cognition (thinking ability) in cognitively normal older adults. Levels of a neurotransmitter (a signaling molecule) known as gamma aminobutyric acid (GABA+) were predicted by age. Levels of myo-inositol relative to creatine (mI/tCr), a ratio of two metabolites in the brain often used to determine disease state, were predicted by age. Levels of GABA+ predicted cognitive performance better than mI/tCr. Additionally, frontal levels of n-acetyl aspartate, another brain metabolite, relative to creatine (tNAA/tCr) were predicted by levels of t-tau, the protein. In cognitively normal older adults, levels of frontal GABA+ and mI/t Cr are predicted by aging. Levels of GABA+ decreased with age. Levels of mI/tCr increased with age. These results suggest that age- and biomarker-related changes in brain metabolites are not only located in the posterior cortex. Additionally, these studies demonstrate that MRS is a viable tool to study aging and aging biomarkers associated with Alzheimer's disease." +"Elevated expression of ?-amyloid (A?1-42) and tau are considered risk-factors for Alzheimer's disease in healthy older adults. We investigated the effect of aging and cerebrospinal fluid levels of A?1-42 and tau on 1) frontal metabolites measured with proton magnetic resonance spectroscopy (MRS) and 2) cognition in cognitively normal older adults (n = 144; age range 50-85). Levels of frontal gamma aminobutyric acid (GABA+) and myo-inositol relative to creatine (mI/tCr) were predicted by age. Levels of GABA+ predicted cognitive performance better than mI/tCr. Additionally, we found that frontal levels of n-acetylaspartate relative to creatine (tNAA/tCr) were predicted by levels of t-tau. In cognitively normal older adults, levels of frontal GABA+ and mI/t Cr are predicted by aging, with levels of GABA+ decreasing with age and the opposite for mI/tCr. These results suggest that age- and biomarker-related changes in brain metabolites are not only located in the posterior cortex as suggested by previous studies and further demonstrate that MRS is a viable tool in the study of aging and biomarkers associated with pathological aging and Alzheimer's disease.","Increased amounts of ?-amyloid (A?1-42) and tau, biological proteins, are considered risk factors for Alzheimer's disease in healthy, older adults. We tested the effect of aging and A?1-42 and tau amounts in brain and spine fluid on 1) energy molecules in the front of the brain and 2) reasoning skills in 144 older adults. Levels of specific chemical signal molecules (GABA+) and sugars (mI/tCr) in the brain were linked to age. Levels of the GABA+ trended with reasoning skills better than Mi/tCr. We found that levels of a specific chemical molecule were linked to levels of t-tau. In normal older adults, the specific chemical signal molecule GABA+ decreased with age while the chemical sugar mI/tCR increased with age. Age- and biomarker-related changes in brain molecules are not only located in the back of the brain as other studies show and that using a radio-wave tool can help study aging and biomarkers linked with aging diseases and Alzheimer's." +"Background: Circular RNAs (circRNAs) have attracted increasing attention in recent years for their potential application as disease biomarkers due to their high abundance and stability. In this study, we attempted to screen circRNAs that can be used to predict postoperative recurrence and survival in patients with gastric cancer (GC). Methods: High-throughput RNA sequencing was used to identify differentially expressed circRNAs in GC patients with different prognoses. The expression level of circRNAs in the training set (n = 136) and validation set (n = 167) was detected by quantitative real-time PCR (qRT-PCR). Kaplan-Meier estimator, receiver operating characteristic (ROC) curve and cox regression analysis were used to evaluate the prognostic value of circRNAs on recurrence-free survival (RFS) and overall survival (OS) in GC patients. CeRNA network prediction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed for the circRNAs with prognostic significance. Results: A total of 259 differentially expressed circRNAs were identified in GC patients with different RFS. We found two circRNAs (hsa_circ_0005092 and hsa_circ_0002647) that highly expressed in GC patients with good prognoses, and subsequently established a predictive model for postoperative recurrence and prognosis evaluation, named circPanel. Patients with circPanellow might have shorter recurrence-free survival (RFS) and overall survival (OS). We also performed circRNA-miRNA-mRNA network prediction and functional analysis for hsa_circ_0005092 and hsa_circ_0002647. Conclusions: CircPanel has the potential to be a prognostic biomarker in GC patients with greater accuracy than a single circRNA and certain traditional tumor markers (e.g., CEA, CA19-9 and CA724).","Circular RNAs (circRNAs) are a special class of RNAs that do not transcribe into (result into) proteins. CircRNAs have attracted increasing attention in recent years for their potential application as disease biomarkers due to their high abundance and stability. Biomarkers are measurable, biological substances that can indicate disease in a patient. The authors aimed to screen circRNAs that can be used to predict post-operation recurrence and survival in patients with gastric cancer (GC), cancer of the stomach. Tests were used to identify differentially (uniquely) expressed circRNAs in GC patients with different prognoses or forecasts of the disease. The expression level of circRNAs in the training and validation sets were detected by laboratory testing. Training and validation sets are used in scientific modeling to train the artificial intelligence machine and then validate its output, respectively. Several statistical tests were used to predict the amount of circRNAs on recurrence-free survival (RFS) and overall survival (OS) in GC patients. Recurrence-free survival (RFS) refers to the time between the day of diagnosis of a disease and the day the patient relapses into illness. Overall survival (OS) refers to the time from the day of disease diagnosis that the patients are still alive. Several bioinformatics tests evaluating disease recurrence and gene expression were performed for the circRNAs with prognostic significance (estimating the future disease course). A total of 259 differentially expressed circRNAs were identified in GC patients with different RFS. Two circRNAs were highly expressed in GC patients with good prognoses. These results established a predictive model for postoperative recurrence (disease relapse) and prognosis evaluation (likely course of disease), named circPanel. Patients with circPanellow might have shorter recurrence-free survival (RFS) and overall survival (OS). Additional tests to predict a circRNA-miRNA-mRNA network were completed on the two identified highly expressed circRNA. CircPanel has the potential to be a prognostic biomarker in GC patients. CircPanel has greater accuracy than a single circRNA and other traditional tumor markers." +"Recent studies have shown that nitric oxide (NO) is a central mediator in diseases occurring with thoracic aortic aneurysm (TAA), such as Marfan syndrome (MFS). The progressive dilation of the aorta in TAA ultimately leads to aortic dissection. Unfortunately, current medical treatments neither halt aortic enlargement nor prevent rupture, leaving surgical repair as the only effective treatment. There is therefore a pressing need for effective therapies to delay or even avoid the need for surgical repair in TAA patients. Here, we summarize the mechanisms through which NO signalling dysregulation causes TAA, particularly in MFS and discuss recent advances based on the identification of new MFS mediators related to pathway overactivation that represent potential disease biomarkers. Likewise, we propose iNOS, sGC, and PRKG1, whose pharmacological inhibition reverses aortopathy in MFS mice, as targets for therapeutic intervention in TAA and candidates for clinical trials.","Recent studies have shown that nitric oxide (NO) is a key mediator (regulator) in diseases occurring with thoracic aortic aneurysm (TAA), such as Marfan syndrome (MFS). Thoracic aortic aneurysm is characterized by an abnormal bulge in the blood vessel. The progressive dilation, or widening, of the aorta (the largest human artery) in TAA ultimately leads to aortic dissection. This is a tear in the inner layer of the blood artery. Unfortunately, current medical treatments neither halt aortic enlargement nor prevent rupture. This leaves surgical repair as the only effective treatment. There is a need for effective therapies to delay or even avoid the need for surgical repair in TAA patients. This paper summarizes the ways NO signaling dysregulation (or dysfunction) causes TAA, particularly in MFS. Additionally, this paper will discuss recent advances on the identification of new MFS mediators that represent potential biomarkers. Biomarkers are measurable, biological substances that can indicate disease in a patient. The authors propose several biological substances as targets for therapeutic intervention in TAA and candidates for clinical trials." +"Background: Primary progressive aphasia (PPA) is associated with amyloid-? (A?) pathology. However, clinical feature of PPA based on A? positivity remains unclear. Objective: We aimed to assess the prevalence of A? positivity in patients with PPA and compare the clinical characteristics of patients with A?-positive (A+) and A?-negative (A-) PPA. Further, we applied A? and tau classification system (AT system) in patients with PPA for whom additional information of in vivo tau biomarker was available. Methods: We recruited 110 patients with PPA (41 semantic [svPPA], 27 non-fluent [nfvPPA], 32 logopenic [lvPPA], and 10 unclassified [ucPPA]) who underwent A?-PET imaging at multi centers. The extent of language impairment and cortical atrophy were compared between the A+ and A-PPA subgroups using general linear models. Results: The prevalence of A? positivity was highest in patients with lvPPA (81.3%), followed by ucPPA (60.0%), nfvPPA (18.5%), and svPPA (9.8%). The A+ PPA subgroup manifested cortical atrophy mainly in the left superior temporal/inferior parietal regions and had lower repetition scores compared to the A-PPA subgroup. Further, we observed that more than 90%(13/14) of the patients with A+ PPA had tau deposition. Conclusion: Our findings will help clinicians understand the patterns of language impairment and cortical atrophy in patients with PPA based on A? deposition. Considering that most of the A+ PPA patents are tau positive, understanding the influence of Alzheimer's disease biomarkers on PPA might provide an opportunity for these patients to participate in clinical trials aimed for treating atypical Alzheimer's disease.","Primary progressive aphasia (PPA), a disease that damages nerve tissue, is associated with amyloid-? (A?) pathology. Amyloid-? (A?) pathology is the accumulation of protein plaques in the brain. However, diagnosis of PPA based on A? positivity (presence) remains unclear. The goal of this paper was to determine the prevalence (frequency) of A? positivity in patients with PPA. The paper also aimed to compare the clinical characteristics of patients with A?-positive (A+) and A?-negative (A- or no presence of A?) PPA. Additionally the authors applied the A? and tau classification system (AT system) in patients with PPA. However, this was only done for patients with available information of a tau (a type of protein) biomarker. Biomarkers are measurable, biological substances that can indicate disease in a patient. This study recruited 110 patients with PPA. Of the 110 patients, there were four PPA groups: 41 semantic [svPPA], 27 non-fluent [nfvPPA], 32 logopenic [lvPPA], and 10 unclassified [ucPPA]). Semantic PPA is characterized by loss of language function. Non-fluent PPA is characterized by the gradual loss of speech. Logopenic PPA is characterized by difficulty in naming and sentence repetition. All recruits underwent A?-PET (brain scan) imaging at multi centers. The extent of language impairment and cortical atrophy, or brain degeneration, were compared between the A+ and A-PPA subgroups. The prevalence of A? positivity was highest in patients with lvPPA, followed by ucPPA, nfvPPA, and svPPA, respectively. The A+ PPA subgroup had cortical atrophy (damage) mainly in the left brain regions and had lower repetition scores when compared to the A- PPA subgroup. The authors observed that >90% of the recruits with A+ PPA had tau or protein deposition. These findings will help clinicians understand the patterns of language impairment and cortical atrophy in patients with PPA based on A? deposition. Most of the A+ PPA patents were tau positive. Due to this, understanding the influence of Alzheimer's disease biomarkers on PPA may allow for these patients to participate in clinical trials that treat atypical Alzheimer's disease." +"Background: Primary progressive aphasia (PPA) is associated with amyloid-? (A?) pathology. However, clinical feature of PPA based on A? positivity remains unclear. Objective: We aimed to assess the prevalence of A? positivity in patients with PPA and compare the clinical characteristics of patients with A?-positive (A+) and A?-negative (A-) PPA. Further, we applied A? and tau classification system (AT system) in patients with PPA for whom additional information of in vivo tau biomarker was available. Methods: We recruited 110 patients with PPA (41 semantic [svPPA], 27 non-fluent [nfvPPA], 32 logopenic [lvPPA], and 10 unclassified [ucPPA]) who underwent A?-PET imaging at multi centers. The extent of language impairment and cortical atrophy were compared between the A+ and A-PPA subgroups using general linear models. Results: The prevalence of A? positivity was highest in patients with lvPPA (81.3%), followed by ucPPA (60.0%), nfvPPA (18.5%), and svPPA (9.8%). The A+ PPA subgroup manifested cortical atrophy mainly in the left superior temporal/inferior parietal regions and had lower repetition scores compared to the A-PPA subgroup. Further, we observed that more than 90%(13/14) of the patients with A+ PPA had tau deposition. Conclusion: Our findings will help clinicians understand the patterns of language impairment and cortical atrophy in patients with PPA based on A? deposition. Considering that most of the A+ PPA patents are tau positive, understanding the influence of Alzheimer's disease biomarkers on PPA might provide an opportunity for these patients to participate in clinical trials aimed for treating atypical Alzheimer's disease.","Pimary progressive aphasia (PPA), a language and speech brain disorder, is linked with amyloid-? (A?), a brain protein segment associated with Alzheimer's disease. However, symptoms of PPA based on A? presence is unclear. We assess the amount of A? presence in patients with PPA and compare the symptoms of PPA patients with A? presence of A?-positive (A+) versus those without A? (A-). We also classified A? and tau type in PPA patients with this available information. We had 110 PPA patients (41 who can't understand words [svPPA], 27 who can't speak but understand words [nfvPPA], 32 who have trouble finding the right word [lvPPA], and 10 unclassified [ucPPA]) undergo A? imaging at multiple centers. The extent of language impairment and brain damage were compared between tehe A+ and A- PPA subgroups. The proportion of A? presence was highest in patients with lvPPA (81.3%), then ucPPA (60.0%), nfvPPA (18.5%), and svPPA (9.8%). The A+ PPA subgroup had brain damage mainly on the left side in the middle regions and had worse scores compared to the A- PPA subgroup. Also, over 90% (13/14) patients with A+ PPA had tau, a brain protein associated with Alzheimer's disease. Our findings will help clinicians understand the patterns of language impairment and brain damage in PPA patients based on A? presence. Since most A+ PPA patients have tau, understanding the effect of Alzheimer's disease markers on PPA may allow these patients to participate in clinical studies aimed for treating atypical Alzheimer's disease." +"Lung cancer accounts for more than half of the new cancers diagnosed world-wide with poor survival rates. Despite the development of chemical, radiological, and immunotherapies, many patients do not benefit from these therapies, as recurrence is common. We performed single-cell RNA-sequencing (scRNA-seq) analysis using Fluidigm C1 systems to characterize human lung cancer transcriptomes at single-cell resolution. Validation of scRNA-seq differentially expressed genes (DEGs) through quantitative real time-polymerase chain reaction (qRT-PCR) found a positive correlation in fold-change values between C-X-C motif chemokine ligand 1 (CXCL1) and 2 (CXCL2) compared with bulk-cell level in 34 primary lung adenocarcinomas (LUADs) from Stage I patients. Furthermore, we discovered an inverse correlation between chemokine mRNAs, miR-532-5p, and miR-1266-3p in early-stage primary LUADs. Specially, miR-532-5p was quantifiable in plasma from the corresponding LUADs. Collectively, we identified markers of early-stage lung cancer that were validated in primary lung tumors and circulating blood.","Lung cancer accounts for more than half of the new cancers diagnosed world-wide. Lung cancer patients have poor survival rates. Despite the development of several therapy types, many patients do not benefit from these therapies. Recurrence, or the return of lung cancer, is common. The authors performed an analysis to characterize human lung cancer transcriptomes at single-cell resolution. The transcriptome is the sum total of messenger RNA within the genetic material of an organism. The analysis found a positive correlation (link) between a gene and a chemokine, both with roles in a pro-inflammatory or infection-fighting response, in human lung cancer cells taken from cancer patients. Chemokines are signaling proteins that attract white blood cells to infection sites. Furthermore, the authors discovered an inverse (opposite) correlation between chemokine messenger RNAs and microRNAs in human lung cancer cells taken from cancer patients. MicroRNA is RNA that is not translated into functioning proteins. Specially, one microRNA (miR-532-5p) was measurable in plasma from the cells. The authors identified markers of early-stage lung cancer that were validated (proven) in primary lung tumors and circulating blood." +"Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS) that involves an intricate and aberrant interaction of immune cells leading to inflammation, demyelination, and neurodegeneration. Due to the heterogeneity of clinical subtypes, their diagnosis becomes challenging and the best treatment cannot be easily provided to patients. Biomarkers have been used to simplify the diagnosis and prognosis of MS, as well as to evaluate the results of clinical treatments. In recent years, research on biomarkers has advanced rapidly due to their ability to be easily and promptly measured, their specificity, and their reproducibility. Biomarkers are classified into several categories depending on whether they address personal or predictive susceptibility, diagnosis, prognosis, disease activity, or response to treatment in different clinical courses of MS. The identified members indicate a variety of pathological processes of MS, such as neuroaxonal damage, gliosis, demyelination, progression of disability, and remyelination, among others. The present review analyzes biomarkers in cerebrospinal fluid (CSF) and blood serum, the most promising imaging biomarkers used in clinical practice. Furthermore, it aims to shed light on the criteria and challenges that a biomarker must face to be considered as a standard in daily clinical practice.","Multiple sclerosis (MS) is a complex disease of the central nervous system (CNS). MS involves an intricate and abnormal interaction of immune cells that leads to inflammation (redness and swelling from fighting an infection), demyelination (destruction of nerve tissue), and neurodegeneration. Neurodegeneration is the loss of structure and/or function of neurons, cells in the brain. Due to the diversity of the types of MS, their diagnosis becomes challenging, and the best treatment cannot be easily provided to patients. Biomarkers, or measurable biological substances that can indicate disease, have been used to simplify the diagnosis and treatment of MS. Biomarkers have also been used to evaluate the results of clinical treatments. In recent years, biomarker research has advanced rapidly due to their ability to be easily and promptly measured, their specificity, and their reproducibility. Biomarkers are classified into several categories. These categories depend on whether the biomarkers address personal or predictive susceptibility (or risk), diagnosis, disease forecast (or progression), disease activity, or response to treatment in different clinical courses of MS. The identified members indicate a variety of causative pathways of MS. These pathways include neuroaxonal damage (nerve degeneration), gliosis (scarring in the CNS), demyelination (nerve tissue destruction), progression of disability, and many others. The present review analyzes biomarkers in cerebrospinal (brain) fluid (CSF) and blood serum. These are the most promising imaging biomarkers used in clinical practice. Furthermore, this paper aims to shed light on the criteria and challenges that a biomarker faces to be routinely used daily clinical practice." +"The detection of chemical compounds in exhaled human breath presents an opportunity to determine physiological state, diagnose disease or assess environmental exposure. Recent advancements in metabolomics research have led to improved capabilities to explore human metabolic profiles in breath. Despite some notable challenges in sampling and analysis, exhaled breath represents a desirable medium for metabolomics applications, foremost due to its non-invasive, convenient and practically limitless availability. Several breath-based tests that target either endogenous or exogenous gas-phase compounds are currently established and are in practical and/or clinical use. This review outlines the concept of breath analysis in the context of these unique tests and their applications. The respective breath biomarkers targeted in each test are discussed in relation to their physiological production in the human body and the development and implementation of the associated tests. The paper concludes with a brief insight into prospective tests and an outlook of the future direction of breath research.","Detection of chemical compounds in exhaled human breath provides an opportunity to determine several aspects about human health. These aspects include evaluating physiological state (how the body is functioning), determining any disease, and/or assessing (measuring) environmental exposures (or things in the environment that can lead to disease). Recent advancements in metabolomics research have led to better opportunities to explore human metabolic profiles in depth. Metabolomics is the study of metabolites within the body. Metabolites are small substances involved in cell metabolism or energy-production. Despite some test challenges, exhaled breath represents a good sample for metabolomics applications. Breath is ideal as it is non-invasive, convenient, and nearly limitless in availability. There are several breath-based tests that target either internal or external chemical compounds. These tests are already established and are in practical and/or clinical use. This paper reviews the concept of breath analysis used for these unique tests and their applications. The breath biomarkers targeted in each test are discussed in relation to their function in the human body. Additionally, the paper evaluates the development and implementation of the associated tests. The paper concludes with a brief insight into prospective (future) tests and an outlook of the future direction of breath research." +"The detection of chemical compounds in exhaled human breath presents an opportunity to determine physiological state, diagnose disease or assess environmental exposure. Recent advancements in metabolomics research have led to improved capabilities to explore human metabolic profiles in breath. Despite some notable challenges in sampling and analysis, exhaled breath represents a desirable medium for metabolomics applications, foremost due to its non-invasive, convenient and practically limitless availability. Several breath-based tests that target either endogenous or exogenous gas-phase compounds are currently established and are in practical and/or clinical use. This review outlines the concept of breath analysis in the context of these unique tests and their applications. The respective breath biomarkers targeted in each test are discussed in relation to their physiological production in the human body and the development and implementation of the associated tests. The paper concludes with a brief insight into prospective tests and an outlook of the future direction of breath research.","Detecting chemical compounds in exhaled human breath may help determine health status, identify disease, or measure environmental exposure. Recent advances in research of small energy molecules (metabolomics) led to better methods to explore human health status in breath. Despite some methodological challenges, exhaled breath is a desirable tool for metabolomics due to its non-surgery, convenient, and limitless availability. Many breath-based tests that target internal or external gas compounds are established and used in practice. This review outlines the concept of breath analysis regarding these unique breath-based tests and their applications. The breath biological disease markers in each test are discussed based on their production in humans and development and use of the associated tests. The paper ends with a short look into future tests and direction of breath research." +"Cystic Echinococcosis or Hydatid disease is caused by the infection with the larval stage of long tapeworm, Echinococcus granulosus. This condition often remains asymptomatic for years before the cyst grows large enough to cause symptoms in affected organs. The most common organs involved are liver and lungs although the heart, brain, bone, central nervous system, and kidney may also be involved. This case is about a young woman who presented with left flank pain and urinary tract infection who was later diagnosed as having left renal hydatid cyst. The cyst was approximately 7.8�6.6�8cm with internal multiple septations at the lower pole cortex of the left kidney. Laparoscopic pericystectomy was performed and with no postoperative complications, she was discharged on albendazole and other supportive medication. With timely management using combination therapy, this condition is curable and the patient can live a healthy life with normal kidney function.","Cystic Echinococcosis, also called Hydatid disease, is caused by the infection of a long tapeworm called Echinococcus granulosus, after it has hatched into the larval stage. A person can often have this condition without symptoms for years before the cyst (growth) grows large enough to cause symptoms in affected organs. The most common organs involved are the liver and lungs although the heart, brain, bone, central nervous system (spinal cord and brain), and kidney may also be involved. This case is about a young woman who presented with left back pain and urinary tract infection (UTI - bladder infection) who was later diagnosed as having left kidney hydatid cyst. The cyst was about 7.8�6.6�8cm with multiple compartments at the lower pole cortex (lower part) of the left kidney. A procedure that uses tiny incisions was performed to remove the cyst and some tissue around the cyst. No complications occurred after the procedure, and she was sent home with anti-worm medicine and other medications. With timely management using several therapies, this condition is curable, and the patient can live a healthy life with normal kidney function." +"Cystic Echinococcosis or Hydatid disease is caused by the infection with the larval stage of long tapeworm, Echinococcus granulosus. This condition often remains asymptomatic for years before the cyst grows large enough to cause symptoms in affected organs. The most common organs involved are liver and lungs although the heart, brain, bone, central nervous system, and kidney may also be involved. This case is about a young woman who presented with left flank pain and urinary tract infection who was later diagnosed as having left renal hydatid cyst. The cyst was approximately 7.8�6.6�8cm with internal multiple septations at the lower pole cortex of the left kidney. Laparoscopic pericystectomy was performed and with no postoperative complications, she was discharged on albendazole and other supportive medication. With timely management using combination therapy, this condition is curable and the patient can live a healthy life with normal kidney function.","Cystic Echinococcosis or Hyadtid disease is caused by infection from baby Echinococcus granulosus, long tapeworms, and leads to cysts or swellings. This disease often shows no symptoms for years before the swelling grows large enough to cause symptoms in affected organs. Most common organs affected are the liver and lungs although the heart, brain, bone, spinal cord, and kidney may also be involved. This case is a young woman with pain on the left side of the waist and infection in the urine-collecting tube due to a left kidney cyst from Hyadtid disease. The cyst was around 7.8�6.6�8cm with many internal divisions at the lower part of the left kidney. Cyst removal surgery by small incisions and a camera was performed with no issues post-operation. She was released with albendazole, anti-parasite medication, and other helpful medication. With proper use of multiple treatments, Hyadtid disease is curable and the patient can live a healthy life with normal kidney function." +"Autosomal dominant polycystic kidney disease (ADPKD) is the leading genetic cause of renal failure. We have recently shown that inhibiting miR-17~92 is a potential novel therapeutic approach for ADPKD. However, miR-17~92 is a polycistronic cluster that encodes microRNAs (miRNAs) belonging to the miR-17, miR-18, miR-19 and miR-25 families, and the relative pathogenic contribution of these miRNA families to ADPKD progression is unknown. Here we performed an in vivo anti-miR screen to identify the miRNA drug targets within the miR-17~92 miRNA cluster. We designed anti-miRs to individually inhibit miR-17, miR-18, miR-19 or miR-25 families in an orthologous ADPKD model. Treatment with anti-miRs against the miR-17 family reduced cyst proliferation, kidney-weight-to-body-weight ratio and cyst index. In contrast, treatment with anti-miRs against the miR-18, 19, or 25 families did not affect cyst growth. Anti-miR-17 treatment recapitulated the gene expression pattern observed after miR-17~92 genetic deletion and was associated with upregulation of mitochondrial metabolism, suppression of the mTOR pathway, and inhibition of cyst-associated inflammation. Our results argue against functional cooperation between the various miR-17~92 cluster families in promoting cyst growth, and instead point to miR-17 family as the primary therapeutic target for ADPKD.","Autosomal dominant polycystic kidney disease (ADPKD) is an inherited condition that causes multiple cysts (growths), usually in the liver, and is the leading genetic cause of kidney failure. Researchers have shown that slowing or stopping the gene miR-17~92 that is involved in cell growth and development is a possible new therapy to help people with ADPKD. However, miR-17~92 is a cluster of many cysts that influence microRNAs (miRNAs), which are RNA molecules that regulate genes and how genes make proteins. How these miRNA families contribute to the development and progression of ADPKD is unknown. In this study, researchers work to identify drugs that will focus on the miRNA. Researchers designed drugs called anti-miRs to individually stop or slow different types of miRNAs from functioning in a genetic model. Treatment with anti-miRs against the miR-17 family reduced cyst development, kidney-weight-to-body-weight ratio and size of the cyst. In contrast, treatment with anti-miRs against the miR-18, 19, or 25 families did not affect cyst growth. The anti-miR-17 treatment is associated with extending the lifespan of energy from certain cells, stopping or slowing cell growth often found in tumors, and stopping or slowing inflammation (redness and swelling from fighting an infection) associated with cysts. These results argue against functional cooperation between the various miRNA (miR-17~92) cluster families in promoting cyst growth, and instead point to the miR-17 family as the main therapeutic target for ADPKD." +"In patients with von Hippel-Lindau (VHL) disease, renal cysts and clear cell renal cell carcinoma (ccRCC) arise from renal tubular epithelial cells containing biallelic inactivation of the VHL tumour suppressor gene. However, it is presumed that formation of renal cysts and their conversion to ccRCC involve additional genetic changes at other loci. Here, we show that cystic lesions in the kidneys of patients with VHL disease also demonstrate activation of the phosphatidylinositol-3-kinase (PI3K) pathway. Strikingly, combined conditional inactivation of Vhlh and the Pten tumour suppressor gene, which normally antagonises PI3K signalling, in the mouse kidney, elicits cyst formation after short latency, whereas inactivation of either tumour suppressor gene alone failed to produce such a phenotype. Interestingly, cells lining these cysts frequently lack a primary cilium, a microtubule-based cellular antenna important for suppression of uncontrolled kidney epithelial cell proliferation and cyst formation. Our results support a model in which the PTEN tumour suppressor protein cooperates with pVHL to suppress cyst development in the kidney.","In patients with von Hippel-Lindau (VHL) disease, kidney cysts (growths) and clear cell renal cell carcinoma (ccRCC), a type of kidney cancer, come from cells in the kidneys called epithelial cells that inactivate (or turn off) the VHL gene. The VHL gene keeps cells from growing and dividing too fast. However, it is believed that formation of kidney cysts and their change to the ccRCC kidney cancer involve additional genetic changes at other locations. This study shows that cystic wounds in the kidneys of patients with VHL disease also show activation of the enzyme called phosphatidylinositol-3-kinase (PI3K) pathway, which regulates key cells processes. When two genes called Vhlh and Pten that keep cells from growing too fast are turned off, this brings about cyst formation in the kidneys of mice after a short delay. However, inactivation of only one of these genes fails to produce this same effect. Interestingly, cells lining these cysts frequently lack primary cilium, that acts like a cell antenna and is important for stopping or slowing kidney epithelial cells from multiplying and for stopping cyst formation. These results support a model in which the PTEN tumor suppressor protein cooperates with pVHL to stop cyst development in the kidney." +"Autosomal dominant polycystic kidney disease is an important cause of end-stage renal disease, for which there is no proven therapy. Mutations in PKD1 (the gene encoding polycystin-1) are the principal cause of this disease. The disease begins in utero and is slowly progressive, but it is not known whether cystogenesis is an ongoing process during adult life. We now show that inactivation of Pkd1 in mice before postnatal day 13 results in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 and later results in cysts only after 5 months. We found that cellular proliferation was not appreciably higher in cystic specimens than in age-matched controls, but the abrupt change in response to Pkd1 inactivation corresponded to a previously unrecognized brake point during renal growth and significant changes in gene expression. These findings suggest that the effects of Pkd1 inactivation are defined by a developmental switch that signals the end of the terminal renal maturation process. Our studies show that Pkd1 regulates tubular morphology in both developing and adult kidney, but the pathologic consequences of inactivation are defined by the organ's developmental status. These results have important implications for clinical understanding of the disease and therapeutic approaches.","Autosomal dominant polycystic kidney disease is an inherited disease that causes many cysts (growths) usually in the kidneys, and is an important cause of end-stage kidney disease, for which there is no proven therapy. Changes in the PKD1 gene (which creates an active kidney protein) are the main causes of this disease. The disease begins before birth and develops slowly, but it is not known whether the development and growth of cysts is an ongoing process during adult life. When the Pkd1 gene is not active in mice within 13 days after birth, this results in many cysts in the kidneys within 3 weeks. However, inactivation (turning off) of Pkd1 at day 14 or later results in cysts only after 5 months. Researchers find that cell growth and development is not higher in samples of cysts than in comparison groups. However, the sudden change of Pkd1 becoming inactive matched a stopping point of kidney growth that is not previously recognized and matched significant changes in how the gene functions. These findings suggest that the effects of inactivating the Pkd1 gene are like a switch that signals the end of the end-stage kidney process. These studies show that Pkd1 regulates changes in both developing kidneys and in adult kidneys, but the process of inactivation are defined by the stage of the organ's development. These results have important connections to the understanding of the disease and treatment approaches." +"Autosomal dominant polycystic kidney disease is an important cause of end-stage renal disease, for which there is no proven therapy. Mutations in PKD1 (the gene encoding polycystin-1) are the principal cause of this disease. The disease begins in utero and is slowly progressive, but it is not known whether cystogenesis is an ongoing process during adult life. We now show that inactivation of Pkd1 in mice before postnatal day 13 results in severely cystic kidneys within 3 weeks, whereas inactivation at day 14 and later results in cysts only after 5 months. We found that cellular proliferation was not appreciably higher in cystic specimens than in age-matched controls, but the abrupt change in response to Pkd1 inactivation corresponded to a previously unrecognized brake point during renal growth and significant changes in gene expression. These findings suggest that the effects of Pkd1 inactivation are defined by a developmental switch that signals the end of the terminal renal maturation process. Our studies show that Pkd1 regulates tubular morphology in both developing and adult kidney, but the pathologic consequences of inactivation are defined by the organ's developmental status. These results have important implications for clinical understanding of the disease and therapeutic approaches.","An inherited disorder of many kidney cysts (swellings) is an important cause of kidney failure, for which there is no treatment. Gene sequence changes in PKD1 (a gene active in kidney cells) are the leading cause of the disease. The disease begins before birth and worsens slowly, but it is not known if creation of cysts is an ongoing process during adult life. We show that silencing of Pkd1 in mice younger than 13 days leads to severely cystic kidneys within 3 weeks. Silencing at day 14 or later results in cysts only after 4 months. We found that cell growth is not higher in those with cysts versus similar-age healthy animals, but the sudden change in response to Pkd1 silencing was linked to a new brake point during kidney growth and changes in gene expression. The effects of Pkd1 silencing may be defined by a developmental switch that signals the end of the final kidney maturation process. Pkd1 monitors development of tubes in growing and adult kidneys, but the disease-related effects of silencing are defined by the organ's developmental status. These results influence clinical understanding of the disease and treatment options." +"Autosomal dominant polycystic kidney disease is a common inherited renal disorder that results from mutations in either PKD1 or PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Downregulation or overexpression of PKD1 or PKD2 in mouse models results in renal cyst formation, suggesting that the quantity of PC1 and PC2 needs to be maintained within a tight functional window to prevent cystogenesis. Here we show that enhanced PC2 expression is a common feature of PKD1 mutant tissues, in part due to an increase in Pkd2 mRNA. However, our data also suggest that more effective protein folding contributes to the augmented levels of PC2. We demonstrate that the unfolded protein response is activated in Pkd1 knockout kidneys and in Pkd1 mutant cells and that this is coupled with increased levels of GRP94, an endoplasmic reticulum protein that is a member of the HSP90 family of chaperones. GRP94 was found to physically interact with PC2 and depletion or chemical inhibition of GRP94 led to a decrease in PC2, suggesting that GRP94 serves as its chaperone. Moreover, GRP94 is acetylated and binds to histone deacetylase 6 (HDAC6), a known deacetylase and activator of HSP90 proteins. Inhibition of HDAC6 decreased PC2 suggesting that HDAC6 and GRP94 work together to regulate PC2 levels. Lastly, we showed that inhibition of GRP94 prevents cAMP-induced cyst formation in vitro. Taken together our data uncovered a novel HDAC6-GRP94-related axis that likely participates in maintaining elevated PC2 levels in Pkd1 mutant cells.","Autosomal dominant polycystic kidney disease is a common inherited kidney disorder that causes many cysts (growths) and is caused by changes in either the PKD1 or PKD2 genes. These genes are used to make the proteins polycystin-1 (PC1) and polycystin-2 (PC2), which regulate cells growth, cell movement, and interaction with other cells. In experiments with mice, when the PKD1 or PKD2 genes are less sensitive to other cells or make too many proteins, it may lead to cysts forming in the kidneys. This suggests that the number of PC1 and PC2 proteins needs to be stable within a brief time period to prevent the formation of cysts. In this study, researchers show that more cells and proteins from PC2 is a common feature of PKD1 changes, in part because of an increase in PKD2. However, this data also suggests that more effective protein folding, which is when a protein changes from a long chain to a functional shape, contributes to more levels of PC2 proteins. Researchers show that the unfolded protein response is active in the kidneys without Pkd1 and in Pkd1 mutant (changed) cells. This effect is in addition to increases in the number of an endoplasmic reticulum protein, called GRP94. The endoplasmic reticulum helps create and package proteins in cells. GRP94 is found to physically interact with PC2, and reducing or slowing GRP94 can lead to a decrease in PC2, suggesting that GRP94 serves as its chaperone (plays a part in the folding of itself as a protein). Also, GRP94 is acetylated (modified structurally) and attaches to histone deacetylase 6 (HDAC6), an enzyme that can control several important proteins and activate other proteins. Slowing or stopping HDAC6 decreases PC2 proteins, suggesting that HDAC6 and GRP94 work together to regulate PC2 levels. Lastly, researchers show that the slowing of GRP94 prevents the formation of cysts in laboratory tests. Together, these data uncover a new HDAC6-GRP94-related point that likely participates in maintaining higher PC2 levels in Pkd1 mutant cells." +"Background: In autosomal dominant polycystic kidney disease (ADPKD), cyst development and enlargement lead to ESKD. Macrophage recruitment and interstitial inflammation promote cyst growth. TWEAK is a TNF superfamily (TNFSF) cytokine that regulates inflammatory responses, cell proliferation, and cell death, and its receptor Fn14 (TNFRSF12a) is expressed in macrophage and nephron epithelia. Methods: To evaluate the role of the TWEAK signaling pathway in cystic disease, we evaluated Fn14 expression in human and in an orthologous murine model of ADPKD. We also explored the cystic response to TWEAK signaling pathway activation and inhibition by peritoneal injection. Results: Meta-analysis of published animal-model data of cystic disease reveals mRNA upregulation of several components of the TWEAK signaling pathway. We also observed that TWEAK and Fn14 were overexpressed in mouse ADPKD kidney cysts, and TWEAK was significantly high in urine and cystic fluid from patients with ADPKD. TWEAK administration induced cystogenesis and increased cystic growth, worsening the phenotype in a murine ADPKD model. Anti-TWEAK antibodies significantly slowed the progression of ADPKD, preserved renal function, and improved survival. Furthermore, the anti-TWEAK cystogenesis reduction is related to decreased cell proliferation-related MAPK signaling, decreased NF-?B pathway activation, a slight reduction of fibrosis and apoptosis, and an indirect decrease in macrophage recruitment. Conclusions: This study identifies the TWEAK signaling pathway as a new disease mechanism involved in cystogenesis and cystic growth and may lead to a new therapeutic approach in ADPKD.","In autosomal dominant polycystic kidney disease (ADPKD), an inherited disorder that causes cysts (growths) in the kidneys, cyst development and enlargement lead to end-stage kidney disease. The recruitment of macrophage cells (a type of white blood cell that surrounds and kills microorganisms, removes dead cells, and activates other immune system cells) and spaces between the kidney becoming swollen are found to promote cyst growth. TWEAK is a type of cytokine (chemical messenger) that regulates inflammatory (infection-fighting) responses, cell growth and division, and cell death. Its receptor Fn14 (TNFRSF12a) that sends and receives signals is expressed in macrophages and a layer of outer lining cells in the kidney called nephron epithelia. To evaluate how the TWEAK cytokine signaling plays a role in cystic disease, researchers evaluate the Fn14 gene development in humans and in experiments with animals of ADPKD. Researchers also looked at the response from cysts to the activation of TWEAK signaling as well as its limited signaling by injections. Data published from animal studies of cystic disease show increases in mRNA (genetic strands with instructions to build proteins) of several parts of the TWEAK signaling pathway. Researchers also found that too many TWEAK and Fn14 gene-derived molecules are in made in mouse ADPKD kidney cysts, and TWEAK is very high in the urine and cystic fluid from patients with ADPKD. TWEAK use started formation of cysts and increased cystic growth, worsening physical traits in an animal ADPKD model. Anti-TWEAK antibodies (a protein used by the immune system to identify and neutralize foreign objects such as harmful bacteria and viruses) significantly slowed the progression of ADPKD, protected kidney function, and improved survival. Additionally, the reduction of cyst formation is related to decreased cell growth and a decrease in macrophage recruitment. In conclusion, this study identifies the TWEAK signaling pathway as a new disease process involved in the growth and formation of many cysts and may lead to a new treatment approach in ADPKD." +"Polycystic kidney disease (PKD) is a genetic disorder characterized by aberrant renal epithelial cell proliferation and formation and progressive growth of numerous fluid-filled cysts within the kidneys. Previously, we showed that there is elevated Notch signaling compared to normal renal epithelial cells and that Notch signaling contributes to the proliferation of cystic cells. Quinomycin A, a bis-intercalator peptide, has previously been shown to target the Notch signaling pathway and inhibit tumor growth in cancer. Here, we show that Quinomycin A decreased cell proliferation and cyst growth of human ADPKD cyst epithelial cells cultured within a 3D collagen gel. Treatment with Quinomycin A reduced kidney weight to body weight ratio and decreased renal cystic area and fibrosis in Pkd1RC/RC ; Pkd2+/- mice, an orthologous PKD mouse model. This was accompanied by reduced expression of Notch pathway proteins, RBPjk and HeyL and cell proliferation in kidneys of PKD mice. Quinomycin A treatments also normalized cilia length of cyst epithelial cells derived from the collecting ducts. This is the first study to demonstrate that Quinomycin A effectively inhibits PKD progression and suggests that Quinomycin A has potential therapeutic value for PKD patients.","Polycystic kidney disease (PKD) is a genetic disorder that causes abnormal growth and formation of kidney epithelial cells, which are important cells for kidney function, and growth of many cysts (swellings) filled with fluid within the kidneys. Previous studies show that, when compared to epithelial cells, there is an increase in cell signaling called Notch signaling that allows direct cell to cell communication. This Notch signaling contributes to the growth and division of cystic cells (cells that cluster together and form a cyst). Quinomycin A is a type of antibiotic (bacteria-fighting medication), has previously shown to target the Notch signaling process, and slow or stop tumor growth in cancer. In this study, researchers show that quinomycin A decreases cell development and cyst growth of cyst epithelial cells taken from humans with inherited PKD and analyzed in a lab. Treatment with quinomycin A reduces kidney weight to body weight ratio and decreases the size of the kidney cysts and the development of fibrous tissues that can impact the lungs. Also, there is a reduced number of proteins that develop from the Notch pathway. Quinomycin A treatments also normalized the length of cilia, hairlike vibrating structures found in large numbers on the surface of cyst epithelial cells. This is the first study to demonstrate that Quinomycin A effectively slows or stops polycystic kidney disease (PKD) progression and suggests that Quinomycin A is a possible therapy for PKD patients." +"Polycystic kidney disease (PKD) is a genetic disorder characterized by aberrant renal epithelial cell proliferation and formation and progressive growth of numerous fluid-filled cysts within the kidneys. Previously, we showed that there is elevated Notch signaling compared to normal renal epithelial cells and that Notch signaling contributes to the proliferation of cystic cells. Quinomycin A, a bis-intercalator peptide, has previously been shown to target the Notch signaling pathway and inhibit tumor growth in cancer. Here, we show that Quinomycin A decreased cell proliferation and cyst growth of human ADPKD cyst epithelial cells cultured within a 3D collagen gel. Treatment with Quinomycin A reduced kidney weight to body weight ratio and decreased renal cystic area and fibrosis in Pkd1RC/RC ; Pkd2+/- mice, an orthologous PKD mouse model. This was accompanied by reduced expression of Notch pathway proteins, RBPjk and HeyL and cell proliferation in kidneys of PKD mice. Quinomycin A treatments also normalized cilia length of cyst epithelial cells derived from the collecting ducts. This is the first study to demonstrate that Quinomycin A effectively inhibits PKD progression and suggests that Quinomycin A has potential therapeutic value for PKD patients.","Polycystic kidney disease (PKD) is an inherited disorder of abnormal kidney cell growth and development of many fluid-filled cysts or swellings in the kidneys. Before, we showed there is increased signaling of a specific cell pathway (Notch) compared to normal kidney cells. This Notch signaling contributes to cystic cell growth. Quinomycin A, a specific protein segment, has been shown to target the Notch cell signaling pathway and block tumor growth in cancer. Here, we show that Quinomycin A decreased cell and cyst growth of human, diseased cyst cells created in an isolated environment. Treatment with Quinomycin A reduced kidney weight to body weight ratio and reduced kidney cystic area and scarred tissue in mice with PKD. Reduced amounts of proteins of the Notch cell signaling patway, RBPjk and HeyL, and reduced cell growth in kidneys of PKD mice also occured with the other effects. Quinomycin A also controlled hairlike structions on cyst cells from kidney tubes. This is the first study to show that Quinomycin A blocks PDK progression and suggests that Quinomycin A has beneficial value for PKD patients." +"DNA damage and alterations in DNA damage response (DDR) signaling could be one of the molecular mechanisms mediating focal kidney cyst formation in autosomal dominant polycystic kidney disease (ADPKD). The aim of this study was to test the hypothesis that markers of DNA damage and DDR signaling are increased in human and experimental ADPKD. In the human ADPKD transcriptome, the number of up-regulated DDR-related genes was increased by 16.6-fold compared with that in normal kidney, and by 2.5-fold in cystic compared with that in minimally cystic tissue (P < 0.0001). In end-stage human ADPKD tissue, ?-H2A histone family member X (H2AX), phosphorylated ataxia telangiectasia and radiation-sensitive mutant 3 (Rad3)-related (pATR), and phosphorylated ataxia telangiectasia mutated (pATM) localized to cystic kidney epithelial cells. In vitro, pATR and pATM were also constitutively increased in human ADPKD tubular cells (WT 9-7 and 9-12) compared with control (HK-2). In addition, extrinsic oxidative DNA damage by hydrogen peroxide augmented ?-H2AX and cell survival in human ADPKD cells, and exacerbated cyst growth in the three-dimensional Madin-Darby canine kidney cyst model. In contrast, DDR-related gene expression was only transiently increased on postnatal day 0 in Pkd1RC/RC mice, and not altered at later time points up to 12 months of age. In conclusion, DDR signaling is dysregulated in human ADPKD and during the early phases of murine ADPKD. The constitutive expression of the DDR pathway in ADPKD may promote survival of PKD1-mutated cells and contribute to kidney cyst growth.","Damage to DNA and changes to the body's response to DNA damage, called DNA damage response or DDR, could be one of the processes involved in the development of kidney cysts (growths) in the inherited disease called autosomal dominant polycystic kidney disease (ADPKD). This study aims to test the idea that certain types of DNA damage and DDR signaling are increased in ADPKD experiments. In the part of the human ADPKD genes that transfer information to molecules, the DNA damage response (DDR) genes increased 16 times compared with that in a normal kidney. DDR also more than doubled in tissues with cysts compared to DDR in tissues with few cysts. In tissues from end-stage human ADPKD, certain genes and protein enzymes involved in the DDR to detect and repair damaged DNA focus on cystic kidney epithelial cells, which are important cells for kidney function. In lab tests, protein enzymes are also increased in human ADPKD cells located in the tubal duct system of the kidneys when compared with normal tubal cells. Additionally, some DNA damage increases genes and cell survival in human ADPKD cells, and worsens cyst growth in one animal experiment. In contrast, DNA damage response (DDR) gene processing is only temporarily increased on the day of birth in mice, and not altered at later times up to 12 months of age. In conclusion, DDR signals to other cells are not controlled well in human ADPKD and during the early phases of animal ADPKD. The use of the DNA damage response in ADPKD may promote survival of gene cells that have mutated (changed) and contribute to cyst growth in the kidneys." +"Tuberous sclerosis complex (TSC) is caused by mutations in either TSC1 or TSC2 genes and affects multiple organs, including kidney, lung, and brain. In the kidney, TSC presents with the enlargement of benign tumors (angiomyolipomata) and cysts, which eventually leads to kidney failure. The factors promoting cyst formation and tumor growth in TSC are incompletely understood. Here, we report that mice with principal cell-specific inactivation of Tsc1 develop numerous cortical cysts, which are overwhelmingly composed of hyperproliferating A-intercalated (A-IC) cells. RNA sequencing and confirmatory expression studies demonstrated robust expression of Forkhead Transcription Factor 1 (Foxi1) and its downstream targets, apical H+-ATPase and cytoplasmic carbonic anhydrase 2 (CAII), in cyst epithelia in Tsc1 knockout (KO) mice but not in Pkd1 mutant mice. In addition, the electrogenic 2Cl-/H+ exchanger (CLC-5) is significantly up-regulated and shows remarkable colocalization with H+-ATPase on the apical membrane of cyst epithelia in Tsc1 KO mice. Deletion of Foxi1, which is vital to intercalated cells viability and H+-ATPase expression, completely abrogated the cyst burden in Tsc1 KO mice, as indicated by MRI images and histological analysis in kidneys of Foxi1/Tsc1 double-knockout (dKO) mice. Deletion of CAII, which is critical to H+-ATPase activation, caused significant reduction in cyst burden and increased life expectancy in CAII/Tsc1 dKO mice vs. Tsc1 KO mice. We propose that intercalated cells and their acid/base/electrolyte transport machinery (H+-ATPase/CAII/CLC-5) are critical to cystogenesis, and their inhibition or inactivation is associated with significant protection against cyst generation and/or enlargement in TSC.","Tuberous sclerosis complex (TSC) is a rare disease that leads to noncancerous (benign) tumors forming in the body. TSC is caused by changes in two specific genes (TSC1 or TSC2) and affects multiple organs, including the kidney, lung, and brain. In the kidney, TSC can cause benign tumors and cysts (fluid swellings) to grow, which eventually leads to kidney failure. The factors promoting cyst formation and tumor growth in TSC are not completely understood. In this study, researchers report that mice with inactivation (turning off) of specific cells develop many cysts in the kidney. Past studies with mice show an increase of the Forkhead Transcription Factor 1 (Foxi1) gene that impacts cell processing in cyst epithelia cells, which are important cells for kidney function. Also, some gene processing is increased and work together with proton pumps called H+-ATPase, which regulate functions such as nutrient intake and regulating acids between cells, on the lining of epithelial cysts cells in mice. Deletion of the Foxi1 gene, which is key to the survival of cells and H+-ATPase processing, overrides the cyst burden in Tsc1 mice. Deletion of the enzyme CAII causes major decreases in cyst burden and increased life expectancy in mice without CAII and Tsc1 versus mice without just Tsc1. Researchers suggest that epithelial cells in the kidneys and their transport mechanisms are important to the formation of many cysts, and slowing or stopping them is associated with significant protection against cyst development and/or enlargement in tuberous sclerosis complex (TSC)." +"This consensus-based guideline was developed by all relevant German pediatric medical societies. Ultrasound is the standard imaging modality for pre- and postnatal kidney cysts and should also exclude extrarenal manifestations in the abdomen and internal genital organs. MRI has selected indications. Suspicion of a cystic kidney disease should prompt consultation of a pediatric nephrologist. Prenatal management must be tailored to very different degrees of disease severity. After renal oligohydramnios, we recommend delivery in a perinatal center. Neonates should not be denied renal replacement therapy solely because of their age. Children with unilateral multicystic dysplastic kidney do not require routine further imaging or nephrectomy, but long-term nephrology follow-up (as do children with uni- or bilateral kidney hypo-/dysplasia with cysts). ARPKD (autosomal recessive polycystic kidney disease), nephronophthisis, Bardet-Biedl syndrome and HNF1B mutations cause relevant extrarenal disease and genetic testing is advisable. Children with tuberous sclerosis complex, tumor predisposition (e. g. von Hippel Lindau syndrome) or high risk of acquired kidney cysts should have regular ultrasounds. Even asymptomatic children of parents with ADPKD (autosomal dominant PKD) should be monitored for hypertension and proteinuria. Presymptomatic diagnostic ultrasound or genetic examination for ADPKD in minors should only be done after thorough counselling. Simple cysts are very rare in children and ADPKD in a parent should be excluded. Complex renal cysts require further investigation.","This guideline was developed by all relevant German pediatric medical societies, which are groups that represent medical professionals that focus on pediatric or child-concerned medicine. An ultrasound is a type of x-ray to see images inside the body and is the common method to view kidney cysts (growths) before and after birth. This method can also exclude cysts in the stomach (abdomen) and inside the genitals. An MRI also takes images of the body and may also be needed in some cases. Suspicion of a cystic kidney disease should lead to consulting a kidney specialist of children. Care provided during pregnancy should align with how serious the disease is and will be slightly different for each patient. Oligohydramnios occur when there is too little amniotic fluid (the fluid that surrounds the baby in the womb) and can sometimes be caused by kidney dysfunction. With this condition, it is recommended that delivery occurs in a birth-delivering center where specialty care is available. Newborns should not be denied therapy that replaces the normal blood-filtering function of the kidneys just because of their age. Children with unilateral multicystic dysplastic kidney, where one kidney is large with cysts and is not functioning, do not require routine x-rays or surgery to remove one or both kidneys. However they will need long-term follow-up with kidney specialists (as do children with other kidney problems where one or both kidneys are not working well and have cysts). Certain diseases such as ARPKD (autosomal recessive polycystic kidney disease - an inherited kidney disease with cysts), nephronophthisis (kidney scarring), and Bardet-Biedl syndrome (a full-body, inherited disease), as well as genetic changes, cause disease outside the kidney, and genetic testing for these conditions is recommended. Children with tuberous sclerosis complex (TSC - a rare disease that leads to noncancerous tumors forming in the body) or a high risk of developing tumors or kidney cysts should have regular ultrasounds to take images of the inside of the body. Even children of parents with ADPKD (autosomal dominant PKD) who do not have symptoms should be monitored for high blood pressure and increased levels of protein in the urine. Testing for ADPKD in minors using an ultrasound or genetic testing should only be done after a great deal of counseling. Simple cysts are very rare in children, and ADPKD in a parent should be excluded. Complex kidney cysts require more investigation." +"This consensus-based guideline was developed by all relevant German pediatric medical societies. Ultrasound is the standard imaging modality for pre- and postnatal kidney cysts and should also exclude extrarenal manifestations in the abdomen and internal genital organs. MRI has selected indications. Suspicion of a cystic kidney disease should prompt consultation of a pediatric nephrologist. Prenatal management must be tailored to very different degrees of disease severity. After renal oligohydramnios, we recommend delivery in a perinatal center. Neonates should not be denied renal replacement therapy solely because of their age. Children with unilateral multicystic dysplastic kidney do not require routine further imaging or nephrectomy, but long-term nephrology follow-up (as do children with uni- or bilateral kidney hypo-/dysplasia with cysts). ARPKD (autosomal recessive polycystic kidney disease), nephronophthisis, Bardet-Biedl syndrome and HNF1B mutations cause relevant extrarenal disease and genetic testing is advisable. Children with tuberous sclerosis complex, tumor predisposition (e. g. von Hippel Lindau syndrome) or high risk of acquired kidney cysts should have regular ultrasounds. Even asymptomatic children of parents with ADPKD (autosomal dominant PKD) should be monitored for hypertension and proteinuria. Presymptomatic diagnostic ultrasound or genetic examination for ADPKD in minors should only be done after thorough counselling. Simple cysts are very rare in children and ADPKD in a parent should be excluded. Complex renal cysts require further investigation.","All relevant German child-care medical groups created the agreed-upon guideline. Ultrasound or sound-wave imaging is the standard imaging for pre- and post-birth kidney cysts (fluid-filled swellings) and should exclude non-kidney growths in the abdomen and genitals. Magnetic resonance imaging or imaging with radio waves and magnetic fields has selected uses. Suspicion of a kidney disease with cysts should prompt talking with a child-care kidney specialist. Pre-birth management should be personalized to different degress of disease severity. After renal oligohydramnios (diseases where scarce fluid surrounds the fetus due to kidney damage), we recommend delivery in a preganancy-specialized center. Newborns should not be denied kidney replacement therapy because of age. Children with a single, enlarged, nonfunctional kidney with cysts do not need regular imaging or kidney removal, but long-term kidney-related follow-ups (as do children with single or multiple kidney abnormalities with cysts). ARPKD (autosomal recessive polycystic kidney disease), an inherited disorder of many kidney cysts, nephronophthisis (kidney inflammation), Bardet-Biedl syndrome (an inherited disorder that impairs kidneys, eyes, and more), and specific liver-related gene mutations cause disease outside the kidneys. Genetic testing is advisable. Children with an inherited disorder leading to tumors in the skin, brain, kidney and more, or a high risk of tumors (e.g. von Hippel Lindau syndrome) or kidney cysts should have regular ultrasounds. Even children without symptoms and of parents with ADPKD (a similar variant of ARPKD) should be monitored for high blood pressure and protein in the urine. Examining for ADPKD in minors via ultrasound or genes should only be done after in-depth counseling. Simple fluid-filled sacs are very rare in children. ADPDK in parents should be excluded. Compex fluid-filled sacs in the kidney need further investigation." +"There have been significant advances in pacing and implantable defibrillator technology over the past decade. The relationships between ventricular activation sequence and cardiac mechanical performance are now better appreciated, and will become more completely understood. Even in the setting of infra-His block and bundle branch block, ventricular activation over the Purkinje system can now be achieved in many patients with direct pacing of the His bundle, providing a more physiologic alternative to RV pacing that should avoid pacing induced ventricular dysfunction, as well as provide an alternative to left ventricular pacing for CRT. Advances in the lead technology will increase ease and use of this form of pacing. When activation of the ventricles from the His Purkinje system is not feasible, LV pacing for cardiac resynchronization therapy (CRT) will continue to be important for patients with depressed ventricular function associated with left bundle branch block. Surprisingly, CRT is often beneficial even though present implementation is limited to the few LV pacing sites accessible through the coronary venous system. The advent of pacing leads with multiple electrodes for placement in the coronary venous system is a notable advance, that in contrast to traditional bipolar leads, provides multiple LV pacing configurations from which to select the optimal site for LV pacing without compromising lead stability. This option also addresses problems of phrenic nerve stimulation and high pacing thresholds that often limit delivery of LV pacing. These leads will also allow performance of simultaneous pacing from multiple LV sites, which may improve mechanical performance in situations other than left bundle branch block.","Over the past decade, there have been major advances in the development of pacemakers and the implantable defibrillator, a device that monitors your heart rate and delivers a strong electrical shock to restore the heartbeat to normal. The relationship between when the lower chambers of the heart are activated and how the heart pumps are now better understood. Activating the lower chambers of the heart (ventricular activation) can now be achieved in many patients with pacing of the His bundle (a part of the electrical conduction system of the heart that transmits pulses). This approach provides an alternative to right ventricle pacing that may cause ventricles in the heart to not function properly. Advances in the technology will increase ease and use of this form of pacing. When it is not possible to activate the ventricles from the His Purkinje system that is the rapid electric conduction in the ventricles, left ventricle pacing for cardiac resynchronization therapy or CRT (treatment that helps the heart beat at the right rhythm) will continue to be important for patients with slower ventricular function. Surprisingly, cardiac resynchronization therapy (CRT) is often beneficial even though current use is limited to the few places in the left ventricle. The development of pacing devices with multiple placements in the heart system is an important advance and provided multiple left ventricle pacing arrangements to select from to find the best site. This option also addresses problems of electric stimulation of the diaphragm and high pacing ceilings that often limit delivery of left ventricle pacing. These leads will also allow performance of simultaneous pacing from multiple left ventricle sites, which may improve mechanical performance in situations other than when there is a delay or blockage of electrical impulses to the left side of the heart." +"Leadless pacemakers (LPs) have revolutionized the field of pacing by miniaturizing pacemakers and rendering them completelty intracardiac, hence reducing complications related to pacemaker pockets and transvenous leads. However, first generation LPs appear to be associated with a higher rate of myocardial perforation as compared to transvenous pacemakers (TV-PPM). Currently, LPs are predominantly designed to pace the right ventricle with no LPs that provide atrial or biventricular pacing. In this article, we review the available data on LPs while advocating for the need for a randomized controlled trial comparing LPs to TV-PPMs. In addition, we review the future directions of leadless devices.","A leadless pacemaker is a small device placed directly into the right ventricle (lower chamber of the heart) which sends pulses to the heart. Leadless pacemakers have changed the field by making pacemakers much smaller and reducing complications related to pacemaker pockets and transvenous (through-vein) leads. However, first generation leadless pacemakers appear to be associated with a higher rate of complications due to punctures as compared to transvenous pacemakers, a temporary pacing technique that places a catheter into the right ventricle (chamber) of the heart and then applies an electric pulse. Currently, leadless pacemakers are mostly designed to pace the right ventricle with none that provide pacing to the upper chambers of the heart or both ventricles. This article reviews the available data on leadless pacemakers while promoting the need for a clinical study that compares leadless pacemakers to transvenous pacemakers. In addition, the future directions of leadless devices is reviewed." +"Pacemakers are adjustable artificial electrical pulse generators, frequently emitting a pulse with a duration between 0.5 and 25 milliseconds with an output of 0.1 to 15 volts, at a frequency up to 300 times per minute. The cardiologist or pacemaker technologist will be able to interrogate and control the pacing rate, the pulse width, and the voltage, whether the device is temporary or permanent. Pacemakers are typically categorized as external or internal. The external variety is almost always placed for temporary stabilization of the patient or to facilitate some type of surgical procedure. The implantable type is usually permanent and often, significantly more complex than the temporary, external variety. Pacemakers are one type of cardiac implantable electronic devices (known as CIED). This broad category also includes implantable cardioverter-defibrillators (ICDs). Collectively, this group of devices was first introduced in the 1950s, shortly after the advent of the transistor. As technology has improved, so has the pacemaker device. The first implantable ICD was developed in 1980, and since that time, it has become more difficult to differentiate between pacemakers and ICDs. This is because every ICD currently implanted has an anti-bradycardia pacing function. It is critical for the patient and any health care provider to understand which device has been implanted to prevent unnecessary ICD therapy. This is most likely to occur with any electromagnetic interference (EMI) and could lead to activation of the device (if it is an ICD). Most types of CIED use several insulated lead wires with non-insulated tips that are implanted in the heart, either by percutaneous vein insertion or directly by a cardiac surgeon. Cardiac pacemakers are made up of two parts: the pulse generator and the leads or electrodes.","Pacemakers are devices that generate artificial electrical pulses. A heart specialist or pacemaker technologist will be able to control the pacing rate and other functions, whether the device is temporary or permanent. Pacemakers are typically categorized as external (main device is outside the body) or internal (device is implanted in the body). The external variety is almost always placed to temporarily stabilize the patient or to assist some type of surgical procedure. The implantable type is usually permanent and often much more complex than the temporary, external variety. Pacemakers are one type of a cardiac implantable electronic device (known as CIED). This broad category also includes implantable cardioverter-defibrillators (ICDs), which are devices designed to directly treat a slow heart rate. Collectively, this group of devices was first introduced in the 1950s, shortly after the creation of the transistor that can record electrical activity inside heart cells. As technology has improved, so has the pacemaker device. The first implantable ICD was developed in 1980, and since that time, it has become more difficult to tell the difference between pacemakers and ICDs. This is because every ICD currently implanted has an anti-bradycardia (anti-slow-heart-rate) pacing function. It is critical for the patient and any health care provider to understand which device has been implanted to prevent unnecessary ICD therapy. This is most likely to occur with interference by another electrical device and could lead to activation of the device (if it is an ICD). Most types of cardiac implantable electronic devices (CIED) use several insulated lead wires with non-insulated tips that are implanted in the heart, either by inserting a catheter into a vein or directly by a heart surgeon. Pacemakers in the heart are made up of two parts: the pulse generator and the leads or electrodes." +"Pacemakers are adjustable artificial electrical pulse generators, frequently emitting a pulse with a duration between 0.5 and 25 milliseconds with an output of 0.1 to 15 volts, at a frequency up to 300 times per minute. The cardiologist or pacemaker technologist will be able to interrogate and control the pacing rate, the pulse width, and the voltage, whether the device is temporary or permanent. Pacemakers are typically categorized as external or internal. The external variety is almost always placed for temporary stabilization of the patient or to facilitate some type of surgical procedure. The implantable type is usually permanent and often, significantly more complex than the temporary, external variety. Pacemakers are one type of cardiac implantable electronic devices (known as CIED). This broad category also includes implantable cardioverter-defibrillators (ICDs). Collectively, this group of devices was first introduced in the 1950s, shortly after the advent of the transistor. As technology has improved, so has the pacemaker device. The first implantable ICD was developed in 1980, and since that time, it has become more difficult to differentiate between pacemakers and ICDs. This is because every ICD currently implanted has an anti-bradycardia pacing function. It is critical for the patient and any health care provider to understand which device has been implanted to prevent unnecessary ICD therapy. This is most likely to occur with any electromagnetic interference (EMI) and could lead to activation of the device (if it is an ICD). Most types of CIED use several insulated lead wires with non-insulated tips that are implanted in the heart, either by percutaneous vein insertion or directly by a cardiac surgeon. Cardiac pacemakers are made up of two parts: the pulse generator and the leads or electrodes.","Pacemakers are adjustable artificial electrical pulse generators commonly to aid heart rate, frequently emitting a pulse between 0.5 and 25 milliseconds with 0.1 to 15 volts, up to 300 times per minute. The heart specialist or pacemaker technologist can assess and control the pacing rate, pulse width, voltage, and whether the device is temporary or permanent. Pacemakers are usually categorized as external or internal. The external type is almost always placed for temporary stabilization of the patient or to help some type of surgery. The implantable type is usually permanent and often, more complex than the temporary, external type. Pacemakers are one type of heart-related or cardiac implantable electronic devices (or CIED). CIEDs also include implantable cardioverter-defibrillators (ICDs), which corrects irregular heart beats. Together, this group of devices was first introduced in the 1950s, shortly after the transistor, which alters electrical signals. As technology improved, so has the pacemaker. The first implantable ICD was created in 1980. Since then, it has become more difficult to differentiate between pacemakers and ICDs. This difficulty is because every ICD currently implanted aids against a slow heart rate. It is important for the patient and clinician to know which device has been implanted to prevent unnecessary ICD therapy. This is likely to occur with any electromagnetic interference (EMI) and may activate the device (if it is an ICD). Most types of CIEDs use many electrically-isolated lead wires with non-electrically-isolated tips impanted in the heart, either by skin vein insertion or directly by a heart surgeon. Heart-related pacemakers are made of the pulse generator and the leads or electrical contact points." +"A pacemaking system consists of an impulse generator and lead or leads to carry the electrical impulse to the patient's heart. Pacemaker and implantable cardioverter defibrillator codes were made to describe the type of pacemaker or implantable cardioverter defibrillator implanted. Indications for pacing and implantable cardioverter defibrillator implantation were given by the American College of Cardiologists. Certain pacemakers have magnet-operated reed switches incorporated; however, magnet application can have serious adverse effects; hence, devices should be considered programmable unless known otherwise. When a device patient undergoes any procedure (with or without anesthesia), special precautions have to be observed including a focused history/physical examination, interrogation of pacemaker before and after the procedure, emergency drugs/temporary pacing and defibrillation, reprogramming of pacemaker and disabling certain pacemaker functions if required, monitoring of electrolyte and metabolic disturbance and avoiding certain drugs and equipments that can interfere with pacemaker function. If unanticipated device interactions are found, consider discontinuation of the procedure until the source of interference can be eliminated or managed and all corrective measures should be taken to ensure proper pacemaker function should be done. Post procedure, the cardiac rate and rhythm should be monitored continuously and emergency drugs and equipments should be kept ready and consultation with a cardiologist or a pacemaker-implantable cardioverter defibrillator service may be necessary.","A pacemaking system consists of a generator the produces pulses and lead or leads to carry the electrical impulse to the patient's heart. Specific codes for pacemaker and implantable cardioverter defibrillator are made to describe the type of pacemaker or implantable cardioverter defibrillator implanted in the patient. The American College of Cardiologists (heart doctors) gave guidelines for connecting and fitting a pacemaker to regulate the heart rate and implanting a cardioverter defibrillator, a battery powered device placed under the skin that keeps track of the heart rate. Certain pacemakers have magnet-operated switches; however, using a magnet can have serious negative effects. Therefore, devices should be considered programmable unless known otherwise. When a patient who has a device undergoes any procedure (with or without anesthesia), special precautions have to be taken including a history of the patient's health and a physical exam, checking the pacemaker before and after the procedure to make sure its working, emergency drugs/temporary pacing and defibrillation, reprogramming of the pacemaker, and disabling certain pacemaker functions if required. Monitoring of problems with electrolytes and the metabolism and avoiding certain drugs and equipments that can interfere with pacemaker function are also reviewed. If unexpected interactions between the pacemaker and other devices are found, consider stopping the procedure until the source of interference can be eliminated or managed. All other measures should be taken to ensure proper pacemaker function. After the procedure, the heart rate and rhythm should be monitored continuously, and emergency drugs and equipment should be ready, if needed. Also, discussing with a heart specialist or a service that focuses on pacemaker-implantable cardioverter defibrillators may be necessary." +"Cardiac implantable electronic devices (CIEDs) provide lifesaving therapy for the treatment of bradyarrhythmias, ventricular tachyarrhythmias, and advanced systolic heart failure. All pacemakers have 2 basic functions: (1) to pace and (2) to sense intrinsic electrical activity of the heart. Most pacemakers are programmed to inhibit pacing when they sense native electrical activity and only pace in the absence of intrinsic electrical activity. More specifically, pacemakers can be programmed to set which chamber or chambers will pace, which chamber or chambers will sense intrinsic electrical activity, how the pacemaker will respond to sensed electrical activity (ie, inhibit pacing), and if rate-adaptive pacing will be used.","Cardiac implantable electronic devices (CIEDs) provide lifesaving therapy for the treatment of slow heart rates (bradyarrhythmias), abnormal heart rhythm in the lower part of the heart (ventricular tachyarrhythmias), and when the heart does not pump enough (advanced systolic heart failure). All pacemakers have 2 basic functions: (1) to pace or get the heart beat back to normal and (2) to sense internal electrical activity of the heart. Most pacemakers are programmed to slow or stop pacing when they sense natural electrical activity and only pace (send pulses) in the absence of this internal electrical activity. More specifically, pacemakers can be programmed to set which part or parts (chambers) will pace, which chamber or chambers will sense internal electrical activity, how the pacemaker will respond to sensed electrical activity (slow or stop pacing), and if rate adjusted pacing will be used." +"Pacemakers are electronic devices that stimulate the heart with electrical impulses to maintain or restore a normal heartbeat. In 1952, Zoll described an effective means of supporting the patients with intrinsic cardiac pacemaker activity and/or conducting tissue by an artificial, electric, external pacemaker. The pacing of the heart was accomplished by subcutaneous electrodes but could be maintained only for a short period. In 1957, complete heart block was treated using electrodes directly attached to the heart. These early observations instilled the idea that cardiac electrical failure can be controlled. It ultimately led to the development of totally implantable pacemaker by Chardack, Gage, and Greatbatch. Since then, there have been several advancements in the pacemakers, and the modern-day permanent pacemaker is subcutaneously placed device. There are 3 types of artificial pacemakers: Implantable pulse generators with endocardial or myocardial electrodes; External, miniaturized, patient portable, battery-powered, pulse generators with exteriorized electrodes for temporary transvenous endocardial or transthoracic myocardial pacing; Console battery or AC-powered cardioverters or monitors with high-current external transcutaneous or low-current endocardial or myocardial circuits for temporary pacing in asynchronous or demand modes, with manual or triggered initiation of pacing. All cardiac pacemakers consist of 2 components: a pulse generator which provides the electrical impulse for myocardial stimulation and 1 or more electrodes or leads which deliver the electrical impulse from the generator to the myocardium.","Pacemakers are electronic devices that stimulate the heart with electrical impulses to maintain or restore a normal heartbeat. In 1952, a physician named Zoll described an effective way of supporting patients with internal heart pacemaker activity and/or sending pulses through tissue by an artificial, electric, external pacemaker device. The pacing of the heart was accomplished by electrodes placed under the skin but could be maintained only for a short period. In 1957, complete heart block was treated using electrodes directly attached to the heart. These early observations started the idea that cardiac electrical failure (in which the heart cannot maintain a normal heart rate) can be controlled. It ultimately led to the development of the totally implantable (permanently under the skin) pacemaker by Chardack, Gage, and Greatbatch. Since then, there have been several advancements in pacemakers, and the modern-day permanent pacemaker is placed under the skin. There are 3 types of artificial pacemakers: Implantable pulse generators; External, miniaturized, patient portable, battery-powered, pulse generators to temporarily control heart rates; Console battery or AC-powered devices or monitors with high-current external pads placed on top of the skin, or low-current inside the body for temporary pacing in uncoordinated contracting of the heart or at infrequent times. All heart pacemakers consist of 2 components: a pulse generator which provides the electrical impulse for stimulation on the heart muscle and 1 or more electrodes or leads which deliver the electrical impulse from the generator to the heart muscle." +"Pacemakers are electronic devices that stimulate the heart with electrical impulses to maintain or restore a normal heartbeat. In 1952, Zoll described an effective means of supporting the patients with intrinsic cardiac pacemaker activity and/or conducting tissue by an artificial, electric, external pacemaker. The pacing of the heart was accomplished by subcutaneous electrodes but could be maintained only for a short period. In 1957, complete heart block was treated using electrodes directly attached to the heart. These early observations instilled the idea that cardiac electrical failure can be controlled. It ultimately led to the development of totally implantable pacemaker by Chardack, Gage, and Greatbatch. Since then, there have been several advancements in the pacemakers, and the modern-day permanent pacemaker is subcutaneously placed device. There are 3 types of artificial pacemakers: Implantable pulse generators with endocardial or myocardial electrodes; External, miniaturized, patient portable, battery-powered, pulse generators with exteriorized electrodes for temporary transvenous endocardial or transthoracic myocardial pacing; Console battery or AC-powered cardioverters or monitors with high-current external transcutaneous or low-current endocardial or myocardial circuits for temporary pacing in asynchronous or demand modes, with manual or triggered initiation of pacing. All cardiac pacemakers consist of 2 components: a pulse generator which provides the electrical impulse for myocardial stimulation and 1 or more electrodes or leads which deliver the electrical impulse from the generator to the myocardium.","Pacemakers are electronics that stimulate the heart with electrical impulses to maintain or restore a normal heartbeat. In 1952, Zoli described a means of supporting patients with internal heart-related pacemaker activity and/or conducting electricity across body parts by an artificial, electric, external pacemaker. Below-skin electrodes (electrical contact points) maintained the heart's beat but only for a short period of time. In 1957, complete heart block was done with electrodes directly attached to the heart. These early observations led to the idea that heart-related electrical failure can be controlled. It led to the creation of totally implantable pacemakers by Chardack, Gage, and Greatbatch. Since then, there have been many advancements in pacemakers. The modern-day permanent pacemaker is placed below the skin. There are 3 types of artificial pacemakers. One is implantable pulse generators with electrodes near the heart or muscle. Another is external, small, portable, battery-powered, pulse generators with external electrodes for temporary insertion near the heart or muscle for pacing. The final is battery- or circuit-powered devices for electric shocks or monitors with high-current external circuits for temporary insertion near the heart and muscle for temporary pacing in inconsistent scenarios, with manual or automatic initiation of pacing. All heart-related pacemakers have a pulse generator, which gives an electrical impoulse for muscle or heart stimulation, and 1 or more electrodes or contact points to give the electrical impulse from the generator to target body part." +"The human heart is a pivotal organ in the circulatory system, and it beats more than 2 billion times during normal life. This functioning of the heart depends on the cardiac conduction system, which includes impulse generators (e.g., sino-atrial node) and the impulse propagating (His-Purkinje) system. The sinoatrial node acts as the natural pacemaker of the heart. The cells present in the sinus node have innate automaticity, which starts the electrical activity in the heart. This innate electrical potential moves from the sinoatrial node to the atrioventricular node and finally into the His-Purkinje system. This movement of electric potential in an orderly manner controls the rhythmic contraction of the heart's chambers. The failure of this intrinsic electrical conduction in the heart can result in different arrhythmic problems. Several diseases and conditions affect the conduction system by involving impulse generation, impulse propagation, or both. Acquired conditions such as myocardial infarction, age-related degeneration, procedural complications, and drug toxicity are the major causes of the native conduction system malfunction. The current standard of care for symptomatic bradyarrhythmias due to conduction system diseases is the implantation of a cardiac implantable electronic device. These pacing devices provide an external electrical stimulus that leads to depolarization of myocytes and helps maintain the electrical excitability of the heart tissue. This process leads to excitation-contraction coupling resulting in the contraction of myocardial tissue.","The human heart is an important organ in the circulatory system in the body that carries blood to and from the heart. It beats more than 2 billion times during normal life. This functioning of the heart depends on the cardiac conduction system that includes heart muscle cells and electrical conducting fibers and provides the heart its automatic heart rhythm. The cardiac conduction system includes impulse generators, such as the sino-atrial node that sends electrical signals, and the impulse propagating (His-Purkinje) system that synchronizes heart beats between the two heart ventricles (chambers). The sinoatrial node acts as the natural pacemaker of the heart. The cells in the sinus node have natural automatic actions, which starts the electrical activity in the heart. This natural electrical potential moves from the sinoatrial node (the heart's natural pacemaker) to the atrioventricular node, a small part of the heart that intensifies these heart impulses, and finally into the His-Purkinje system. This movement of electric potential in an orderly manner controls the rhythmic contraction of the heart's chambers. The failure of this internal electrical conduction in the heart can result in different problems with the heart beat. Several diseases and conditions affect the conduction system by involving impulse generation, impulse travel through the path of the His-Purkinje system, or both. Acquired conditions such as a heart attack, age-related changes in the heart, complications from heart procedures, and negative reactions to drugs are the major causes of the body's conduction system problems. The current standard of care for symptomatic bradyarrhythmias (slower than normal heart beats) due to conduction system diseases is to implant a cardiac implantable electronic device, a device that is placed under the skin to help treat a slow heart rate. These pacing devices provide an external electrical stimulus that leads to changes in cells and helps maintain the electrical ability to send pulses to stimulate the heart tissue. This process leads to the development of an electrical impulse to the contraction of muscles in the heart that results in the contraction (pushing blood in and out of the heart) of heart muscle tissue." +"Introduction: Cardiac stimulation evolved from life-saving devices to prevent asystole to the treatment of heart rhythm disorders and heart failure, capable of remote patient and disease-progression monitoring. Cardiac stimulation nowadays aims to correct the electrophysiologic roots of mechanical inefficiency in different structural heart diseases. Areas covered: Clinical experience, as per available literature, has led to awareness of the concealed risks of customary cardiac pacing, that can inadvertently cause atrio-ventricular and inter/intra-ventricular dyssynchrony. New pacing modalities have emerged, leading to a new concept of what truly represents 'physiologic pacing' beyond maintenance of atrio-ventricular coupling. In this article we will analyze the emerging evidence in favor of the available strategies to achieve an individualized physiologic setting in bradycardia pacing, and the hints of future developments. Expert opinion: 'physiologic stimulation' technologies should evolve to enable an effective and widespread adoption. In one way new guiding catheters and the adoption of electrophysiologic guidance and non-fluoroscopic lead implantation are needed to make His-Purkinje pacing successful and effective at long term in a shorter procedure time; in the other way leadless stimulation needs to upgrade to a superior physiologic setting to mimic customary DDD pacing and possibly His-Purkinje pacing.","The process of stimulating the heart grew from life-saving devices that prevent asystole (when the activity in the heart stops or ""flatline"") to the treatment of heart rhythm disorders and heart failure. Cardiac stimulation nowadays aims to correct the physical root cause of heart problems in different heart diseases. Doctors' experiences have led to an awareness of the hidden risks of standard pacing methods to get the heart beat back to normal that can lead to unexpected heart problems. New pacing methods have come about, leading to a new idea of what truly represents 'physiologic pacing' beyond making sure the two parts of the heart beat in a good rhythm. This article analyzes new evidence that supports the available methods to create a setting in bradycardia (slow heart beat) pacing that is tailored for the individual. The article also discusses future developments. The expert opinion is that 'physiologic stimulation' methods should develop to allow effective and far-reaching use. In one way, new guiding catheters (flexible tubes), the use of specific tests to check the heart's electrical system, and implanting devices using imaging tools are needed to make pacing successful and effective in the long term, but leads to a shorter procedure time. In the other way, stimulation without using wires needs to upgrade to a better physical setting to mimic customary DDD (dual-chamber antibradycardia that can stimulate the chambers of the heart) pacing and possibly His-Purkinje pacing, the rapid electric conduction in the ventricles (lower heart chambers)." +"The first cardiac implantable electronic device (CIED), the electronic pacemaker, maintains cardiac contraction during bradycardia. The implantable cardioverter-defibrillator (ICD) manages ventricular tachycardia (VT) or fibrillation (VF) and saves lives primarily through the use of high-energy shocks. The cardiac resynchronization therapy (CRT) device restores interventricular and intraventricular dyssynchrony in patients with heart failure (HF). Despite >50 years of pacing and 40 years of ICD therapy, the lead remains the weakest link between the device and the patient.","The first cardiac implantable electronic device (CIED), the electronic pacemaker, maintains the pumping of blood in and out of the heart when heart beats are unusually slow. The implantable cardioverter-defibrillator (ICD) manages a heart rhythm that beats too fast or fibrillation (an irregular heart beat) and saves lives primarily through the use of high-energy shocks. The cardiac resynchronization therapy (CRT) device send electrical signals to the lower chambers of the heart and restores the ability of the two parts of the heart to beat in sync in patients with heart failure. Despite >50 years of pacing and 40 years of ICD therapy, the lead pacemaker (device with wires that run between the part that generates pulses and the heart) remains the weakest link between the device and the patient." +"The first cardiac implantable electronic device (CIED), the electronic pacemaker, maintains cardiac contraction during bradycardia. The implantable cardioverter-defibrillator (ICD) manages ventricular tachycardia (VT) or fibrillation (VF) and saves lives primarily through the use of high-energy shocks. The cardiac resynchronization therapy (CRT) device restores interventricular and intraventricular dyssynchrony in patients with heart failure (HF). Despite >50 years of pacing and 40 years of ICD therapy, the lead remains the weakest link between the device and the patient.","The first heart-related or cardiac implantable electronic device (CIED), the electronic pacemaker, maintains heart-related contraction during a slow heart rate. The implantable cardioverter-defibrillator (ICD), which corrects irregular heart beats, manages fast heart rate or irregular contractions and saves lives by high-energy shocks. The heart-related or cardiac resynchronization therapy (CRT) device restores irregular heart pumps in patients with heart failure (HF). Despite >50 years of pacing and 40 years of ICD therapy, the lead or contact point remains the weakest link between the device and patient." +"This article provides an overview of current cardiac device management, complications, and future areas for development. The last 70 years have seen huge advances in the field of implantable cardiac devices, from diagnostic tools to electrical therapies for bradycardia, ventricular arrhythmia and cardiac resynchronisation. While out-of-hours specialist cardiology cover and regional arrhythmia pathways are increasingly established, they are not universal, and the management of arrhythmia remains an important facet of clinical medicine for the general physician. This article discusses core recommendations from international guidelines with respect to heart rhythm diagnostics, pacing for bradycardia, cardiac resynchronisation and implantable cardioverter defibrillators, along with common complications. Finally, future innovations such as the diagnostic potential of portable technologies, antibiotic envelopes for cardiac devices and the increasing use of leadless pacemakers are described.","This article provides an overview of current heart device management, complications, and future areas for development. The last 70 years have seen huge advances in the field of implantable cardiac devices, from tools to diagnose conditions to electrical therapies to address slower heart rates, ventricular arrhythmia that causes irregular heart beats that don't send enough blood to the body, and cardiac resynchronisation to help the heart beat at the right rhythm. While out-of-hours specialist cardiology cover and regional (localized) arrhythmia pathways are increasingly established, they are not universal, and the management of arrhythmia remains an important part of clinical medicine for the general physician. This article discusses recommendations on diagnosing heart rhythms, pacing for bradycardia (slower than normal heart beat), cardiac resynchronization and implantable cardioverter defibrillator devices to treat fast heart beats, along with common complications. Finally, future developments such as the potential of portable devices to help with diagnosing problems, enclosing cardiac devices in a mesh covering that has antibiotic (bacteria-fighting) medicines, and the increasing use of pacemakers that do not include any wires are described." +"Background: A severe mismatch between the supply and demand of oxygen is the common feature of all types of shock. We present a newly developed, clinically oriented classification of the various types of shock and their therapeutic implications. Results: There are only four major categories of shock, each of which is mainly related to one of four organ systems. Hypovolemic shock relates to the blood and fluids compartment while distributive shock relates to the vascular system; cardiogenic shock arises from primary cardiac dysfunction; and obstructive shock arises from a blockage of the circulation. Hypovolemic shock is due to intravascular volume loss and is treated by fluid replacement with balanced crystalloids. Distributive shock, on the other hand, is a state of relative hypovolemia resulting from pathological redistribution of the absolute intravascular volume and is treated with a combination of vasoconstrictors and fluid replacement. Cardiogenic shock is due to inadequate function of the heart, which shall be treated, depending on the situation, with drugs, surgery, or other interventional procedures. In obstructive shock, hypoperfusion due to elevated resistance shall be treated with an immediate life-saving intervention. Pathogenesis and pathophysiology: The characteristic feature of both, hemorrhagic and traumatic hemorrhagic shock is bleeding. However, differences exist between the two subcategories in terms of the extent of soft tissue damage. Clinically the most significant cause of hemorrhagic shock is acute bleeding from an isolated injury to a large blood vessel, gastrointestinal bleeding, nontraumatic vascular rupture (e.g., aortic aneurysm), obstetric hemorrhage (e.g., uterine atony), and hemorrhage in the region of the ear, nose, and throat (vascular erosion). The shock is triggered by the critical drop in circulating blood volume; massive loss of red blood cells intensifies the tissue hypoxia.","Inequality between the supply and demand of oxygen is the common feature of shock. This study presents a newly developed, patient-treatment oriented classification of the various types of shock and their therapeutic (helpful) implications. There are four major categories of shock. Each category is mainly related to one of four organ systems. One category, known as hypovolemic shock, relates to the blood and fluids compartment. Distributive shock relates to the vascular system or blood vessels. Cardiogenic shock arises from primary cardiac or heart dysfunction. Obstructive shock arises from a blockage of circulation. Hypovolemic shock is due to volume loss with blood vessels or blood vascular system. This type of shock is treated by replacement with balanced fluids. Distributive shock is a state of low blood plasma. This type of shock comes from volume displacement in blood vessels. It is treated with a combination of vasoconstrictors, drugs that constrict blood vessels to increase blood pressure, and fluid replacement. Cardiogenic shock is caused by inadequate function of the heart, which shall be treated, depending on the situation, with drugs, surgery, or other treatment methods. In obstructive shock, circulatory failure due to increased resistance will be treated with an immediate life-saving intervention. Both hemorrhagic (excessive bleeding from a ruptured blood vessel) and traumatic hemorrhagic (internal bleeding from an injury) shock feature bleeding. However, differences exist between the two subcategories in terms of how much soft tissue damage they create. The most significant cause of hemorrhagic shock is bleeding from an isolated injury to a critical portion of the body. Some of examples of this include injuries to blood vessels or blood within the intestines. The shock is caused by a critical drop in circulating blood volume. Massive loss of red blood cells increases tissue hypoxia (below normal level of oxygen)." +"The term ""shock"" refers to a life-threatening circulatory failure caused by an imbalance between the supply and demand of cellular oxygen. Hypovolemic shock is characterized by a reduction of intravascular volume and a subsequent reduction in preload. The body compensates the loss of volume by increasing the stroke volume, heart frequency, oxygen extraction rate, and later by an increased concentration of 2,3-diphosphoglycerate with a rightward shift of the oxygen dissociation curve. Hypovolemic hemorrhagic shock impairs the macrocirculation and microcirculation and therefore affects many organ systems (e.g. kidneys, endocrine system and endothelium). For further identification of a state of shock caused by bleeding, vital functions, coagulation tests and hematopoietic procedures are implemented. Every hospital should be in possession of a specific protocol for massive transfusions. The differentiated systemic treatment of bleeding consists of maintenance of an adequate homeostasis and the administration of blood products and coagulation factors.","""Shock"" refers to a life-threatening circulatory failure. Shock is caused by an imbalance between the supply and demand of oxygen within cells. Hypovolemic shock is characterized by a decreased volume in blood vessels and a subsequent reduction in preload (volume of blood within the heart when its relaxed). The body compensates the volume loss by increasing stroke volume, heart frequency, and oxygen extraction rate. Following these steps, the body will then increase 2,3-diphosphoglycerate (a chemical that controls oxygen movement) to increase available oxygen. Hypovolemic shock is due to volume loss with blood vessels or blood vascular system. Hypovolemic hemorrhagic shock impairs blood circulation. Because of this, this type of shock affects many organ systems. Vital functions, coagulation (blood) tests, and hematopoietic (blood cell creation) procedures are used to identify a state of shock caused by bleeding. Every hospital should have a specific protocol for massive transfusions (transfers). Treatment of bleeding within the body consists of homeostasis (bodily equilibrium) maintenance and administration (use) of blood products and blood clothing (scabbing) medications." +"The term ""shock"" refers to a life-threatening circulatory failure caused by an imbalance between the supply and demand of cellular oxygen. Hypovolemic shock is characterized by a reduction of intravascular volume and a subsequent reduction in preload. The body compensates the loss of volume by increasing the stroke volume, heart frequency, oxygen extraction rate, and later by an increased concentration of 2,3-diphosphoglycerate with a rightward shift of the oxygen dissociation curve. Hypovolemic hemorrhagic shock impairs the macrocirculation and microcirculation and therefore affects many organ systems (e.g. kidneys, endocrine system and endothelium). For further identification of a state of shock caused by bleeding, vital functions, coagulation tests and hematopoietic procedures are implemented. Every hospital should be in possession of a specific protocol for massive transfusions. The differentiated systemic treatment of bleeding consists of maintenance of an adequate homeostasis and the administration of blood products and coagulation factors.","The term ""shock"" refers to a life-threatening blood-flow-related failure caused by an imbalance between supply and demand of oxygen for cells. Hypovolemic shock is due to a reduced amount of blood in vessels and subsequently reduced amount of blood and oxygen to pump. The body compensates for the loss of volume by increasing blood volume per pump, heart rate, oxygen extraction rate, and increasing the amount of a specific molecule that increases oxygen release. Hypovolemic shock from blood loss impairs blood circulation and affects many organs (e.g., kidneys, hormonal system, and blood vessel tubing). For futher identification of shock due to bleeding, vital functions, blood clotting or thickening tests and procedures assessing blood cell development are used. Every hospital should have a specific guideline for massive transfusions or transfers. The personalized full-body treatment of bleeding includes maintaing a proper balance in the body and administering blood substances and factors for blood clotting." +"Hypovolemic shock exists as a spectrum, with its early stages characterized by subtle pathophysiologic tissue insults and its late stages defined by multi-system organ dysfunction. The importance of timely detection of shock is well known, as early interventions improve mortality, while delays render these same interventions ineffective. However, detection is limited by the monitors, parameters, and vital signs that are traditionally used in the intensive care unit (ICU). Many parameters change minimally during the early stages, and when they finally become abnormal, hypovolemic shock has already occurred. The compensatory reserve (CR) is a parameter that represents a new paradigm for assessing physiologic status, as it comprises the sum total of compensatory mechanisms that maintain adequate perfusion to vital organs during hypovolemia. When these mechanisms are overwhelmed, hemodynamic instability and circulatory collapse will follow. Previous studies involving CR measurements demonstrated their utility in detecting central blood volume loss before hemodynamic parameters and vital signs changed. Measurements of the CR have also been used in clinical studies involving patients with traumatic injuries or bleeding, and the results from these studies have been promising. Moreover, these measurements can be made at the bedside, and they provide a real-time assessment of hemodynamic stability. Given the need for rapid diagnostics when treating critically ill patients, CR measurements would complement parameters that are currently being used. Consequently, the purpose of this article is to introduce a conceptual framework where the CR represents a new approach to monitoring critically ill patients. Within this framework, we present evidence to support the notion that the use of the CR could potentially improve the outcomes of ICU patients by alerting intensivists to impending hypovolemic shock before its onset.","Hypovolemic shock is a spectrum of reactions. In the early stages of hypovolemic shock, there is subtle pathophysiologic tissue insults. In the late stages of hypovolemic shock, there is multi-system organ dysfunction. Hypovolemic shock is due to volume loss with blood vessels or blood vascular system. Timely detection of shock is important. Early interventions (treatments) decrease the chance of death. Intervention delays can make the same interventions ineffective. Detection can be limited by monitoring, parameters, and vital signs that are used in the intensive care unit (ICU). Most parameters barely change during the early stages. When the signs finally become abnormal, hypovolemic shock has already occurred. The compensatory reserve (CR) is a parameter. It is a new model for assessing body function. CR represents all of the mechanisms or ways the body compensates for internal conditions that dysregulate blood flow to vital organs during hypovolemia. When these mechanisms are overwhelmed, unstable blood pressure, and circulatory failure will follow. Previous studies involving CR measurements have shown its use in detecting central blood volume loss before blood pressure parameters and vital signs changed. CR measurements have also been used in clinical studies involving patients with traumatic injuries or bleeding. The results from these clinical studies have been promising. CR measurements can be made at the bedside. They also provide a real-time assessment of blood flow. There is a need for rapid diagnostics when treating critically ill patients. CR measurements would complement parameters that are currently being used. The aim of this article is to introduce a conceptual framework where the CR represents a new approach to monitoring critically ill patients. Within this framework, the authors present evidence to support the how the use of the CR could potentially improve the outcomes of ICU patients. CR could improve alerting doctors to impending hypovolemic shock before its onset." +"Development of a human model of hemorrhage has provided a unique opportunity to investigate the underlying physiology that defines the individual capacity to avoid the life-threatening clinical condition of inadequate tissue oxygenation known as �shock.� The experimental approach of progressively reducing central blood volume to the point of hemodynamic decompensation with the use of lower body negative pressure has revealed stark distinctions in the physiological compensatory responses between individuals with high compared with low tolerances to blood loss. High tolerance to hemorrhage is defined by a capacity to maintain systemic perfusion pressure and reduce the rate of cerebral hypoperfusion by: (1) protecting cardiac output with greater elevations in heart rate associated with greater cardiac vagal withdrawal and sympathetically mediated adrenergic stimulation; (2) greater increases in systemic peripheral vascular resistance associated with higher sympathetic nerve activation and levels of circulating vasopressor endocrine responses; (3) alternating blood flow between the brain and peripheral tissue with greater sympathetically mediated oscillatory patterns of systemic pressure and flow; and (4) enhancing cardiac filling and cerebral perfusion pressure gradient by optimizing the respiratory pump. When the capacity for these compensatory responses is exhausted, an active vasodilation drops resistance to blood flow allowing for increased perfusion of peripheral tissue. When cardiac filling is no longer adequate to maintain systemic pressure and flow, a reflex-mediated pronounced bradycardia leads to the initiation of decompensatory shock.","A human model of hemorrhage (excessive bleeding) provides the opportunity to investigate the underlying mechanisms that can help someone avoid the life-threatening condition of inadequate tissue oxygenation known as ""shock."" This is completed by experimentally reducing central blood volume. Blood volume is progressively decreased to the point of critically low blood pressure. This test approach has shown differences in the bodily responses between individuals with high tolerances versus low tolerances to blood loss. High tolerance to hemorrhage is defined by maintaining body wide blood flow pressure and prevent decreased brain blood pressure. This is done by one of four ways. First, by protecting cardiac output with greater elevations in heart rate associated with greater cardiac vagal withdrawal and sympathetically mediated adrenergic stimulation. Second, a greater increases in systemic peripheral vascular resistance (blood vessel resistance) associated with higher sympathetic nerve activation (fight-or-flight reaction) and levels of circulating vasopressor endocrine responses (responses from chemical messengers). Third, an alternating blood flow between the brain and peripheral tissue with greater sympathetically mediated oscillatory patterns of systemic pressure and flow. Lastly, by enhancing cardiac filling and cerebral perfusion pressure gradient (pressure driving oxygen to brain tissue) by optimizing the respiratory pump (muscles that help the lung extract and contract). When these compensatory responses are exhausted, an active vasodilation (enlargement of blood vessels) drops resistance to blood flow allowing for increased perfusion of peripheral tissue. When the body no is longer able to maintain systemic pressure and flow, a decreased heart rate leads to the initiation of decompensatory shock." +"This review addresses the pathophysiology and treatment of hemorrhagic shock - a condition produced by rapid and significant loss of intravascular volume, which may lead sequentially to hemodynamic instability, decreases in oxygen delivery, decreased tissue perfusion, cellular hypoxia, organ damage, and death. Hemorrhagic shock can be rapidly fatal. The primary goals are to stop the bleeding and to restore circulating blood volume. Resuscitation may well depend on the estimated severity of hemorrhage. It now appears that patients with moderate hypotension from bleeding may benefit by delaying massive fluid resuscitation until they reach a definitive care facility. On the other hand, the use of intravenous fluids, crystalloids or colloids, and blood products can be life saving in those patients who are in severe hemorrhagic shock. The optimal method of resuscitation has not been clearly established. A hemoglobin level of 7-8 g/dl appears to be an appropriate threshold for transfusion in critically ill patients with no evidence of tissue hypoxia. However, maintaining a higher hemoglobin level of 10 g/dl is a reasonable goal in actively bleeding patients, the elderly, or individuals who are at risk for myocardial infarction. Moreover, hemoglobin concentration should not be the only therapeutic guide in actively bleeding patients. Instead, therapy should be aimed at restoring intravascular volume and adequate hemodynamic parameters.","This review paper addresses the mechanisms and treatment of hemorrhagic shock. Hemorrhagic shock is a condition produced by rapid and significant loss of blood. It can lead to abnormal blood pressure, decreases in oxygen delivery, decreased tissue fluid volume, reduced oxygen in cells, organ damage, and death. Hemorrhagic shock can quickly cause death. The primary goals are to stop the bleeding and restore circulating blood volume. Resuscitation (revival) depends on the estimated severity of hemorrhage. Patients with moderate hypotension (decreased blood pressure) from bleeding may benefit by delaying fluid replacement until they reach a definitive care facility. However, the use of restorative fluids and blood products can be life saving in those patients who are in severe hemorrhagic shock. The best method of resuscitation has not been clearly established. A hemoglobin level of 7-8 g/dl is an appropriate threshold for transfusion (transfer) in critically ill patients with no evidence of oxygen depravation in tissues. Hemoglobin is a protein in red blood cells. However, it is the goal to maintain a hemoglobin level of 10 g/dl in actively bleeding patients, the elderly, or individuals who are at risk of having a heart attack. Hemoglobin concentration should not be the only therapeutic guide in actively bleeding patients. Instead, therapy should be aimed at restoring blood volume, blood pressure, and heart rate." +"This review addresses the pathophysiology and treatment of hemorrhagic shock - a condition produced by rapid and significant loss of intravascular volume, which may lead sequentially to hemodynamic instability, decreases in oxygen delivery, decreased tissue perfusion, cellular hypoxia, organ damage, and death. Hemorrhagic shock can be rapidly fatal. The primary goals are to stop the bleeding and to restore circulating blood volume. Resuscitation may well depend on the estimated severity of hemorrhage. It now appears that patients with moderate hypotension from bleeding may benefit by delaying massive fluid resuscitation until they reach a definitive care facility. On the other hand, the use of intravenous fluids, crystalloids or colloids, and blood products can be life saving in those patients who are in severe hemorrhagic shock. The optimal method of resuscitation has not been clearly established. A hemoglobin level of 7-8 g/dl appears to be an appropriate threshold for transfusion in critically ill patients with no evidence of tissue hypoxia. However, maintaining a higher hemoglobin level of 10 g/dl is a reasonable goal in actively bleeding patients, the elderly, or individuals who are at risk for myocardial infarction. Moreover, hemoglobin concentration should not be the only therapeutic guide in actively bleeding patients. Instead, therapy should be aimed at restoring intravascular volume and adequate hemodynamic parameters.","This review articles looks at the disease-related mechanisms and treatment of hemorrhagic shock. It is a condition produced by rapid, significant blood loss, which may cause blood flow instability, decreases in oxygen delivery, reduced flow of molecules in the body, reduced oxygen in cells, organ damage, and death. Hemorrhagic shock can cause a quick death. The main goals are to stop the bleeding and restore the blood amount in the body. Revival may depend on the estimated severity of hemorrhage. It now appears that patients with moderately low blood pressure from bleeding may benefit by delaying massive fluid revival until they reach a special medical center. However, the use of inner-blood-vessel fluids, special crystals or gels, and substances commonly found in blood can be life saving in patients with severe hemorrhagic shock. The best method of revival has not been clearly established. A level of 7-8 gram/deciliter of hemoglobin (an oxygen-carrying component of red blood cells) appears to be a proper amount for transfusion or transfer in critically ill patients with no evidence of reduced oxygen levels in body parts. However, maintaining a higher hemoglobin level of 10 grams/deciliter is a reasonable goal in actively bleeding patients, the elderly, or those at risk for heart attacks. Also, hemoglobin levels should not be the only guide in actively bleeding patients. Instead, therapy should be aimed at restoring blood amount in vessels and blood flow parameters." +"Etiology: Though most commonly thought of in the setting of trauma, there are numerous causes of hemorrhagic shock that span many systems. Blunt or penetrating trauma is the most common cause, followed by upper and lower gastrointestinal sources. Obstetrical, vascular, iatrogenic, and even urological sources have all been described. Bleeding may be either external or internal. A substantial amount of blood loss to the point of hemodynamic compromise may occur in the chest, abdomen, or retroperitoneum. The thigh itself can hold up to 1 L to 2 L of blood. Pathophysiology: Hemorrhagic shock is due to the depletion of intravascular volume through blood loss to the point of being unable to match the tissues demand for oxygen. As a result, mitochondria are no longer able to sustain aerobic metabolism for the production of oxygen and switch to the less efficient anaerobic metabolism to meet the cellular demand for adenosine triphosphate. In the latter process, pyruvate is produced and converted to lactic acid to regenerate nicotinamide adenine dinucleotide (NAD+) to maintain some degree of cellular respiration in the absence of oxygen. The body compensates for volume loss by increasing heart rate and contractility, followed by baroreceptor activation resulting in sympathetic nervous system activation and peripheral vasoconstriction. Typically, there is a slight increase in the diastolic blood pressure with narrowing of the pulse pressure. As diastolic ventricular filling continues to decline and cardiac output decreases, systolic blood pressure drops. Due to sympathetic nervous system activation, blood is diverted away from noncritical organs and tissues to preserve blood supply to vital organs such as the heart and brain. While prolonging heart and brain function, this also leads to other tissues being further deprived of oxygen causing more lactic acid production and worsening acidosis. This worsening acidosis along with hypoxemia, if left uncorrected, eventually causes the loss of peripheral vasoconstriction, worsening hemodynamic compromise, and death. The body�s compensation varies by cardiopulmonary comorbidities, age, and vasoactive medications. Due to these factors, heart rate and blood pressure responses are extremely variable and, therefore, cannot be relied upon as the sole means of diagnosis.","Though most found in trauma cases, there are numerous causes of hemorrhagic (excessive bleeding) shock stemming from various organ systems. Blunt or penetrating trauma (injury) is the most common cause. Additional causes include upper and lower gastrointestinal (stomach) sources. Obstetrical (related to childbirth), vascular (related to blood vessels), iatrogenic (illness caused by medical exams), and even urological (related to the urinary tract) sources have all been described. Bleeding may be either external or internal. A substantial amount of blood loss, to the point of dysregulated (incorrect) blood flow, may occur in the chest, abdomen, or in the retroperitoneum. The retroperitoneum is area in the back of the abdomen not covered by the peritoneum. The thigh can hold up to 1 L to 2 L of blood. Hemorrhagic shock is caused by the blood loss in vessels to the point of being unable to match the tissues demand for oxygen. As a result, mitochondria (cell part responsible for making chemical energy) are unable to sustain metabolisms needed for oxygen production. Mitochondria switch to the less efficient metabolism to meet cell demand. Pyruvate, a chemical product of energy production, is produced and converted to maintain some cellular respiration (energy creation) in the absence of oxygen. The body compensates for volume loss by increasing heart rate and contractions. These alterations are followed by baroreceptor activation, which is the increased activity of receptors to regulate blood pressure. The resulting endpoints are sympathetic nervous system activation (fight-or-flight activation) and constriction of blood vessels. The sympathetic nervous system is responsible for heart rate, blood pressure, breathing rate, and pupil size. There is normally a slight increase in the diastolic blood pressure (when the heart is relaxed) with decreased pulse pressure. As the rate in which the heart fills with blood declines and cardiac output decreases, systolic blood pressure (heart is contracting) drops. Due to sympathetic nervous system activation, blood is moved away from noncritical organs and tissues. This is done to preserve blood supply to vital organs like the heart and brain. While prolonging heart and brain function, this blood movement leads to other tissues being deprived of oxygen. This deprivation can cause more lactic acid production and a build up of acid in the blood. This acid build up along with low blood oxygen, if left uncorrected, eventually causes the loss of peripheral vasoconstriction (narrowed blood vessels), decreased blood flow, and death. How the body handles this varies by accompanying heart and lung diseases, age, and blood pressure medications. Due to these factors, heart rate and blood pressure responses are extremely different between patients. Therefore, heart rate and blood pressure cannot be the sole reasons of diagnosis." +"Introduction: Hemorrhage is the leading cause of preventable death in combat, although early recognition of hemorrhage is still challenging on the battlefield. Hypothesis/Problem: The objective of this study was to describe the shock index (SI) in a healthy military population, and to measure its variation during a controlled blood loss, simulated by blood donation. Methods: A prospective observational study that enrolled military subjects, volunteers for blood donation, was conducted. Demographic and clinical information, concerning both the patient and the blood collection, were recorded. Baseline vital signs were measured, before and after donation, in a 45� supine position. Statistical analysis was performed after calculation of SI. Results: A total of 483 participants were included in the study. The mean blood donation volume was 473mL (SD = 44mL). The median pre- and post-blood donation SI were significantly different: 0.54 (IQR = 0.48-0.63) and 0.57 (IQR = 0.49-0.66), respectively (P = .002). Changes in pre-/post-donation blood pressure (BP) and heart rate (HR) also reached statistical difference but represented a clinically poor relevance. The multivariate analysis showed no significant associations between SI variations and age, sex, body mass index (BMI), sport activities, blood donation volume, and enteral volume replacement (EVR). Conclusion: In this model of mild hemorrhage, SI exhibited significant variations but failed to reach clinical relevance. Further studies are needed to prove the benefit of SI calculation as a possible parameter for early recognition of hemorrhage in combat casualties at the point of injury.","Hemorrhage (excessive bleeding) is the leading cause of preventable death in combat. However, early recognition of hemorrhage is still challenging on the battlefield. The aim of this study was to describe the shock index (SI) in a healthy military population. Additionally, the paper aimed to measure SI variation during a controlled blood loss, simulated by blood donation. A study that enrolled military subjects, volunteers for blood donation, was conducted. Demographic (e.g. age, race) and clinical information, concerning both the patient and the blood collection, were recorded. Vital signs were measured before and after donation. Statistical analysis was performed after calculation of SI. A total of 483 participants were included in the study. The average blood donation volume was 473 mL. The median (average) pre- and post-blood donation SI were significantly different. Changes in pre-/post-donation blood pressure and heart rate were also different. However, the difference was of clinically poor relevance. A statistical analysis showed no significant associations between SI variations and age, sex, body mass index (BMI), sport activities, blood donation volume, and enteral (intestinal) volume replacement (EVR). The study concluding that SI exhibited significant variations (differences) but failed to reach clinical relevance. Further studies are needed to prove the benefit of SI calculation as a possible method of early recognition of hemorrhage in combat casualties." +"Current monitoring technologies are unable to detect early, compensatory changes that are associated with significant blood loss. We previously introduced a novel algorithm to calculate the Compensatory Reserve Index (CRI) based on the analysis of arterial waveform features obtained from photoplethysmogram recordings. In the present study, we hypothesized that the CRI would provide greater sensitivity and specificity to detect blood loss compared with traditional vital signs and other hemodynamic measures. Continuous noninvasive vital sign waveform data, including CRI, photoplethysmogram, heart rate, blood pressures, SpO2, cardiac output, and stroke volume, were analyzed from 20 subjects before, during, and after an average controlled voluntary hemorrhage of ?1.2 L of blood. Compensatory Reserve Index decreased by 33% in a linear fashion across progressive blood volume loss, with no clinically significant alterations in vital signs. The receiver operating characteristic area under the curve for the CRI was 0.90, with a sensitivity of 0.80 and specificity of 0.76. In comparison, blood pressures, heart rate, SpO2, cardiac output, and stroke volume had significantly lower receiver operating characteristic area under the curve values and specificities for detecting the same volume of blood loss. Consistent with our hypothesis, CRI detected blood loss and restoration with significantly greater specificity than did other traditional physiologic measures. Single measurement of CRI may enable more accurate triage, whereas CRI monitoring may allow for earlier detection of casualty deterioration.","Current monitoring technologies are unable to detect early changes associated with significant blood loss. A novel model to calculate the Compensatory Reserve Index (CRI) was previously introduced by the authors in a secondary study. CRI measures physiological reserve, or how an organ responds to stress, which can be used as an indicator of how a patient will respond to intensive care. In the present study, the authors hypothesized that the CRI would provide greater sensitivity and specificity to detect blood loss compared to traditional methods. Vital signs were analyzed from 20 subjects before, during, and after an average controlled voluntary hemorrhage (excessive blood loss) of ?1.2 L of blood. CRI decreased across progressive blood volume loss, with no clinically significant alterations in vital signs. Statistical analysis of CRI showed high confidence in the ability of the test to produce accurate results. In contrast, blood pressures, heart rate, SpO2, cardiac output, and stroke volume had significantly lower confidence for detection and specificity rates. CRI detected blood loss and restoration with greater specificity than did other traditional measures. Single measurement of CRI may enable more accurate assessment of health emergencies. CRI monitoring may allow for earlier detection of declining health." +"Current monitoring technologies are unable to detect early, compensatory changes that are associated with significant blood loss. We previously introduced a novel algorithm to calculate the Compensatory Reserve Index (CRI) based on the analysis of arterial waveform features obtained from photoplethysmogram recordings. In the present study, we hypothesized that the CRI would provide greater sensitivity and specificity to detect blood loss compared with traditional vital signs and other hemodynamic measures. Continuous noninvasive vital sign waveform data, including CRI, photoplethysmogram, heart rate, blood pressures, SpO2, cardiac output, and stroke volume, were analyzed from 20 subjects before, during, and after an average controlled voluntary hemorrhage of ?1.2 L of blood. Compensatory Reserve Index decreased by 33% in a linear fashion across progressive blood volume loss, with no clinically significant alterations in vital signs. The receiver operating characteristic area under the curve for the CRI was 0.90, with a sensitivity of 0.80 and specificity of 0.76. In comparison, blood pressures, heart rate, SpO2, cardiac output, and stroke volume had significantly lower receiver operating characteristic area under the curve values and specificities for detecting the same volume of blood loss. Consistent with our hypothesis, CRI detected blood loss and restoration with significantly greater specificity than did other traditional physiologic measures. Single measurement of CRI may enable more accurate triage, whereas CRI monitoring may allow for earlier detection of casualty deterioration.","Current monitoring technologies cannot detect early, counterbalancing changes associated with significant blood loss. We previously showed a new mathematical equation to calculate the counterbalancing blood flow mechanics or Compensatory Reserve Index (CRI) based on analysis of blood vessel wave patterns from blood flow recordings. In the present study, we theorized that CRI would give better accuracy to detect blood loss compared to standard vital signs and other blood flow measures. We analyzed 20 subjects before, during, and after a regular, controlled voluntary blood loss of 1.2 liters for continuous non-surgical vital sign wave data, including CRI, recordings, heart rate, blood pressure, oxygen levels, blood flow output, and blood volume. CRI decreased by 33% in a linear trend across increasing blood volume loss, with no changes in vital signs. CRI had high accuracy for detecting blood volume loss. In comparison, blood pressure, heart rate, oxygen levels, blood flow output and blood volume had less accuracy for detecting the same amount of blood loss. Consistent with out theory, CRI detected blood loss and restoration better than other traditional body measures. Single measurement of CRI may enable better identification, while CRI monitoring may allow earlier detection of patient status trending towards death." +"Background: We endeavored to develop clinically translatable nonhuman primate (NHP) models of severe polytraumatic hemorrhagic shock. Methods: NHPs were randomized into five severe pressure-targeted hemorrhagic shock (PTHS) � additional injuries scenarios: 30-min PTHS (PTHS-30), 60-min PTHS (PTHS-60), PTHS-60 + soft tissue injury (PTHS-60+ST), PTHS-60+ ST + femur fracture (PTHS-60+ST+FF), and decompensated PTHS+ST+FF (PTHS-D). Physiologic parameters were recorded and blood samples collected at five time points with animal observation through T = 24 h. Results presented as mean � SEM; statistics: log transformation followed by two-way ANOVA with Bonferroni multiple comparisons, Wilcoxon nonparametric test for comparisons, and the Friedmans' one-way ANOVA; significance: P < 0.05. Results: Percent blood loss was 40% � 2, 59% � 3, 52% � 3, 49% � 2, and 54% � 2 for PTHS-30, PTHS-60, PTHS-60+ST, PTHS-60+ST+FF, and PTHS-D, respectively. All animals survived to T = 24 h except one in each of the PTHS-60 and PTHS-60+ST+FF groups and seven in the PTHS-D group. Physiologic, coagulation, and inflammatory parameters demonstrated increasing derangements with increasing model severity. Conclusion: NHPs exhibit a high degree of resilience to hemorrhagic shock and polytrauma as evidenced by moderate perturbations in metabolic, coagulation, and immunologic outcomes with up to 60 min of profound hypotension regardless of injury pattern. Extending the duration of PTHS to the point of decompensation in combination with polytraumatic injury, evoked derangements consistent with those observed in severely injured trauma patients which would require ICU care. Thus, we have successfully established a clinically translatable NHP trauma model for use in testing therapeutic interventions to trauma.","This study aimed to develop nonhuman primate (monkey) (NHP) models of severe polytraumatic (many-injury) hemorrhagic (excessive bleeding) shock that are applicable to human health settings. NHPs were placed into five pressure-targeted hemorrhagic shock (PTHS) scenarios. The scenarios were as follows: 30-min PTHS (PTHS-30), 60-min PTHS (PTHS-60), PTHS-60 + soft tissue injury (PTHS-60+ST), PTHS-60+ ST + femur (leg) fracture (PTHS-60+ST+FF), and decompensated PTHS+ST+FF (PTHS-D). Physiologic parameters were recorded. Blood samples were collected at five time points with animal observation through 24 hours. Blood loss percentages were 40%, 59%, 52%, 49%, and 54% for PTHS-30, PTHS-60, PTHS-60+ST, PTHS-60+ST+FF, and PTHS-D, respectively. All animals survived till the end of the study except one in the PTHS-60 and PTHS-60+ST+FF groups. Seven did not survive till the end of the study in the PTHS-D group. Physiologic (overall health), coagulation (blood clotting), and inflammatory (infection-fighting) parameters showed increased disturbance with increasing model severity. NHPs show a high degree of resilience to hemorrhagic shock and polytrauma (more than one injury). This was shown by moderate disturbances in metabolic, coagulation, and immunologic outcomes with low blood pressure in all injury groups. Increasing PTHS duration to the point of organ failure with polytraumatic injury, evoked (led to) disturbances consistent with those observed in severely injured trauma patients requiring ICU care. This study has successfully established a clinically translatable NHP trauma model for use in testing therapeutic interventions to trauma." +"Uncontrolled bleeding is the leading cause of shock in trauma patients and delays in recognition and treatment have been linked to adverse outcomes. For prompt detection and management of hypovolaemic shock, ATLS(�) suggests four shock classes based upon vital signs and an estimated blood loss in percent. Although this classification has been widely implemented over the past decades, there is still no clear prospective evidence to fully support this classification. In contrast, it has recently been shown that this classification may be associated with substantial deficits. A retrospective analysis of data derived from the TraumaRegister DGU(�) indicated that only 9.3% of all trauma patients could be allocated into one of the ATLS(�) shock classes when a combination of the three vital signs heart rate, systolic blood pressure and Glasgow Coma Scale was assessed. Consequently, more than 90% of all trauma patients could not be classified according to the ATLS(�) classification of hypovolaemic shock. Further analyses including also data from the UK-based TARN registry suggested that ATLS(�) may overestimate the degree of tachycardia associated with hypotension and underestimate mental disability in the presence of hypovolaemic shock. This finding was independent from pre-hospital treatment as well as from the presence or absence of a severe traumatic brain injury. Interestingly, even the underlying trauma mechanism (blunt or penetrating) had no influence on the number of patients who could be allocated adequately. Considering these potential deficits associated with the ATLS(�) classification of hypovolaemic shock, an online survey among 383 European ATLS(�) course instructors and directors was performed to assess the actual appreciation and confidence in this tool during daily clinical trauma care. Interestingly, less than half (48%) of all respondents declared that they would assess a potential circulatory depletion within the primary survey according to the ATLS(�) classification of hypovolaemic shock. Based on these observations, a critical reappraisal of the current ATLS(�) classification of hypovolaemic seems warranted.","Uncontrolled bleeding is the leading cause of shock in trauma patients. Delays in recognition and treatment have been linked to adverse outcomes. For quick detection and management of hypovolemic shock, ATLS(�) suggests four shock classes. These classes are based upon vital signs and an estimated blood loss in percent. Hypovolemic shock is due to volume loss with blood vessels or blood vascular system. Although this classification has been widely used, there is no clear evidence to fully support this classification. In contrast, it has recently been shown that this classification may be associated with substantial deficits. Evaluation of data derived from the TraumaRegister DGU(�) indicated only 9.3% of all trauma patients could be placed into one of the ATLS(�) shock classes when a combination of the three vital signs was assessed (measured). Because of this, more than 90% of all trauma patients could not be classified according to the ATLS(�) classification of hypovolemic shock. Further review included data from the UK-based TARN registry. This evaluation suggested that ATLS(�) may overestimate the degree of tachycardia (high heart rate) associated with low blood pressure and underestimate mental disability in the presence of hypovolemic shock. This finding was independent from pre-hospital treatment and from the presence or absence of a severe traumatic brain injury. The underlying trauma mechanism, or what caused the injury, had no influence on the number of patients who could be categorized. Considering these potential gaps associated with the ATLS(�) classification of hypovolemic shock, an online survey was conducted. The survey assessed 383 European ATLS(�) course instructors and directors. The survey was completed to assess the understanding and confidence in this tool during daily clinical trauma care. Less than half of all respondents declared that they would assess a potential circulatory depletion within the primary survey according to the ATLS(�) classification of hypovolemic shock. Based on these observations, a critical reappraisal (revision) of the current ATLS(�) classification of hypovolemic is needed." +"Background: Effect of nifedipine on pressure ulcer (PU) healing has not been evaluated in the human subjects yet. Study question: In this study, the effect of topical application of nifedipine 3% ointment on PU healing in critically ill patients was investigated. Study design: This was a randomized, double-blind, placebo-controlled clinical. Measures and outcomes: In this study, 200 patients with stage I or II PU according to 2-digit Stirling Pressure Ulcer Severity Scale were randomized to receive topical nifedipine 3% ointment or placebo twice daily for 14 days. Changes in the size and stage of the ulcers were considered as primary outcome of the study. The stage of the ulcers at baseline and on day 7 and day 14 of study was determined by using 2-digit stirling scale. In addition, the surface area of the wounds was estimated by multiplying width by length. Results: In total, 83 patients in each group completed the study. The groups were matched for the baseline stage and size of PUs. Mean decrease in the stage of PU in the nifedipine group was significantly higher than the placebo group on day 7 (-1.71 vs. -0.16, respectively, P < 0.001) and day 14 (-0.78 vs. -0.09, respectively, P < 0.001). Furthermore, the mean decrease in the surface area of PU was significantly higher in the nifedipine group compared with the placebo group on day 7 (-1.44 vs. -0.32, respectively, P < 0.001) and day 14 (-2.51 vs. -0.24, respectively, P < 0.001) of study. Conclusions: Topical application of nifedipine 3% ointment for 14 days significantly improved the healing process of stage I or II PUs in critically ill patients.","Scientists have not yet measured the effect of nifedipine, a drug to treat high blood pressure and chest pain, on bedsores in humans. In this study, we looked at the effect of applying nifedipine 3% ointment to the skin on bedsore healing in critically ill patients. This was a medical study involving human participants in which neither side knew who was getting what treatment and ointment with no medicine was given to a control group. In this study, we randomly gave 200 patients with stage I or II, according to a common scoring system to measure the severity of bedsores, nifedipine ointment applied to the skin or ointment with no medicine two times a day for 14 days. The most important outcome was changes in the size and stage of bedsores. We used the bedsore scoring scale to measure bedsore stage at the beginning of the study and on study days 7 and 14. We estimated the surface area of the bedsores by multiplying width by length. In total, 83 patients in each group completed the study. We compared patients with similar bedsore stage and size at the beginning of the study. The group given nifedipine had significantly higher average decrease in bedsore stage than the group not given nifedipine on days 7 and 14. The group given nifedipine had significantly higher average decrease in bedsore surface area than the group not given nifedipine on days 7 and 14. We conclude that nifedipine 3% ointment applied to the skin for 14 days significantly improved the healing process of stage I or II bedsores in critically ill patients." +"Background: Effect of nifedipine on pressure ulcer (PU) healing has not been evaluated in the human subjects yet. Study question: In this study, the effect of topical application of nifedipine 3% ointment on PU healing in critically ill patients was investigated. Study design: This was a randomized, double-blind, placebo-controlled clinical. Measures and outcomes: In this study, 200 patients with stage I or II PU according to 2-digit Stirling Pressure Ulcer Severity Scale were randomized to receive topical nifedipine 3% ointment or placebo twice daily for 14 days. Changes in the size and stage of the ulcers were considered as primary outcome of the study. The stage of the ulcers at baseline and on day 7 and day 14 of study was determined by using 2-digit stirling scale. In addition, the surface area of the wounds was estimated by multiplying width by length. Results: In total, 83 patients in each group completed the study. The groups were matched for the baseline stage and size of PUs. Mean decrease in the stage of PU in the nifedipine group was significantly higher than the placebo group on day 7 (-1.71 vs. -0.16, respectively, P < 0.001) and day 14 (-0.78 vs. -0.09, respectively, P < 0.001). Furthermore, the mean decrease in the surface area of PU was significantly higher in the nifedipine group compared with the placebo group on day 7 (-1.44 vs. -0.32, respectively, P < 0.001) and day 14 (-2.51 vs. -0.24, respectively, P < 0.001) of study. Conclusions: Topical application of nifedipine 3% ointment for 14 days significantly improved the healing process of stage I or II PUs in critically ill patients.","The effect of nifedipine (a common vasodilator medication that widens blood vessels) on pressure ulcers (PU), or bedsores, has not been measured in humans. In this study, the effect of skin-level application of nifedipine 3% ointment on PU healing in very ill patients was investigated. This was a randomized study with a sham treatment group. In this study, 200 patients with mild and moderate PU were randomzed to receive topical nifedipine 3% ointment or dummy treatment twice daily for 14 days. Changes in the size and severity of ulcers were the main measures of the study. The severity of ulcers at baseline, on day 7, and on day 14 of the study was measured. Also, the area of the wounds was estimated by multiplying width by length. In total, 83 patients in each group completed the study. The groups were matched for starting severity and size of PUs. Average decrease in the severity of PU in the nifedipine group was higher than the dummy treatment group on day 7 and day 14. Also, the average decrease in the area of PU was higher in the nifedipine group compared with the sham treatment group on day 7 and 14 of the study. Skin-level application of nifedipine 3% ointment for 14 days improved the healing process of mild or moderate PUs in very ill patients." +"Chronic wounds unresponsive to existing treatments constitute a serious disease burden. Factors that contribute to the pathogenesis of chronic ulcers include oxidative stress, comorbid microbial infections, and the type of immune system response. Preclinically, and in a case study, a formulation containing a Ceratothoa oestroides olive oil extract promoted wound healing. Patients with chronic venous and pressure ulcers, clinically assessed as being unresponsive to healing agents, were treated for 3 months with an ointment containing the C oestroides extract combined with antibiotic and/or antiseptic agents chosen according to the type of bacterial infection. Treatment evaluation was performed using the Bates-Jensen criteria with +WoundDesk and MOWA cell phone applications. After 3 months of treatment, C oestroides resulted in an average decrease of 36% in the Bates-Jensen score of ulcers (P < .000), with the decrease being significant from the first month (P < .007). The combined use of topically applied antibiotics and antiseptics efficiently controlled microbial ulcer infection and facilitated wound healing. In relation to other factors such as initial wound size, chronicity appeared to be an important prognostic factor regarding the extent of wound healing. Future clinical investigations assessing the wound healing efficacy of the C oestroides olive oil extract are warranted.","Long-lasting wounds that do not respond to available treatments have serious impacts. Things that determine how bedsores progress include low antioxidant levels, other infections caused by microbes (microorganisms), and the type of immune system response. Before symptoms, and in a detailed study, a mixture containing a Ceratothoa oestroides (fish parasite) olive oil extract increased wound healing. Patients with long-lasting leg ulcers (sores) due to blood flow problems and bedsores, determined by doctors as not responding to healing treatments, were treated for 3 months with an ointment with C oestroides extract combined with antibiotics (kill bacteria) and/or antiseptics (slow bacteria growth) based on type of bacterial infection. We evaluated treatment using a common tool used to track wound healing with two cell phone apps. After 3 months of treatment, C oestroides caused an average score decrease of 36% on a common tool used to track wound healing. Applying both antibiotics and antiseptics controlled ulcer infection by microorganisms and helped wound healing. Compared to things like initial wound size, how long lasting the wound was seemed to be an important factor in predicting how much the wound healed. Future studies looking at how well C oestroides olive oil extract works to heal wounds are needed." +"Products that provide a protective skin barrier play a vital role in defending the skin against the corrosive effect of bodily fluids, including wound exudate, urine, liquid faeces, stoma output and sweat. There are many products to choose from, which can be broadly categorised by ingredients. This article describes the differences in mechanisms of action between barrier products comprising petrolatum and/or zinc oxide, silicone film-forming polymers and cyanoacrylates, and compares the evidence on them. The literature indicates that all types of barrier product are clinically effective, with little comparative evidence indicating that any one ingredient is more efficacious than another, although film-forming polymers and cyanoacrylates have been found to be easier to apply and more cost-effective. However, laboratory evidence, albeit limited, indicates that a concentrated cyanoacrylate produced a more substantial and adherent layer on a porcine explant when compared with a diluted cyanoacrylate and was more effective at protecting skin from abrasion and repeated exposure to moisture than a film-forming polymer. Finally, a silicone-based cream containing micronutrients was found to significantly reduce the incidence of pressure ulceration when used as part of a comprehensive prevention strategy.","Products that serve as a barrier to protect the skin are important in defending the skin against chemically damaging effects of bodily fluids, including fluid produced from the healing process, urine, liquid faeces, output from an opening in the body and sweat. Many treatments exist, which can be grouped based on ingredients. This study describes the differences in how barrier products work, including petroleum jelly (Vaseline) and/or zinc oxide, polymers (substances made of very large molecules) that form silicone (type of polymer) film, and cyanoacrylates (group of strong fast-acting adhesives). Studies suggest all barrier products work, with few studies that compare ingredients to show one works better than another. Film-forming polymers and cyanoacrylates are easier to apply and cost less. Limited lab data suggest that a concentrated cyanoacrylate made a more notable layer that stuck more to pig tissue than a less-concentrated cyanoacrylate and protected the skin from rubbing and moisture better than a film-forming polymer. Finally, a silicon-based cream with vitamins and minerals needed by the body in very small amounts significantly reduced bedsore occurrence when used with other approaches." +"Objective: To evaluate the effectiveness of topical pentoxifylline (PTX) on pressure ulcer (PU) healing in critically ill patients. Method: In this randomised, double blind, placebo-controlled clinical trial, patients with category I or II PUs were randomly assigned to receive either topical PTX 5% or a placebo twice daily for 14 days. Changes in PU characteristics (category and size) were assessed. The category of the PU was determined by the Stirling Pressure Ulcer Severity Scale (two-digit) at baseline (day zero), day seven and day 14 of treatment. PU length and width was measured with a disposable ruler and expressed as cm2. Results: A total of 112 adult patients were enrolled in the study. Median PU size and score at day zero were 32 (10.00-69.33)cm2 and 1(1.00-2.00) respectively. In the PTX group, the mean differences (95% confidence interval, CI) of all PU scores and sizes decreased significantly across the intervals (day seven versus day zero, day 14 versus day zero, and day 14 versus day seven), compared with the placebo group Conclusion: The severity and size of PUs improved significantly in patients who received topical PTX 5% ointment twice a day for 14 days compared with those in the placebo group. Topical PTX may be considered as a potential option in the treatment of categories I and II PUs in critically ill patients.","We aimed to rate how well pentoxifylline (PTX) applied to the skin worked to heal bedsores in critically ill patients. This was a medical study involving human participants in which neither side knew who was getting what treatment, and either PTX 5% or ointment with no medicine was applied to the skin twice a day for 14 days. We measured changes in bedsore category and size. We used a common scoring system to measure the severity of bedsores and bedsore stage at the beginning of the study and on study days 7 and 14. We measured bedsore length and width with a disposable ruler. We studied a total of 112 adult patients. Median (average) bedsore size and score at the beginning of the study were 32cm2 and 1, respectively. The average differences of bedsore scores and sizes decreased significantly between measurement days (day seven versus day zero, day 14 versus day zero, and day 14 versus day seven) compared to the ointment with no medicine. We conclude that the seriousness and size of bedsores improved significantly in patients who received PTX 5% ointment applied to the skin twice a day for 14 days compared to those who received ointment with no medicine. PTX applied to the skin may be a potential treatment option for stage I or II bedsores in critically ill patients." +"Objective: To evaluate the effectiveness of topical pentoxifylline (PTX) on pressure ulcer (PU) healing in critically ill patients. Method: In this randomised, double blind, placebo-controlled clinical trial, patients with category I or II PUs were randomly assigned to receive either topical PTX 5% or a placebo twice daily for 14 days. Changes in PU characteristics (category and size) were assessed. The category of the PU was determined by the Stirling Pressure Ulcer Severity Scale (two-digit) at baseline (day zero), day seven and day 14 of treatment. PU length and width was measured with a disposable ruler and expressed as cm2. Results: A total of 112 adult patients were enrolled in the study. Median PU size and score at day zero were 32 (10.00-69.33)cm2 and 1(1.00-2.00) respectively. In the PTX group, the mean differences (95% confidence interval, CI) of all PU scores and sizes decreased significantly across the intervals (day seven versus day zero, day 14 versus day zero, and day 14 versus day seven), compared with the placebo group Conclusion: The severity and size of PUs improved significantly in patients who received topical PTX 5% ointment twice a day for 14 days compared with those in the placebo group. Topical PTX may be considered as a potential option in the treatment of categories I and II PUs in critically ill patients.","The study's objective is to evaulate the success of topical pentoxifylline (PTX) (a blood flow medication) on pressure ulcer (PU), or bedsore, healing in very ill patients. In this study, patients with mild or moderate PUs were randomly assigned to receive either skin-level PTX 5% or a sham treatment twice daily for 14 days. Changes in PU (severity and size) were measured. The severity of PU was determined with a special scale at starting (day zero), day seven, and day 14 of the treatment. PU length and width was measured with a ruler in cm2. 112 adult patients enrolled in the study. Average PU size and score at day 0 were 32 cm2 and 1 respectively. In the PTX group, the average differences of all PU scores and sizes decreased greatly across the intervals (day seven vs day zero, day 14 vs day zero, and day 14 vs day seven), compared with the sham treatment group. The severity and size of PUs improved greatly in patients who received skin-level PTX 5% ointment twice a day for 14 days compared to those in the dummy treatment group. Skin-level PTX may be a possible option to treat mild and moderate PUs in very ill patients." +"Aims: To describe the utilization of clostridial collagenase ointment (CCO) and medicinal honey debridement methods in real-world inpatient and outpatient hospital settings among pressure ulcer (PU) patients and compare the frequency of healthcare re-encounters between CCO- and medicinal honey-treated patients. Materials and methods: De-identified hospital discharge records for patients receiving CCO or medicinal honey methods of debridement and having an ICD-9 code for PU were extracted from the US Premier Healthcare Database. Multivariable analysis was used to compare the frequency of inpatient and outpatient revisits up to 6 months after an index encounter for CCO- vs medicinal honey-treated PUs. Results: The study identified 48,267 inpatients and 2,599 outpatients with PUs treated with CCO or medicinal honeys. Among study inpatients, n = 44,725 (93%) were treated with CCO, and n = 3,542 (7%) with medicinal honeys. CCO and medicinal honeys accounted for 1,826 (70%) and 773 (30%), respectively, of study outpatients. In adjusted models, those treated with CCO had lower odds for inpatient readmissions (OR = 0.86, 95% CI = 0.80-0.94) after inpatient index visits, and outpatient re-encounters both after inpatient (OR = 0.73, 95% CI = 0.67-0.79) and outpatient (OR = 0.78, 95% CI = 0.64-0.95) index visits in 6 months of follow-up. Limitations: The study was observational in nature, and did not adjust for reasons why patients were hospitalized initially, or why they returned to the facility. Although the study adjusted for differences in a variety of demographic, clinical, and hospital characteristics between the treatments, we are not able to rule out selection bias. Conclusion: Patients with CCO-treated PUs returned to inpatient and outpatient hospital settings less often compared with medicinal honey-treated PUs. These results from real-world administrative data help to gain a better understanding of the clinical characteristics of patients with PUs treated with these two debridement methods and the economic implications of debridement choice in the acute care setting.","We aim to describe the use of clostridial collagenase ointment (CCO - a medication with special proteins) and medical honey to remove damaged tissue in hospitals among bedsore patients and compare how often CCO- and medical honey-treated patients return to the hospital. We obtained hospital discharge records from a national database for patients getting CCO or medical honey methods of removing damaged tissues with an official diagnosis of bedsores. We used statistical models to compare how often patients who did and did not stay at least one night in the hospital returned to the hospital up to 6 months after bedsore treatment with either CCO or medical honey. We looked at 48,267 and 2,599 patients with bedsores treated with CCO or medicine honeys who did and did not stay at least one night at the hospital, respectively. CCO and medical honeys made up 44,725 (93%) and 3,542 (7%), respectively, of people who stayed at least one night in the hospital. CCO and medical honeys made up 1,826 (70%) and 773 (30%), respectively, of people who did not stay a night in the hospital. Based on models, patients treated with CCO were less likely to be readmitted to the hospital after being admitted, and to return to the hospital but not stay a night after either going to the hospital and staying or not staying at least one night over the following 6 months. Study limitations included not considering why patients were hospitalized or why they returned to the hospital. Even though we took into account differences in many population, clinical, and hospital characteristics between the treatments, the study population may have not been completely random. We conclude that bedsore patients treated with CCO returned to the hospital less often than those treated with medical honey. These results based on real-world data help us better understand treatment characteristics of bedsore patients related with these two days to remove damaged tissue and connect to method costs related to short-term care." +"Background: Pressure ulcers often seriously affect the quality of life of patients. Moist Exposed Burn Ointment (MEBO) has been developed to treat patients with pressure ulcers. The present study aimed to evaluate the efficacy and safety of MEBO in the treatment of pressure ulcers in Chinese patients. Methods: Seventy-two patients with pressure ulcers were randomly assigned to 2 groups who received a placebo or MEBO for 2 months. The primary outcomes included the wound surface area (WSA) and pressure ulcer scale for healing (PUSH) tool. The secondary outcomes included a visual analog scale (VAS), questionnaire of ulcer status, and adverse effects. Results: Sixty-seven patients completed the study. After 2 months of treatment, the difference of mean change from the baseline was greater for MEBO (vs placebo) for WSA mean (SD) -6.0 (-8.8, -3.3), PUSH Tool -2.6 (-4.7, -1.5), and VAS score -2.9 (-4.4, -1.7). On the basis of the questionnaire, the pressure ulcers were ""completely healed"" (50.0% vs 16.7%) (P < .05) in patients after 2 months of treatment with MEBO versus placebo. No major adverse effects were found in the 2 groups. Conclusion: We showed that MEBO is effective and well tolerated for improving wound healing in Chinese patients with pressure ulcers.","Bedsores often seriously affect the quality of life of patients. Bedsores can be treated with Moist Exposed Burn Ointment (MEBO). Our study aimed to rate how well MEBO works and how safe MEBO is in the treatment of bedsores in Chinese patients. We randomly put 72 bedsore patients in two groups and gave them MEBO or ointment with no medicine for 2 months. The most important outcomes were wound surface area and a common bedsore scoring tool. We also looked at a common scoring tool for pain, questionnaire of ulcer (sore) status, and side effects. Sixty-seven patients did the study. After 2 months of treatment, MEBO resulted in a greater average change from the beginning of the study compared to ointment with no medicine for wound surface area and both scoring tools. The questionnaire indicated MEBO ""completely healed"" bedsores in patients after 2 months of treatment versus ointment with no medicine. We found no major side effects in the 2 groups. We showed that MEBO works with no major side effects for improving would healing in Chinese patients with bedsores." +"Background: Pressure ulcers, also known as bedsores, decubitus ulcers and pressure injuries, are localised areas of injury to the skin or the underlying tissue, or both. Dressings are widely used to treat pressure ulcers and promote healing, and there are many options to choose from including alginate, hydrocolloid and protease-modulating dressings. Topical agents have also been used as alternatives to dressings in order to promote healing. A clear and current overview of all the evidence is required to facilitate decision-making regarding the use of dressings or topical agents for the treatment of pressure ulcers. Such a review would ideally help people with pressure ulcers and health professionals assess the best treatment options. This review is a network meta-analysis (NMA) which assesses the probability of complete ulcer healing associated with alternative dressings and topical agents. Main results: We included 51 studies (2947 participants) in this review and carried out NMA in a network of linked interventions for the sole outcome of probability of complete healing. The network included 21 different interventions (13 dressings, 6 topical agents and 2 supplementary linking interventions) and was informed by 39 studies in 2127 participants, of whom 783 had completely healed wounds. We judged the network to be sparse: overall, there were relatively few participants, with few events, both for the number of interventions and the number of mixed treatment contrasts; most studies were small or very small. The consequence of this sparseness is high imprecision in the evidence, and this, coupled with the (mainly) high risk of bias in the studies informing the network, means that we judged the vast majority of the evidence to be of low or very low certainty. We have no confidence in the findings regarding the rank order of interventions in this review (very low-certainty evidence), but we report here a summary of results for some comparisons of interventions compared with saline gauze. We present here only the findings from evidence which we did not consider to be very low certainty, but these reported results should still be interpreted in the context of the very low certainty of the network as a whole. It is not clear whether regimens involving protease-modulating dressings increase the probability of pressure ulcer healing compared with saline gauze (risk ratio (RR) 1.65, 95% confidence interval (CI) 0.92 to 2.94) (moderate-certainty evidence: low risk of bias, downgraded for imprecision). This risk ratio of 1.65 corresponds to an absolute difference of 102 more people healed with protease modulating dressings per 1000 people treated than with saline gauze alone (95% CI 13 fewer to 302 more). It is unclear whether the following interventions increase the probability of healing compared with saline gauze (low-certainty evidence): collagenase ointment (RR 2.12, 95% CI 1.06 to 4.22); foam dressings (RR 1.52, 95% CI 1.03 to 2.26); basic wound contact dressings (RR 1.30, 95% CI 0.65 to 2.58) and polyvinylpyrrolidone plus zinc oxide (RR 1.31, 95% CI 0.37 to 4.62); the latter two interventions both had confidence intervals consistent with both a clinically important benefit and a clinically important harm, and the former two interventions each had high risk of bias as well as imprecision. Authors' conclusions: A network meta-analysis (NMA) of data from 39 studies (evaluating 21 dressings and topical agents for pressure ulcers) is sparse and the evidence is of low or very low certainty (due mainly to risk of bias and imprecision). Consequently we are unable to determine which dressings or topical agents are the most likely to heal pressure ulcers, and it is generally unclear whether the treatments examined are more effective than saline gauze. More research is needed to determine whether particular dressings or topical agents improve the probability of healing of pressure ulcers. The NMA is uninformative regarding which interventions might best be included in a large trial, and it may be that research is directed towards prevention, leaving clinicians to decide which treatment to use on the basis of wound symptoms, clinical experience, patient preference and cost.","Bedsores are areas of injury to the skin or underlying tissue, or both, found in a certain part of the body. Doctors often use dressings to treat bedsores and promote healing, and there are many options to choose from. Doctors have also used medications applied to the skin instead of dressings to promote healing. A clear and current summary of the scientific data is needed to help make decisions about the use of dressings or medicines applied to the skin to treat bedsores. This review would ideally help people with bedsores and doctors decide the best treatment options. This review compares multiple studies to measure the likelihood of complete ulcer (bedsore) healing based on different dressings and medicines applied to the skin. We included 51 studies (2947 people) in this review and compared treatments based on the likelihood of complete healing. We compared 21 different treatments (13 dressings, 6 medicines applied to the skin and 2 mixed treatments) and looked at 39 studies in 2127 people, 783 of whom had completely healed wounds. We thought the data were limited, with relatively few participants, with few wounds, both for the number of treatments and the number of mixed treatments, and mostly small or very small studies. We thought that most of the data were low or very low quality due to unclear data combined with high likelihood of misleading results. We are not sure our ranking of interventions (treatments) is correct, but we summarize our results to compare treatments to saline gauze often used to as a wound dressing. We report only results from data we did not think was low quality, but these reported results should be considered keeping in mind the overall low certainty of data used. We are not sure whether protease-modulating (protein-altering) dressings increased the likelihood of bedsore healing compared to saline gauze. For every 1000 people, 102 more people healed with protease modulating dressings than people treated with only saline gauze. We are not sure collagenase (enzyme) ointment, foam dressings, basic wound contact dressings, and polyvinylpyrrolidone (water-soluble biological molecule) plus zinc oxide increased the likelihood of bedsore healing compared to saline gauze. We conclude that comparing data from 39 studies (rating 21 dressings and medicines applied to the skin for bedsores) is limited and the data are not reliable (due to unclear data and high likelihood of misleading results). Therefore, we cannot tell which dressings or medicines applied to the skin are the most likely to heal bedsores nor whether the treatments we looked at work better than saline gauze. More research is needed to find out whether certain dressings or medicines applied to the skin improve the likelihood of bedsore healing. Our study does not help decide which treatments might best be part of a large trial, and studies may need to focus on prevention, leaving doctors to decide which treatment to use based on wound symptoms, professional experience, what the patients want and cost." +"Background: Pressure ulcers, also known as bedsores, decubitus ulcers and pressure injuries, are localised areas of injury to the skin or the underlying tissue, or both. Dressings are widely used to treat pressure ulcers and promote healing, and there are many options to choose from including alginate, hydrocolloid and protease-modulating dressings. Topical agents have also been used as alternatives to dressings in order to promote healing. A clear and current overview of all the evidence is required to facilitate decision-making regarding the use of dressings or topical agents for the treatment of pressure ulcers. Such a review would ideally help people with pressure ulcers and health professionals assess the best treatment options. This review is a network meta-analysis (NMA) which assesses the probability of complete ulcer healing associated with alternative dressings and topical agents. Main results: We included 51 studies (2947 participants) in this review and carried out NMA in a network of linked interventions for the sole outcome of probability of complete healing. The network included 21 different interventions (13 dressings, 6 topical agents and 2 supplementary linking interventions) and was informed by 39 studies in 2127 participants, of whom 783 had completely healed wounds. We judged the network to be sparse: overall, there were relatively few participants, with few events, both for the number of interventions and the number of mixed treatment contrasts; most studies were small or very small. The consequence of this sparseness is high imprecision in the evidence, and this, coupled with the (mainly) high risk of bias in the studies informing the network, means that we judged the vast majority of the evidence to be of low or very low certainty. We have no confidence in the findings regarding the rank order of interventions in this review (very low-certainty evidence), but we report here a summary of results for some comparisons of interventions compared with saline gauze. We present here only the findings from evidence which we did not consider to be very low certainty, but these reported results should still be interpreted in the context of the very low certainty of the network as a whole. It is not clear whether regimens involving protease-modulating dressings increase the probability of pressure ulcer healing compared with saline gauze (risk ratio (RR) 1.65, 95% confidence interval (CI) 0.92 to 2.94) (moderate-certainty evidence: low risk of bias, downgraded for imprecision). This risk ratio of 1.65 corresponds to an absolute difference of 102 more people healed with protease modulating dressings per 1000 people treated than with saline gauze alone (95% CI 13 fewer to 302 more). It is unclear whether the following interventions increase the probability of healing compared with saline gauze (low-certainty evidence): collagenase ointment (RR 2.12, 95% CI 1.06 to 4.22); foam dressings (RR 1.52, 95% CI 1.03 to 2.26); basic wound contact dressings (RR 1.30, 95% CI 0.65 to 2.58) and polyvinylpyrrolidone plus zinc oxide (RR 1.31, 95% CI 0.37 to 4.62); the latter two interventions both had confidence intervals consistent with both a clinically important benefit and a clinically important harm, and the former two interventions each had high risk of bias as well as imprecision. Authors' conclusions: A network meta-analysis (NMA) of data from 39 studies (evaluating 21 dressings and topical agents for pressure ulcers) is sparse and the evidence is of low or very low certainty (due mainly to risk of bias and imprecision). Consequently we are unable to determine which dressings or topical agents are the most likely to heal pressure ulcers, and it is generally unclear whether the treatments examined are more effective than saline gauze. More research is needed to determine whether particular dressings or topical agents improve the probability of healing of pressure ulcers. The NMA is uninformative regarding which interventions might best be included in a large trial, and it may be that research is directed towards prevention, leaving clinicians to decide which treatment to use on the basis of wound symptoms, clinical experience, patient preference and cost.","Pressure ulcers, or bedsores, decubitus ulcers and pressure injuries are restricted areas of injury to the skin or underlying body tissue, or both. Dressings (ointment or gauze to cover wounds) are widely used to treat pressure ulcers and promote healing. THere are many varied dressings to choose from. Skin-level agents also have been used as alternatives to dressings for healing. A clear and current overview of all the evidence is required to help make decisions regarding using dressings or skin-level agents to treat pressure ulcers. This review would ideally help those with pressure ulcers and health professionals choose treatments. This review is a study which assesses the probability of complete ulcer healing associated with alternative dressings and skin-level treatments. We included 51 studies (2947 participants) in this review and analyzed the treatments solely to measure the probability of complete healing. The study included 21 different treatments (13 dressings, 6 skin-level treatments, and 2 additional linking treatments). It included data from 39 studies in 2127 participants, of whom 783 had completely healed wounds. We judged the study network to be scattered. Overall, there were few participants, with few events, both for number of treatments and mixed treatment analysis. Most studies were small or very small. The effect of this sparseness is low reliability in the evidence. This, along with the (mainly) high risk of bias (or prejudice) in the studies, means we judged the majority of evidence to be low or very low quality. We have no confidence in the results regarding the rank order of treatments in this review (very low-quality evidence), but we report a summary of results for some comparisons of treatments compared with standard gauze. We present here only results from evidence we did not consdier to be very low quality, but the reported results should be interpreted while knowing of the very low quality regarding the whole study network. It is not clear if treatments with special protein-breakdown dressings increase the probability of pressure ulcer healing compared with standard gauze. 102 more people were healed with special protein-breakdown dressings per 1000 people than those with standard gauze alone. It is unclear if any of the other treatments examined increase the probability of healing compared with standard gauze (low-quality evidence). Some showed metrics consistent with a clinically important benefit and harm. Others had a high risk of bias and unreliability. A large analysis of data from 39 studies (examining 21 dressings and skin-level agents for pressure ulcers) is scattered. The evidence is also of low or very low quality (due to risk of bias and unreliability). Therefore, we are unable to determine which dressings or skin-level agents are best to heal pressure ulcers. It is unclear whether the treatments are more effective than standard gauze. More research is needed to tell if certain dressings or skin-level agents improve the chance of healing for pressure ulcers. This analysis is uninformative regarding which treatments may best be included in a large trial. It may that research is focused on prevention, leaving clinicians to decide which treatment to use based on wound symptoms, clinical experience, patient preference and cost." +"Objective: The aim of this study was to investigate the effect of Ma Yinglong Shexiang Hemorrhoids Cream combined with pearl powder on pain and complications in patients with severe pressure ulcers. Methods: One hundred seventeen patients with severe pressure ulcers hospitalized and treated in our hospital (January 2019--December 2019) were divided into Ma Yinglong Musk Hemorrhoid Cream Group (MY Group), Pearl Powder Group (PP Group), and combination with Ma Yinglong Musk Hemorrhoid Cream and Pearl Powder Group (MP group), 39 patients in each group. There was no significant difference in the general data of patients in MY group, PP group, and MP group. By analyzing the differences in clinical efficacy, secondary effects, scar incidence, pain, and clinical indicators of patients in the MY group, PP group, and MP group, the effects of Mayinglong Shexiang Hemorrhoid Cream combined with pearl powder in the treatment of pain and complications in patients with severe pressure ulcers were explored. Results: After treatment, compared with the MY group and the PP group, the MP group had a higher clinical efficacy than the MY group and the PP group. Compared with MY group and PP group, the healing time, dressing change times, and dressing change time of MP group were better than MY group (P < .05). After treatment, the VAS score and incidence of secondary effects of the MP group was significantly lower than that of the MY group and PP group (P < .05). The incidence and area of scar formation in the MP group were lower than those in the MY group and the PP group (P < .05). Conclusion: Compared with Ma Yinglong Musk Hemorrhoid Cream or Pearl Powder, combination of Ma Yinglong Musk Hemorrhoid Cream and Pearl Powder are more effective in treating severe pressure ulcer patients, and can significantly reduce the pain in the affected area and reduce the occurrence of complications.","We aimed to study the effect of Ma Yinglong Shexiang Hemorrhoids Cream combined with pearl powder on pain and side effects in patients with serious bedsores. We divided 117 patients hospitalized with serious bedsores in our hospital (January 2019-December 2019) into the Ma Yinglong Musk Hemorrhoid Cream Group (MY Group), Pearl Powder Group (PP Group), and combination with Ma Yinglong Musk Hemorrhoid Cream and Pearl Powder Group (MP group), 39 patients in each group. Patients in the three groups generally were similar. We looked at the effects of Mayinglong Shexiang Hemorrhoid Cream combined with pearl powder in the treatment of pain and side effects in patients with serious bedsores based on differences in how well a treatment works, side effects, scar occurrence, pain, and quality of care of patients in the MY, PP, and MP groups. The MP group treatment worked better than the MY and PP groups. The MP group had better healing time and dressing change times than the MY group. The MP group had a better score on a common scoring tool for pain and fewer side effects than the MY and PP groups. The MP group had less occurrence of scars and smaller scar area than the MY and PP groups. A combination of Ma Yinglong Musk Hemorrhoid Cream and Pearl Powder worked better than either treatment by itself in treating severe bedsore patients, and can significantly reduce pain in the affected area and side effects." +"Pressure ulcer (PU) is a worldwide problem that is hard to heal because of its prolonged inflammatory response and impaired ECM deposition caused by local hypoxia and repeated ischemia/reperfusion. Our previous study discovered that the non-fouling zwitterionic sulfated poly (sulfobetaine methacrylate) (SBMA) hydrogel can improve PU healing with rapid ECM rebuilding. However, the mechanism of the SBMA hydrogel in promoting ECM rebuilding is unclear. Therefore, in this work, the impact of the SBMA hydrogel on ECM reconstruction is comprehensively studied, and the underlying mechanism is intensively investigated in a rat PU model. The in vivo data demonstrate that compared to the PEG hydrogel, the SBMA hydrogel enhances the ECM remolding by the upregulation of fibronectin and laminin expression as well as the inhibition of MMP-2. Further investigation reveals that the decreased MMP-2 expression of zwitterionic SBMA hydrogel treatment is due to the activation of autophagy through the inhibited PI3K/Akt/mTOR signaling pathway and reduced inflammation. The association of autophagy with ECM remodeling may provide a way in guiding the design of biomaterial-based wound dressing for chronic wound repair.","Bedsores are a worldwide problem that is hard to heal because it causes long-lasting inflammation (redness and swelling from fighting an infection) and harms the extracellular matrix (ECM; secreted by cells and surrounds cells in tissues) from not enough oxygen and blood flow. The study we did before found that non-fouling zwitterionic (inner salts to which proteins and bacteria cannot stick) sulfated poly (sulfobetaine methacrylate) (SBMA) hydrogel can improve bedsore healing and quickly rebuild ECM. However, scientists are unsure how SBMA hydrogel rebuilds ECM. In this study, we look at how SBMA hydrogel rebuilds ECM using a rat bedsore model. SMBA hydrogel helps remodel ECM better than PEG hydrogel, another bedsore treatment. The relationship between autophagy (cleaning out of damaged cells) with ECM remodeling may influence the design of wound dressings with substances that interact with biological systems for long-term wound repair." +"Introduction: Treatment of decubitus ulcers is a grave medical problem. In many cases, it is difficult to cure a pressure ulcer, especially when it is deep and extensive, and prognosis is usually unfavourable. Treatment of decubitus ulcers requires new specialist dressings, which play an important role in the healing process. Aim: To evaluate therapeutic efficacy of active specialist medical dressings in the treatment of decubitus. Material and methods: Research involved 40 patients - 18 (45%) women and 22 (55%) men, suffering from decubitus ulcers of different size and depth, localized in the sacral region, lasting from 1.5 to 30 months. Patients were randomly assigned to two research groups (20 people each), were treated for 4 weeks with 2 different specialist dressings. ATRAUMAN Ag, which contains silver ions, was used in the first group, while paraffin gauze of BACTIGRAS type was used in the second group. An assessment of pressure ulcers' healing progress was done with a planimetric method, which evaluates the wound surface area. Results: The analysis results showed a significant statistical decrease in an average decubitus ulcer surface area in both research groups: in the first group by 60.2% (p = 0.001), and in the second group by 32.95% (p < 0.001), which speaks in favour of dressings with silver ions as having better therapeutic effectiveness. Conclusions: Using specialist dressings results in a significant decrease in the decubitus ulcer surface area, depending on the type of dressing and active substances contained within, while silver ions support curative effectiveness of the dressing used.","Treatment of bedsores is a serious medical problem. Often, a bedsore is hard to cure, especially when it is deep and covers a large area, and usually has a poor prognosis (plan for recovery). Treating bedsores requires specialized dressings, which play an important role in the healing process. We aim to rate how well active specialized dressings, which promote healing by keeping the wound moist, work to treat bedsores. We looked at 40 patients, 18 (45%) women and 22 (55%) men, with bedsores differing in size and depth, located near the bottom of the spine, lasting from 1.5 to 3.0 months. We randomly assigned patients to two groups of 20 people each and treated them with two different specialist dressings for 4 weeks. We used ATRAUMAN ag, which contains silver ions, in the first group and paraffin (waxy) gauze of BACTIGRAS type in the second group. We measured the progress of bedsore healing by measuring the wound's boundaries, which calculates the surface area. Results showed average bedsore surface area significantly decreased in the first group by 60.2% and in the second group by 32.95%, suggesting dressings with silver ions worked better. We conclude that specialist dressings significantly decrease bedsore surface area, and dressings with silver ions work better than those without." +"Introduction: Treatment of decubitus ulcers is a grave medical problem. In many cases, it is difficult to cure a pressure ulcer, especially when it is deep and extensive, and prognosis is usually unfavourable. Treatment of decubitus ulcers requires new specialist dressings, which play an important role in the healing process. Aim: To evaluate therapeutic efficacy of active specialist medical dressings in the treatment of decubitus. Material and methods: Research involved 40 patients - 18 (45%) women and 22 (55%) men, suffering from decubitus ulcers of different size and depth, localized in the sacral region, lasting from 1.5 to 30 months. Patients were randomly assigned to two research groups (20 people each), were treated for 4 weeks with 2 different specialist dressings. ATRAUMAN Ag, which contains silver ions, was used in the first group, while paraffin gauze of BACTIGRAS type was used in the second group. An assessment of pressure ulcers' healing progress was done with a planimetric method, which evaluates the wound surface area. Results: The analysis results showed a significant statistical decrease in an average decubitus ulcer surface area in both research groups: in the first group by 60.2% (p = 0.001), and in the second group by 32.95% (p < 0.001), which speaks in favour of dressings with silver ions as having better therapeutic effectiveness. Conclusions: Using specialist dressings results in a significant decrease in the decubitus ulcer surface area, depending on the type of dressing and active substances contained within, while silver ions support curative effectiveness of the dressing used.","Treating decubitus ulcers (bedsores) is a serious medical problem. In many cases, it is difficult to cure a pressure ulcer or bedsore, especially when it is deep and extensive. Recovery is usually poor. Treating bedsores requires new specialized dressings (e.g., ointments, gauze), which are important for healing. We aim to evaluate the success of active specialized medical dressings for treating bedsores. Research included 40 patients - 18 (45% women) and 22 (55%) men, suffering from bedsores of various size and depth, in the lower back, lasting from 1.5 to 30 months. Patients were randomly split to two groups (20 people each) and treated for 4 weeks with either ATRAUMAN Ag, a dressing with silver, or gauze with paraffin (a waxy substance commonly used for coating and sealing candles and rubbers) from BACTIGRAS. Measuring pressure ulcer healing was done by measuring the wound surface area. The results showed a decrease in average bedsore area in both treatment groups: in the first group by 60.2% and in the second group by 32.95%, which speaks in favour of dressings with silver as better treatments. Using specialized dressings leads to a decrease in bedsore area, depending on the dressing type and substances contained within it. Silver supports the healing properties of the dressing used." +"Background: Tissue-nonspecific alkaline phosphatase (TNSALP) encoded by the ALPL gene is of particular importance for bone mineralization. Mutation in the ALPL gene can lead to persistent low ALP activity resulting in the rare disease Hypophosphatasia (HPP) that is characterized by disturbed bone and dental mineralization. While severe forms are extremely rare with an estimated prevalence of 1/100.000, recent studies suggest that moderate form caused by heterozygous mutations are much more frequent with an estimated prevalence of 1/508. The purpose of this study was to estimate the prevalence of low AP levels in the population based on laboratory measurements. Methods: In this study, the prevalence of low AP activity and elevated pyridoxal-5-phosphate (PLP) levels was analyzed in 6.918.126 measurements from 2011 to 2016 at a single laboratory in northern Germany. Only laboratory values of subjects older than 18 years of age were included. Only the first measurement was included, all repeated values were excluded. Results: In total, 8.46% of the measurements of a total of 6.918.126 values showed a value < 30 U/L. 0.59% of the subjects with an ALP activity below 30 U/L had an additional PLP measurement. Here, 6.09% showed elevated pyridoxal-5-phosphate (PLP) levels. This suggest that 0.52% (1:194) of subjects show laboratory signs of HPP. Conclusion: These data support the genetic estimation that the prevalence of moderate forms of HPP may be significantly higher than expected. Based on these data, we recommend automatically measurement of PLP in the case of low ALP activity and a notification to the ordering physician that HPP should be included in the differential diagnosis and further exploration is recommended.","Background: Tissue-nonspecific alkaline phosphatase (TNSALP) is an enzyme that assists in breaking down phosphate groups. Phosphate groups are important in activating proteins. TNSALP is encoded by a gene, known as ALPL, that is of particular importance for bone mineralization or when minerals deposit onto bone. Mutation, or a structural change, in the ALPL gene can cause persistent low alkaline phosphatase (ALP) activity. ALP is an enzyme that helps bone strength. Low ALP activity can result in the rare disease Hypophosphatasia (HPP). HPP is characterized by disturbed bone and dental or tooth mineralization. Severe forms of HPP are extremely rare. However, there is an estimated prevalence of 1/100,000 people. Recent studies suggest that moderate HPP is more common with an estimated prevalence of 1/508 people. The aim of this study was to estimate the prevalence of low ALP levels in the population based on laboratory measurements. The prevalence of low AP activity and elevated pyridoxal-5-phosphate (PLP) levels was analyzed in 6,918,126 measurements from 2011 to 2016. PLP is a co-enzyme or helper in several body processes. Only laboratory values of subjects older than 18 years of age were included. Only the first measurement was included. All repeated values were excluded. In total, 8.46% of the measurements showed a value < 30 U/L. 0.59% of the subjects with an ALP activity below 30 U/L had an additional PLP measurement. Of the participants, 6.09% showed elevated pyridoxal-5-phosphate (PLP) levels. This suggest that 0.52% of subjects show signs of HPP. These data support the estimation that the prevalence of moderate forms of HPP is higher than expected. The authors recommend automatic measurement of PLP in cases of low ALP activity. Physicians should be notified that HPP should be included in the diagnosis and further exploration is recommended." +"Background: Low serum levels of alkaline phosphatase (ALP) are a hallmark of hypophosphatasia. However, the clinical significance and the underlying genetics of low ALP in unselected populations are unclear. Methods: In order to clarify this issue, we performed a clinical, biochemical and genetic study of 42 individuals (age range 20-77yr) with unexplained low ALP levels. Results: Nine had mild hyperphosphatemia and three had mild hypercalcemia. ALP levels were inversely correlated with serum calcium (r=-0.38, p=0.012), pyridoxal phosphate (PLP; r=-0.51, p=0.001) and urine phosphoethanolamine (PEA; r=-0.49, p=0.001). Although many subjects experienced minor complaints, such as mild musculoskeletal pain, none had major health problems. Mutations in ALPL were found in 21 subjects (50%), including six novel mutations. All but one, were heterozygous mutations. Missense mutations were the most common (present in 18 subjects; 86%) and the majority were predicted to have a damaging effect on protein activity. The presence of a mutated allele was associated with tooth loss (48% versus 12%; p=0.04), slightly lower levels of serum ALP (p=0.002), higher levels of PLP (p<0.0001) and PEA (p<0.0001), as well as mildly increased serum phosphate (p=0.03). Ten individuals (24%) had PLP levels above the reference range; all carried a mutated allele. Conclusion: One-half of adult individuals with unexplained low serum ALP carried an ALPL mutation. Although the associated clinical manifestations are usually mild, in approximately 50% of the cases, enzyme activity is low enough to cause substrate accumulation and may predispose to defects in calcified tissues.","Low serum levels of alkaline phosphatase (ALP) are a sign of hypophosphatasia (genetic disease that affects bone and tooth development). ALP is an enzyme that helps bone strength. However, the clinical significance and the underlying genetics of low ALP in unselected populations are unclear. To better understand this issue, the authors performed a study of 42 individuals with unexplained low ALP levels. The participants were between 20 to 77 years old. Nine had mild hyperphosphatemia (high serum phosphate) and three had mild hypercalcemia (high blood calcium). ALP levels were inversely related with serum calcium, pyridoxal phosphate, and urine phosphoethanolamine. These are all compounds within the body that play a role in bone health. Many subjects experienced minor complaints, such as mild muscle or bone pain. However, none had major health problems. Mutations in ALPL were found in 21 subjects, including six novel mutations. All but one were heterozygous mutations, which is a mutation only affecting one form of a gene. Missense mutations, or mistakes in the DNA, were the most common. Most of the mutations were predicted to have a damaging effect on protein activity. The presence of a mutated allele was associated with tooth loss, slightly lower levels of serum (blood) ALP, higher levels of PLP and PEA, as well as mildly increased serum phosphate. Ten individuals had PLP levels above the reference range. All carried a mutated allele or gene copy. One-half of adult individuals with unexplained low serum ALP carried an ALPL mutation. In almost half of the cases, enzyme activity is low enough to cause substrate (cell substance) accumulation. This may make an individual more likely to experience defects in calcified tissues, such as bone." +"Background: Low serum levels of alkaline phosphatase (ALP) are a hallmark of hypophosphatasia. However, the clinical significance and the underlying genetics of low ALP in unselected populations are unclear. Methods: In order to clarify this issue, we performed a clinical, biochemical and genetic study of 42 individuals (age range 20-77yr) with unexplained low ALP levels. Results: Nine had mild hyperphosphatemia and three had mild hypercalcemia. ALP levels were inversely correlated with serum calcium (r=-0.38, p=0.012), pyridoxal phosphate (PLP; r=-0.51, p=0.001) and urine phosphoethanolamine (PEA; r=-0.49, p=0.001). Although many subjects experienced minor complaints, such as mild musculoskeletal pain, none had major health problems. Mutations in ALPL were found in 21 subjects (50%), including six novel mutations. All but one, were heterozygous mutations. Missense mutations were the most common (present in 18 subjects; 86%) and the majority were predicted to have a damaging effect on protein activity. The presence of a mutated allele was associated with tooth loss (48% versus 12%; p=0.04), slightly lower levels of serum ALP (p=0.002), higher levels of PLP (p<0.0001) and PEA (p<0.0001), as well as mildly increased serum phosphate (p=0.03). Ten individuals (24%) had PLP levels above the reference range; all carried a mutated allele. Conclusion: One-half of adult individuals with unexplained low serum ALP carried an ALPL mutation. Although the associated clinical manifestations are usually mild, in approximately 50% of the cases, enzyme activity is low enough to cause substrate accumulation and may predispose to defects in calcified tissues.","Low blood levels of alkaline phosphatase (ALP), a protein that influences the high-energy molecule phosphate, indicates low blood phosphate levels. However, the importance and genetics of low ALP in random groups is unknown. To clarify this issue, we performed a clinical, biochemical and genetic study of 42 individuals with unexplained low ALP levels. Nine had mildly high blood phosphate levels. Three had mildly high blood calcium levels. ALP levels trended oppositely with blood calcium, pyridoxal phosphate (PLP) or active vitamin B6, and urine phosphoethanolamine (PEA), a key molecule to build cell boundaries. Although many had minor complains, like mild musculoskeletal pain, none had major health problems. Gene sequence changes in ALPL, the gene encoding ALP, were found in 21 subjects (50%), including six new changes. Mutations that change a protein segment were the most common (present in 18 subjects; 86%). The majority were predicted to have a harmful effect on protein activity. Having a mutated gene was linked with tooth loss, slightly lower levels of blood ALP, higher levels of PLP and PEA, and mildly higher blood phosphate. Ten people had above-average PLP levels. All had a mutated gene. Half of the adults with unexplained low blood ALP had an ALPL mutation. Although the associated physical symptoms are usually mild, in around 50% of the cases, protein enzyme activity is low enough to cause phosphate accumulation and may predispose to defects in high-calcium body parts." +"Summary: Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or 'osteoporosis' to identify a low ALP level is recommended. Learning points: Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss. Antiresorptive therapy is contraindicated in HPP. Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis. Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory. Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly. Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.","Hypophosphatasia (HPP) is a rare and under-recognized genetic defect in bone mineralization. Bone mineralization is when bone become calcified. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis (brittle bones). These patients may be prescribed antiresorptive therapy, or drugs that block the breakdown of bone. These drugs may increase fracture risk. Adult-onset HPP was identified in a 40-year-old woman. She had with femur fractures after 4 years of using denosumba, a drug to treat osteoporosis. A low serum (blood) alkaline phosphatase (ALP) and increased serum vitamin B6 level signaled the diagnosis. Her diagnosis of HPP was later confirmed by identification of two recessive gene mutations of the ALPL gene. ALP is an enzyme that helps bone strength. ALPL is the gene that encodes ALP. The patient was treated with teriparatide (an osteoporosis drug) due to the unavailability of ALP enzyme-replacement therapy. The fractures healed. However, her mobility was impaired. HPP makes someone more likely to experience femur fractures during antiresorptive therapy. Because of this, bisphosphonates (drugs that limit bone density) and denosumab should not be given to people with this condition. Healthcare workings should screen patients with fracture or 'osteoporosis' to identify a low ALP level. HPP is a rare and under-recognized cause of bone fragility. HPP is caused by impaired mineralization that can be misdiagnosed as a fragility fracture due to age-related bone loss. Antiresorptive therapy is not recommended in HPP treatment. Low serum alkaline phosphatase (ALP) can aid in diagnosis. Elevated serum vitamin B6 (a chemical that works with ALP) is suggestive of HPP. Identifying mutations within the ALPL gene can confirm HPP status. Therapy with a chemical ALP reacts with, known as asfotase alfa, is currently unmanageably expensive. Treatment with anabolic (repairing) bone agents has been reported. However, if this treatment helps normally mineralized bone form needs further study." +"Hypophosphatasia (HPP) is the heritable dento-osseous disease caused by loss-of-function mutation(s) of the gene ALPL that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphomonoester phosphohydrolase expressed in healthy people especially in the skeleton, liver, kidneys, and developing teeth. In HPP, diminished TNSALP activity leads to extracellular accumulation of its natural substrates including inorganic pyrophosphate (PPi), an inhibitor of mineralization, and pyridoxal 5'-phosphate (PLP), the principal circulating form of vitamin B6 (B6). Autosomal dominant and autosomal recessive inheritance involving >450 usually missense defects scattered throughout ALPL largely explains the remarkably broad-ranging severity of this inborn-error-of-metabolism. In 1985 when we identified elevated plasma PLP as a biochemical hallmark of HPP, all 14 investigated affected children and adults had markedly increased PLP levels. However, pyridoxal (PL), the dephosphorylated form of PLP that enters cells to cofactor many enzymatic reactions, was not low but often inexplicably elevated. Levels of pyridoxic acid (PA), the B6 degradation product quantified to assess B6 sufficiency, were unremarkable. Canonical signs or symptoms of B6 deficiency or toxicity were absent. B6-dependent seizures in infants with life-threatening HPP were later explained by their profound deficiency of TNSALP activity blocking PLP dephosphorylation to PL and diminishing gamma-aminobutyric acid synthesis in the brain. Now, there is speculation that altered B6 metabolism causes further clinical complications in HPP. Herein, we assessed the plasma PL and PA levels accompanying previously reported elevated plasma PLP concentrations in 150 children and adolescents with HPP. Their mean (SD) plasma PL level was nearly double the mean for our healthy pediatric controls: 66.7 (59.0) nM versus 37.1 (22.2) nM (P < 0.0001), respectively. Their PA levels were broader than our pediatric control range, but their mean value was normal; 40.2 (25.1) nM versus 39.3 (9.9) nM (P = 0.7793), respectively. In contrast, adults with HPP often had plasma PL and PA levels suggestive of dietary B6 insufficiency. We discuss why the B6 levels of our pediatric patients with HPP would not cause B6 toxicity or deficiency, whereas in affected adults dietary B6 insufficiency can develop.","Hypophosphatasia (HPP) is the heritable, tooth and bone disease. HPP is caused by mutations of the gene ALPL. ALPL encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is an enzyme that assists in breaking down phosphate groups. Phosphate groups are important in activating proteins. TNSALP is expressed in healthy people, especially in the skeleton, liver, kidneys, and developing teeth. In HPP, decreased TNSALP activity leads to extracellular accumulation of its natural substrates, including pyridoxal 5'-phosphate (PLP). PLP is the principal circulating form of vitamin B6 (B6). Different mutations of ALPL largely explains the remarkably broad-ranging severity of this genetic inborn-error-of-metabolism. In 1985, elevated (blood) plasma PLP was identified as hallmark of HPP. In the study, all 14 investigated affected children and adults had increased PLP levels. However, pyridoxal (PL), an alternate form of PLP that enters cells to cofactor (help) many enzymatic reactions, was often unexplainably elevated. Levels of pyridoxic acid (PA), a compound used to determine B6 levels in the body, were unremarkable. Signs or symptoms of B6 deficiency or toxicity were absent. B6-dependent seizures in infants with life-threatening HPP were later explained by their low TNSALP activity. Lack of TNSALP activity was blocking PLP dephosphorylation, removal of phosphate groups, to PL. This diminished formation of gamma-aminobutyric acid, a neurotransmitter, in the brain. It is theorized that abnormal B6 metabolism causes further health complications in HPP. This study assessed (measured) the blood PL and PA levels in patients with previously reported elevated plasma PLP concentrations. The evaluated patient pool consisted of 150 children and adolescents with HPP. Their average plasma PL level was nearly double the average of healthy pediatric controls. Their PA levels were broader than our pediatric (child) control range with a normal average value. In contrast, adults with HPP often had plasma PL and PA levels that suggest a dietary B6 insufficiency. This paper discusses why B6 levels of children with HPP would not cause B6 toxicity or deficiency, whereas in affected adults dietary B6 insufficiency can develop." +"Background: Hypophosphatasia (HPP) is an inborn disease caused by pathogenic variants in ALPL. Low levels of alkaline phosphatase (ALP) are a biochemical hallmark of the disease. Scarce knowledge about the prevalence of HPP in Scandinavia exists, and the variable clinical presentations make diagnostics challenging. The aim of this study was to investigate the prevalence of ALPL variants as well as the clinical and biochemical features among adults with endocrinological diagnoses and persistent hypophosphatasaemia. Methods: A biochemical database containing ALP measurements of 26,121 individuals was reviewed to identify adults above 18 years of age with persistently low levels of ALP beneath range (? 35 � 2.7 U/L). ALPL genetic testing, biochemical evaluations and assessment of clinical features by a systematic questionnaire among included patients, were performed. Results: Among 24 participants, thirteen subjects (54.2%) revealed a disease-causing variant in ALPL and reported mild clinical features of HPP, of which musculoskeletal pain was the most frequently reported (n = 9). The variant c. 571G > A; p.(Glu191 Lys) was identified in six subjects, and an unreported missense variant (c.1019A > C; p.(His340Pro)) as well as a deletion of exon 2 were detected by genetic screening. Biochemical analyses showed no significant differences in ALP (p = 0.059), the bone specific alkaline phosphatase (BALP) (p = 0.056) and pyridoxal-5'-phosphate (PLP) (p = 0.085) between patients with an ALPL variant and negative genetic screening. Patients with a variant in ALPL had significantly higher PLP levels than healthy controls (p = 0.002). We observed normal ALP activity in some patients classified as mild HPP, and slightly increased levels of PLP in two subjects with normal genetic screening and four healthy controls. Among 51 patients with persistent hypophosphatasaemia, fifteen subjects (29.4%) received antiresorptive treatment. Two patients with unrecognized HPP were treated with bisphosphonates and did not show complications due to the treatment. Conclusions: Pathogenic variants in ALPL are common among patients with endocrinological diagnoses and low ALP. Regarding diagnostics, genetic testing is necessary to identify mild HPP due to fluctuating biochemical findings. Antiresorptive treatment is a frequent reason for hypophosphatasaemia and effects of these agents in adults with a variant in ALPL and osteoporosis remain unclear and require further studies.","Hypophosphatasia (HPP) is a disease caused by mutations within the gene ALPL. Hypophosphatasia (HPP) is the heritable, tooth and bone disease. The gene ALPL encodes for alkaline phosphatase (ALP), an enzyme that helps bone strength. Low levels of alkaline phosphatase (ALP) are a hallmark of the disease. There is little knowledge about the prevalence of HPP in Scandinavia. Due to the variation in HPP clinical presentations, diagnosing the disease is challenging. The aim of this study was to investigate the prevalence of ALPL variants (gene types). The study also aimed to identify HPP biological identifiers among adults. This study was specifically interested in adults with HPP along with endocrine (hormonal) disorders and persistent hypophosphatasemia (low body phosphorus levels). A database containing ALP measurements of 26,121 individuals was reviewed to identify adults above 18 years of age with persistently low levels of ALP. ALPL genetic testing, evaluation of body compound levels, and assessment of health by a systematic questionnaire among included patients, were performed. Among 24 participants, thirteen subjects revealed a disease-causing variant in ALPL and reported mild health effects of HPP. Of these mild health effects, musculoskeletal pain was the most frequently reported. The same genetic variant was identified in six subjects. An unreported missense (gene-altered) variant and a genetic deletion were detected by genetic screening. Analysis of compound levels within the body showed no significant differences between patients with an ALPL variant and negative (no-detection) genetic screening. Patients with a variant in ALPL had significantly higher PLP levels than control patients. Normal ALP activity was observed in some patients classified as mild HPP. A slightly increased level of PLP was found in two subjects with normal genetic screening and four healthy controls. Among 51 patients with persistent hypophosphatasemia, 15 received treatment to increase bone strength. Two patients with undiagnosed HPP were treated with bisphosphonates, drugs that slow bone loss. They did not show complications due to the treatment. Genetic variations in ALPL are common among patients with endocrine disorders and low ALP. Genetic testing is necessary to identify mild HPP due to fluctuating body compound level findings. Treatment to increase bone strength is a frequent reason for hypophosphatasemia. Effects of these agents in adults with a variant in ALPL and osteoporosis (brittle bones) remain unclear and require further studies." +"Background: Hypophosphatasia (HPP) is an inborn disease caused by pathogenic variants in ALPL. Low levels of alkaline phosphatase (ALP) are a biochemical hallmark of the disease. Scarce knowledge about the prevalence of HPP in Scandinavia exists, and the variable clinical presentations make diagnostics challenging. The aim of this study was to investigate the prevalence of ALPL variants as well as the clinical and biochemical features among adults with endocrinological diagnoses and persistent hypophosphatasaemia. Methods: A biochemical database containing ALP measurements of 26,121 individuals was reviewed to identify adults above 18 years of age with persistently low levels of ALP beneath range (? 35 � 2.7 U/L). ALPL genetic testing, biochemical evaluations and assessment of clinical features by a systematic questionnaire among included patients, were performed. Results: Among 24 participants, thirteen subjects (54.2%) revealed a disease-causing variant in ALPL and reported mild clinical features of HPP, of which musculoskeletal pain was the most frequently reported (n = 9). The variant c. 571G > A; p.(Glu191 Lys) was identified in six subjects, and an unreported missense variant (c.1019A > C; p.(His340Pro)) as well as a deletion of exon 2 were detected by genetic screening. Biochemical analyses showed no significant differences in ALP (p = 0.059), the bone specific alkaline phosphatase (BALP) (p = 0.056) and pyridoxal-5'-phosphate (PLP) (p = 0.085) between patients with an ALPL variant and negative genetic screening. Patients with a variant in ALPL had significantly higher PLP levels than healthy controls (p = 0.002). We observed normal ALP activity in some patients classified as mild HPP, and slightly increased levels of PLP in two subjects with normal genetic screening and four healthy controls. Among 51 patients with persistent hypophosphatasaemia, fifteen subjects (29.4%) received antiresorptive treatment. Two patients with unrecognized HPP were treated with bisphosphonates and did not show complications due to the treatment. Conclusions: Pathogenic variants in ALPL are common among patients with endocrinological diagnoses and low ALP. Regarding diagnostics, genetic testing is necessary to identify mild HPP due to fluctuating biochemical findings. Antiresorptive treatment is a frequent reason for hypophosphatasaemia and effects of these agents in adults with a variant in ALPL and osteoporosis remain unclear and require further studies.","Low levels of blood phosphate, a high-energy molecule, or hypophosphatasia (HPP) is a from-birth disease caused by disease-causing variations in ALPL (the gene for alkaline phosphatase or a protein that influences phosphate levels). Low levels of alkaline phosphatase (ALP) are a marker of HPP. Little is known about the amount of HPP in Scandinavia. The diverse symptoms make identification challenging. The study aimed to investigate the amount of ALPL variants and physical and biochemical markers among adults with hormonal diagnoses and persistant low ALP levels. We reviewed a database of ALP measurements from 26,121 individuals to identify adults over 18 years with persistently low levels of ALP. ALPL gene testing, biological tests, and assessment of symptoms by a questionnaire among included patients were performed. Among 24 patients, thirteen (54.2%) had a disease-causing variant in ALPL and mild symptoms of HPP, of which musculoskeletal pain was the most frequent. A specific gene mutation that altered a protein segment was found in six subjects. A similar gene mutation and deletion of a gene segment was detected by genetic tests. Tests showed no differences in ALP, bone-specific ALP, and pyridoxal phosphate (PLP) or active vitamin B6 between patients with an ALPL mutation and no genetic diseases. Patients with an ALPL mutation had much higher PLP levels than healthy patients. We saw normal ALP activity in some patients with mild HPP. We also saw slightly increased PLP in two subjects with no gene diseases and four healthy patients. Among 51 with persistent low ALP levels, fifteen (29.4%) had anti-bone-breakdown treatment. Two patients with unrecognized HPP were treated with anti-bone-breakdown drugs and did not show side effects from treatment. Disease-causing mutations in ALPL are common in patients with hormonal diagnoses and low ALP. Regarding detection, gene testing is needed to identify mild HPP due to diverse biochemical findings. Anti-bone-breakdown treatment is frequent reason for low ALP levels and treatment effects in adults with an ALPL mutation and bone breakdown remain unclear and need further studies." +"Background: Severe hypercalcemia is rare in newborns; even though often asymptomatic, it may have important sequelae. Hypophosphatemia can occur in infants experiencing intrauterine malnutrition, sepsis and early high-energy parenteral nutrition (PN) and can cause severe hypercalcemia through an unknown mechanism. Monitoring and supplementation of phosphate (PO4) and calcium (Ca) in the first week of life in preterm infants are still debated. Case presentation: We report on a female baby born at 29 weeks' gestation with intrauterine growth retardation (IUGR) experiencing sustained severe hypercalcemia (up to 24 mg/dl corrected Ca) due to hypophosphatemia while on phosphorus-free PN. Hypercalcemia did not improve after hyperhydration and furosemide but responded to infusion of PO4. Eventually, the infant experienced symptomatic hypocalcaemia (ionized Ca 3.4 mg/dl), likely exacerbated by contemporary infusion of albumin. Subsequently, a normalization of both parathyroid hormone (PTH) and alkaline phosphatase (ALP) was observed. Conclusions: Although severe hypercalcemia is extremely rare in neonates, clinicians should be aware of the possible occurrence of this life-threatening condition in infants with or at risk to develop hypophosphatemia. Hypophosphatemic hypercalcemia can only be managed with infusion of PO4, with strict monitoring of Ca and PO4 concentrations.","Severe hypercalcemia, or too high calcium blood levels, is rare in newborns. Even though hypercalcemia often shows no symptoms, it may have important effects on overall health. Hypophosphatemia is when the body has low levels of phosphorous. Hypophosphatemia can occur in infants experiencing malnutrition while in the womb, blood infection, and early high-energy parenteral nutrition (PN). PN is when a mother is given nutrients through IV. Hypophosphatemia can cause severe hypercalcemia through an unknown mechanism. It is debated if phosphate (PO4) and calcium (Ca) should be given in the first week of life in preterm infants. This study reports on a female baby born at 29 weeks' gestation (time in womb). The infant had intrauterine growth retardation (IUGR) and long-term severe hypercalcemia due to hypophosphatemia while on phosphorus-free PN. IUGR is when a baby does not grow to normal weight during pregnancy. Hypercalcemia did not improve after excess water intake but responded to infusion of PO4. Eventually, the infant experienced symptoms of hypocalcemia. This was likely worsened by infusion of albumin, a blood protein. Following this, parathyroid hormone (PTH), which controls calcium and phosphorus in the blood, and alkaline phosphatase (ALP), which removes phosphate groups, returned to normal levels. Severe hypercalcemia is extremely rare in newborns. However, doctors should be aware of the possible occurrence of this life-threatening condition in infants with or at risk to develop hypophosphatemia. Hypophosphatemic hypercalcemia can only be managed with infusion of PO4, with strict monitoring of Ca and PO4 concentrations." +"Purpose: The study aimed to define the clinical, biochemical and genetic features of adult patients with osteopenia/osteoporosis and/or bone fragility and low serum alkaline phosphatase (sALP). Methods: Twenty-two patients with at least two sALP values below the reference range were retrospectively enrolled after exclusion of secondary causes. Data about clinical features, mineral and bone markers, serum pyridoxal-5'-phosphate (PLP), urine phosphoethanolamine (PEA), lumbar and femur bone densitometry, and column X-ray were collected. Peripheral blood DNA of each participant was analyzed to detect ALPL gene anomalies. Results: Pathogenic ALPL variants (pALPL) occurred in 23% and benign variants in 36% of patients (bALPL), while nine patients harbored wild-type alleles (wtALPL). Fragility fractures and dental anomalies were more frequent in patients harboring pALPL and bALPL than in wtALPL patients. Of note, wtALPL patients comprised women treated with tamoxifen for hormone-sensitive breast cancer. Mineral and bone markers were similar in the three groups. Mean urine PEA levels were significantly higher in patients harboring pALPL than those detected in patients harboring bALPL and wtALPL; by contrast, serum PLP levels were similar in the three groups. A 6-points score, considering clinical and biochemical features, was predictive of pALPL detection [P = 0.060, OR 1.92 (95% CI 0.972, 3.794)], and more significantly of pALPL or bALPL [P = 0.025, OR 14.33 (95% CI 1.401, 14.605)]. Conclusion: In osteopenic/osteoporotic patients, single clinical or biochemical factors did not distinguish hypophosphatasemic patients harboring pALPL or bALPL from those harboring wtALPL. Occurrence of multiple clinical and biochemical features is predictive of ALPL anomalies, and, therefore, they should be carefully identified. Tamoxifen emerged as a hypophosphatasemic drug.","The study aimed to define the health, biochemical, and genetic features of adult patients with bone strength issues and low serum (blood) alkaline phosphatase (sALP), a protein that helps bone strength. Twenty-two patients with at least two sALP measurements below the desired range were enrolled. Any patients with additional disease or health complications were excluded. Several data points for patient health and biological indicators of disease status were collected. Patient DNA was analyzed to detect ALPL gene anomalies. Several types of mutations within the ALPL gene were found amongst the participant population. These variants include pathogenic (harmful) ALPL variants (pALPL), benign (harmless) variants (bALPL), and wild-type (normal) variants (wtALPL). pALPL are variants that increases a person's chance to get sick from a disease. bALPL are mutations that do not impact human health. wtALPL variants are genes that are not mutated or changed in form. Bone and tooth damage were more frequent in patients harboring pALPL and bALPL than in wtALPL patients. Of note, wtALPL patients comprised women treated with tamoxifen, a drug for breast cancer. Mineral and bone markers were similar in the three groups. Average urine phosphoethanolamine, a compound that can indicate bone disease, was significantly higher in patients with pALPL than the other two variant types. By contrast, serum pyridoxal-5'-phosphate, an indicator of vitamin B6 volume, was similar in the three groups. Certain hospital evaluation techniques were able to predict pALPL and bALPL. In patients with osteoporosis (brittle bones), visible health effects and biological compound indicators do not distinguish hypophosphatasemia (low serum ALP) patients harboring pALPL or bALPL variants from those harboring wtALPL. However, visible health effects and biological compound indicators can be predictive of ALPL anomalies. Therefore, they should be carefully identified. Tamoxifen emerged as a drug to treat hypophosphatasemia." +"A majority of adults with persistently low serum alkaline phosphatase values carry a pathogenic or likely pathogenic variant in the ALPL gene and also have elevated alkaline phosphatase substrate values in serum and urine. These adults may fall within the spectrum of the adult form of hypophosphatasia. Introduction: The primary objective of this study was to determine what proportion of adults with persistently low serum alkaline phosphatase values (hypophosphatasemia) harbor mutations in the ALPL gene or have elevated alkaline phosphatase (ALP) substrates. Some adults with persistent hypophosphatasemia share clinical and radiographic features with the adult form of hypophosphatasia (HPP). In HPP, ALPL mutations result in persistent hypophosphatasemia and ALP substrate accumulation in plasma (pyridoxal-5-phosphate (PLP)) and urine (phosphoethanolamine (PEA)). Methods: Biochemical analyses, including serum ALP activity, bone-specific ALP, plasma PLP, and urine PEA, were performed in adults with persistent hypophosphatasemia. Mutational analyses were performed using PCR and Sanger sequencing methods. Gene variants were classified as pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), likely benign (LB), and benign (B). P and LP variants were further grouped as ""Positive ALPL variants"" and LB and B grouped as ""Negative ALPL variants."" Results: Fifty subjects completed all mutational and biochemical analyses. Sixteen percent carried only Negative ALPL variants. Of the remaining 42 subjects, 67% were heterozygous for a P variant, 19% for an LP variant, and 14% for a VUS. Biochemical results were highly inter-correlated and consistent with the expected inverse relationship between ALP and its substrates. Subjects harboring Positive ALPL variants showed lower ALP and BSAP and higher PLP and PEA values compared with subjects harboring only Negative ALPL variants. Approximately half of all subjects harboring Positive ALPL variants or ALPL VUS showed elevations in plasma PLP, and three quarters showed elevations in urine PEA. Conclusion: Adults with persistent hypophosphatasemia frequently harbor ALPL mutations and have elevated ALP substrates. These adults may fall within the spectrum of the adult form of hypophosphatasia. Clinicians should take note of persistent hypophosphatasemia in their patients and be cautious in prescribing bisphosphonates when present. Clinicians should take note of persistent hypophosphatasemia in their patients and be cautious in prescribing bisphosphonates when present.","Most adults with persistently low serum (blood) alkaline phosphatase values have a mutation in the ALPL gene that encodes it. These adults also most likely have elevated alkaline phosphatase substrate values in serum and urine. Alkaline phosphatase can indicate bone health. These adults may suffer from the adult form of hypophosphatasia, an inherited disorder that affects bone and tooth development. The aim of this study was to determine what proportion of adults with hypophosphatasemia (low serum alkaline phosphatase) also have ALPL gene mutations or elevated alkaline phosphatase (ALP) substrates. Some adults with hypophosphatasemia share observable or radiographic (seen through x-ray) features with the adult form of hypophosphatasia (HPP). In HPP, ALPL mutations cause persistent hypophosphatasemia and ALP substrate (protein) accumulation in plasma (pyridoxal-5-phosphate (PLP)) and urine (phosphoethanolamine (PEA)). Analyses of compounds from biological samples, including serum ALP activity, bone-specific ALP, plasma PLP, and urine PEA, were performed in adults with persistent hypophosphatasemia. Analysis to determine ALPL mutations were performed. Variations of the gene ALPL were classified as pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), likely benign (LB), and benign (B). Pathogenic mutations often make a person more susceptible to disease. Benign mutations do not affect human health. P and LP variants were further grouped as ""Positive ALPL variants"" and LB and B grouped as ""Negative ALPL variants."" A total of 50 subjects completed all mutational and biochemical analyses. Sixteen percent carried only Negative ALPL variants. Of the remaining 42 subjects, 67% were heterozygous for a P variant, 19% for an LP variant, and 14% for a VUS. Biochemical results were associated with the inverse (opposite) relationship between ALP and its substrates. Subjects harboring Positive ALPL variants had lower ALP and BSAP and higher PLP and PEA values. Approximately half of all subjects harboring Positive ALPL variants or ALPL VUS showed elevations in plasma PLP. Most also showed elevations in urine PEA. Adults with persistent hypophosphatasemia often have ALPL mutations and have elevated ALP substrates. These adults may fall within the spectrum of the adult form of hypophosphatasia. Clinicians should note long-lasting hypophosphatasia in patients and be cautious in giving them anit-bone-breakdown drugs." +"A majority of adults with persistently low serum alkaline phosphatase values carry a pathogenic or likely pathogenic variant in the ALPL gene and also have elevated alkaline phosphatase substrate values in serum and urine. These adults may fall within the spectrum of the adult form of hypophosphatasia. Introduction: The primary objective of this study was to determine what proportion of adults with persistently low serum alkaline phosphatase values (hypophosphatasemia) harbor mutations in the ALPL gene or have elevated alkaline phosphatase (ALP) substrates. Some adults with persistent hypophosphatasemia share clinical and radiographic features with the adult form of hypophosphatasia (HPP). In HPP, ALPL mutations result in persistent hypophosphatasemia and ALP substrate accumulation in plasma (pyridoxal-5-phosphate (PLP)) and urine (phosphoethanolamine (PEA)). Methods: Biochemical analyses, including serum ALP activity, bone-specific ALP, plasma PLP, and urine PEA, were performed in adults with persistent hypophosphatasemia. Mutational analyses were performed using PCR and Sanger sequencing methods. Gene variants were classified as pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), likely benign (LB), and benign (B). P and LP variants were further grouped as ""Positive ALPL variants"" and LB and B grouped as ""Negative ALPL variants."" Results: Fifty subjects completed all mutational and biochemical analyses. Sixteen percent carried only Negative ALPL variants. Of the remaining 42 subjects, 67% were heterozygous for a P variant, 19% for an LP variant, and 14% for a VUS. Biochemical results were highly inter-correlated and consistent with the expected inverse relationship between ALP and its substrates. Subjects harboring Positive ALPL variants showed lower ALP and BSAP and higher PLP and PEA values compared with subjects harboring only Negative ALPL variants. Approximately half of all subjects harboring Positive ALPL variants or ALPL VUS showed elevations in plasma PLP, and three quarters showed elevations in urine PEA. Conclusion: Adults with persistent hypophosphatasemia frequently harbor ALPL mutations and have elevated ALP substrates. These adults may fall within the spectrum of the adult form of hypophosphatasia. Clinicians should take note of persistent hypophosphatasemia in their patients and be cautious in prescribing bisphosphonates when present. Clinicians should take note of persistent hypophosphatasemia in their patients and be cautious in prescribing bisphosphonates when present.","Many adults with persistently low blood levels of alkaline phosphatase, a protein that influences levels of the high-energy molecule phosphate, possibly have a mutation in the ALPL gene that encodes alkaline phosphatase. Many adults also have increased phosphate-carrying compounds in blood and urine. These adults may have low blood phosphate levels (hypophosphatasia). The study determines what proportion of adults with persistently low blood alkaline phosphatase levels (hypophosphatasemia) have mutations in the ALPL gene or accumulated phosphate-carrying compounds. Some adults with persistent hypophosphatasemia share symptoms with the adult form of low blood phosphate levels or hypophosphatasia (HPP). In HPP, ALPL mutations lead to persistent hypophosphatasemia and phosphate-carrying compounds in blood (pyridoxal-5-phosphate (PLP) or active vitamin B6) and urine (phosphoethanolamine (PEA) or a key molecule to build cell boundaries). Blood ALP activity, bone-specific ALP, blood PLP, and urine PEA were measured in adults with persistently low levels of ALP. Variations of the ALPL gene were classified as disease-causing or pathogenic (P), likely pathogenic (LP), variants of uncertain significance (VUS), likely harmless or benign (LB), and benign (B). P and LP variants were also grouped as ""Positive ALPL variants"". LB and B were grouped as ""Negative ALPL variants."" Fifty subjects completed all the tests. Sixteen percent had only Negative ALPL variatns. Of the remaining 42, 67% had at least one copy of the P variant, 19% for an LP variant, and 14% for a VUS. Tests results agreed with each other and showed that the amount of ALP trended oppositely with the quantity of the molecules that it acts upon. Those with Positive ALPL variants had lower ALP and bone-specific ALP and had higher PLP and PEA than those with Negative ALPL variants. Around half of those with Positive ALPL variants or ALPL VUS had increases in blood PLP. Three quarters had increases in urine PEA. Adults with persistently low ALP levels frequently had ALPL mutations and increased phosphate-carrying compounds. These adults may have low blood phosphate levels." +"Hypophosphatasia (HPP) is the inborn-error-of-metabolism that features low serum alkaline phosphatase (ALP) activity (hypophosphatasemia) caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of ALP (TNSALP). Autosomal recessive or autosomal dominant inheritance from among >300 TNSALP (ALPL) mutations largely explains HPP's remarkably broad-ranging severity. TNSALP is a cell-surface homodimeric phosphohydrolase richly expressed in the skeleton, liver, kidney, and developing teeth. In HPP, TNSALP substrates accumulate extracellularly. Among them is inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. Superabundance of extracellular PPi explains the hard tissue complications of HPP that feature premature loss of deciduous teeth and often rickets or osteomalacia as well as calcific arthropathies in some affected adults. In infants with severe HPP, blocked entry of minerals into the skeleton can cause hypercalcemia, and insufficient hydrolysis of pyridoxal 5'-phosphate (PLP), the major circulating form of vitamin B6, can cause pyridoxine-dependent seizures. Elevated circulating PLP is a sensitive and specific biochemical marker for HPP. Also, the TNSALP substrate phosphoethanolamine (PEA) is usually elevated in serum and urine in HPP, though less reliably for diagnosis. Pathognomonic radiographic changes occur in pediatric HPP when the skeletal disease is severe. TNSALP mutation analysis is essential for recurrence risk assessment for HPP in future pregnancies and for prenatal diagnosis. HPP was the final rickets/osteomalacia to have a medical treatment. Now, significant successes using asfotase alfa, a mineral-targeted recombinant TNSALP, are published concerning severely affected newborns, infants, and children. Asfotase alfa was approved by regulatory agencies multinationally in 2015 typically for pediatric-onset HPP.","Hypophosphatasia (HPP) is a genetic condition that blocks metabolic pathways. HPP features low serum (blood) alkaline phosphatase (ALP - a protein which indicates bone health) activity (hypophosphatasemia). This is caused by mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme (form) of ALP (TNSALP). This mutation renders the gene unable to complete it function. Variations in the type of mutations largely explains HPP's remarkably broad-ranging severity. TNSALP is an enzyme expressed in the skeleton, liver, kidney, and developing teeth. In HPP, TNSALP substrates (proteins altered by TNSALP) accumulate outside of cells. One substrate is inorganic pyrophosphate (PPi), a potent inhibitor (blocker) of mineralization. Superabundance of extracellular PPi explains the hard tissue complications of HPP. These complications include premature loss of deciduous teeth, rickets or bone softening, and joint swelling in some affected adults. In infants with severe HPP, blocked entry of minerals into the skeleton can cause hypercalcemia (high calcium levels). Additionally, insufficient breakdown of pyridoxal 5'-phosphate (PLP), the major circulating form of vitamin B6, can cause seizures. Elevated circulating PLP is a sensitive and specific biological marker, or a measurable compound in the body that can indicate health status, for HPP. Also, the TNSALP substrate phosphoethanolamine (PEA) is usually elevated in serum and urine in HPP. However, this biological marker is less reliable for diagnosis. Disease-specific changes occur in pediatric (child) HPP when the skeletal disease is severe. TNSALP mutation analysis is needed to determine recurrence (reappearance) for HPP in future pregnancies and for prenatal (at or before birth) diagnosis. HPP was the last bone condition to have a medical treatment. Now, significant successes using asfotase alfa, a prescription drug, are published concerning severely affected newborns, infants, and children. Asfotase alfa was approved by regulatory agencies around the world in 2015 typically for pediatric-onset HPP." +"Hypophosphatasia is the inborn error of metabolism characterized by low serum alkaline phosphatase activity (hypophosphatasaemia). This biochemical hallmark reflects loss-of-function mutations within the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). TNSALP is a cell-surface homodimeric phosphohydrolase that is richly expressed in the skeleton, liver, kidney and developing teeth. In hypophosphatasia, extracellular accumulation of TNSALP natural substrates includes inorganic pyrophosphate, an inhibitor of mineralization, which explains the dento-osseous and arthritic complications featuring tooth loss, rickets or osteomalacia, and calcific arthopathies. Severely affected infants sometimes also have hypercalcaemia and hyperphosphataemia due to the blocked entry of minerals into the skeleton, and pyridoxine-dependent seizures from insufficient extracellular hydrolysis of pyridoxal 5'-phosphate, the major circulating form of vitamin B6, required for neurotransmitter synthesis. Autosomal recessive or dominant inheritance from ~300 predominantly missense ALPL (also known as TNSALP) mutations largely accounts for the remarkably broad-ranging expressivity of hypophosphatasia. High serum concentrations of pyridoxal 5'-phosphate represent a sensitive and specific biochemical marker for hypophosphatasia. Also, phosphoethanolamine levels are usually elevated in serum and urine, though less reliably for diagnosis. TNSALP mutation detection is important for recurrence risk assessment and prenatal diagnosis. Diagnosing paediatric hypophosphatasia is aided by pathognomic radiographic changes when the skeletal disease is severe. Hypophosphatasia was the last type of rickets or osteomalacia to await a medical treatment. Now, significant successes for severely affected paediatric patients are recognized using asfotase alfa, a bone-targeted recombinant TNSALP.","Hypophosphatasia is genetic condition that blocks metabolic pathways. It is characterized by hypophosphatasemia or low serum (blood) levels of a protein, alkaline phosphatase, that indicates bone health. This biomarker, or a measurable compound to determine health status, reflects mutations within the gene that encodes the tissue-nonspecific isoenzyme (form) of alkaline phosphatase (TNSALP). TNSALP is an enzyme that is expressed in the skeleton, liver, kidney and developing teeth. In hypophosphatasia, accumulation of TNSALP natural substrates (substances altered by TNSALP) occurs. These substrates include inorganic pyrophosphate, an inhibitor (blocker) of mineralization. Accumulation of inorganic pyrophosphate explains the tooth loss, rickets or bone softening, and joint swelling. Severely affected infants sometimes also have hypercalcemia (high calcium levels) and hyperphosphatasemia (high alkaline phosphatase levels). This is due to the blocked entry of minerals into the skeleton and pyridoxine-dependent seizures. The seizures are cause by insufficient breakdown of pyridoxal 5'-phosphate, the major circulating form of vitamin B6. The different types of possible mutations of ALPL (which encodes for alkaline phosphatase) largely accounts for the wide range of severity of hypophosphatasia (a rare, genetic bone disorder). High serum concentrations of pyridoxal 5'-phosphate represent an accurate and specific biomarker for hypophosphatasia. Also, levels of phosphoethanolamine (which helps construct cell boundaries) are usually elevated in serum and urine. However, these biomarkers are less reliable for diagnosis. TNSALP mutation detection is important to determine is recurrence may occur and prenatal diagnosis. Diagnosing pediatric (child) hypophosphatasia is aided by observing disease-specific changes when the skeletal disease is severe. Hypophosphatasia was the last bone disease to receive a medical treatment. Now, significant successes for severely affected child patients are recognized using asfotase alfa, a prescription drug." +"BACKGROUND Lipedema is a common condition that presents as excessive fat deposition in the extremities, initially sparing the trunk, ankles, and feet, and is found mainly in women, usually occurring after puberty or pregnancy. Lipedema can progress to include lipo-lymphedema of the ankles and feet. This report is of a 41-year old woman with Stage 3 lipedema and lipo-lymphedema with excessive fat of the lower body since puberty, with progression to swollen ankles and feet despite dietary caloric restriction. CASE REPORT A 41-year-old woman noticed increased fat in her legs since age 12. Her weight and leg size increased until age 21, when she reached a maximum weight of 165 kg, and underwent a Roux-En-Y gastric bypass. Over 12 months, she lost 74.8 kg. Her trunk significantly reduced in weight, but her legs did not. Fifteen years later, during recovery from hysterectomy surgery, she became progressively weaker and swollen over her entire body. Laboratory test results showed hypoalbuminemia (2.0 g/dL), lymphopenia, and hypolipoproteinemia. She was diagnosed with protein and calorie malnutrition with marked gut edema requiring prolonged parenteral nutrition. After restoration of normal protein, her health returned and her pitting edema resolved, but her extremities remained enlarged. She was subsequently diagnosed with lipedema. CONCLUSIONS This report demonstrates that early and correct diagnosis of lipedema is important, as women who believe the condition is due to obesity may suffer the consequences of calorie or protein-calorie deficiency in an attempt to lose weight.","Lipedema is a common condition where there is too much fat in the arms and legs and is found mainly in women, usually occurring after puberty (when a child's body changes to become an adult) or pregnancy. Lipedema can progress to include lipo-lymphedema, which is a build up of fluid in addition to excess fat, in the ankles and feet. This report is of a 41-year old woman with Stage 3 lipedema and lipo-lymphedema with excessive fat of the lower body since puberty. The woman's condition has advanced to swollen ankles and feet despite being on a low calorie diet. The 41-year-old woman noticed increased fat in her legs since age 12. Her weight and leg size increased until age 21, when she reached a maximum weight of 364 pounds (165 kg), and had a procedure called gastric bypass that involves a doctor placing a small pouch in the stomach and food only goes into that pouch. Over 12 months, she lost 165 pounds (74.8 kg). Her trunk (chest, stomach, and back) significantly reduced in weight, but her legs did not. Fifteen years later, during recovery from surgery, she became continuously weaker and swollen over her entire body. Lab test results showed hypoalbuminemia (low levels of the albumin protein in the blood), making it harder to move substances in the body. Tests also show low levels of white blood cells and low levels of fat lipids in the blood. She was not eating enough protein and energy (through calories) to meet nutritional needs with edema (swelling) in the stomach, requiring that more nutrition be given through the vein. After restoring protein to normal levels, her health returned and her pitting edema due to excess fluid resolved, but her arms and legs remained enlarged. She was later diagnosed with lipedema. In conclusion, this report shows that early and correct diagnosis of lipedema is important. Women who believe the condition is due to obesity may suffer from not enough calorie or protein-calories in an attempt to lose weight." +"BACKGROUND In lymphedema, an imbalance in the formation and absorption of lymph causes accumulation of protein-rich fluid in the interstitium of the most gravity-dependent parts of the body. Diagnosis is usually made based on patient medical history and a physical examination showing a typical appearance of the affected body part. Differential diagnosis is confirmed by imaging. CASE REPORT Primary lymphedema is inherited in through an autosomal dominant pattern. Congestive cardiac failure and non-filarial infections predispose patients to the secondary form of lymphedema, elephantiasis nostras verrucosa (ENV). We present the case of a 65-year-old man with lymphedema praecox complicated by congestive cardiac failure. The patient was experiencing worsening left leg swelling and had a prior history of unilateral leg swelling at puberty. The condition was inherited through an autosomal dominant pattern, as his father, elder brother, and nephew were diagnosed with the same disease. The left leg showed non-pitting edema with indurated, woody skin and lichenification. The right leg had mild pitting edema. There were numerous verrucous folds and cobblestone-like nodules, and plaques and a painless ulcer on the left leg. Laboratory evaluation demonstrated an elevated B-type natriuretic peptide. He was treated with compression stockings and inelastic multi-layer bandaging and was administered limb decongestive treatment. After 1 week of therapy, his swelling had somewhat improved. CONCLUSIONS Various conditions can cause ENV and it can superimpose on any form of hereditary lymphedema. The most effective strategy for this condition seems to be a thorough workup of the underlying cause of the ENV and early intervention.","In lymphedema, an imbalance of a fluid called lymph causes a build up of protein-rich fluid, usually in the arms and legs. Diagnosis is usually made based on patient medical history and a physical examination of the affected body part. The diagnosis may be confirmed by imaging, such as x-rays or another scan. Primary lymphedema, also called hereditary lymphedema, is inherited (passed down from parent to child) through genes. Congestive heart failure (inefficient heart pumping) and infections from soil particles make it easier for patients to develop the secondary form of lymphedema, elephantiasis nostras verrucosa (ENV). ENV is a rare chronic condition caused by ongoing infections with bacteria and causes a part of the body, usually the lower part of the body, to be extremely enlarged. Researchers describe the case of a 65-year-old man with lymphedema complicated by congestive heart failure. The patient was experiencing worsening left leg swelling and had a prior history of leg swelling at puberty (when a child's body changes to become an adult) due to disease. The condition was inherited, as his father, elder brother, and nephew were diagnosed with the same disease. The left leg showed non-pitting edema (there was no indentation when the area of swelling is pressed) with woody skin due to scaring that was also thick and leathery. The right leg had mild pitting edema. There were numerous folds and cobblestone-like lumps, raised red patches of the skin, and a painless ulcer (sore) on the left leg. Lab tests showed high levels of a hormone made by the heart called B-type natriuretic peptide. He was treated with compression stockings and bandaging and given decongestive treatment in the limb which includes several techniques such as draining fluid. After 1 week of therapy, his swelling had somewhat improved. In conclusion, various conditions can cause elephantiasis nostras verrucosa (ENV), and it can be an additional condition on any form of hereditary lymphedema. The most effective strategy for this condition seems to be a detailed workup of the underlying cause of the ENV and early treatment and management." +"May-Thurner syndrome (MTS) is a clinical condition characterized by the compression of the left iliac vein by the right iliac artery. This condition predisposes the patient to deep venous thrombosis (DVT). We present the case of a 30-year?-old female who arrived at the emergency department of our facility with progressive left leg swelling for four weeks, with low-risk probability for DVT. Examination revealed left leg swelling with pitting edema extending up to the knee. Her calf muscle was tender to palpation. Dorsalis pedis, anterior tibial, and posterior tibial pulsations were fairly palpable due to the edema; however, the rest of her pulsations were appropriately felt. Therefore, the provisional diagnosis of possible DVT was made, and further investigations were requested. We present this case intending to highlight the clinical presentation of May-Thurner syndrome, its diagnosis, and treatment.","May-Thurner syndrome (MTS) is a clinical condition where the left iliac vein located in the abdomen that goes into the left leg is compressed by the right iliac artery which is a vein that goes into the right leg. Having this condition makes it easier for the patient to develop deep venous thrombosis (DVT), a serious condition where a blood clot forms in the vein. Researchers present the case of a 30-year?-old female who arrived at the emergency room with gradual left leg swelling for four weeks, with low-risk for developing DVT. An exam revealed left leg swelling with pitting edema up to the knee, a condition where excess fluid builds up in one part of the body and pressing into the swollen area leaves a pit or indentation. Her calf muscle was tender to light touch. Veins in the foot, in the leg called the anterior tibial, and in the lower leg can be fairly felt due to the edema; however, the rest of her pulses were appropriately felt. Therefore, the early diagnosis of possible DVT was made, and further investigations were requested. Researchers present this case intending to highlight the clinical signs and symptoms of May-Thurner syndrome, its diagnosis, and treatment." +"May-Thurner syndrome (MTS) is a clinical condition characterized by the compression of the left iliac vein by the right iliac artery. This condition predisposes the patient to deep venous thrombosis (DVT). We present the case of a 30-year?-old female who arrived at the emergency department of our facility with progressive left leg swelling for four weeks, with low-risk probability for DVT. Examination revealed left leg swelling with pitting edema extending up to the knee. Her calf muscle was tender to palpation. Dorsalis pedis, anterior tibial, and posterior tibial pulsations were fairly palpable due to the edema; however, the rest of her pulsations were appropriately felt. Therefore, the provisional diagnosis of possible DVT was made, and further investigations were requested. We present this case intending to highlight the clinical presentation of May-Thurner syndrome, its diagnosis, and treatment.","May-Thurner syndrome (MTS) is a condition in which the main right leg blood vessel compresses the main left leg blood vessel. MTS puts the patient at risk of deep venous thrombosis (DVT), or deep blood clotting. We describe a 30-year-old female who arrived at the emergency department with worsening left leg swelling for four weeks, with low-risk chance for DVT. Exams showed left leg swelling with serious swelling up to the knee. Her lower leg calf muscle was tender to touch. Various blood vessel pulsations in the leg were noticeable due to the swelling. However, the rest of her pulsations were examined by touch. Therefore, the identification of possibly DVT was made. Further invesetigations were requested. We present this case to highlight the symptoms of May-Thurner syndrome, its identification, and treatment." +"Background: Leg edema is a common adverse effect of dihydropyridine Calcium Channel Blockers (CCB) that may need dose reduction or drug withdrawal, adversely affecting the antihypertensive efficacy. Leg edema is reported to occur less often with (S)-amlodipine compared to conventional racemic amlodipine. We aimed to find the incidence of leg edema as a primary outcome and antihypertensive efficacy with (S)-amlodipine compared to conventional amlodipine. Methods: This prospective, double-blind, controlled clinical trial randomized 172 hypertensive patients, not controlled on beta-blockers (BB) and angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB), to either conventional amlodipine (5-10 mg; n = 86) or (S)-amlodipine (2.5-5 mg; n = 86), while continuing their previous anti-hypertensive medications. Sample was sufficient to find a difference in edema between the interventions with 80 % power at 5 % significance level. Intension to treat analysis (ITT) for safety data and per protocol analysis for efficacy data was performed. Fischer's exact test was applied to observe difference between responder rates and proportions of subjects having peripheral edema in the two groups. Pitting edema test scores were compared using Mann-Whitney test. Results: Altogether 146 patients (amlodipine, n = 76 and (S)-amlodipine, n = 70) completed 120 days treatment. Demographic variables and treatment adherence were comparable in the two groups. Incidence of new edema after randomization was 31.40 % in test group and 46.51 % in control group [p = 0.03; absolute risk reduction (ARR) = 15.1 %; Number Needed to Treat (NNT) = 7, ITT analysis]. Pitting edema score and patient rated edema score increased significantly in the control compared to test group (p = 0.038 and 0.036 respectively) after treatment period. Edema scores increased significantly in the control group from baseline (p < 0.0001). Responders in blood pressure were 98.57 % in test and 98.68 % in control group. Most common adverse events (AE) were pitting edema and increased urinary frequency. Incidence of all AEs other than edema was similar in both groups. Two serious AEs occurred unrelated to therapy. Biochemical and ECG parameters in the two groups were comparable. Conclusions: In hypertensive patients not controlled on prior BB and ACEI/ARB therapy, addition of (S)-amlodipine besylate at half the dose of conventional amlodipine provides better tolerability with reduced incidence of peripheral edema, and equal antihypertensive efficacy compared to amlodipine given at usual doses.","Leg edema is a common side effect of dihydropyridine Calcium Channel Blockers (CCB), medicines taken to control blood pressure and other conditions. The dose amount of CBB drugs may need to be reduced or stopped, negatively impacting the drugs' use to control blood pressure. Leg edema (fluid swelling) is reported to occur less often with a type of CBB medicine called (S)-amlodipine compared to the regular racemic amlodipine medicine. Researchers aim to find the number of times leg edema appeared and how well blood pressure is lowered with (S)-amlodipine compared to conventional amlodipine. This clinical trial followed 172 patients with high blood pressure, not controlled by using beta-blockers (BB) drugs or angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) that keep blood vessels open. These patients are randomly placed in groups to receive either standard amlodipine (86 patients) or (S)-amlodipine (86 patients), while continuing their previous anti-hypertensive medications. The number of patients in this study is sufficient to find a difference in edema between the two groups. Data from both treatment groups are analyzed during the study. Data are analyzed to observe the difference between the two groups on how they responded to the treatment and the number of people who develop peripheral edema (swelling in lower legs and hands). Pitting edema, a condition where excess fluid builds up in one part of the body and pressing into the swollen area leaves a pit or indentation, is measured and scored. Altogether 146 patients completed 120 days treatment: 76 patients in the standard amlodipine group and 70 in the (S)-amlodipine group. Characteristics such as age and sex and how well patients took the medicine as directed are compared between the two groups. New edema is 31.40 % in the (S)-amlodipine group and 46.51 % in the standard group. Pitting edema score and patient rated edema score increase significantly in the amlodipine compared to (S)-amlodipine group after the treatment period. Edema scores increase significantly in the amlodipine group from the start of the study. Responders in blood pressure are 98.57 % in (S)-amlodipine and 98.68 % in amlodipine group. Most common side effects are pitting edema and increase in urinary frequency. Number of all side effects other than edema is similar in both groups. Two serious side effects occur that are unrelated to therapy. Results from other blood and heart tests in the two groups are similar. In patients with high blood pressure not controlled on prior BB and ACEI/ARB therapy, adding (S)-amlodipine besylate at half the dose of standard amlodipine provides few side effects. There is also a reduced number of peripheral edema, and equal ability to lower blood pressure compared to amlodipine given at usual doses." +"We encountered an elderly male patient who after cardiac surgery for mitral stenosis had refractory pitting edema in both legs involving painful leg joints after a 1-month history of waxing and waning arthralgia. His family doctor had prescribed a combination of diuretics, 40 mg furosemide and 25 mg spironolactone; however, pitting edema in his lower legs persisted. He was diagnosed with worsening of congestive heart failure because of a previous cardiac surgery and was transferred to our hospital. On admission, we closely observed the patient's condition and noticed that his body temperature increased to 38.0 �C every evening. Furthermore, his ankle joints felt feverish and were swollen. Therefore, we suspected polyarthritis as an etiology, although we initially suspected rheumatoid arthritis (RA). Antibody testing did not support RA diagnosis; therefore we concluded the association of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome with his condition. After daily treatment with 15 mg prednisolone, the refractory edema symptom dramatically improved. The concept of RS3PE syndrome could explain such as an impressive clinical course. .","Doctors saw an elderly male patient who after heart surgery had pitting edema in both legs, a condition where excess fluid builds up in part of the body and pressing into the swollen area leaves a pit or indentation. The man also had painful leg joints after a 1-month history of periodic changes in joint stiffness. His family doctor had prescribed a combination of diuretics, medicines that help remove salt and water from the body; however, pitting edema in his lower legs continued. He was diagnosed with worsening of congestive heart failure (inefficient heart pumping) because of a previous heart surgery and transferred to the hospital. On admission to the hospital, doctors closely observed the patient's condition and noticed that his body temperature increased to 100.4 F (38.0 C) every evening. Additionally, his ankle joints felt feverish and were swollen. Therefore, doctors suspected arthritis in at least five joints (polyarthritis) as a potential cause, although doctors first thought it was rheumatoid arthritis (RA - a long-lasting arthritis from immune cells attacking healthy cells). Testing did not support a rheumatoid arthritis diagnosis; therefore, doctors concluded the association of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome with his condition. RS3PE is a rare disease with swollen joints and pitting edema. After daily treatment with a steroid medication called prednisolone, the edema symptom greatly improved. The concept of RS3PE syndrome could explain such as an impressive clinical result. Doctors encounter patients with pitting edema of unknown cause in daily clinical practice. In particular, heart specialists (cardiologists) usually tend to prescribe diuretics for patients with pitting edema in their legs. Cardiologists should consider RS3PE syndrome as a differential (potential) diagnosis, for patients with pitting edema in one location in their limbs. This report cautions prescribing diuretics for localized pitting edema." +"46 year old male with past medical history of schizoaffective disorder and chronic lower back pain, was admitted for management of worsening depression and anxiety. He was started on gabapentin, 300mg twice daily for his back pain and anxiety symptoms. His only other medication was hydrocodone. Over next few days, he started developing worsening bilateral lower extremity edema. He did not have any cardiovascular related symptoms. Physical exam was only significant for 3+ pitting edema with all laboratory values and imaging being unremarkable. Gabapentin was discontinued and his lower extremity swelling improved over subsequent days. Incidence of pedal edema with gabapentin use is approximately 7 to 7.5% with all studies being in elderly patients receiving doses above 1200 mg/day. This case illustrates that lower doses of gabapentin can also cause this adverse effect. It is important to recognize this adverse effect because gabapentin is used in conditions like diabetic neuropathy, which is associated with multiple co-morbidities that can give rise to bilateral leg swelling. Presence of gabapentin induced leg swelling can thus confound the clinical picture.","A 46 year old male with past medical history of schizoaffective (reality-distorting) disorder, a mental disorder, and chronic lower back pain, is admitted to a medical facility to manage worsening depression and anxiety. He is started on a medicine called gabapentin (nerve pain medication) for his back pain and anxiety symptoms. His only other medication is an opioid pain reliever called hydrocodone. Over the next few days, he starts developing worsening edema, swelling caused by too much fluid trapped in the body's tissues, in both legs. He does not have any cardiovascular (heart) related symptoms. A physical exam found pitting edema, where pressing into the swollen area leaves a pit or indentation. All other lab tests and imaging scans did not show anything significant. Gabapentin is stopped and the swelling in his legs improved over the following days. In other studies, the occurrence of swollen feet (pedal edema) while on gabapentin is about 7 to 7.5% in elderly patients receiving doses above 1200 mg/day. This case illustrates that lower doses of gabapentin can also cause this negative effect. It is important to recognize this negative effect because gabapentin is used in conditions like nerve damage common with diabetes (diabetic neuropathy), which is associated with multiple illnesses that can give rise to swelling in both legs. " +"46 year old male with past medical history of schizoaffective disorder and chronic lower back pain, was admitted for management of worsening depression and anxiety. He was started on gabapentin, 300mg twice daily for his back pain and anxiety symptoms. His only other medication was hydrocodone. Over next few days, he started developing worsening bilateral lower extremity edema. He did not have any cardiovascular related symptoms. Physical exam was only significant for 3+ pitting edema with all laboratory values and imaging being unremarkable. Gabapentin was discontinued and his lower extremity swelling improved over subsequent days. Incidence of pedal edema with gabapentin use is approximately 7 to 7.5% with all studies being in elderly patients receiving doses above 1200 mg/day. This case illustrates that lower doses of gabapentin can also cause this adverse effect. It is important to recognize this adverse effect because gabapentin is used in conditions like diabetic neuropathy, which is associated with multiple co-morbidities that can give rise to bilateral leg swelling. Presence of gabapentin induced leg swelling can thus confound the clinical picture.","We admitted a 46 year old male to treat his worsening depression and anxiety. He had a prior history of symptoms of schizophrenia and mood disorders and long-lasting lower back pain. He was started on gabapentin (nerve pain medication), 300 mg twice daily for his back pain and anxiety symptoms. His only other medication was hydrocodone, a pain and cough medication. Over the next few days, he developed worsening swelling in both legs. He did not have any heart-related symptoms. Physical exam only noted serious swelling with all lab values and imaging not being serious. Gabapentin use was stopped, and his leg swelling improved over the next few days. Frequency of leg swelling with gabapentin use is around 7 to 7.5% with all studies being in elderly patients receiving doses above 1200 mg/day. This case shows that lower doses of gabapentin can also cause this harmful effect. This serious effect should be noted since gabapentin is used in conditions like diabetic nerve pain, which is linked with other diseases that can give rise to swelling in both legs. Presence of gabapentin-caused leg swelling can thus confuse the diagnosis." +"Symmetrical leg swelling formed in the course of the years is a common and in most cases benign phenomenon that is mostly encountered in the aged population, especially in women. Venous insufficiency of the lower limbs is the most common cause of symmetrical leg swelling among those over 50 years of age. Diseases of the essential organs such as the heart, the liver and the kidneys are excluded during the initial stage. Pitting edema occurs both in venous insufficiency and in right-sided heart failure. Basic tests and drug history are usually sufficient to exclude a host of general causes of the edema.","Leg swelling in both legs over time is common, and in most cases unharmful, and is mostly found in the older population, especially in women. Veins in the lower limbs that do not allow enough blood to flow to the heart, called venous insufficiency, is the most common cause of swelling in legs among those over the age of 50. Diseases of the important organs such as the heart, the liver and the kidneys are excluded during the first stage. Pitting edema, a condition where excess fluid builds up in one part of the body and pressing into the swollen area leaves a pit or indentation, occurs both in venous insufficiency and in right-sided heart failure. Basic tests and drug history are usually enough to exclude a number of general causes of the edema." +"Aim: Leg edema, observed on comprehensive geriatric assessment (CGA) of 142 elderly outpatients with a variety of chronic diseases, was studied clinically to clarify its incidence and its associated risk factors. Methods: The severity of pitting edema was assessed at 3 points, namely, the pretibial edge, medial malleolus, and the dorsum of the foot. On palpation, edema was graded as 0 to 3 for each point on one leg, the sum of which was used as the edema score. According to the edema score, subjects were divided into 3 groups; the moderate to severe (MS) group, the slight to mild (SM) group, and the group without pitting edema. The MS group was defined as having an edema score of 4 or more or edema of grade 2 or more, while the SM group was defined as having an edema score of 2 to 3 points without edema of grade 2 or more. The status of underlying disease, vascular risks, varicose veins, medications, daily activity, nutrition, total protein (TP), albumin, brain natriuretic peptide (BNP), and the estimated glomerular filtration rate (eGFR) were compared among the 3 groups. Results: There were 36 subjects in the MS group and 19 subjects in the SM group. Diabetes, atrial fibrillation, varicose veins, and polypharmacy were more frequent in the MS group than in the control group. Sedentary life style, house-bound, and gait trouble were significantly more frequent in the MS and SM groups. There were no significant differences in the scores of the Mini-Nutritional Assessment Short Form among the groups, although both the body weight and calf circumference in the MS group were significantly greater than those in the group without pitting edema. Low serum TP, albumin and eGFR were seen in the MS group as well as high BNP levels. Multiple regression analysis revealed diabetes, varicose veins, sedentarism, and hypoalbuminemia as risk factors associated with leg edema (R(2)=0.365, p<0.0001). Conclusion: Leg edema was frequent in the elderly outpatients and was associated strongly with diabetes, varicose veins, sedentarism, and hypoalbuminemia. These findings suggest that advising against a sedentary life style could help the resolution of edema, and also indicates the clinical usefulness of CGA. Furthermore, leg edema should be seriously considered along with nutritional assessment because edema could influence various anthropometric parameters.","In this study, leg edema (fluid swelling) is studied to understand how frequently it occurs and its associated risk factors. Leg edema is observed on a detailed evaluation of older and frail people called the comprehensive geriatric (elderly) assessment of 142 elderly outpatients with a variety of chronic diseases. The severity of pitting edema, a condition where excess fluid builds up in one part of the body and pressing into the swollen area leaves a pit or indentation, is assessed at 3 places: the shins, the bony bump on the inside of the ankle, and the top part of the foot that faces up when standing. When pressing on the swollen area, edema is graded as 0 to 3 for each point on one leg, the sum of which was used as the edema score. According to the edema score, patients are divided into 3 groups; the moderate to severe group, the slight to mild group, and the group without pitting edema. The moderate to severe group is defined as having an edema score of 4 or more or edema of grade 2 or more, while the slight to mild group is defined as having an edema score of 2 to 3 points without edema of grade 2 or more. The following tests and measurements are compared among the 3 groups: the status of underlying disease, risks to developing heart problems, varicose (twisted, enlarged) veins, medications, daily activity, nutrition, tests for proteins in the body, and tests for how well the kidneys are working. There are 36 patients in the moderate to severe group and 19 subjects in the slight to mild group. Diabetes, an irregular heart beat (atrial fibrillation), varicose veins, and being on multiple drugs at one time are more frequent in the moderate to severe group than in the comparison group. Sedentary life style (no or little physical activity), house-bound, and walking trouble are much more frequent in the moderate to severe and slight to mild groups. There are no significant differences in the scores on malnourishment (poor nutrition) among the groups, although both the body weight and calf circumference (size) in the moderate to severe group are much greater than those in the group without pitting edema. Low levels of total protein in the blood, another protein made by liver called albumin, and kidney function tests are seen in the moderate to severe group as well as high levels of a protein made by heart and blood vessels called BNP. Data analysis revealed diabetes, varicose veins, sedentarism (inactivity), and low levels of the protein albumin as risk factors associated with leg edema. In conclusion, leg edema is frequent in the elderly outpatients and is associated strongly with diabetes, varicose veins, sedentarism, and low levels of albumin in the blood. These findings suggest that advising against an inactive life style could help resolve edema, and also indicates the usefulness of comprehensive geriatric assessment to evaluate older populations. Furthermore, leg edema should be seriously considered along with evaluating the diet of patients because edema could influence various physical measurements of the body." +"Edema is an accumulation of fluid in the interstitial space that occurs as the capillary filtration exceeds the limits of lymphatic drainage, producing noticeable clinical signs and symptoms. The rapid development of generalized pitting edema associated with systemic disease requires timely diagnosis and management. The chronic accumulation of edema in one or both lower extremities often indicates venous insufficiency, especially in the presence of dependent edema and hemosiderin deposition. Skin care is crucial in preventing skin breakdown and venous ulcers. Eczematous (stasis) dermatitis can be managed with emollients and topical steroid creams. Patients who have had deep venous thrombosis should wear compression stockings to prevent postthrombotic syndrome. If clinical suspicion for deep venous thrombosis remains high after negative results are noted on duplex ultrasonography, further investigation may include magnetic resonance venography to rule out pelvic or thigh proximal venous thrombosis or compression. Obstructive sleep apnea may cause bilateral leg edema even in the absence of pulmonary hypertension. Brawny, nonpitting skin with edema characterizes lymphedema, which can present in one or both lower extremities. Possible secondary causes of lymphedema include tumor, trauma, previous pelvic surgery, inguinal lymphadenectomy, and previous radiation therapy. Use of pneumatic compression devices or compression stockings may be helpful in these cases.","Edema is a build up of fluid in the body's tissues and does not drain properly, producing noticeable clinical signs and symptoms. The rapid development of pitting edema, which is when pressing into the swollen area leaves a pit or indentation, associated with diseases that affects other parts of the body requires timely diagnosis and management. The ongoing build up of edema in one or both lower legs often suggests veins in the lower limbs are not allowing enough blood to flow to the heart, especially in the presence of gravity-related swelling and build up of iron deposits under the skin that has a shade of brown pigment. Skin care is crucial in preventing skin breakdown and venous ulcers, open sores on the skin from abnormal vein function. Inflamed skin in the lower legs called eczematous (stasis) dermatitis is a kind of eczema (skin swelling) caused by poor circulation and can be helped with moisturizers and topical steroid creams. Patients who have had a condition where a blood clot forms in the vein called deep venous thrombosis should wear compression stockings. If a doctor believes a diagnosis for deep venous thrombosis is possible even after negative (no detection) results are noted on tests, further investigation may include imaging scans to rule out pelvic or thigh proximal venous thrombosis or compression. Occasional airflow blockage during sleep called obstructive sleep apnea may cause edema in both legs even in the absence of high blood pressure. Discolored, non-pitting (non-indentable) skin with edema is often a sign of lymphedema, fluid build-up in soft tissues when the lymph system is damaged or blocked, which can present in one or both lower limbs. Possible other causes of lymphedema include tumor, trauma, previous pelvic surgery, inguinal lymphadenectomy (lymph node dissection), and previous radiation therapy. Use of compression devices that are inflatable sleeves worn on the legs or compression stockings may be helpful in these cases." +"Edema is an accumulation of fluid in the interstitial space that occurs as the capillary filtration exceeds the limits of lymphatic drainage, producing noticeable clinical signs and symptoms. The rapid development of generalized pitting edema associated with systemic disease requires timely diagnosis and management. The chronic accumulation of edema in one or both lower extremities often indicates venous insufficiency, especially in the presence of dependent edema and hemosiderin deposition. Skin care is crucial in preventing skin breakdown and venous ulcers. Eczematous (stasis) dermatitis can be managed with emollients and topical steroid creams. Patients who have had deep venous thrombosis should wear compression stockings to prevent postthrombotic syndrome. If clinical suspicion for deep venous thrombosis remains high after negative results are noted on duplex ultrasonography, further investigation may include magnetic resonance venography to rule out pelvic or thigh proximal venous thrombosis or compression. Obstructive sleep apnea may cause bilateral leg edema even in the absence of pulmonary hypertension. Brawny, nonpitting skin with edema characterizes lymphedema, which can present in one or both lower extremities. Possible secondary causes of lymphedema include tumor, trauma, previous pelvic surgery, inguinal lymphadenectomy, and previous radiation therapy. Use of pneumatic compression devices or compression stockings may be helpful in these cases.","Edema is a buildup of fluid in the body that occurs as the filtration rate exceeds the drainage rate, producing noticeable symptoms. The rapid development of swelling linked with full-body disease needs timely identification and treatment. The long-lasting buildup of fluid in one or both legs often indicates blood vessel impairment, especially in the presence of swelling in the limbs and iron buildup. Skin care is needed in preventing skin breakdown and vein-related open sores. Skin inflammation from swelling in the legs can be managed with specific moisturizers and steroid creams. Patients who have had deep venous thrombosis (deep vein blood clotting) should wear compression socks to prevent its symptoms like pain and swelling. If clinicians remain suspicious of deep venous thrombosis even when lab tests do not detect it, further lab tests may be performed to rule out other forms of blood clotting and compression. Obstructuve sleep apnea (disorder in which breathing is consistently interrupted during sleep by a blockage) may cause swelling in both legs even without lung-related high blood pressure. Sturdy skin with swelling characterizes lymphedema (fluid buildup when the body's drainage system is blocked), which can present in one or both legs. Possible secondary causes of lymphedema include tumor, blunt force, previous hip surgery, lymph node (immune system organ) removal, and previous radiation therapy. Use of compression devices to prevent blood clotting or socks may be helpful in these cases." +"Rheumatologists are increasingly aware of the entity synovitis with pitting edema. The remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome has been reported with an array of conditions that include polymyalgia rheumatica, rheumatoid arthritis, Sj�gren's syndrome and psoriatic arthropathy. Synovitis with pitting edema is now being increasingly recognized with systemic lupus erythematosus (SLE). We report a patient who presented with edema of hands and feet and was diagnosed eventually with definite SLE. With magnetic resonance imaging, joint effusions and tenosynovitis were confirmed to be associated with the otherwise-unexplained extremity edema.","Specialists who treat diseases in the joints, muscles, and bones, called rheumatologists, are increasingly aware of swollen joints (synovitis) with pitting edema, a condition where excess fluid builds up in one part of the body and pressing into the swollen area leaves a pit or indentation. The remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is a rare disease with swollen joints and pitting edema. RS3PE has been reported with a number of conditions that include polymyalgia rheumatica (a disorder that causes muscle pain and stiffness, mainly in the shoulders and hips), rheumatoid arthritis (arthritis whereby immune cells attack healthy cells), an immune system disorder that causes dry eyes and mouth called Sj�gren's syndrome, and a type of arthritis linked to psoriasis (a skin disease causing red, itchy scaly patches). Synovitis with pitting edema is now being increasingly seen in patients with systemic lupus erythematosus (lupus), a chronic disease where the body's immune system mistakenly attacks healthy cells and tissues. Researchers report a patient who presented with edema (swelling) of hands and feet and was diagnosed eventually with definite lupus. With imaging tools, fluid build up in the joints and inflammation (redness and swelling from fighting an infection) of the top layer of tendons (tenosynovitis) were confirmed to be associated with the otherwise-unexplained edema in the limbs." +"Purpose: To evaluate the practical value of initial C-reactive protein (CRP) in the diagnosis of bacterial infection in children. Methods: The subjects comprised 11 children, six boys and five girls, aged 3 months through to 3 years (median age 16 months), whose initial CRP levels were < 1.0 mg/dL despite bacterial infection. C-reactive protein was quantitated at the first medical examination by nephelometry. Results: The diagnosis was urinary tract infection (n = 4), bacterial meningitis (n = 2), sepsis (n = 2), pneumonia (n = 2) and arthritis of the hip joint (n = 1). The CRP levels were significantly elevated during the course of infection, ranging from 7.6 to 28.5 mg/dL. The bacterial etiology was non-specific. Eight patients were examined within 12 h of onset, three exhibited negative CRP values despite the duration of the insult over 12 h. Six patients were tentatively diagnosed as having a bacterial infection, but the other five were not. Each patient was treated, leading to a favorable outcome without any serious complications. Conclusions: Low levels of CRP do not rule out the possibility of bacterial infection in children. The initial value of CRP may be negative, even in patients with severe bacterial infection or even after 12 h from onset. The data suggest that pediatricians should consistently be aware of the possibility of bacterial infection even if the initial CRP test result is negative and that serial CRP measurements appear to be practical.","The aim of this paper was to determine how C-reactive protein volume in patients can help diagnose bacterial infections in children. C-reactive protein is a type of protein found in the blood that increases during times of internal inflammation (redness and swelling from infection-fighting). The study evaluated 11 children. The group consisted of six boys and five girls that were between 3 months to 3 years of age. All of the children's' initial CRP levels were < 1.0 mg/dL despite bacterial infection. C-reactive protein was measured at the first medical examination. The eleven children were diagnosed with various illnesses. These include: 4 with urinary tract infection, 2 with bacterial meningitis (inflammation with intense headaches), 2 with sepsis (life-threatening condition when the body's response to infection damages itself), 2 with pneumonia (lung infection) and 1 with arthritis of the hip joint. CRP levels were increased during the course of infection. The cause of the bacterial infections were not specified. Eight patients were examined within 12 h of illness. Three showed negative CRP values despite the duration of the illness over 12 h. Six patients were tentatively diagnosed as having a bacterial infection. The other five were not. Each patient was treated. Treatment led to better health status without any serious complications. Low levels of CRP do not rule out the possibility of bacterial infection in children. The initial value of CRP may be negative, even in patients with severe bacterial infection or even after 12 h from onset. The data suggest that doctors of children should always be aware of the possibility of bacterial infection even if the initial CRP test result is negative (no detection) and that serial (multiple) CRP measurements appear to be practical." +"Sarcoidosis is characterized by granuloma formation, the macrophage being the most important building block. The activated macrophage in sarcoidosis produces interleukin-1 (II-1). It is well known that interleukin-1, among other functions, stimulates the hepatic production of C-reactive protein. We therefore prospectively measured the serum C-reactive protein in 17 patients with active pulmonary sarcoidosis, 10 patients with other chronic interstitial lung diseases of unknown etiology, 11 patients with active lung tuberculosis, and 10 healthy volunteers. Serum C-reactive protein was assayed by enzymoimmunodiffusion test. The serum C-reactive protein was negative in 13 patients suffering from active sarcoidosis and positive in four. Patients with other interstitial lung diseases had negative results in 7 and positive in 3 cases. The analyses of C-reactive protein in patients with sputum positive lung tuberculosis were positive in 10 cases. All the healthy controls had negative C-reactive protein measurements. The difference between the groups was statistically significant when sarcoidosis and tuberculosis serum C-reactive protein measurements were compared (p less than 0.01), as well as the difference between the group of other interstitial lung diseases and tuberculosis (p less than 0.01). In this respect, the measurements of serum C-reactive protein are valuable in the differentiation of sarcoidosis and other chronic interstitial lung diseases of unknown etiology from tuberculosis and other diseases which are known to induce an acute phase response.","Sarcoidosis is a disease that is characterized by granuloma formation or the tiny growth collections of inflammation (infection-fighting) cells. One of these cell types is the immune cell, macrophage. Macrophages are one of the most important building blocks of this disease. Macrophage in sarcoidosis produces interleukin-1 (II-1), a protein that helps fight infections. Interleukin-1 has many functions, including the stimulation of the hepatic (liver) production of C-reactive protein. C-reactive protein is a type of protein found in the blood that increases during times of internal inflammation (redness and swelling from infection-fighting). Serum (blood) C-reactive protein was measured in 48 patients. Seventeen of the patients had active sarcoidosis in the lung. Ten patients had other lung diseases of unknown origin. Eleven patients had active lung tuberculosis (a serious lung infection). Ten patients were healthy volunteers. Serum C-reactive protein was measured. The serum C-reactive protein was negative (no detection) in 13 patients suffering from active sarcoidosis and positive in four. Patients with other lung diseases had negative results in 7 cases and positive (was detected) in 3 cases. The analyses of C-reactive protein in patients with lung tuberculosis were positive in 10 cases. All the healthy controls had negative C-reactive protein measurements. The difference between the groups was statistically significant when sarcoidosis and tuberculosis serum C-reactive protein measurements were compared. There was also a significant difference between the group of other lung diseases and tuberculosis. Levels of serum C-reactive protein are valuable in the identification of sarcoidosis and other lung diseases of unknown origin from tuberculosis and other diseases." +"Sarcoidosis is characterized by granuloma formation, the macrophage being the most important building block. The activated macrophage in sarcoidosis produces interleukin-1 (II-1). It is well known that interleukin-1, among other functions, stimulates the hepatic production of C-reactive protein. We therefore prospectively measured the serum C-reactive protein in 17 patients with active pulmonary sarcoidosis, 10 patients with other chronic interstitial lung diseases of unknown etiology, 11 patients with active lung tuberculosis, and 10 healthy volunteers. Serum C-reactive protein was assayed by enzymoimmunodiffusion test. The serum C-reactive protein was negative in 13 patients suffering from active sarcoidosis and positive in four. Patients with other interstitial lung diseases had negative results in 7 and positive in 3 cases. The analyses of C-reactive protein in patients with sputum positive lung tuberculosis were positive in 10 cases. All the healthy controls had negative C-reactive protein measurements. The difference between the groups was statistically significant when sarcoidosis and tuberculosis serum C-reactive protein measurements were compared (p less than 0.01), as well as the difference between the group of other interstitial lung diseases and tuberculosis (p less than 0.01). In this respect, the measurements of serum C-reactive protein are valuable in the differentiation of sarcoidosis and other chronic interstitial lung diseases of unknown etiology from tuberculosis and other diseases which are known to induce an acute phase response.","Sarcoidosis is a disease characterized by growths of inflammatory cells in the body. The activated macrophage, a specialized white blood cell defender against invaders, in sarcoidosis produces interleukin-1 (Il-1), a molecule which signals inflammation. Interleukin-1, among other functions, activates the liver production of C-reactive protein, a marker of inflammation. We measured the blood C-reactive protein in 17 patients with active lung-related sarcoidosis, 10 with other long-lasting lung diseases of unknown cause, 11 with active lung tuberculosis (a bacterial lung infection), and 10 healthy volunteers. Blood C-reactive protein was measured with a specific lab test. The blood C-reactive protein was not detected in 13 patients with active sacroidosis and was detected in four. C-reactive protein was not detected in 7 patients with other lung diseases and was detected in 3 cases. The tests of C-reactive protein in patients with lung tuberculosis-related mucus was detected in 10 cases. No C-reactive protein was detected in healthy patients. There was a difference between groups when sarcoidosis and tuberculosis blood C-reactive protein measurements were compared, along with a difference between the group of other lung diseases and tuberculosis. Measuring blood C-reactive protein is valuable to differentiate sacroidosis and other lung-lasting lung diseases of unknown causes from tuberculosis and other diseases known to cause an immediate response." +"The role of subclinical intrauterine infection in preterm labor was evaluated prospectively in 40 patients and appropriate control subjects. The 24 preterm labor patients (60%) with a negative C-reactive protein value responded to tocolysis 95.8% of the time, with a mean delay of delivery of 35.5 days and a mean gestational age of 36.9 weeks. The 16 patients (40%) with a positive C-reactive protein value responded to tocolysis only 37.5% of the time, with a mean delay of delivery of 14.4 days and a mean gestational age of 33.2 weeks. Pathologic evidence of chorioamnionitis was present in 32.9% of 310 preterm deliveries as compared to only 22.3% of 1631 term deliveries. The presence of subclinical infection must be considered in cases of preterm labor, especially among patients for whom tocolytic therapy is unsuccessful.","The role of undetected infection within the uterus in preterm labor (between week 20 and 27 of pregnancy) was evaluated in 40 patients and control subjects. The 24 preterm labor patients with a negative (no detection) C-reactive protein value responded to tocolysis, a procedure to delay delivery, most of the time. These patients had an average delay of delivery for 35.5 days and an average gestational (pregnant) age of 36.9 weeks. C-reactive protein is a type of protein found in the blood that increases during times of internal inflammation (redness and swelling from infection-fighting). The 16 patients with a positive (with detection of) C-reactive protein value responded to tocolysis less than half of the time. These patients had an average delay of delivery of 14.4 days and an average gestational age of 33.2 weeks. Evidence of chorioamnionitis, an infection within the membranes surrounding a fetus, was present in 32.9% of 310 preterm deliveries. Evidence of chorioamnionitis was only found in 22.3% of 1631 term deliveries. The presence of undetected infection must be considered in cases of preterm labor, especially among patients for whom tocolytic therapy is unsuccessful." +"Background: There is no agreeing if rescue therapy can avoid short-term colectomy in patients treated for severe steroid-refractory ulcerative colitis. Aims: The aim of our study was to identify predictors of response to infliximab and cyclosporine A. Methods: In this cross-sectional study, 49 patients with severe ulcerative colitis were included. Response to therapy was defined as three or more point reductions in Mayo score after 6 months of treatment and avoidance of colectomy after 1 year. The predictors analysed were gender, age, time from ulcerative colitis diagnosis, months of steroid or/and azathioprine therapy before onset of the severe phase, smoking habits, extension of the disease, laboratory analyses and Mayo score. Results: Patients treated with infliximab showed a statistically significant higher response rate in case of moderate Mayo score (P = 0.04). Ex-smokers had very low chance of response to infliximab (P = 0.03). In the group treated with cyclosporine A, patients with C-reactive protein >3 mg/L had a response rate significantly higher than those with C-reactive protein <3 mg/L (P = 0.03); those with negative C-reactive protein and moderate Mayo score did not responded to therapy, while in the ones with elevated C-reactive protein and/or severe Mayo score, 15 versus 4 responded (P = 0.008). Conclusions: Our data suggest that cyclosporine A is advisable in ex-smokers. In never smokers or active smokers, infliximab can be prescribed in case of Mayo score ?10 and/or negative CRP, while cyclosporine A is indicated in case of Mayo score >10 and positive CRP.","It is unknown if rescue therapy, or therapy given after an ailment does not respond to normal treatment, can avoid colectomy (removal of all or parts of colon) in patients treated for severe steroid-refractory ulcerative colitis. Steroid-refractory ulcerative colitis is chronic inflammatory bowel disease that no longer responds to steroid treatment. The aim of this study was to identify predictors of response to infliximab and cyclosporine A, drugs that aim to improve the immune system. In this study, 49 patients with severe ulcerative colitis were included. Response to therapy was characterized as three or more point reductions in Mayo score (a disease ranking system) after 6 months of treatment and avoidance of colectomy after 1 year. Increased Mayo score indicated worsened disease condition. The predictors evaluated were gender, age, time from ulcerative colitis diagnosis, months of steroid or/and azathioprine therapy before onset of the severe phase, smoking habits, extension of the disease, laboratory analyses and Mayo score. Azathioprine is a medication given to improve immune function. Patients treated with infliximab showed a statistically significant higher response rate in case of moderate Mayo score. Ex-smokers had very low chance of response to infliximab. In the group treated with cyclosporine A, patients with a higher volume of C-reactive protein had a response rate significantly higher than those with lower C-reactive protein volume. Patients with negative (no detected) C-reactive protein volume and moderate Mayo score did not responded to therapy. Patients with elevated C-reactive protein and/or severe Mayo score predominately respond. C-reactive protein is a type of protein found in the blood that increases during times of internal inflammation (redness and swelling from infection-fighting). This study suggests that cyclosporine A is advisable as treatment in ex-smokers. In never smokers or active smokers, infliximab can be prescribed in case of Mayo score ?10 and/or negative CRP. However, cyclosporine A is indicated as a better option in case of Mayo score >10 and positive CRP." +"We analyzed the short-term and long-term outcome of 42 patients with distal type aortic dissection. Twenty-eight patients underwent intensive medical therapy within two weeks after the onset of pain (acute dissection). The remaining 14 patients had chronic dissection. The goals of medical treatment were to control blood pressure and to attain a negative C-reactive protein test result. Hospital survival rate in the patients with acute dissection was 96% (27/28). In-hospital complications included changes in mental status, renal dysfunction, bradycardia, orthostatic hypotension, and liver dysfunction, all of which were managed medically. Three of these patients underwent surgical therapy in the chronic phase and were discharged uneventfully. Fifteen (62.5%) of the 24 medically treated patients were discharged with negative C-reactive protein tests. Spontaneous resolution of a dissection was demonstrated by radiological examinations in 8 cases. Five-year survival rates in 24 medically treated patients was 93%. Hospital survival rate in the patients with chronic dissection was 100% (14/14). The rigorous control of blood pressure in the acute phase, and subsequent meticulous evaluation of the dissection by radiological tests and C-reactive protein test provides acceptable short-term and long-term outcomes of patients with acute distal dissection without the need for emergency surgical intervention.","This study evaluated the short- and long-term outcome of 42 patients with distal type aortic dissection. Distal type aortic dissection is when an injury occurs to the inner layer of the aorta (main artery of the body), and blood flows between the layers of the aortic wall. Twenty-eight patients underwent intensive medical therapy within two weeks after the onset of pain (acute dissection). The remaining 14 patients had chronic dissection, meaning they were treated after more than 2 weeks had passed since pain onset (started). The goals of treatment were to control blood pressure and to attain a negative (no detected) C-reactive protein test result. C-reactive protein is a type of protein found in the blood that increases during times of internal inflammation (redness and swelling from infection-fighting). Hospital survival rate in the patients with acute dissection was 96% (27/28). There were several complications that occurred in-hospital during treatment. These complications include changes in mental status, kidney dysfunction, bradycardia (low heart rate), low blood pressure, and liver dysfunction. All of these complications were managed medically. Three of these patients underwent surgical therapy in the chronic phase and were discharged without issue. Fifteen of the 24 medically treated patients were discharged with negative C-reactive protein tests. Spontaneous resolution of a dissection was demonstrated by x-rays in 8 cases. Nearly all of the 24 medically treated patients had five-year survival rates. Hospital survival rate in the patients with chronic dissection was 100%. Strict control of blood pressure and evaluation of the dissection by x-rays and C-reactive protein tests provide acceptable outcomes of patients with acute distal dissection. These measures eliminate the need for emergency surgical intervention." +"We analyzed the short-term and long-term outcome of 42 patients with distal type aortic dissection. Twenty-eight patients underwent intensive medical therapy within two weeks after the onset of pain (acute dissection). The remaining 14 patients had chronic dissection. The goals of medical treatment were to control blood pressure and to attain a negative C-reactive protein test result. Hospital survival rate in the patients with acute dissection was 96% (27/28). In-hospital complications included changes in mental status, renal dysfunction, bradycardia, orthostatic hypotension, and liver dysfunction, all of which were managed medically. Three of these patients underwent surgical therapy in the chronic phase and were discharged uneventfully. Fifteen (62.5%) of the 24 medically treated patients were discharged with negative C-reactive protein tests. Spontaneous resolution of a dissection was demonstrated by radiological examinations in 8 cases. Five-year survival rates in 24 medically treated patients was 93%. Hospital survival rate in the patients with chronic dissection was 100% (14/14). The rigorous control of blood pressure in the acute phase, and subsequent meticulous evaluation of the dissection by radiological tests and C-reactive protein test provides acceptable short-term and long-term outcomes of patients with acute distal dissection without the need for emergency surgical intervention.","We analyzed the short- and long-term outcome of 42 patients with distal type aortic dissection (a tear in the major blood vessel near the heart). Twenty-eight patients underwent intense treatment within two weeks after the start of pain (acute dissection or immediate rupture). The remaining 14 patients had long-lasting dissection or gradual breakdown of the major blood vessel near the heart. The goals of treatment were to control blood pressure and detect no C-reactive protein (a measure of inflammation). Hospital survival rate in patients with acute dissection was 96% (27/28). In-hospital issues included changes in mental status, kidney dysfunction, slowed heart beat, low blood pressure from standing, and liver dysfunction, all of which were managed medically. Three of these patients had surgery in the long-lasting phase and were released without issue. Fifteen (62.5%) of the 24 medically treated patients were released with no C-reactive protein detected. Random solving of a dissection (tear) was demonstrated by medical imaging in 8 cases. Five-year survival rates in 24 medically treated patients was 93%. Hospital survival rate in patients with long-lasting dissection was 100% (14/14). The rigorous control of blood pressure in the immediate phase, and subsequent monitoring of the dissection or tear by imaging and C-reactive protein tests provide good short- and long-term outcomes of patients with immediate distal dissection without emergency surgery." +"Background: Corona virus disease 2019 has become a global health issue. The goal of this study was to investigate the characteristics and outcomes of patients with corona virus disease 2019 undergoing invasive mechanical ventilation and identify factors associated with mortality. Methods: Ninety four consecutive critically ill patients with confirmed corona virus disease 2019 undergoing invasive mechanical ventilation were included in this retrospective, single-center, observational study. The outcome variable was mortality of patients undergoing invasive mechanical ventilation and factors associated with it during intensive care unit stay. Results: Seventy nine (84%) out of 94 patients with confirmed corona virus disease 2019 who underwent invasive mechanical ventilation didn't survive. Ninety four percent of patients who had Type 2 Diabetes Mellitus did not survive in comparison to 72 percent of patients who didn't have Type 2 Diabetes Mellitus. Similarly, 48 (94.1%) out of 51 patients with a positive C-reactive protein value didn't survive in comparison to 31 (72%) out of 43 patients with a negative C-reactive protein. Conclusions: The presence of Type 2 Diabetes Mellitus and a positive C-reactive protein value were strongly associated with mortality. Patients with a Sequential organ failure assessment score of more than eight at intensive care unit admission and peak D-dimer level of more than or equal to two during intensive care unit stay didn't show significant association with mortality. These findings need further exploration through larger prospective studies.","Corona virus disease 2019, or COVID-19 (a viral, respiratory illness), has become a global health issue. The goal of this study was to investigate the characteristics and outcomes of patients with COVID-19 undergoing invasive mechanical ventilation (being helped to breathe by a machine). This study also aimed to identify factors associated with death. Ninety four critically ill COVID-19 patients undergoing invasive mechanical ventilation were included in this study. The studied variable of interest was death of the patients undergoing invasive mechanical ventilation and factors associated with death during intensive care unit stay. Seventy nine out of 94 patients with COVID-19 who underwent invasive mechanical ventilation didn't survive. Ninety four percent of patients who had Type 2 Diabetes Mellitus did not survive. This is compared to 72% of patients who didn't have Type 2 Diabetes Mellitus. Similarly, 48 out of 51 patients with a positive C-reactive protein value didn't survive in comparison to 31 out of 43 patients with a negative C-reactive protein. C-reactive protein is a type of protein found in the blood that increases during times of internal inflammation (redness and swelling from infection-fighting). The presence of Type 2 Diabetes Mellitus and a positive C-reactive protein value were strongly associated with death. Patients with a Sequential organ failure assessment score, a ranking system to determine patient's organ function, of >8 at ICU admission and peak D-dimer (protein fragment from dissolved blood clotting) level of ? 2 during ICU stay didn't show significant association with death. These findings need further exploration in larger studies." +"We evaluated the impact of tumor shrinkage (TS) induced by molecular targeted therapy as the first-line systemic therapy on the survival of patients with metastatic renal cell carcinoma (mRCC). A total of 67 patients with mRCC who received first-line molecular targeted therapy were included in this study. Sixty patients were evaluable by response evaluation criteria in solid tumors. Patients underwent the first evaluation at 8-12 weeks after the start of the therapy. Twenty patients had TS ?30%, 32 from 30% to -20%, and 8 ?-20%. The median overall survival periods of patients who achieved TS ?30%, from 30% to -20%, and ?-20% at first evaluation were 41.0, 35.0, and 11.5 months, respectively. Univariate and multivariate analyses showed that TS of?0%, in addition to negative C-reactive protein and the absence of bone metastasis were good predictors of overall survival. The patients who achieved 0% or more at the initial evaluation had longer survival than those who had no tumor reduction (40.0 months vs 12.0 months, p<0. 001). These findings suggest that early TS affects overall survival in real practice. We should consider alternative therapies for patients who have not achieved tumor reduction at the initial evaluation.","This study evaluated the impact of tumor shrinkage (TS) caused by molecular targeted therapy as the first-line systemic (full-body) therapy on the survival of patients with metastatic renal cell carcinoma (mRCC). mRCC is kidney cancer that has spread to other organs. Molecular targeted therapy is a treatment type that uses drugs to target specific molecules involved in the growth and spread of cancer cells. A total of 67 patients with mRCC who received molecular targeted therapy were included in this study. Sixty patients were evaluated by response evaluation criteria in solid tumors. Patients underwent the first evaluation at 8-12 weeks after the start of the therapy. Twenty patients had TS ? 30%, 32 from 30% to -20%, and 8 ? -20%. The median (average) overall survival periods of patients who achieved TS ?30%, from 30% to -20%, and ?-20% at first evaluation were 41.0, 35.0, and 11.5 months, respectively. Analyses showed that TS of ?0%, partnered with negative C-reactive protein and the absence of bone metastasis (cancer spreading), were good predictors of overall survival. C-reactive protein is a type of protein found in the blood that increases during times of internal inflammation (redness and swelling from infection-fighting). The patients who achieved 0% or more at the initial evaluation had longer survival times than those who had no tumor reduction. These findings suggest that early TS affects overall survival in real practice. Alternative therapies should be considered for patients who have not achieved tumor reduction at the initial evaluation." +"Objective: To compare the accuracy of procalcitonin and C-reactive protein as diagnostic markers of bacterial infection in critically ill children at the onset of systemic inflammatory response syndrome (SIRS). Design: Prospective cohort study. Setting: Tertiary care, university-affiliated pediatric intensive care unit (PICU). Patients: Consecutive patients with SIRS. Interventions: From June to December 2002, all PICU patients were screened daily to include cases of SIRS. At inclusion (onset of SIRS), procalcitonin and C-reactive protein levels as well as an array of cultures were obtained. Diagnosis of bacterial infection was made a posteriori by an adjudicating process (consensus of experts unaware of the results of procalcitonin and C-reactive protein). Baseline and daily data on severity of illness, organ dysfunction, and outcome were collected. Measurements and main results: Sixty-four patients were included in the study and were a posteriori divided into the following groups: bacterial SIRS (n = 25) and nonbacterial SIRS (n = 39). Procalcitonin levels were significantly higher in patients with bacterial infection compared with patients without bacterial infection (p = .01). The area under the receiver operating characteristic curve for procalcitonin was greater than that for C-reactive protein (0.71 vs. 0.65, respectively). A positive procalcitonin level (>or=2.5 ng/mL), when added to bedside clinical judgment, increased the likelihood of bacterial infection from 39% to 92%, while a negative C-reactive protein level (<40 mg/L) decreased the probability of bacterial infection from 39% to 2%. Conclusions: Procalcitonin is better than C-reactive protein for differentiating bacterial from nonbacterial SIRS in critically ill children, although the accuracy of both tests is moderate. Diagnostic accuracy could be enhanced by combining these tests with bedside clinical judgment.","The aim of this study was to evaluate the accuracy of procalcitonin (involved in calcium balance) and C-reactive protein as measurable, biological indicators, or biomarkers, of bacterial infection. Specifically, this study evaluated the use of these biomarkers in critically ill children at the start of systemic inflammatory response syndrome (SIRS). C-reactive protein is a type of protein found in the blood that increases during times of internal inflammation (redness and swelling from infection-fighting). This study evaluated patients who were alike in many ways but differed by specific characteristics. This study was based in the tertiary care, university-affiliated pediatric intensive care unit (PICU) for child care. The study evaluated patients with SIRS. From June to December 2002, all PICU patients were screened daily to include cases of SIRS. At inclusion (onset of SIRS), procalcitonin and C-reactive protein levels, along with several bacterial cultures (bacterial groups grown in a lab), were obtained. Diagnosis of bacterial infection was made following examination of the cultures. Baseline (before study) and daily data on severity of illness, organ dysfunction, and outcome were collected. Sixty-four patients were included in the study. All patients were divided into the one of two groups: bacterial SIRS (25 patients) and nonbacterial SIRS (39 patients). Procalcitonin levels were significantly higher in patients with bacterial infection compared with patients without bacterial infection. Volume of procalcitonin was more predictive of bacterial infection than C-reactive protein. A positive (detected) procalcitonin level increased the likelihood of bacterial infection. A negative (not detected) C-reactive protein level decreased the probability of bacterial infection. Procalcitonin is better than C-reactive protein for differentiating (identifying) bacterial from nonbacterial SIRS in critically ill children. However, the accuracy of both biomarkers is moderate. Diagnostic accuracy could be enhanced by combining these tests with bedside clinical judgment." +"Objective: To compare the accuracy of procalcitonin and C-reactive protein as diagnostic markers of bacterial infection in critically ill children at the onset of systemic inflammatory response syndrome (SIRS). Design: Prospective cohort study. Setting: Tertiary care, university-affiliated pediatric intensive care unit (PICU). Patients: Consecutive patients with SIRS. Interventions: From June to December 2002, all PICU patients were screened daily to include cases of SIRS. At inclusion (onset of SIRS), procalcitonin and C-reactive protein levels as well as an array of cultures were obtained. Diagnosis of bacterial infection was made a posteriori by an adjudicating process (consensus of experts unaware of the results of procalcitonin and C-reactive protein). Baseline and daily data on severity of illness, organ dysfunction, and outcome were collected. Measurements and main results: Sixty-four patients were included in the study and were a posteriori divided into the following groups: bacterial SIRS (n = 25) and nonbacterial SIRS (n = 39). Procalcitonin levels were significantly higher in patients with bacterial infection compared with patients without bacterial infection (p = .01). The area under the receiver operating characteristic curve for procalcitonin was greater than that for C-reactive protein (0.71 vs. 0.65, respectively). A positive procalcitonin level (>or=2.5 ng/mL), when added to bedside clinical judgment, increased the likelihood of bacterial infection from 39% to 92%, while a negative C-reactive protein level (<40 mg/L) decreased the probability of bacterial infection from 39% to 2%. Conclusions: Procalcitonin is better than C-reactive protein for differentiating bacterial from nonbacterial SIRS in critically ill children, although the accuracy of both tests is moderate. Diagnostic accuracy could be enhanced by combining these tests with bedside clinical judgment.","The study's objective is to compare the accuracy of procalcitonin (a prototype molecule for a calcium-regulating molecule) and C-reactive protein (a marker of inflammation) as markers of bacterial infection in very ill children at the start of full-body or systemic inflammatory response syndrome (SIRS), an exaggerated immune response to a harmful stressor. The study takes place at a university-partnered child-care unit. Patients include those with SIRS. Treatment was that from June to December 2002, all hospital patients were tested daily to include cases of SIRS. At inclusion (start of SIRS), we measured procalcitonin, C-reactive protein, and some cell types. Identification of bacterial infection was made based on facts and judgment of experts unaware of the procalcitonin and C-reactive protein measures. Starting and daily data on illness severity, organ dysfunction, and health outcome were collected. Sixty-four patients were included in the study and divided into either bacterial SIRS group, with 25 patients, or nonbacterial SIRS group, with 39 patients. Procalcitonin levels were higher in patients with bacterial infection than those without. Accuracy was higher for procalcitonin than for C-reactive protein. Detecting high procalcitonin, when added to bedside clinical judgment, increased the chance of bacterial infection from 39% to 92%. Not detecting C-reactive protein decreased the chance of bacterial infection from 39% to 2%. Procalcitonin is better than C-reactive protein for detecting bacterial from nonbacterial SIRS in very ill children, although the accuracy of both tests is moderate. Detection accuracy could be enhanced by combining the tests with bedside clinical judgment." +"Fever after cardiac surgery in children may be due to bacterial infection or noninfectious origin like systemic inflammatory response syndrome (SIRS) secondary to bypass procedure. A marker to distinguish bacterial from nonbacterial fever in these conditions is clinically important. The purpose of our study was to evaluate, in the early postcardiac surgery period, whether serial measurement of C-reactive protein (CRP) and its change over time (CRP velocity) can assist in detecting bacterial infection. A series of consecutive children who underwent cardiac surgery with bypass were tested for serum levels of CRP at several points up to 5 days postoperatively and during febrile episodes (>38.0�C). Findings were compared among febrile patients with proven bacterial infection (FWI group; sepsis, pneumonia, urinary tract infection, deep wound infection), febrile patients without bacterial infection (FNI group), and patients without fever (NF group). In all, 121 children were enrolled in the study, 31 in the FWI group, 42 in the FNI group, and 48 patients in the NF group. Ages ranged from 4 days to 17.8 years (median 19.0, mean 46 � 56 months). There was no significant difference among the groups in mean CRP level before surgery, 1 hour, and 18 hours after. A highly significant interaction was found in the change in CRP over time by FWI group compared with FNI group (P < .001). Mean CRP velocity ([fCRP - 18hCRP]/[fever time (days) - 0.75 day]) was significantly higher in the infectious group (4.0 � 4.2 mg/dL per d) than in the fever-only group (0.60 � 1.6 mg/dL per d; P < .001). A CRP velocity of 4 mg/dL per d had a positive predictive value (PPV) of 85.7% for bacterial infection with 95.2% specificity. Serial measurements of CRP/CRP velocity after cardiac surgery in children may assist clinicians in differentiating postoperative fever due to bacterial infection from fever due to noninfectious origin.","Fever after heart surgery in children may be due to bacterial infection. The fever may also be caused by a noninfectious origin like systemic (full-body) inflammatory (infection-fighting) response syndrome (SIRS). A marker to distinguish bacterial from nonbacterial fever in these conditions is important. The aim of this study was to evaluate, in the period after heart surgery, whether measurement of C-reactive protein (CRP) and its change over time (CRP velocity) can help detect bacterial infection. C-reactive protein is a type of protein found in the blood that increases during times of internal inflammation (redness and swelling from infection-fighting). Children who underwent heart surgery with bypass (diverted blood flow) were tested for serum (blood) levels of CRP at several points up to 5 days after surgery and/or when they had a fever. Evidence was compared among three patient groups. The groups include: patients with fever with proven bacterial infection (FWI group), febrile (near-fever) patients without bacterial infection (FNI group), and patients without fever (NF group). In all, 121 children were enrolled in the study, 31 in the FWI group, 42 in the FNI group, and 48 patients in the NF group. Ages ranged from 4 days to 17.8 years. There was no significant difference among the groups in mean CRP level before surgery, 1 hour, and 18 hours after. A highly significant interaction was found in the change in CRP over time by the FWI group compared with the FNI group. Mean CRP velocity was significantly higher in the infectious group than in the fever-only group. Specific CRP velocity could positively predict bacterial infection with 95.2% specificity (accuracy). Serial (consistent) measurements of CRP/CRP velocity after heart surgery in children may assist clinicians in differentiating (identifying) post-operation fever due to bacterial infection from fever due to noninfectious origin." +"C-reactive protein (CRP) is a phylogenetically highly conserved plasma protein, with homologs in vertebrates and many invertebrates, that participates in the systemic response to inflammation. Its plasma concentration increases during inflammatory states, a characteristic that has long been employed for clinical purposes. CRP is a pattern recognition molecule, binding to specific molecular configurations that are typically exposed during cell death or found on the surfaces of pathogens. Its rapid increase in synthesis within hours after tissue injury or infection suggests that it contributes to host defense and that it is part of the innate immune response. Recently, an association between minor CRP elevation and future major cardiovascular events has been recognized, leading to the recommendation by the Centers for Disease Control and the American Heart Association that patients at intermediate risk of coronary heart disease might benefit from measurement of CRP. This review will largely focus on our current understanding of the structure of CRP, its ligands, the effector molecules with which it interacts, and its apparent functions.","C-reactive protein (CRP) is a protein that has remained relatively unchanged from evolution. CRP has similar forms in vertebrates and many invertebrates and participates in the systemic (full-body) response to inflammation (infection-fighting). Its plasma (blood) concentration increases during inflammation. This is a characteristic that has long been employed for clinical purposes. CRP is a pattern recognition molecule. This means CRP binds to specific molecular configurations typically found during cell death or on the surfaces of pathogens (foreign organisms). The rapid increase in CRP production within hours after tissue injury or infection suggests that it contributes to host defense. This also indicates that CRP is part of the innate immune response. Recently, an association between minor CRP elevation and future major heart-related events has been recognized. This has lead to government health agencies recommending that patients at intermediate risk of coronary heart disease (damage in the heart's major blood vessels) might benefit from measurement of CRP. This review focuses on the current understanding of the structure of CRP, the molecules it binds and interacts with, and its functions." +"Pancreatic islet-cell antibodies (I.C.Ab) were detected in 31 patients with organ-specific autoimmune disorders, 4 first-degree relatives of I.C.Ab-positive diabetics, and 1 apparently normal subject, none of whom had clinical evidence of diabetes. 10 of these 36 subjects were found to have diabetic glucose-tolerance tests (G.T.T.S), 4 had lag storage, and 22 had normal G.T.T.S.2 had latent diabetes, as evidenced by diabetic G.T.T.S during pregnancy and thyrotoxicosis; another 2 subsequently developed insulin-dependent diabetes (I.D.D.) Serum from 26 subjects had been stored for 1-11 yr before the G.T.T.S were done. The titres in some were shown to rise and fall over the years, while in others they remained remarkably constant. There was no correlation between the titre, change in titre or the duration of I.C.Ab or the presence of HLA-B8, BW15, or CW3 and the result of the G.T.T. In addition to acting as a marker for asymptomatic and latent diabetes and prediabetes, it seems that the presence of I.C.Ab in the serum may define a new group of potential diabetics with normal G.T.T.S. Many such subjects have one or more organ-specific autoimmune disorders (irrespective of diabetic family history), but some are first-degree relatives of I.C.Ab-positive subjects (mainly I.D.D.). About 0-5% of the general population also have I.C.Ab in their serum.","We found pancreatic islet-cell antibodies (I.C.Ab; proteins made against insulin-producing cells in the pancreas) in 31 patients with disorders where the body's defense system attacks certain organs; 4 parents, siblings, or children of people with I.C.Ab-positive diabetes, and 1 apparently normal person, none of whom had symptoms of diabetes. Of these 36 people, glucose (sugar molecule)-tolerance tests (G.T.T.S) showed 10 had diabetes, 4 had lag storage (normal glucose levels spike and return to normal), and 22 had normal results. Two people had latent diabetes (slow progressing with features of both type 1 and type 2 diabetes) while pregnant and thyrotoxicosis (too much metabolism-regulating thyroid hormone in the body) and another 2 later developed type 1 diabetes. Blood from 26 people had been stored for 1-11 years before we did the oral (by mouth) tests that measures the body's response to sugar (glucose). I.C.Ab measurements rose and fell in some patients and stayed constant in other patients. No relationship existed between the measurement, change in measurement, or the length of I.C.Ab or the presence of antigens (substances that causes the body to defend itself) and the G.T.T. result. I.C.Ab in the blood can indicate diabetes without symptoms and slow-progressing diabetes and prediabetes and may signal a new group of possible diabetics with normal G.T.T.S. Many possible diabetics with normal G.T.T.S. have at least one disorder where the body's defense system attacks certain organs (regardless of family history of diabetes), but some are parents, siblings, or children of people with I.C.Ab (mainly type 1 diabetes). About 0-5% of the general population also have I.C.Ab in their blood." +"A monoclonal islet cell antibody, HISL-19, reactive with human, bovine, and porcine pancreatic islets has been used to identify and characterize a novel group of islet cell proteins (p120, p69, p67, and p56). Besides the islets, HISL-19-reactive antigenic determinants are also expressed on selected cell types, namely, gut endocrine cells, thyroid parafollicular cells (p120), anterior pituitary cells (p40 and p24), specific hypothalamic neuroendocrine cells, and a single layer of large pyramidal cells of the cerebral cortex, thus defining a new family of neuroendocrine molecules.","A lab-made islet cell antibody (proteins made against insulin-producing cells), HISL-19, that reacts with clusters of cells that produce hormones in the sugar-regulating pancreas of the human, cow, and pig has been used to find and describe a new group of islet (pancreatic) cell proteins (p120, p69, p67, and p56). HISL-19 is also reactive with other related tissues that can be grouped into a new family of neuroendocrine (cells like nerve cells that make hormones) molecules." +"It has been suggested that screening all patients with diabetes diagnosed in later life for islet cell antibodies (ICA) would help predict insulin dependence. We have surveyed the case notes of 55 patients (22 male; ages 37-88 years) who were found to be ICA positive over a 9-year screening period to assess what contribution knowledge of ICA status made to their management. Forty-two patients had been put on insulin (half within 6 months of diagnosis and the rest after up to 6 years). Of the 13 patients not on insulin, six were on diet alone and seven on oral hypoglycaemic agents after a median follow-up of 3 years. In 37 of the 42 patients, insulin treatment was started for clinical rather than immunological reasons (diabetic ketoacidosis, ketonuria, weight loss and/or severe symptoms). Five patients were started on insulin because of ICA status when there was no compelling reason on clinical grounds. Knowledge that seven non-insulin-treated patients were ICA positive made doctors reluctant to discharge them from clinic. The data suggest that routine ICA estimation in this age group is unnecessary, as the decision to treat with insulin is best made on clinical grounds, and ICA estimation can lead to unwarranted insulin treatment, or anxiety in patients and doctors who are aware of a positive result.","Checking all people with diabetes detected later in life for islet cell antibodies (ICA; proteins made against insulin-producing cells) may help predict dependence on insulin. We read doctor notes of 55 patients (22 male; ages 37-88 years) who were found to be ICA positive (with ICA) over a 9-year checking period to determine what role ICA status made to their treatment. Forty-two patients had been put on insulin (half within 6 months of diagnosis and half after up to 6 years). Of the 13 patients not on insulin, six were on health diet and seven were on oral (by mouth) medication after about 3 years. In 37 of the 42 patients, insulin treatment was started due to observable symptoms (high levels of blood acids called ketones, high levels of ketones in urine, weight loss, and/or serious symptoms) rather than issues related to the body's defense system. Five patients were started on insulin due to ICA status where no observable symptoms existed. Doctors were hesitant to send home 7 non-insulin-treated, ICA-positive patients. The data suggest that regularly estimating ICA in this age group is not needed, as the decision to treat with insulin should be based on observable symptoms, and ICF estimation can cause unneeded insulin treatment, or anxiety in patients and doctors due to a positive result." +"Basal insulin secretion was compared in nine islet-cell antibody positive, non-diabetic first-degree relatives of children with Type 1 (insulin-dependent) diabetes mellitus and nine normal control subjects matched for age, sex and weight. Acute insulin responses to a 25 g intravenous glucose tolerance test were similar in the two groups (243 (198-229) vs 329 (285-380) mU.l-1 x 10 min-1, mean (+/- SE), p = 0.25). Fasting plasma insulin was assayed in venous samples taken at one min intervals for 2 h. Time series analysis was used to demonstrate oscillatory patterns in plasma insulin. Autocorrelation showed that regular oscillatory activity was generally absent in the islet-cell antibody-positive group, whereas a regular 13 min cycle was shown in control subjects (p less than 0.0001). Fourier transformation did, however, show a 13 min spectral peak in the islet-cell antibody positive group, consistent with intermittent pulsatility. We conclude that overall oscillatory patterns of basal insulin secretion are altered in islet-cell antibody positive subjects even when the acute insulin response is within the normal range.","We compared background insulin release in nine islet-cell antibody (protein made against insulin-producing cells) positive, non-diabetic parents or siblings of children with type 1 (insulin-dependent) diabetes and nine normal people matched for age, sex and weight. Short-term insulin responses to an I.V. (injected) glucose tolerance test were similar in the two groups. We measured blood insulin in people who had not had anything to eat for a period of time in blood samples taken every minute for 2 hours. We looked at blood insulin over time to see how it rises and falls. The islet-cell antibody-positive group (group with the antibody) did not have a regular pattern, but normal people had a 13-minute cycle. The islet-cell antibody-positive group did have a peak every 13 minutes. We conclude that the overall rise and fall of background insulin release is changed in islet-cell antibody positive people even when the short-term insulin response is normal." +"Insulin-dependent diabetes mellitus (IDDM) is associated with the formation of autoantibodies against different antigens in the islets of Langerhans, so-called islet cell antibodies (ICA). The expression of a major autoantigen, the beta-cell specific enzyme glutamic acid decarboxylase (GAD), is glucose-dependent in vitro and correlated to insulin release in vitro. In this study the expression of islet autoantigens was examined in vivo and the relationship between beta-cell function and islet cell surface antibody (ICSA) reactivity was tested. Rats were fed for 10 days with glipizide or diazoxide, in order to stimulate or inhibit insulin release, respectively. Frozen sections of pancreata were incubated with ten ICA-positive IDDM sera and analyzed by indirect immunofluorescence. Two sera with a ""beta-cell restricted"" staining, five with an ""all-islet cell"" staining and three with a ""mixed"" pattern were employed. In all three groups, the highest end-point titres were obtained when pancreata of rats treated with glipizide were used. Intermediate titres were seen in control animals and the lowest titres were observed on pancreata from diazoxide-treated rats, regardless of the serum used. In contrast to these observations, no correlation between ICSA reactivity and islet cell activity could be demonstrated. Conflicting results concerning ICSA in previous reports and our failure to show a glucose regulation of ICSA reactivity, indicate that ICSA is a phenomenon with a low degree of specificity.","Type 1 diabetes is associated with the formation of self-made proteins against different toxins in the islets of Langerhans (a group of insulin-producing cells in the pancreas), known as islet cell antibodies (ICA). The expression of a major self-made marker, glutamic acid decarboxylase (GAD; substance found only in insulin-producing cells), depends on glucose (sugar) levels and is related to insulin release when observed in a test tube. We looked at expression of islet self-made markers in pancreatic cells and tested the relationship between beta-cell (insulin-producing cell) function and islet cell surface antibody (ICSA) reactivity. We fed rats glipizide or diazoxide (insulin-treating drugs) for 10 days to increase or decrease insulin release, respectively. Sections of the pancreas were analyzed. We saw the highest measurements in rats given glipizide. We saw medium measurements in animals not given drugs, and the lowest measurements in rats given diazoxide. Opposite to these findings, we could not show a relationship between ICSA reactivity and islet cell activity. Conflicting results concerning ICSA in previous reports and our failure to show an energy regulation of ICSA reactivity, indicate that ICSA is a phenomenon with a low degree of specific detection." +"Measurement of beta-cell function is an important marker of progression to diabetes in individuals at risk for the disease. Although the peak incidence for the disease occurs before 17 years of age, normal values for insulin secretion were not available in this age group. We performed a simplified intravenous glucose tolerance test in 167 normal children, and in 98 islet cell antibody (ICA)-negative and 12 ICA-positive siblings of diabetic patients. Their age range was 1-16 yr. The first phase of insulin secretion, evaluated as the sum of plasma insulin concentrations at 1 and 3 min, increased with age and was significantly lower in ICA-negative siblings (86 +/- 6 microU/ml, P < 0.002) than in normal controls (115 +/- 6 microU/ml). This difference was not apparent before 8 yr of age. None of the ICA-negative siblings developed diabetes after an average of 4.5 yr. ICA-positive siblings at first study had a first phase insulin response similar to that of ICA negative siblings, but significantly lower than that of the normal controls (74 +/- 13 microU/ml, P < 0.02). The reason for the decreased insulin secretion in ICA-negative siblings is unknown, but could involve a defect in the growth of beta-cell mass or insulin secretion that could be part of the multifactorial pathogenesis of type 1 diabetes.","Measurement of cells that make insulin is an important indicator of diabetes development in people at risk for diabetes. Although the disease most often happens before 17 years of age, normal values for insulin release were not available for this age group. We did an I.V. (injected) glucose tolerance test in 167 normal children, and in 98 islet cell antibody (ICA; proteins made against insulin-producing cells)-negative (without ICA) and 12 ICA-positive (with ICA) siblings of diabetic patients. The children ranged from 1-16 years of age. The first part of insulin release, measured as the total blood insulin levels at 1 and 3 minutes, increased with age and was significantly lower in ICA-negative siblings than in normal children. We did not see a difference in the first part of insulin release before 8 years of age. None of the ICA-negative siblings developed diabetes after an average of 4.5 years. The first part of insulin response was similar in ICA-positive and ICA-negative siblings, but significantly lower than in normal children. We do not know the reason ICF-negative siblings had lower insulin release, but it could have to do with insulin-producing cells growing incorrectly or insulin release that could be part of the complicated development of type 1 diabetes." +"We studied the effect of severe reduction of beta-cell mass by 90% pancreatectomy on the immune tolerance to the endocrine pancreas. Four months after subtotal pancreatectomy all LEW.Han rats had developed mononuclear infiltration of islets and 9 of 14 rats were positive for islet-cell antibodies. Electron microscopy revealed lymphocytic invasion of endocrine tissue, lysis of beta cells and phagocytotic macrophages. None of these changes were seen 2 weeks after 90% pancreatectomy or 4 months after 10% pancreatectomy. Weekly substitution of islet antigens in the form of a homogenate of 100 islets into 90% pancreatectomized LEW.Han rats almost completely prevented the development of insulitis and autoantibodies. The dependence of insulitis on T cells was shown when 90% pancreatectomy in LEW.rnu rats (i.e., the congenic athymic nude strain), did not result in islet infiltration. The exocrine tissue remained normal in all experimental groups. During the observation period insulitis was not associated with overt diabetes but was accompanied by substantial enlargement of islets and of beta-cell mass, as shown by morphometry. Suppression of islet inflammation by injection of islet antigens abolished beta-cell regeneration, despite continuing metabolic stress in rats with 90% pancreatectomy. The findings indicate induction of islet autoimmunity in response to 90% but not to 10% pancreatectomy. We conclude that severe reduction of the islet-antigen mass allows the development of T-cell-dependent islet autoimmunity which indicates a loss of immune tolerance. In addition, the data suggest the existence of islet-antigen autoreactive immune cells in rats not genetically predisposed to autoimmune diabetes. Finally, we conclude that selective beta-cell regeneration occurs in association with insulitis.","We studied the effect of drastically reducing beta-cell (insulin-producing cell) mass by removing 90% of the pancreas on immune tolerance (state of unresponsiveness of the body's defense) to the endocrine pancreas, which controls blood sugar levels. Four months after removal of almost all of the pancreas, all rats had developed signs of long-term inflammation (infection-fighting) response of islets (clusters of cells that produce hormones) and 9 of 14 rats had islet-cell antibodies (proteins made against insulin-producing cells). Using microscopes, we saw immune white blood cells going into the part of the pancreas that produces substances (enzymes) that help with digestion, death of beta cells, and white blood cells that remove dying and dead cells. We saw none of these changes 2 weeks after removing 90% of the pancreas or 4 months after removing 10% of the pancreas. Weekly substitution of islet antigens (substances that causes the body to defend itself) in rats with 90% of the pancreas removed prevented insulitis (disease of the pancreas caused by the infiltration of immune white blood cells) and self-made proteins. Insulitis was shown to be dependent on T cells (part of the body's defense system). The tissue that produces substances (enzymes) that help with digestion did not change in any group. During the observation period, insulitis was not related to diabetes, but we saw a sizeable increase in the sizes of islets and beta-cell mass. Decreasing islet inflammation by injecting islet antigens (fragments) stopped beta-cell regrowth, even though low energy continued in rats with 90% of the pancreas removed. The results suggest removing 90% but not 10% of the pancreas causes the body to mistakenly destroy its islets. We conclude that drastically reducing the islet-antigen mass allows the body to mistakenly destroy its islets, which shows a loss of immune tolerance. Also, the results suggest islet-antigen autoreactive immune cells exist in rats not likely to develop autoimmune diabetes (diabetes from the body mistakenly destroying its own cells). Finally, we conclude that some beta-cell regrowth happens with insulitis." +"Objective: Obese youth clinically diagnosed with type 2 diabetes mellitus (T2DM) frequently have evidence of islet cell autoimmunity (proteins made against insulin-producing cells). We investigated the clinical and biochemical differences, and therapeutic modalities among autoantibody positive (Ab+) vs. autoantibody negative (Ab-) youth at the time of diagnosis and over time in a multi-provider clinical setting. Study design: Chart review of 145 obese youth diagnosed with T2DM from January 2003 to July 2012. Of these, 70 patients were Ab+ and 75 Ab-. The two groups were compared with respect to clinical presentation, physical characteristics, laboratory data, and therapeutic modalities at diagnosis and during follow up to assess the changes in these parameters associated with disease progression. Results: At presentation, Ab+ youth with a clinical diagnosis of T2DM were younger, had higher rates of ketosis, higher hemoglobin A1c (HbA1c) and glucose levels, and lower insulin and c-peptide concentrations compared with the Ab- group. The Ab- group had a higher body mass index (BMI) z-score and cardiometabolic risk factors at diagnosis and such difference remained over time. Univariate analysis revealed that treatment modality had no effect on BMI in either group. Generalized estimating equations for longitudinal data analysis revealed that (i) BMI z-score and diastolic blood pressure (DBP) were significantly affected by duration of diabetes; (ii) systolic blood pressure (SBP) and ALT were affected by changes in BMI z-score; and (iii) changes in HbA1c had an effect on lipid profile and cardiometabolic risk factors regardless of antibody status. Conclusions: Irrespective of antibody status and treatment modality, youth who present with obesity and diabetes, show no improvement in obesity status over time, with the deterioration in BMI z-score affecting blood pressure (BP) and ALT, but the lipid profile being mostly impacted by HbA1c and glycemic control. Effective control of BMI and glycemia are needed to lessen the future macrovascular complications irrespective of antibody status.","Obese youth diagnosed with type 2 diabetes by a doctor often have islet cell autoimmunity (in which immune cells attack healthy cells). We looked at the observable and biochemical differences, and treatment types of self-made protein positive (Ab+) vs. self-made protein negative (Ab-) youth at diagnosis and over time at a medical facility. We reviewed medical charts of 145 obese youth diagnosed with type 2 diabetes from January 2003 to July 2012. Of these 145 youth, 70 patients were Ab+ and 75 Ab-. We compared the disease symptoms, physical qualities, lab findings, and treatment types of the two groups at diagnosis and during follow up to rate the changes in these things related to disease development. At the doctor, Ab+ youth with a doctor's diagnosis of type 2 diabetes were younger, had higher rates of not enough carbohydrates to burn, higher hemoglobin A1c (HbA1c - which indicates average blood sugar levels) and blood sugar levels, and lower insulin and signs of insulin production compared with the Ab- group. The Ab- group had a higher body mass index (BMI) score adjusted for weight and gender and risk factors for heart disease and metabolic disorders at diagnosis and did not change over time. Treatment type had no effect on BMI in either group. We found that: (i) length of diabetes affected BMI score adjusted for weight and gender and diastolic blood pressure, (ii) changes In BMI score adjusted for weight and gender affected systolic blood pressure and ALT (alanine transaminase; released into the blood when liver cells are damaged), and (iii) changes in HbA1c affected lipid profile (panel of blood tests used to find abnormalities in lipids, such as cholesterol and triglycerides) and risk factors for heart disease and metabolic disorders independent of antibody (infection-fighting protein) status. Regardless of antibody status and treatment type, obese and diabetic youth do not become less obese over time, with higher BMI affecting blood pressure and ALT, and blood sugar levels affecting the lipid profile. Controlling BMI and blood sugar levels are needed to lessen future large blood vessel problems regardless of antibody status." +"Islet cell antibodies (ICA) continue to serve as the basis of the principal serological test for definition of active autoimmunity of beta-cells. Its disadvantages are the need for human pancreatic tissue and difficulty in obtaining quantitative results. In the past decade biochemically-defined beta-cell toxins were described, leading to the development of sensitive and specific autoantibody assays, to predict insulin-dependent diabetes mellitus (IDDM). We examined the value of combined biochemically-based serological assays, such as autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and ICA512 (ICA512A) to replace the traditional ICA assay. Blood samples of 114 newly diagnosed IDDM patients, aged 12 +/- 5 yrs (range 2 months-29 years) were tested for ICA (indirect immunofluorescence), IAA, GADA and ICA512A (radiobinding assay). The latter 2 assays were performed using recombinant human [35S]-labeled antigen produced by in vitro transcription/translation. We found that fewer sera scored positive for ICA and/or IAA (80.7%, 92/114) than for 1 or more of IAA, GAD, or ICA512 (88.6%, 101/114). We conclude that combined testing for IAA, GAD and ICA512 can replace the traditional ICA/IAA test to predict IDDM and is helpful in the differential diagnosis of insulin-dependent and noninsulin-dependent diabetes.","The main blood test to determine active attack of the insulin-producing beta-cells by the body is based on islet cell antibodies (ICA; proteins made against insulin-producing cells). The main ICA test has drawbacks like needing human tissue from the pancreas and difficulty in getting results in the form of a number. Based on the description of beta-cell proteins in test tubes in the past 10 years, new measuring tools for self-made proteins were made with high accuracy for disease detection and no detection to predict type 1 diabetes. We looked at whether combined blood tests in test tubes, such as self-made proteins to insulin (IAA), the enzyme glutamic acid decarboxylase (GADA), and ICA512 (ICA512A), could replace the main ICA test. We tested blood samples of 114 newly diagnosed type 1 diabetes patients, aged 12 plus or minus 5 years (ranging from 2 months to 29 year) for ICA, IAA, GADA, and ICA512A. We found that more blood samples scored positive (detected the presence of the disease) for 1 or more of IAA, GAD, or ICA512 than for ICA and/or IAA. We conclude that testing for IAA, GAD and ICA512 together can replace the traditional ICA/IAA test to predict type 1 diabetes and is helpful to doctors in telling the different between type 1 and type 2 diabetes." +"Islet cell antibodies (ICA; proteins made against insulin-producing cells) are a marker of insulin-dependent diabetes mellitus (IDDM). ICA are detected in 60-80% of the patients with IDDM at the onset of the disease. The presence of ICA in patients with non-insulin-dependent diabetes mellitus (NIDDM) indicates that the patients are likely to develop IDDM. However, as ICA are measured by the indirect immunofluorescent method, the reliability of the ICA assay is not high in some institutes. Use of the pancreas tissue having high antigenicity is recommended as one solution for a reliable assay. Standardization of the ICA assay is under way with the use of an ICA positive standard sera as 80 JDF units. Anti-glutamate decarboxylase (GAD) antibody assays using a radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA) have recently been developed. The significance of anti-GAD antibodies is comparable to that of ICA. Since the anti-GAD assay is reproducible and easy to perform, it should be used widely in parallel with the ICA assay.","Islet cell antibodies (ICA) are an indicator of type 1 diabetes. ICA are found in 60-80% of patients with type 1 diabetes when symptoms first appear. Type 2 diabetics with ICA are likely to develop type 1 diabetes. The current way to measure ICA is not always reliable. A reliable standardized test could use pancreas tissue, tissue from an organ that monitors blood sugar levels. A standardized test to measure ICA is under way. Scientists have recently developed a standardized test to measure anti-glutamate decarboxylase (GAD) antibody, a rare protein. Anti-GAD antibodies and ICA have similar meanings. The standardized test to measure anti-GAD can be repeated and is easy to do, so it should be used widely at the same time as the test to measure ICA." +"Aim: To examine whether mild early time-restricted eating (eating dinner at 18:00 vs. at 21:00) improves 24-h blood glucose levels and postprandial lipid metabolism in healthy adults. Methods: Twelve participants (2 males and 10 females) were included in the study. In this 3-day (until the morning of day 3) randomized crossover study, two different conditions were tested: eating a late dinner (at 21:00) or an early dinner (at 18:00). During the experimental period, blood glucose levels were evaluated by each participant wearing a continuous blood glucose measuring device. Metabolic measurements were performed using the indirect calorimetry method on the morning of day 3. The study was conducted over three days; day 1 was excluded from the analysis to adjust for the effects of the previous day's meal, and only data from the mornings of days 2 and 3 were used for the analysis. Results: Significant differences were observed in mean 24-h blood glucose levels on day 2 between the two groups (p = 0.034). There was a significant decrease in the postprandial respiratory quotient 30 min and 60 min after breakfast on day 3 in the early dinner group compared with the late dinner group (p < 0.05). Conclusion: Despite a difference of only 3 h, eating dinner early (at 18:00) has a positive effect on blood glucose level fluctuation and substrate oxidation compared with eating dinner late (at 21:00).","The aim of this study is to examine whether mild early time-restricted eating (eating dinner at 6:00pm vs. at 9:00pm) improves 24 hour blood sugar levels and the breakdown of fats after meals in healthy adults. Twelve participants (2 males and 10 females) are included in the study. In this 3-day (until the morning of day 3) study, two different conditions are tested: eating a late dinner at 9:00pm (at 21:00) or an early dinner at 6:00pm (at 18:00). During the experimental period, each participant wore a blood sugar device that continuously evaluated blood sugar levels. Measurements for metabolism are performed on the morning of day 3. The study is conducted over three days; day 1 is excluded from the analysis to adjust for the effects of the previous day's meal, and only data from the mornings of days 2 and 3 are used for the analysis. Significant differences are observed in the average 24 hour blood sugar levels on day 2 between the two groups. There was a big decrease in the respiratory quotient, a measure of how nutrients are used and a measure oxygen absorbed in the body, 30 min and 60 min after breakfast on day 3 in the early dinner group compared with the late dinner group. Despite a difference of only 3 hours, eating dinner early at 6:00pm (at 18:00) has a positive effect on blood sugar levels and oxygen being added compared with eating dinner late 9:00pm (at 21:00)." +"To date, nutritional studies have focused on the total intake of dietary fiber rather than intake timing. In this study, we examined the effect of the timing of daily Helianthus tuberosus ingestion on postprandial and 24 h glucose levels, as well as on intestinal microbiota in older adults. In total, 37 healthy older adults (age = 74.9 � 0.8 years) were recruited. The participants were randomly assigned to either a morning group (MG, n = 18) or an evening group (EG, n = 17). The MG and EG groups were instructed to take Helianthus tuberosus powder (5 g/day) just before breakfast or dinner, respectively, for 1 week after the 1-week control period. The glucose levels of all participants were monitored using a continuous glucose monitoring system throughout the 2 weeks. The intestinal microbiota was analyzed by sequencing 16S rRNA genes from feces before and after the intervention. There were no significant differences in the physical characteristics or energy intake between groups. Helianthus tuberosus intake led to decreases in tissue glucose levels throughout the day in both groups (p < 0.01, respectively). As a result of examining the fluctuations in tissue glucose levels up to 4 hours after each meal, significant decreases in the areas under the curves (AUCs) were observed for all three meals after intervention, but only in the MG (breakfast: p = 0.012, lunch: p = 0.002, dinner: p = 0.005). On the other hand, in the EG, there was a strong decrease in the AUC after dinner, but only slight decreases after breakfast and lunch (breakfast: p = 0.017, lunch: p = 0.427, dinner: p = 0.002). Moreover, the rate of change in the peak tissue glucose level at breakfast was significantly decreased in the MG compared to the EG (p = 0.027). A greater decrease was observed in the change in the blood glucose level after the ingestion of Helianthus tuberosus in the MG than in the EG. Furthermore, the relative abundance of Ruminococcus in the MG at the genus level was significantly higher at baseline than in the EG (p = 0.016) and it was also significantly lower after the intervention (p = 0.013). Our findings indicate that Helianthus tuberosus intake in the morning might have relatively stronger effects on the intestinal microbiota and suppress postprandial glucose levels to a greater extent than when taken in the evening.","To date, nutritional studies have focused on the total amount of dietary fiber consumed rather than when the fiber was consumed. In this study, researchers examine the effect of the timing of daily ingestion of Jerusalem artichoke (sunroot, Helianthus tuberosus) on blood sugar levels after meals and at 24 hours, as well as on gut bacteria in older adults. In total, 37 healthy older adults (age = 74.9 � 0.8 years) are recruited. The participants are randomly assigned to either a morning group (18 participants) or an evening group (17 participants). The morning group is instructed to take Jerusalem artichoke powder just before breakfast, and the evening group to take it just before dinner. Each group took the powder for 1 week. The blood sugar levels of all participants are monitored using a continuous blood sugar monitoring system throughout the 2 weeks. The gut bacteria is analyzed from feces (poop) before and after participants consumed the Jerusalem artichoke. There are no significant differences in the physical characteristics or the amount of calories consumed between groups. Consuming Jerusalem artichoke leads to decreases in tissue blood sugar levels throughout the day in both groups. As a result of examining the changes in tissue blood glucose levels up to 4 hours after each meal, big decreases in the overall exposure to the Jerusalem artichoke in the body is observed for all three meals after intervention (treatment), but only in the morning group. On the other hand, in the evening group, there is a strong decrease in the overall exposure to the plant after dinner, but only slight decreases after breakfast and lunch. Additionally, the rate of change in the max tissue blood sugar level at breakfast is significantly decreased in the morning group compared to the evening group. A greater decrease is observed in the change in the blood sugar level after the ingestion of Jerusalem artichoke in the morning group than in the evening group. Furthermore, the relative abundance of a gut bacteria that can break down fiber called Ruminococcus in the morning group is much higher at the start of the study than in the evening group, and it is also much lower after the study. The findings suggest that consuming Jerusalem artichoke in the morning might have relatively stronger effects on the gut bacteria and slow post-meal blood sugar levels to a greater extent than when taken in the evening." +"Background: In diabetic patients, postprandial glucose levels, which have a major impact on metabolic control, are determined by the rate of nutrient delivery into the intestine, absorption of nutrients from the small intestine, and the metabolism of the absorbed nutrients by the liver. The present study addresses whether Type 1 diabetic patients have increased intestinal permeability and intestinal permeability predicts postprandial glucose variability. Material and methods: Thirty Type 1 diabetic patients together with 15 sex- and age-matched healthy controls were enrolled in the study. After an overnight fasting all patients and controls received 100 micro Ci 51 Cr of EDTA as a radioactive tracer and the percentage of the isotope excreted in a 24-h urinary specimen was the permeability measure. Instant blood glucose was measured just before the test, and the patients performed and recorded self-monitoring of fasting and 2nd-hour postprandial blood glucose levels during the following week. Results: We found that intestinal permeability is increased in Type 1 diabetic patients compared with age- and sex-matched healthy controls. Increased intestinal permeability is related at least in part to the instant blood glucose level and the presence of diabetic autonomic neuropathy. Conclusion: Increased intestinal permeability leads to higher variation in postprandial blood glucose levels, thereby worsening metabolic control.","In diabetic patients, blood sugar levels after meals, which have a major impact on how nutrients in the body are used, are determined by several factors: the rate of nutrient delivery into the stomach, absorption of nutrients from the small intestine that helps further digestion of food, and the metabolism of the nutrients absorbed by the liver. The present study addresses whether Type 1 diabetic patients have increased intestinal permeability, the control of material passing from the stomach and to the rest of the body, and how intestinal permeability predicts different levels of blood sugar after meals. Thirty Type 1 diabetic patients and 15 healthy people as controls (comparison group) are enrolled in the study. After an overnight fasting (no food), all patients and controls receive a substance called EDTA that allows internal images of the body to be seen, and the amount of the substance released in a 24-hour urine sample is how intestinal permeability is measured. During the following week, instant blood sugar is measured just before the test, and the patients performed and recorded self-monitoring of fasting and blood sugar levels 2 hours after meals. Researchers found that intestinal permeability is increased in Type 1 diabetic patients compared with healthy controls. Increased intestinal permeability is related at least in part to the instant blood sugar level and the presence of a type of nerve damage that can occur with diabetes. Increased intestinal permeability that allows substances to pass from the stomach to the body leads to higher differences in post-meal blood sugar levels, thereby worsening the body's ability to control the use and distribution of nutrients." +"Objective: To determine the effect of morning exercise in the fasting condition vs afternoon exercise on blood glucose responses to resistance exercise (RE). Research design and methods: For this randomized crossover design, 12 participants with type 1 diabetes mellitus [nine females; aged 31 � 8.9 years; diabetes duration, 19.1 � 8.3 years; HbA1c, 7.4% � 0.8% (57.4 � 8.5 mmol/mol)] performed ?40 minutes of RE (three sets of eight repetitions, seven exercises, at the individual's predetermined eight repetition maximum) at either 7 am (fasting) or 5 pm. Sessions were performed at least 48 hours apart. Venous blood samples were collected immediately preexercise, immediately postexercise, and 60 minutes postexercise. Interstitial glucose was monitored overnight postexercise by continuous glucose monitoring (CGM). Results: Data are presented as mean � SD. Blood glucose rose during fasting morning exercise (9.5 � 3.0 to 10.4 � 3.0 mmol/L), whereas it declined with afternoon exercise (8.2 � 2.5 to 7.4 � 2.6 mmol/L; P = 0.031 for time-by-treatment interaction). Sixty minutes postexercise, blood glucose concentration was significantly higher after fasting morning exercise than after afternoon exercise (10.9 � 3.2 vs 7.9 � 2.9 mmol/L; P = 0.019). CGM data indicated more glucose variability (2.7 � 1.1 vs 2.0 � 0.7 mmol/L; P = 0.019) and more frequent hyperglycemia (12 events vs five events; P = 0.025) after morning RE than after afternoon RE. Conclusions: Compared with afternoon RE, morning (fasting) RE was associated with distinctly different blood glucose responses and postexercise profiles.","The objective of this study is to determine the effect of morning exercise after fasting (no food or drink except water for 8 to 10 hours) vs afternoon exercise on blood sugar responses to resistance exercise, also known as strength or weight training to build muscle. In this study, 12 participants with type 1 diabetes perform about 40 minutes of resistance exercise (three sets of eight repetitions, seven exercises) at either 7 am (fasting) or 5 pm. Sessions are performed at least 48 hours apart. Blood samples are collected immediately before exercise, immediately after exercise, and 60 minutes after exercise. Interstitial sugar is taken from the fluid surrounding the cells of tissues rather the blood. Interstitial sugar is monitored overnight after exercise by using continuous sugar monitoring device. Blood sugar rises during fasting morning exercise, whereas it declined with afternoon exercise. Sixty minutes after exercise, blood sugar is significantly higher after fasting morning exercise than after afternoon exercise. Data from the continuous sugar monitoring device indicated more changes in sugar levels and more frequent hyperglycemia (high blood sugar) after morning resistance exercise than after afternoon resistance exercise. Compared with afternoon resistance exercise, morning (fasting) resistance exercise is associated with distinctly different blood sugar responses and post-exercise responses." +"Background: Although physical exercise (PE) is recommended for individuals with type 1 diabetes (DM1), participation in exercise is challenging because it increases the risk of severe hypoglycemia and the available therapeutic options to prevent it frequently result in hyperglycemia. There is no clear recommendation about the best timing for exercise. The aim of this study was to compare the risk of hypoglycemia after morning or afternoon exercise sessions up to 36 hours postworkout. Methods: This randomized crossover study enrolled subjects with DM1, older than 18 years of age, on sensor-augmented insulin pump (SAP) therapy. Participants underwent 2 moderate-intensity exercise sessions; 1 in the morning and 1 in the afternoon, separated by a 7 to 14 day wash-out period. Continuous glucose monitoring (CGM) data were collected 24 hours before, during and 36 hours after each session. Results: Thirty-five subjects (mean age 30.31 � 12.66 years) participated in the study. The rate of hypoglycemia was significantly lower following morning versus afternoon exercise sessions (5.6 vs 10.7 events per patient, incidence rate ratio, 0.52; 95% CI, 0.43-0.63; P < .0001). Most hypoglycemic events occurred 15-24 hours after the session. On days following morning exercise sessions, there were 20% more CGM readings in near-euglycemic range (70-200 mg/dL) than on days prior to morning exercise (P = .003). Conclusions: Morning exercise confers a lower risk of late-onset hypoglycemia than afternoon exercise and improves metabolic control on the subsequent day.","Although physical exercise is recommended for individuals with type 1 diabetes, participation in exercise is challenging because it increases the risk of severe hypoglycemia (very low blood sugar) and the available treatment options to prevent it often result in hyperglycemia (high blood sugar). There is no clear recommendation about the best timing for exercise. The aim of this study is to compare the risk of hypoglycemia after morning or afternoon exercise sessions up to 36 hours after a workout. This study included participants with type 1 diabetes, older than 18 years of age, and on sensor-augmented insulin pump (SAP) therapy, a device that monitors blood sugar, detects when it has dropped below a certain level, and can adjust the amount of insulin released in the body. Participants performed 2 exercise sessions of moderate intensity; 1 in the morning and 1 in the afternoon, separated by a 7 to 14 day wash-out period, where participants will stop exercising so the effects of the exercise sessions can be monitored. Using a continuous glucose monitoring device that monitors blood sugar, data are collected 24 hours before, during and 36 hours after each session. This study included 35 participants. The rate of hypoglycemia is significantly lower following morning versus afternoon exercise sessions. Most hypoglycemic events occurred 15-24 hours after the session. On days following morning exercise sessions, there are 20% more continuous glucose monitoring readings in near-normal blood sugar range than on days prior to morning exercise. In conclusion, morning exercise provides a lower risk of late-onset hypoglycemia than afternoon exercise and improves blood sugar control on the following day." +"Objectives: Afternoon napping is a common habit in China. We used data obtained from the Dongfeng-Tongji cohort to examine if duration of habitual afternoon napping was associated with risks for impaired fasting plasma glucose (IFG) and diabetes mellitus (DM) in a Chinese elderly population. Methods: A total of 27,009 participants underwent a physical examination, laboratory tests, and face-to-face interview. They were categorized into four groups according to nap duration (no napping, <30, 30 to <60, 60 to <90, and > or =90 min). Logistic regression models were used to examine the odds ratios (ORs) of napping duration with IFG and DM. Results: Of the participants, 18,515 (68.6%) reported regularly taking afternoon naps. Those with longer nap duration had considerably higher prevalence of IFG and DM. Napping duration was associated in a dose-dependent manner with IFG and DM (P<.001). After adjusting for possible confounders, longer nap duration (>60 min; all P<.05) was still significantly associated with increased risk for IFG, and longer nap duration (>30 min) was associated with increased risk for DM; however, this finding was not significant in the group with a nap duration of 60-90 min. Conclusions: Longer habitual afternoon napping was associated with a moderate increase for DM risk, independent of several covariates. This finding suggests that longer nap duration may represent a novel risk factor for DM and higher blood glucose levels.","Afternoon napping is a common habit in China. Researchers use data obtained from an existing study to examine if duration of regular afternoon napping is associated with risks for impaired fasting (no food and/or water for a period of time) plasma (blood) glucose (pre-diabetes) and diabetes in a Chinese elderly population. A total of 27,009 participants undergo a physical examination, lab tests, and face-to-face interview. They are placed into groups based on nap duration. The groups are: no napping, less than 30 minutes, 30 to less than 60 minutes, 60 to less than 90 minutes, and 90 minutes or more. Statistical analyses are used to examine the odds of napping duration with getting pre-diabetes and diabetes. Of the participants, 18,515 (68.6%) reported regularly taking afternoon naps. Those with longer naps have much higher numbers of pre-diabetes and diabetes. Napping duration is associated (linked) with pre-diabetes and diabetes. After adjusting the analysis to account for things that impact the results, longer nap duration (>60 minutes) is still significantly associated with increased risk for pre-diabetes. Also, longer nap duration (>30 minutes) is associated with increased risk for diabetes; however, this finding is not significant in the group with a nap duration of 60-90 minutes. In conclusion, longer habitual afternoon napping is associated with a moderate increase for diabetes risk. This finding suggests that longer nap duration may represent a new risk factor for diabetes and higher blood sugar levels." +"Context: Endogenous glucocorticoid excess (Cushing's syndrome) predominantly increases postprandial glucose concentration. The pattern of hyperglycemia induced by prednisolone has not been well characterized. Objective: Our objective was to define the circadian effect of prednisolone on glucose concentration to optimize management of prednisolone-induced hyperglycemia. Design and setting: This was a cross-sectional study in a teaching hospital. Participants: Participants included 60 consecutive consenting subjects with chronic obstructive pulmonary disease admitted to hospital: 13 without known diabetes admitted for other indications and not treated with glucocorticoids (group 1), 40 without known diabetes admitted with an exacerbation of chronic obstructive pulmonary disease and treated with prednisolone (group 2, prednisolone = 30 � 6 mg/d), and seven with known diabetes treated with prednisolone (group 3, prednisolone = 26 � 9 mg/d). Main outcome measure: Interstitial glucose concentration was assessed during continuous glucose monitoring. Results: Significantly more subjects in group 2 [21 of 40 (53%), P = 0.02] and group 3 [seven of seven (100%), P = 0.003] recorded a glucose of at least 200 mg/dl (?11.1 mmol/liter) during continuous glucose monitoring than in group 1 [one of 13 (8%)]. The mean glucose concentration between 2400-1200 h for group 3 (142 � 36 mg/dl) was significantly greater than in the other two groups (P < 0.005), whereas mean glucose concentrations between 2400-1200 h in group 1 (108 � 16 mg/dl) and group 2 (112 � 22 mg/dl) were not significantly different. In contrast, the mean glucose concentrations between 1200-2400 h for group 2 (142 � 25 mg/dl) and group 3 (189 � 32 mg/dl) were both significantly greater than group 1 (117 � 14 mg/dl, P < 0.05 for both comparisons). Conclusions: Prednisolone predominantly causes hyperglycemia in the afternoon and evening. Treatment of prednisolone-induced hyperglycemia should be targeted at this time period.","Endogenous glucocorticoid excess (Cushing's syndrome) is caused when the body has too much of the stress hormone cortisol over a long period of time. It increases the level of blood sugar concentration up to 4 hours after eating a meal. The pattern of hyperglycemia (high blood sugar) caused by prednisolone, a steroid drug made to act like the cortisol hormone, has not been well described. The objective of this study is to define the 24 hour effect of prednisolone on blood sugar concentration to help manage hyperglycemia brought about by prednisolone. This study takes place in a teaching hospital. Participants include 60 people with chronic obstructive pulmonary disease (COPD), a lung disease making it difficult to breathe, admitted to the hospital and placed into groups. Thirteen participants (group 1) without known diabetes are admitted for other problems and not treated with glucocorticoids, drugs used to fight inflammation (effects of infection-fighting). Forty participants without known diabetes are admitted with an extreme COPD and treated with prednisolone (group 2). Seven participants with known diabetes are treated with prednisolone (group 3). Interstitial glucose concentration is taken from the fluid surrounding the cells of tissues rather the blood and is assessed (measured) during continuous glucose monitoring that regularly check sugar levels. Significantly more participants in group 2 and group 3 recorded a glucose of at least 200 mg/dl during continuous glucose monitoring than in group 1. The average glucose concentration between midnight and noon (2400-1200 hours) for group 3 is much greater than in the other two groups, whereas the average glucose concentrations between midnight and noon (2400-1200 hours) in group 1 and group 2 are not significantly different. In contrast, the average glucose concentrations between noon and midnight (1200-2400 hours) for group 2 and group 3 ae both much greater than group 1. Prednisolone mainly causes hyperglycemia in the afternoon and evening. Treatment of hyperglycemia that is brought on by prednisolone should be targeted at this time period." +"Aims: Individuals with Type 1 diabetes mellitus are susceptible to hypoglycaemia during and after continuous moderate-intensity exercise, but hyperglycaemia during intermittent high-intensity exercise. The combination of both forms of exercise may have a moderating effect on glycaemia in recovery. The aims of this study were to compare the physiological responses and associated glycaemic changes to continuous moderate-intensity exercise vs. continuous moderate-intensity exercise + intermittent high-intensity exercise in athletes with Type 1 diabetes. Methods: Interstitial glucose levels were measured in a blinded fashion in 11 trained athletes with Type 1 diabetes during two sedentary days and during 2 days in which 45 min of afternoon continuous moderate-intensity exercise occurred either with or without intermittent high-intensity exercise. The total amount of work performed and the duration of exercise was identical between sessions. Results: During exercise, heart rate, respiratory exchange ratio, oxygen utilization, ventilation and blood lactate levels were higher during continuous moderate-intensity + intermittent high-intensity exercise vs. continuous moderate-intensity exercise (all P < 0.05). Despite these marked cardiorespiratory differences between trials, there was no difference in the reduction of interstitial glucose or plasma glucose levels between the exercise trials. Nocturnal glucose levels were higher in continuous moderate-intensity + intermittent high-intensity exercise and in sedentary vs. continuous moderate-intensity exercise (P < 0.05). Compared with continuous moderate-intensity exercise alone, continuous moderate-intensity + intermittent high-intensity exercise was associated with less post-exercise hypoglycaemia (5.2 vs. 1.5% of the time spent with glucose < 4.0 mmol/l) and more post-exercise hyperglycaemia (33.8 vs. 20.4% of time > 11.0 mmol/l). Conclusions: Although the decreases in glucose level during continuous moderate-intensity exercise and continuous moderate-intensity + intermittent high-intensity exercise are similar, the latter form of exercise protects against nocturnal hypoglycaemia in athletes with Type 1 diabetes.","People with Type 1 diabetes are vulnerable to developing low blood sugar, also called hypoglycemia, during and after continuous moderate-level exercise, but they are also at risk of high blood sugar (hyperglycemia) during periodic high-intensity exercise. The combination of both moderate and high-intensity exercise may have an effect on blood sugar levels. The aims of this study are to compare the body's physical responses and blood sugar changes to continuous moderate-intensity exercise vs. continuous moderate-intensity exercise + periodic high-intensity exercise in athletes with Type 1 diabetes. Interstitial sugar levels are taken from the fluid surrounding the cells of tissues in 11 trained athletes with Type 1 diabetes. Samples are taken during two days when they were not active and during 2 days in which 45 minutes of afternoon continuous moderate-intensity exercise occurred either with or without periodic high-intensity exercise. The total amount of work performed and the duration of exercise is identical between sessions. During exercise, heart rate, respiratory exchange ratio to determine how the body is getting energy, oxygen utilization, ventilation (breathing) and blood lactatic acid (waste build-up from exercise) levels are higher during continuous moderate-intensity + intermittent high-intensity exercise vs. continuous moderate-intensity exercise. Despite these noticeable heart-lung differences, there is no difference in the reduction of interstitial sugar or blood sugar levels between the exercise trials. Nighttime sugar levels are higher in continuous moderate-intensity + periodic high-intensity exercise and in inactive vs. continuous moderate-intensity exercise. Compared with continuous moderate-intensity exercise alone, continuous moderate-intensity + periodic high-intensity exercise is associated with less hypoglycemia after exercise and more hyperglycemia after exercise. Although the decreases in sugar level during continuous moderate-intensity exercise and continuous moderate-intensity + periodic high-intensity exercise are similar, the latter form of exercise protects against nighttime hypoglycemia in athletes with Type 1 diabetes." +"The objective of this study was to evaluate whether first-degree relatives (FDRs) of patients with type 2 diabetes had abnormal circadian insulin secretion and, if so, whether this abnormality affected their glucose metabolism. Six African-American FDRs with normal glucose tolerance and 12 matched normal control subjects (who had no family history of diabetes) were exposed to 48 h of hyperglycemic clamping (approximately 12 mmol/l). Insulin secretion rates (ISRs) were determined by deconvolution of plasma C-peptide levels using individual C-peptide kinetic parameters. Detrending and smoothing of data (z-scores) and computation of autocorrelation functions were used to identify ISR cycles. During the initial hours after start of glucose infusions, ISRs were approximately 60% higher in FDRs than in control subjects (585 vs. 366 nmol/16 h, P < 0.05), while rates of glucose uptake were the same (5.6 mmol x kg(-1) x h(-1)), indicating that the FDRs were insulin resistant. Control subjects had well-defined circadian (24 h) cycles of ISR and plasma insulin that rose in the early morning, peaked in the afternoon, and declined during the night. In contrast, FDRs had several shorter ISR cycles of smaller amplitude that lacked true periodicity. This suggested that the lack of a normal circadian ISR increase had made it impossible for the FDRs to maintain their compensatory insulin hypersecretion beyond 18 h of hyperglycemia. As a result, ISR decreased to the level found in control subjects, and glucose uptake fell below the level of control subjects (61 vs. 117 micromol x kg(-1) x min(-1), P < 0.05). In summary, we found that FDRs with normal glucose tolerance had defects in insulin action and secretion. The newly recognized insulin secretory defect consisted of disruption of the normal circadian ISR cycle, which resulted in reduced insulin secretion (and glucose uptake) during the ascending part of the 24 h ISR cycle.","Insulin secretion is the body's release of insulin, the hormone that helps control blood sugar and metabolism. The objective of this study is to evaluate whether first-degree relatives (a person's parent, sibling, or child) of patients with type 2 diabetes have abnormal 24 hour insulin secretion and, if so, whether this abnormality affected their glucose metabolism. Six African-American first-degree relatives with normal blood sugar level and 12 normal control participants (who had no family history of diabetes) were exposed to 48 hours of hyperglycemic clamping, a technique to keep blood sugar levels stable. Insulin secretion rates (ISRs) are determined by calculating plasma C-peptide levels, which are substances that signal if the body is creating insulin. During the initial hours after giving people infusions of sugar (glucose), insulin secretion rates are about 60% higher in first-degree relatives than in the comparison (control) subjects, while rates of sugar uptake are the same. This finding suggests that the first-degree relatives are insulin resistant, which is when the body doesn't respond well to the insulin hormone and can't use blood sugar for energy. Control subjects have well-defined 24 hour cycles of insulin secretion rates and plasma insulin that increase in the early morning, peak in the afternoon, and decline during the night. In contrast, first-degree relatives have several shorter insulin secretion rate cycles. This suggests that the lack of a normal increase in the 24 hour insulin secretion rate makes it impossible for the first-degree relatives to keep their insulin excess secretion beyond 18 hours of hyperglycemia (high blood sugar). As a result, insulin secretion rate decreased to the level found in control subjects, and blood sugar uptake fell below the level of control subjects. In summary, researchers found that first-degree relatives with normal blood sugar levels had defects in insulin action and secretion. The new insulin secretory defect includes disrupting the normal 24 hour insulin secretion rate cycle, which resulted in reduced insulin secretion (and blood sugar uptake) during the upward part of the 24 hour insulin secretion rate cycle." +"Time-restricted feeding (TRF) is a form of intermittent fasting that involves having a longer daily fasting period. Preliminary studies report that TRF improves cardiometabolic health in rodents and humans. Here, we performed the first study to determine how TRF affects gene expression, circulating hormones, and diurnal patterns in cardiometabolic risk factors in humans. Eleven overweight adults participated in a 4-day randomized crossover study where they ate between 8 am and 2 pm (early TRF (eTRF)) and between 8 am and 8 pm (control schedule). Participants underwent continuous glucose monitoring, and blood was drawn to assess cardiometabolic risk factors, hormones, and gene expression in whole blood cells. Relative to the control schedule, eTRF decreased mean 24-hour glucose levels by 4 � 1 mg/dl (p = 0.0003) and glycemic excursions by 12 � 3 mg/dl (p = 0.001). In the morning before breakfast, eTRF increased ketones, cholesterol, and the expression of the stress response and aging gene SIRT1 and the autophagy gene LC3A (all p < 0.04), while in the evening, it tended to increase brain-derived neurotropic factor (BNDF; p = 0.10) and also increased the expression of MTOR (p = 0.007), a major nutrient-sensing protein that regulates cell growth. eTRF also altered the diurnal patterns in cortisol and the expression of several circadian clock genes (p < 0.05). eTRF improves 24-hour glucose levels, alters lipid metabolism and circadian clock gene expression, and may also increase autophagy and have anti-aging effects in humans.","Intermittent fasting is a type of eating schedule where a person doesn't eat any calories for a period of time. Time-restricted feeding is a form of intermittent fasting that involves having a longer daily fasting period. Early studies report that time-restricted feeding improves the health of the heart and metabolism in rodents and humans. In this study, researchers perform the first study to determine how time-restricted feeding affects how information from genes are used, how circulating hormones that travel in blood and attach to cells can change the cell function, and how daily patterns in the heart and metabolism can be risk factors in humans. Eleven overweight adults participated in a 4-day study where they ate between 8 am and 2 pm (early time-restricted feeding) and between 8 am and 8 pm (control group for comparison). Participants have their sugar continuously monitored, and blood is drawn to assess risk factors to the heart and metabolism, hormones, and gene development in blood cells. Relative to the comparison group's schedule, early time-restricted feeding decreased the average 24-hour sugar levels and changes in blood sugar. In the morning before breakfast, early time-restricted feeding increased ketones (substances that the body makes if cells don't get enough blood sugar), cholesterol, and the activity of the stress response and aging gene SIRT1 and the gene LC3A that cleans out damaged cells. While in the evening, time-restricted feeding tends to increase brain-derived neurotropic factor, which is a helpful protein in the spinal cord and brain, and also increases the expansion of the MTOR gene, a major nutrient-sensing protein that regulates cell growth. Early time-restricted feeding changes daily patterns in the cortisol stress hormone and use of several genes. Early time-restricted feeding improves 24 hour blood sugar levels, changes how fats are broken down, and how gene functions are used. Early time-restricted feeding may also increase cleaning of damaged cells and anti-aging effects in humans." +"More than 2 million people in the United States have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We performed targeted, broad-spectrum metabolomics to gain insights into the biology of CFS. We studied a total of 84 subjects using these methods. Forty-five subjects (n = 22 men and 23 women) met diagnostic criteria for ME/CFS by Institute of Medicine, Canadian, and Fukuda criteria. Thirty-nine subjects (n = 18 men and 21 women) were age- and sex-matched normal controls. Males with CFS were 53 (�2.8) y old (mean � SEM; range, 21-67 y). Females were 52 (�2.5) y old (range, 20-67 y). The Karnofsky performance scores were 62 (�3.2) for males and 54 (�3.3) for females. We targeted 612 metabolites in plasma from 63 biochemical pathways by hydrophilic interaction liquid chromatography, electrospray ionization, and tandem mass spectrometry in a single-injection method. Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic syndrome. Pathway abnormalities included sphingolipid, phospholipid, purine, cholesterol, microbiome, pyrroline-5-carboxylate, riboflavin, branch chain amino acid, peroxisomal, and mitochondrial metabolism. Area under the receiver operator characteristic curve analysis showed diagnostic accuracies of 94% [95% confidence interval (CI), 84-100%] in males using eight metabolites and 96% (95% CI, 86-100%) in females using 13 metabolites. Our data show that despite the heterogeneity of factors leading to CFS, the cellular metabolic response in patients was homogeneous, statistically robust, and chemically similar to the evolutionarily conserved persistence response to environmental stress known as dauer.","More than 2 million people in the United States have myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). This diseases is characterized by immense fatigue, pain, and abnormal sleep. This study performed metabolomics, or evaluated biological metabolites or energy-regulating molecules, to gain insights into the biology of CFS. This study evaluated a total of 84 subjects. Forty-five subjects (22 men and 23 women) met diagnostic criteria for ME/CFS. Thirty-nine subjects (18 men and 21 women) were age- and sex-matched normal controls. Males with CFS were on average 53 (�2.8) years old. Females were on average 52 (�2.5) years old. The Karnofsky performance scores (a scoring system to determine ability to perform tasks) were 62 for males and 54 for females. The study targeted 612 metabolites in plasma (blood) from 63 biochemical pathways. Patients with CFS showed abnormalities in 20 metabolic pathways. Eighty percent of the diagnostic metabolites were decreased, consistent with a hypometabolic, or abnormally low metabolic rate, syndrome. Pathway abnormalities included several types of dysregulated metabolisms. High accuracy for diagnosis was found in both males and females using metabolite levels. The data show that, despite several different factors leading to CFS, the cellular metabolic response in patients was the same, statistically robust, and chemically similar to the environmental stress known as dauer." +"Background: Phosphatidylserine (PS) may have beneficial effects on cognitive functions. We evaluated the efficacy of a novel preparation of PS containing omega-3 long-chain polyunsaturated fatty acids attached to its backbone (PS-DHA) in non-demented elderly with memory complaints. Methods: 157 participants were randomized to receive either PS-DHA or placebo for 15 weeks. Efficacy measures, assessed at baseline and endpoint, included the Rey Auditory Verbal Learning Test, Rey Complex Figure Test, and a computerized cognitive battery. Clinicians' Global Impression of Change was assessed following 7 and 15 weeks of treatment. Results: 131 participants completed the study although 9 were excluded from the efficacy analysis due to protocol violation. At endpoint, verbal immediate recall was significantly improved in the PS-DHA group compared to the placebo group. Post-hoc analysis revealed that a subset of participants with relatively good cognitive performance at baseline had significant treatment-associated improvements in immediate and delayed verbal recall, learning abilities, and time to copy complex figure. These favorable results were further supported by responder analysis. Conclusions: The results indicate that PS-DHA may improve cognitive performance in non-demented elderly with memory complaints. Post-hoc analysis of subgroups suggests that participants with higher baseline cognitive status were most likely to respond to PS-DHA. The results of this exploratory study should be followed up by additional studies aimed at confirming the present tentative conclusions.","Phosphatidylserine (PS), a fatty substance, may have beneficial effects on cognitive (or thinking-related) functions. This study evaluated the effectiveness of a unique formula of PS (PS-DHA or PS with omega-3 fatty acids) in non-demented elderly with memory complaints. The study evaluated 157 participants. The participants were randomly assigned one of two treatment groups: PS-DHA or placebo (sham treatment). Treatments were given for 15 weeks. Effectiveness measures were assessed before and after treatment. Clinicians' Global Impression of Change (a point scale to determine if illness has improved) was assessed (measured) following 7 and 15 weeks of treatment. 131 participants completed the study. However, 9 were excluded as they did not follow the study rules. At the end of the study, verbal immediate recall was significantly improved in the PS-DHA group compared to the placebo group. Post-study analysis showed that a subset of participants with relatively good cognitive performance prior to treatment had significant treatment-associated improvements in cognitive function. These favorable results were further supported by the proportion of participants who achieved a pre-defined level of improvement. The results indicate that PS-DHA may improve cognitive performance in non-demented elderly with memory complaints. Post-study analysis of subgroups suggests that participants with higher baseline cognitive status were most likely to respond to PS-DHA. The results of this study should be followed up by additional studies to confirm the tentative conclusions made here." +"Membrane Lipid Replacement is the use of functional oral supplements containing cell membrane glycerolphospholipids and antioxidants to safely replace damaged membrane lipids that accumulate during aging and in various chronic and acute diseases. Most if not all clinical conditions and aging are characterized by membrane phospholipid oxidative damage, resulting in loss of membrane and cellular function. Clinical trials have shown the benefits of Membrane Lipid Replacement supplements in replenishing damaged membrane lipids and restoring mitochondrial function, resulting in reductions in fatigue in aged subjects and patients with a variety of clinical diagnoses. Recent observations have indicated that Membrane Lipid Replacement can be a useful natural supplement strategy in a variety of conditions: chronic fatigue, such as found in many diseases and disorders; fatiguing illnesses (fibromyalgia and chronic fatigue syndrome); chronic infections (Lyme disease and mycoplasmal infections); cardiovascular diseases; obesity, metabolic syndrome and diabetes; neurodegenerative diseases (Alzheimer's disease); neurobehavioral diseases (autism spectrum disorders); fertility diseases; chemical contamination (Gulf War illnesses); and cancers (breast, colorectal and other cancers). Membrane Lipid Replacement provides general membrane nutritional support during aging and illness to improve membrane function and overall health without risk of adverse effects.","Membrane Lipid Replacement is a treatment that uses oral (by mouth) supplements to safely replace damaged membrane lipids (fatty substances on cell boundaries). Lipids are organic compounds such as fats, waxes, oils, and hormones. These damaged lipids accumulate during aging and various diseases. The majority of clinical conditions and aging are characterized by membrane phospholipid oxidative damage. This damage results in loss of membrane and cellular function. Clinical trials have shown the benefits of Membrane Lipid Replacement supplements in replenishing damaged membrane lipids and restoring mitochondrial function. These supplements help reduce fatigue in aged subjects and patients with a variety of clinical diagnoses. Recent observations have indicated that Membrane Lipid Replacement can be a useful natural supplement strategy in a variety of conditions. Some of these conditions include chronic fatigue (long-lasting tiredness), chronic infections, and cancers. Membrane Lipid Replacement provides general membrane nutritional support during aging and illness. This improves membrane function and overall health without risk of adverse effects." +"Background: Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed behavioural disorder of childhood, affecting 3-5% of school-age children. The present study investigated whether the supplementation of soy-derived phosphatidylserine (PS), a naturally occurring phospholipid, improves ADHD symptoms in children. Methods: Thirty six children, aged 4-14 years, who had not previously received any drug treatment related to ADHD, received placebo (n = 17) or 200 mg day(-1) PS (n = 19) for 2 months in a randomised, double-blind manner. Main outcome measures included: (i) ADHD symptoms based on DSM-IV-TR; (ii) short-term auditory memory and working memory using the Digit Span Test of the Wechsler Intelligence Scale for Children; and (iii) mental performance to visual stimuli (GO/NO GO task). Results: PS supplementation resulted in significant improvements in: (i) ADHD (P < 0.01), AD (P < 0.01) and HD (P < 0.01); (ii) short-term auditory memory (P < 0.05); and (iii) inattention (differentiation and reverse differentiation, P < 0.05) and inattention and impulsivity (P < 0.05). No significant differences were observed in other measurements and in the placebo group. PS was well-tolerated and showed no adverse effects. Conclusions: PS significantly improved ADHD symptoms and short-term auditory memory in children. PS supplementation might be a safe and natural nutritional strategy for improving mental performance in young children suffering from ADHD.","Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed behavioral disorder of childhood. It affects 3-5% of school-age children. This study investigated if supplementation of soy-derived phosphatidylserine (PS), a naturally occurring phospholipid or the fatty part of a cell's boundaries, improves ADHD symptoms in children. Thirty six children, aged 4-14 years, who had not previously received any drug treatment related to ADHD, were recruited. 17 kids received placebos (sham treatment) for 2 months, and 19 kids received 200 mg/day PS for 2 months. Several measurements were taken to determine effectiveness. PS supplementation resulted in significant improvements in: ADHD, AD, and HD. There was also improvement in short-term auditory memory, inattention, and impulsivity. No significant differences were observed in other measurements and in the placebo group. PS was well-tolerated and showed no adverse effects. PS significantly improved ADHD symptoms and short-term auditory memory in children. PS supplementation might be a safe and natural nutritional strategy for improving mental performance in young children suffering from ADHD." +"Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue, commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance, fever, lymphadenopathy, and irritable bowel syndrome (IBS). The extent to which the gastrointestinal microbiome and peripheral inflammation are associated with ME/CFS remains unclear. We pursued rigorous clinical characterization, fecal bacterial metagenomics, and plasma immune molecule analyses in 50 ME/CFS patients and 50 healthy controls frequency-matched for age, sex, race/ethnicity, geographic site, and season of sampling. Results: Topological analysis revealed associations between IBS co-morbidity, body mass index, fecal bacterial composition, and bacterial metabolic pathways but not plasma immune molecules. IBS co-morbidity was the strongest driving factor in the separation of topological networks based on bacterial profiles and metabolic pathways. Predictive selection models based on bacterial profiles supported findings from topological analyses indicating that ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Increased abundance of unclassified Alistipes and decreased Faecalibacterium emerged as the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS. Despite findings of differences in bacterial taxa and metabolic pathways defining ME/CFS subgroups, decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside degradation were the top metabolic pathways in ME/CFS without IBS as well as in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures including pain, fatigue, and reduced motivation were correlated with the abundance of distinct bacterial taxa and metabolic pathways. Conclusions: Independent of IBS, ME/CFS is associated with dysbiosis and distinct bacterial metabolic disturbances that may influence disease severity. However, our findings indicate that dysbiotic features that are uniquely ME/CFS-associated may be masked by disturbances arising from the high prevalence of IBS co-morbidity in ME/CFS. These insights may enable more accurate diagnosis and lead to insights that inform the development of specific therapeutic strategies in ME/CFS subgroups.","Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by unexplained persistent fatigue (long-lasting tiredness). ME/CFS is commonly accompanied by cognitive dysfunction, sleeping disturbances, orthostatic intolerance (inability to stand up quickly), fever, lymphadenopathy (swollen lymph nodes), and irritable bowel syndrome (IBS - colon disorder that leads to belly pain, gas, diarrhea, and constipation). The extent to which the stomach microbiome (gut bacteria) and inflammation (redness and swelling from infection-fighting) are associated (linked) with ME/CFS is unknown. This study evaluated 50 ME/CFS patients and 50 healthy controls. Analysis revealed associations between IBS co-morbidity, body mass index, fecal (poop) bacterial composition, and bacterial metabolic pathways. No associated was found between ME/CFS status and plasma (blood) immune molecules. IBS co-morbidity (co-diagnosis) was the most strongly associated endpoint with ME/CFS status. ME/CFS subgroups, defined by IBS status, could be distinguished from control subjects with high predictive accuracy. Bacterial taxa (bacterial groups) predictive of ME/CFS patients with IBS were distinct from taxa associated with ME/CFS patients without IBS. Two bacteria, Alistipes and Faecalibacterium, emerged as the top biomarkers of ME/CFS with IBS. Two bacteria, Bacteroides and Bacteroides vulgatus, were the top biomarkers of ME/CFS without IBS. Decreased metabolic pathways associated with unsaturated fatty acid biosynthesis and increased atrazine (herbicide) degradation pathways were independent of IBS co-morbidity. Increased vitamin B6 biosynthesis/salvage and pyrimidine ribonucleoside (DNA building blocks) degradation were the top metabolic pathways in ME/CFS without IBS. These pathways were also top in the total ME/CFS cohort. In ME/CFS subgroups, symptom severity measures were correlated with the abundance of distinct bacterial taxa and metabolic pathways. Independent of IBS, ME/CFS is associated with gut microbiome imbalance and distinct bacterial metabolic disturbances. These factors may influence disease severity. These findings indicate that gut microbial imbalance features associated with ME/CFS may be hidden by IBS. These findings may enable more accurate diagnosis and improve therapeutic (treatment) strategies in ME/CFS subgroups." +"Loss of function in mitochondria, the key organelle responsible for cellular energy production, can result in the excess fatigue and other symptoms that are common complaints in almost every chronic disease. At the molecular level, a reduction in mitochondrial function occurs as a result of the following changes: (1) a loss of maintenance of the electrical and chemical transmembrane potential of the inner mitochondrial membrane, (2) alterations in the function of the electron transport chain, or (3) a reduction in the transport of critical metabolites into mitochondria. In turn, these changes result in a reduced efficiency of oxidative phosphorylation and a reduction in production of adenosine-5'-triphosphate (ATP). Several components of this system require routine replacement, and this need can be facilitated with natural supplements. Clinical trials have shown the utility of using oral replacement supplements, such as L-carnitine, alpha-lipoic acid (?-lipoic acid [1,2-dithiolane-3-pentanoic acid]), coenzyme Q10 (CoQ10 [ubiquinone]), reduced nicotinamide adenine dinucleotide (NADH), membrane phospholipids, and other supplements. Combinations of these supplements can reduce significantly the fatigue and other symptoms associated with chronic disease and can naturally restore mitochondrial function, even in long-term patients with intractable fatigue.","Loss of function in mitochondria, the key organelle responsible for cellular energy production, can result in the excess fatigue and other symptoms commonly found in chronic diseases. A reduction in mitochondrial function occurs as a result of several changes. These include: maintenance loss of the transmembrane (trans-cell-boundary electrical) potential of the inner mitochondrial membrane, abnormal function of the electron transport chain, or reduced transport of critical metabolites (energy-regulating molecules) into mitochondria. These changes result in a reduced efficiency of oxidative phosphorylation (energy creation) and reduced production of adenosine-5'-triphosphate (ATP - the main currency of energy in a cell). Several components of this system require routine replacement. This system can be assisted with natural supplements. Clinical trials have shown the utility of using oral (by mouth) replacement supplements. Combinations of these supplements can reduce the fatigue and other symptoms associated with chronic disease. These supplements can naturally restore mitochondrial function, even in long-term patients with uncontrollable fatigue." +"Evidence is put forward to suggest that myalgic encephalomyelitis, also known as chronic fatigue syndrome, may be associated with persistent viral infection. In turn, such infections are likely to impair the ability of the body to biosynthesise n-3 and n-6 long-chain polyunsaturated fatty acids by inhibiting the delta-6 desaturation of the precursor essential fatty acids--namely, alpha-linolenic acid and linoleic acid. This would, in turn, impair the proper functioning of cell membranes, including cell signalling, and have an adverse effect on the biosynthesis of eicosanoids from the long-chain polyunsaturated fatty acids dihomo-gamma-linolenic acid, arachidonic acid and eicosapentaenoic acid. These actions might offer an explanation for some of the symptoms and signs of myalgic encephalomyelitis. A potential therapeutic avenue could be offered by bypassing the inhibition of the enzyme delta-6-desaturase by treatment with virgin cold-pressed non-raffinated evening primrose oil, which would supply gamma-linolenic acid and lipophilic pentacyclic triterpenes, and with eicosapentaenoic acid. The gamma-linolenic acid can readily be converted into dihomo-gamma-linolenic acid and thence arachidonic acid, while triterpenes have important free radical scavenging, cyclo-oxygenase and neutrophil elastase inhibitory activities. Furthermore, both arachidonic acid and eicosapentaenoic acid are, at relatively low concentrations, directly virucidal.","Scientific evidence suggests that myalgic encephalomyelitis, also known as chronic fatigue syndrome or long-lasting tiredness, may be associated with persistent viral infection. These infections may impair the body's ability to biosynthesize (create) fatty acids by inhibiting (blocking) the enzymatic reaction associated with essential fatty acids. This would, in turn, impair the proper functioning of cell membranes (cell boundaries), including cell signaling, and have an adverse effect on the biosynthesis of signaling molecules. These actions might offer an explanation for some of the symptoms and signs of myalgic encephalomyelitis. A potential treatment could be found in virgin cold-pressed primrose oil. The oil would supply gamma-linolenic acid and lipophilic pentacyclic triterpenes (specific fatty substances). The resulting acid and triterpenes would be further converted into beneficial compounds. Furthermore, the resulting compounds are virucidal or can destroy inactive viruses." +"Abnormalities of Essential Fatty Acid (EFA) incorporation into phospholipid are found in chronic diseases. More recently changes in circulating EFA metabolites (EFAM) together with EFAM hypo-responsiveness of immune cells and EFAM production from cells have been found associated with disease. We hypothesize that changes in ratio of EFAMs are the normal physiological responses to stressors, but when stressors are excessive or prolonged, EFAM systems may become unpredictably hypo-responsive owing to factors such as receptor down regulation and substrate depletion. In time, many homeostatic system become deranged and held in that state by minor stressors. Literature review of chronic fatigue syndrome (CFS) shows hyper and hypo-responsiveness in immune function, several Hypothalamo-Pituitary (HP) axes and sympathetic nervous system, all relatable to dysfunctional changes in EFA metabolism. For the first time, we explain chronic immune system activation and hypo-responsive immune function in CFS; through EFAMs. Dietary EFA modulation (DEFA) can alter ratios of both membrane EFAs and produced EFAMs, and if maintained can restore hypo-responsive function. We discuss dietary strategies and relevance in CFS, and a case series of CFS patients applying DEFA with other titrated published managements which saw 90% gaining improvement within 3 months and more than 2/3 fit for full time duties. This hypothesis and DEFA may have relevance in other chronic conditions.","Abnormalities of Essential Fatty Acid (EFA) incorporation into phospholipid (fatty molecules that build a cell's wall) are found in chronic diseases. Changes in circulating EFA metabolites (EFAM) decrease EFAM responsiveness of immune cells, and cellular EFAM production have been associated with disease. This study hypothesized that changes in EFAM ratio is the normal response to stressors. However, when stressors are excessive or prolonged, EFAM systems may become unresponsive. Many stable systems become deranged and held in that state by minor stressors. Literature review of chronic fatigue syndrome (CFS - long-lasting tiredness) shows several abnormal biological response related to dysfunctional changes in EFA metabolism. This study explains chronic immune system activation and hypo-responsive immune function in CFS through EFAMs. Dietary EFA modulation (DEFA) can alter ratios of both membrane EFAs and produced EFAMs. If maintained, DEFA can restore hypo-responsive function. This study discusses dietary strategies and relevance in CFS. This study also evaluated a case series of CFS patients applying DEFA with other titrated (concentrated) published managements. This hypothesis and DEFA may be relevant in other chronic conditions." +"Sixty-three adults with the diagnosis of the postviral fatigue syndrome were enrolled in a double-blind, placebo-controlled study of essential fatty acid therapy. The patients had been ill for from one to three years after an apparently viral infection, suffering from severe fatigue, myalgia and a variety of psychiatric symptoms. The preparation given contained linoleic, gamma-linolenic, eicosapentaenoic and docosahexaenoic acids and either it, or the placebo, was given as 8 x 500 mg capsules per day over a 3-month period. The trial was parallel in design and patients were evaluated at entry, one month and three months. In consultation with the patient the doctors assessed overall condition, fatigue, myalgia, dizziness, poor concentration and depression on a 3-point scale. The essential fatty acid composition of their red cell membrane phospholipids was analysed at the first and last visits. At 1 month, 74% of patients on active treatment and 23% of those on placebo assessed themselves as improved over the baseline, with the improvement being much greater in the former. At 3 months the corresponding figures were 85% and 17% (p less than 0.0001) since the placebo group had reverted towards the baseline state while those in the active group showed continued improvement. The essential fatty acid levels were abnormal at the baseline and corrected by active treatment. There were no adverse events. We conclude that essential fatty acids provide a rational, safe and effective treatment for patients with the post-viral fatigue syndrome.","Sixty-three adults diagnosed with postviral fatigue (tiredness) syndrome were enrolled in a study of essential fatty acid therapy. The patients had been ill for from one to three years after an apparently viral infection. They all suffered from severe fatigue, muscle pain, and a variety of psychiatric symptoms. The participants were given one of two treatments: a formulated mixture or a placebo (sham treatment). The mixture contained linoleic, gamma-linolenic, eicosapentaenoic and docosahexaenoic acids (fatty molecules). The treatments were administered as 8 x 500 mg capsules per day over a 3-month period. Patients were evaluated before treatment, after one month, and after three months. Doctors assessed overall condition, fatigue, muscle pain, dizziness, poor concentration, and depression. Essential fatty acid composition of their red cell membrane phospholipids (building blocks for the cell's wall) was analyzed at the first and last visits. At 1 month, 74% of patients on active treatment and 23% of those on placebo assessed (measured) themselves as improved over the baseline. Improvement being much greater in the active treatment group. At 3 months the corresponding figures were 85% and 17%. This is because the placebo group had reverted towards the baseline state while those in the active group showed continued improvement. The essential fatty acid levels were abnormal at the baseline and corrected by active treatment. There were no adverse (side) events. The authors concluded essential fatty acids provide a rational, safe and effective treatment for patients with the post-viral fatigue syndrome." +"This is a comprehensive literature review of chronic fatigue syndrome (CFS). We provide a description of the background, etiology, pathogenesis, diagnosis, and management regarding CFS. CFS is a multifaceted illness that has many symptoms and a wide array of clinical presentations. As of recent, CFS has been merged with myalgic encephalomyelitis (ME). Much of the difficulty in its management has stemmed from a lack of a concrete understanding of its etiology and pathogenesis. There is a potential association between dysfunction of the autoimmune, neuroendocrine, or autonomic nervous systems and the development of CFS. Possible triggering events, such as infections followed by an immune dysregulation resulting have also been proposed. In fact, ME/CFS was first described following Epstein Barr virus (EBV) infections, but it was later determined that it was not always preceded by EBV infection. Patient diagnosed with CFS have shown a noticeably earlier activation of anaerobic metabolism as a source of energy, which is suggestive of impaired oxygen consumption. The differential diagnoses range from tick-borne illnesses to psychiatric disorders to thyroid gland dysfunction. Given the many overlapping symptoms of CFS with other illnesses makes diagnosing it far from an easy task. The Centers for Disease Control and Prevention (CDC) considers it a diagnosing of exclusion, stating that self-reported fatigue for at minimum of six months and four of the following symptoms are necessary for a proper diagnosis: memory problems, sore throat, post-exertion malaise, tender cervical or axillary lymph nodes, myalgia, multi-joint pain, headaches, and troubled sleep. In turn, management of CFS is just as difficult. Treatment ranges from conservative, such as cognitive behavioral therapy (CBT) and antidepressants, to minimally invasive management. Minimally invasive management involving ranscutaneous electrical acupoint stimulation of target points has demonstrated significant improvement in fatigue and associated symptoms in a 2017 randomized controlled study. The understanding of CFS is evolving before us as we continue to learn more about it. As further reliable studies are conducted, providing a better grasp of what the syndrome encompasses, we will be able to improve our diagnosis and management of it.","This study is a literature review of chronic fatigue syndrome (CFS - long-lasting tiredness). This study provides a description of the background, cause, development, diagnosis, and management regarding CFS. CFS is a multifaceted illness that has many symptoms and a wide array of clinical presentations. As of recent, CFS has been merged with myalgic encephalomyelitis (ME). ME is a disease characterized with profound fatigue, abnormal sleep, and pain. Much of the difficulty in its management has stemmed from a lack of a concrete understanding of its cause and development. There is a potential association between dysfunction of the autoimmune (immune cells attacking healthy cells), neuroendocrine (brain- and hormonal-related system), or autonomic nervous systems and CFS development. Possible triggering events, such as infections followed by an immune dysregulation, have been proposed as potential causes. ME/CFS was first described following Epstein Barr virus (EBV - herpes virus) infections. It was later determined that it was not always preceded by EBV infection. Patient diagnosed with CFS have shown a noticeably earlier activation of anaerobic metabolism (no-oxygen energy production on the cellular level) as a source of energy. This suggests impaired oxygen consumption. The differential (different) diagnoses range from tick-borne illnesses to psychiatric disorders to metabolism-regulating thyroid gland dysfunction. The many overlapping symptoms of CFS with other illnesses makes diagnosis very hard. The Centers for Disease Control and Prevention (CDC) considers it a diagnosing of exclusion, meaning other illnesses have to first be excluded before CFS diagnosis can be offered. The CDC states that self-reported fatigue for a minimum of six months and four additional symptoms are necessary for diagnosis. These symptoms include: memory problems, sore throat, post-exertion illness, tender cervical (neck) or axillary (armpit) lymph nodes, muscle pain, multi-joint pain, headaches, and troubled sleep. Management of CFS is just as difficult. Treatment ranges from conservative (e.g. antidepressants) to minimally invasive (surgical) management. Minimally invasive management can involve transcutaneous electrical acupoint stimulation (non-surgical electrical pain relief) of target points. This treatment was shown to improve fatigue and associated symptoms in a 2017 study. The understanding of CFS is continuously evolving as the medical community tries to learn more about it. Further reliable studies will be conducted, providing a better grasp of what the syndrome encompasses. From this, researchers will be able to improve diagnosis and management of the disease." +"Clinical characteristics: Pallister-Hall syndrome (referred to as PHS in this entry) is characterized by a spectrum of anomalies ranging from polydactyly, asymptomatic bifid epiglottis, and hypothalamic hamartoma at the mild end to laryngotracheal cleft with neonatal lethality at the severe end. Individuals with mild PHS may be incorrectly diagnosed as having isolated postaxial polydactyly type A. Individuals with PHS can have pituitary insufficiency and may die as neonates from undiagnosed and untreated adrenal insufficiency. Diagnosis/testing: The diagnosis of Pallister-Hall syndrome can be established in a proband with both hypothalamic hamartoma and mesoaxial polydactyly. Identification of a heterozygous pathogenic variant in GLI3 confirms the diagnosis. Management: Treatment of manifestations: Urgent treatment for endocrine abnormalities, especially cortisol deficiency; management of epiglottic abnormalities depending on the abnormality and the extent of respiratory compromise. Bifid epiglottis, the most common abnormality, typically does not need treatment. Standard treatment of anal atresia or stenosis; symptomatic treatment of seizures; elective repair of polydactyly; developmental intervention or special education for developmental delays. Prevention of secondary complications: Biopsy or resection of hypothalamic hamartoma may result in complications and lifelong need for hormone replacement; seizures may begin or worsen with use of stimulants for attention deficit disorder. Surveillance: During childhood, annual developmental assessment and annual medical evaluation to assess growth and monitor for signs of precocious puberty. Genetic counseling: Pallister-Hall syndrome is inherited in an autosomal dominant manner. Individuals with PHS may have an affected parent or may have the disorder as the result of a de novo pathogenic variant. About 25% of individuals have a de novo pathogenic variant. Persons with a de novo pathogenic variant are generally more severely affected than those with a family history of PHS. The risk to offspring of an affected individual is 50%. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known. The reliability of ultrasound examination for prenatal diagnosis is unknown.","Pallister-Hall syndrome (PHS) ranges from mild to severe cases. Mild cases include polydactyly, in which people have six fingers or toes, a harmless split in the epiglottis (a small leaf-shaped structure that prevents food and drink from entering the windpipe) and hypothalamic hamartoma, a noncancerous growth in the base of the brain that can cause seizures and other problems. The severe cases include laryngotracheal cleft, a defect in which the baby's airway and food passages are connected, which can lead to newborn's death if the food and saliva get into the lungs. Mild PHS might be confused with babies having one or more extra finger or toe at birth, called postaxial polydactyly type A. In people with PHS pituitary gland, located in the brain, might not produce enough hormones (substances that regulate growth, metabolism and other functions). People with PHS may have adrenal insufficiency, a condition in which the adrenal glands do not produce enough hormones to control blood pressure, metabolism and the immune system. If these conditions are not recognized and treated in newborns, they may die. Hypothalamic hamartoma (non-cancer growth in the brain) and extra fingers or toes may be caused by Pallister-Hall syndrome. Genetic testing confirms the patients have PHS. Urgent treatments are needed if the glands do not produce enough hormones, especially cortisol. The defect in the flap that covers the windpipe needs treatment if it can lead to problems with breathing. Bifid epiglottis, the split in the flap that covers the windpipe, typically does not need treatment. Standard treatments are used for problems with anus, such as narrowing of the anal canal. Patients can choose to repair extra fingers. Seizures are treated as needed. Special education and other support are provided for developmental delays. Treatments of the problems caused by PHS can have complications. After surgery for the hypothalamic hamartoma patients may need to take hormones for the rest of their life. Drugs for attention deficit disorder may cause or worsen seizures. Every year, children with PHS need evaluation of their mental development, growth, and signs of their body changing into that of an adult (puberty) too soon. Either parent passes down the disease. A child will have PHS if either parent passes down the disease or if a new variant develops before birth. About a quarter of the PHS patients have a new harmful variant. Persons with a new harmful variant have a more severe disease than those with a family history of PHS. Chances of getting or not getting the disease from the parent are equal. If the harmful variant runs in the family, the developing baby may be tested during pregnancy. It is not known if ultrasound during pregnancy will show PHS." +"Polydactyly is a relatively common abnormality in infants. However, it can be a marker of a wide variety of neurological and systemic abnormality. Hence, it is important for pediatrician and physician to have insight into the various association of this apparently innocuous anomaly. In this write-up, we report an extremely rare syndrome associated with polydactyly that is Pallister-Hall syndrome. A 10-month-old male child born by lower segment cesarean section presented with global delay associated with microcephaly, frontal bossing, hypertelorism, flat nose, short philtrum, incomplete cleft in the upper lip and hard palate, polydactyly, and syndactyly. The child presented with repeated vomiting and crying episodes. The patient was investigated which revealed a hypothalamic hamartomas. Pallister-Hall syndrome is a very rare autosomal dominant genetic disorder due to mutation in GLI3 gene in the short arm of chromosome 7 with variable penetrance and expressivity.","Extra fingers or toes are relatively common in newborns. It can be a sign of different problems with the nervous and other systems. Doctors need to know about the conditions that cause extra fingers and toes. Pallister-Hall syndrome is a rare condition associated with having extra fingers and toes. A 10-month-old male child had a small head, unusually prominent forehead, increased distance between the eyes, flat nose, a shorter than normal distance between the upper lip and the nose, incomplete cleft (slit) in the upper lip and the roof of the mouth, extra fingers, and fused fingers. The child vomited and cried repeatedly. An examination showed the child had hypothalamic hamartomas, a non-cancer growth of tissue in the brain. Pallister-Hall syndrome is a rare disorder passed down by one of the parents. It ranges from mild to severe. " +"Pallister Hall syndrome is autosomal dominant disorder usually diagnosed in infants and children. Current diagnostic criteria include presence of hypothalamic hamartoma, post axial polydactyly and positive family history, but the disease has variable manifestations. Herein we report Pallister Hall syndrome diagnosed in a family where both patients were adults. A 59 year old man developed seizures 4 years prior to our evaluation of him, at which time imaging showed a hypothalamic hamartoma. The seizures were controlled medically. He did well until he had visual changes after a traumatic head injury. Repeat MRI showed slight expansion of the mass with formal visual field testing demonstrating bitemporal hemianopsia. There was no evidence of pituitary dysfunction except for large urine volume. He underwent surgery to debulk the hamartoma and the visual field defects improved. There was no hypopituitarism post-operatively, and the polydyspia resolved. His 29 year old daughter also had seizures and hypothalamic hamartoma. Both patients had had polydactyly with prior surgical correction in childhood. The daughter underwent genetic testing, which revealed a previously undescribed heterozygous single base pair deletion in exon 13 of the GLI3 gene causing a frameshift mutation. Further investigation into family history revealed multiple members in previous generations with polydactyly and/or seizures. Pallister-Hall syndrome is caused by an inherited autosomal dominant or de novo mutation in GLI3 gene. This rare syndrome has not had prevalence defined, however. Generally, diagnoses are made in the pediatric population. Our report adds to the few cases detected in adulthood.","Pallister Hall syndrome is passed down by one of the parents. It is usually diagnosed in infants and children. It is diagnosed if it runs in the family, and the children have hypothalamic hamartoma (a non-cancer growth of tissues in the brain), and extra fingers or toes, but these are not the only signs of the disease. We diagnosed Pallister Hall syndrome in a family where both patients were adults. A 59 year old man developed seizures 4 years before we examined him. An imaging examination showed a hypothalamic hamartoma. The seizures were under control. He did well until he had changes in eyesight after a head injury. MRI showed the mass has expanded slightly and the patient's vision was missing in the outer half of both the right and left eye. There were no signs of problems with the hormones made in the pituitary gland (which maintain body functions), except for large amount of urine. The patient had surgery to reduce the hamartoma and his vision improved. After the surgery, the pituitary gland functioned normally, and the patient no longer was excessively thirsty. His 29 year old daughter also had seizures and hypothalamic hamartoma. Both patients had surgery to remove the extra fingers in childhood. The daughter had genetic testing that showed she had a variant that caused the disease. Many family members in previous generations had extra fingers and seizures. Pallister-Hall syndrome is caused by either parent passing down the disease or a new harmful change in the genes. It is not known how many people have this rare disease. Generally, the disease is recognized in children. We described some of the few cases detected in adults." +"Pallister-Hall syndrome (PHS) is an extremely rare syndrome of unknown prevalence with autosomal dominant inheritance due to GLI3 gene mutations classically characterized by the presence of a hypothalamic hamartoma and polydactyly. Additional diagnostic criteria include bifid epiglottis, imperforate anus, small nails, hypopituitarism, growth hormone deficiency, and genital hypoplasia. It is typically diagnosed in infancy and early childhood, presenting with seizures and/or precocious puberty due to the hypothalamic hamartoma, and with limb anomalies due to central polydactyly. Our patient had presented with polysyndactyly at birth. However, as this is not uncommon in infants and is usually as part of the sporadic, isolated form of polydactyly, no further work up was done. He then presented at age 16 years with a headache and subjective visual changes, with brain imaging revealing a hypothalamic hamartoma. He did not have a history of seizures or central precocious puberty. Genotyping revealed a pathogenic variant affecting the GLI3 gene. We encourage all clinicians to consider PHS or an associated syndrome with a clinical finding of polydactyly. Further, as the natural history continues to reveal itself, this patient's presentation provides important new data to the broad phenotypic spectrum of PHS.","Pallister-Hall syndrome (PHS) is a rare disease. It is not known how many people have the disease. It is caused by harmful changes in the genes that are passed down by either parent. The disease is characterized by the presence of a hypothalamic hamartoma (a non-cancer growth in the brain) and extra fingers or toes. Other signs include a split in the flap that protects the windpipe, missing or blocked opening to the anus, small nails, reduced function of the pituitary gland, which controls body functions and growth through chemical substances called hormones, dwarfism, and poor development of the reproductive organs. It is usually recognized in infancy and early childhood by the presence of seizures, signs of the child's body changing to that of an adult too soon, and extra fingers or toes. Our patient had extra and fused fingers at birth. Because extra fingers are common and may have different causes, no tests were done. At the age of 16 he started having headaches and changes in vision. Brain imaging showed a hypothalamic hamartoma, a non-cancer growth in the brain tissues. He did not have seizures or premature puberty. Genetic testing showed harmful variants. Clinicians should think about PHS when they see extra fingers and toes. The disease signs in this patient add new knowledge about PHS." +"Introduction: Pallister-Hall syndrome (PHS) is a rare autosomal dominant syndrome characterized by polydactyly, bifid or shortened epiglottis, visceral anomalies, hypothalamic hamartoma often combined with hypopituitarism. PHS is characterized by significant variability in the expression of clinical symptoms. The clinical course ranges from mild with a good prognosis to severe and which can lead to death during the neonatal period. Case report: Two-years-old girl with facial dysmorphia, skeletal malformations of hand and feet and growth hormone deficiency. PHS was diagnosed on the basis of the presented symptoms and genetic tests. Summary: Skeletal malformations, such as polydactyly or oligodactyly, are a markers which can be associated with endocrinological disorders. Quick and correct diagnosis would help in planning treatment during childhood and giving family counseling, including prenatal advice regarding the next pregnancy of the child's mother.","Pallister-Hall syndrome (PHS) is a rare disease passed down from one of the parents. Its signs are six fingers and toes, shortened or split flap that protects the windpipe, problems with the organs in the chest and belly, non-cancer mass in the brain that often causes problems with pituitary gland, which regulates body functions and growth. Signs of PHS in different patients are very different. PHS ranges from mild with good outcomes to severe that can lead to death of the newborns. We describe a two-year-old girl with deformities of the face, hand and feet and dwarfism. PHS was diagnosed on the basis of the presented symptoms and genetic tests. Abnormalities, such as the presence of extra or fewer than five fingers or toes, are associated with disorders of the endocrine system, which includes the glands that regulate body functions through chemicals called hormones. Quick and correct diagnosis would help in planning treatment for the child and advise the family regarding the next pregnancy of the child's mother. " +"Pallister-Hall syndrome was initially recognized under fairly unique circumstances involving exhumation of the very first case. The first two cases had dramatic and unusual features including a hypothalamic hamartoblastoma, imperforate anus, an unusual type of polydactyly with the extra digit being central, hypopituitarism with secondary hypoadrenalism, and lethality after birth (probably due to hypoadrenalism). Within a short time frame, four additional cases were identified. As the full spectrum and variability of anomalies was recognized, it became clear that it was not such a rare disorder. Shortly after familial cases were recognized, the responsible gene was identified at GLI3. However, since other different conditions also involved GLI3, elaborating the domains of the gene and the types of mutations needed to be defined in order to have a clear correlation of the genotype-phenotype relations.","Pallister-Hall syndrome was first identified in unearthed human remains. The first two bodies had unusual features including a brain mass, missing anus, a sixth finger in the center, and death after birth. As more cases were found, it became clear that PHS is not such a rare disorder. Shortly after, it was recognized that the disease runs in the families due to changes in the gene called GLI3. Other problems can be caused by changes in the same gene GLI3. Different changes in the different parts of the gene cause different problems." +"Pallister-Hall syndrome (PHS) is a rare disorder caused by mutations in GLI3 that produce a transcriptional repressor (GLI3R). Individuals with PHS present with a variably penetrant variety of urogenital system malformations, including renal aplasia or hypoplasia, hydroureter, hydronephrosis or a common urogenital sinus. The embryologic mechanisms controlled by GLI3R that result in these pathologic phenotypes are undefined. We demonstrate that germline expression of GLI3R causes renal hypoplasia, associated with decreased nephron number, and hydroureter and hydronephrosis, caused by blind-ending ureters. Mice with obligate GLI3R expression also displayed duplication of the ureters that was caused by aberrant common nephric duct patterning and ureteric stalk outgrowth. These developmental abnormalities are associated with suppressed Hedgehog signaling activity in the cloaca and adjacent vesicular mesenchyme. Mice with conditional expression of GLI3R were utilized to identify lineage-specific effects of GLI3R. In the ureteric bud, GLI3R expression decreased branching morphogenesis. In Six2-positive nephrogenic progenitors, GLI3R decreased progenitor cell proliferation reducing the number of nephrogenic precursor structures. Using mutant mice with Gli3R and Gli3 null alleles, we demonstrate that urogenital system patterning and development is controlled by the levels of GLI3R and not by an absence of full-length GLI3. We conclude that the urogenital system phenotypes observed in PHS are caused by GLI3R-dependent perturbations in nephric duct patterning, renal branching morphogenesis and nephrogenic progenitor self-renewal.","Pallister-Hall syndrome (PHS) is a rare disorder caused by changes in the gene called GLI3. Patients with PHS have a variety of problems with reproduction and urinary organs, including poor development of the kidneys, backup of urine in the duct between the kidney and the bladder, swelling of the kidneys, or a shared opening for the birth canal and the urinary tract. It is not known how the specific problems arise We show that variations in the GLI3 gene cause poor development of the kidneys, and a closed end in the duct that runs between the kidney and the bladder, which causes swelling of the kidneys and the duct. Mice with the same change in the GLI3 gene also had two ducts that connected a kidney to the bladder The abnormal development is caused by the lack of information the embryonic cells (cells that forms when eggs are fertilized) need for proper development. Using mutant mice, we show that the development of the reproduction and urinary organs is controlled by the variants in the GLI3 gene. Different problems in PHS are caused by the different mistakes in the development of the urinary organs due to the information provided by the variants of the GLI3 gene." +"Pallister-Hall syndrome (PHS) is a rare, single-gene, malformation syndrome that includes central polydactyly, hypothalamic hamartoma, bifid epiglottis, endocrine dysfunction, and other anomalies. The syndrome has variable clinical manifestations and is inherited in an autosomal dominant pattern. We sought to determine whether psychiatric disorders and/or neuropsychological impairment were characteristic of PHS. We prospectively conducted systematic neuropsychiatric evaluations with 19 PHS subjects ranging in age from 7 to 75 years. The evaluation included detailed clinical interviews, clinician-rated and self-report instruments, and a battery of neuropsychological tests. Seven of 14 adult PHS subjects met diagnostic criteria for at least one DSM-IV Axis I disorder. Three additional subjects demonstrated developmental delays and/or neuropsychological deficits on formal neuropsychological testing. However, we found no characteristic psychiatric phenotype associated with PHS, and the frequency of each of the diagnoses observed in these subjects was not different from that expected in this size sample. The overall frequency of psychiatric findings among all patients with PHS cannot be compared to point prevalence estimates of psychiatric disease in the general population because of biased ascertainment. This limitation is inherent to the study of behavioral phenotypes in rare disorders. The general issue of psychiatric evaluation of rare genetic syndromes is discussed in light of this negative result.","Pallister-Hall syndrome (PHS) is a rare disease caused by changes in a single gene (the basic unit of inheritance.) The abnormalities include extra fingers and toes, growth of non-cancer masses in the brain, changes in the flap that protect the windpipe, improper function of the endocrine system that regulates body functions through hormones, and other problems. The signs of this disease vary and are passed down through either parent. We studied if PHS causes any mental health problems. We measured how well the brain is working in 19 PHS patients ranging in age from 7 to 75 years. The evaluation included clinical examination, patients' reports and tests of brain functions. Seven of 14 adults had at least one of the mental health conditions most commonly found in the public. Three other patients had delays in mental development or low scores on the tests that measure how well the brain is working. The tests usually evaluate reading, use of language, attention, learning, reasoning, remembering, problem-solving, and more. We did not find mental health problems specifically associated with PHS. The frequency of each of the problems in these patients was the same as expected in the group of 19 people. The rate of mental problems in PHS cannot be compared to the overall rate of mental problems in the general population because of the way this study collected the data. " +"We report on three infants with hand anomalies and congenital hypopituitarism. In two of the cases, a hypothalamic tumor was found; the third infant died without postmortem brain studies. Family history in the first case suggested possible familial recurrence; the mother's sister had died at 17 hr of age with polydactyly, microglossia, and flat nasal bridge (no autopsy done). Our second case was born by cesarean section after a pregnancy complicated by extremely low maternal estriols. At birth, hypopituitarism was diagnosed, a cranial CT scan was read as normal, and hormonal replacement was begun with thyroxine, hydrocortisone, and growth hormone. At 11.5 mo of age she developed seizures; and a repeat CT scan showed a mass extending beneath the hypothalamus. This tumor was removed surgically at 12 mo, the first successful treatment of this disorder. Our third possible case had a bifid epiglottis, hypopituitarism, and hand anomalies. A CT scan at birth failed to reveal a mass in the hypothalamus. This child died from complications of untreated hypopituitarism, and no neuropathology studies were done. These three cases were conceived between March 10th and April 17th in three different years in three geographically contiguous counties of Vermont. Clustering in time and space and possible familial recurrence, in one of these cases, suggest a possible gene/environment interaction.","We report on three infants born with hands born with hand defects and defects of the pituitary gland, which regulates body functions and growth through chemical substances called hormones. Two of the newborns had hypothalamic tumors (noncancerous growths in the base of their brains). The brain of the third newborn was not examined. In one case, the disease runs in the family. The mother's sister died at the age of 17. She had extra fingers, extremely small tongue, and flat nose. The mother of the second newborn had very low levels of estriol, a hormone made during pregnancy that is used to measure the unborn baby's health. When this baby was born, brain imaging was normal, but the levels of hormones that regulate growth and development were low. Treatment with growth and other hormones was started. At 11.5 months the baby started having seizures. A new brain imaging showed a mass in the lower part of the brain. Surgery to remove this mass at 12 months was the first successful treatment of this disorder. The third newborn had a split in the flap that protects the windpipe, lack of hormones that regulate growth and development, and abnormal hands. Brain imaging at birth did not show a mass in the lower part of the brain. This child died from complications of a brain mass that was not showing in the image. These three babies were conceived between March 10th and April 17th in three different years in three neighboring counties of Vermont. Close locations and possible other PHS cases in one of these families suggest inheritance and environment might interact." +"Pallister-Hall syndrome (PHS, M146510) was first described in 1980 in six newborns. It is a pleiotropic disorder of human development that comprises hypothalamic hamartoma, central polydactyly, and other malformations. This disorder is inherited as an autosomal dominant trait and has been mapped to 7p13 (S. Kang et al.Autosomal dominant Pallister-Hall syndrome maps to 7p13. Am. J. Hum. Genet. 59, A81 (1996)), co-localizing the PHS locus and the GLI3 zinc finger transcription factor gene. Large deletions or translocations resulting in haploinsufficiency of the GLI3 gene have been associated with Greig cephalopolysyndactyly syndrome (GCPS; M175700) although no mutations have been identified in GCPS patients with normal karyotypes. Both PHS and GCPS have polysyndactyly, abnormal craniofacial features and are inherited in an autosomal dominant pattern, but they are clinically distinct. The polydactyly of GCPS is commonly preaxial and that of PHS is typically central or postaxial. No reported cases of GCPS have hypothalamic hamartoma and PHS does not cause hypertelorism or broadening of the nasal root or forehead. The co-localization of the loci for PHS and GCPS led us to investigate GLI3 as a candidate gene for PHS. Herein we report two PHS families with frameshift mutations in GLI3 that are 3' of the zinc finger-encoding domains, including one family with a de novo mutation. These data implicate mutations in GLI3 as the cause of autosomal dominant PHS, and suggest that frameshift mutations of the GLI3 transcription factor gene can alter the development of multiple organ systems in vertebrates.","Pallister-Hall syndrome (PHS) was first described in 1980 in six newborns. It is caused by a single gene that is involved in development of multiple body parts. The problems include a non-cancer mass in the lower part of the brain and extra fingers and toes, among others. This disorder is passed down by either parent, and the involved gene is located on chromosome 7, associating PHS with the gene called GLI3. Variants of the the GLI3 gene in which some genetic information is missing or misplaced are associated with Greig cephalopolysyndactyly syndrome (GCPS) that affects development of the hands, feet, head, and face. Patients with both PHS and GCPS have extra or merged fingers and toes, and abnormal heads and faces. Both PHS and GCPS are passed down from either parent, but the clinical signs of these diseases are different. The additional finger in GCPS is usually located next to the thumb. In PHS, the extra finger is in the center or next to the little finger (pinky). The extra toes follow the same pattern: in GCPS the sixth toe is next to the big toe. No reported cases of GCPS have non-cancer growth in the lower part of the brain, and PHS does not cause increased distance between the eyes or broadening of the nose or forehead. Because the generic changes for PHS and GCPS share the location on the chromosome, we study GLI3 as a gene potentially responsible for PHS. We describe two PHS families with large changes in the GLI3 gene. In one family the change is new and there is no family history of PHS. The data show that changes in the GLI3 gene, which are passed down in the family or happen for the first time, cause PHS. Large-scale changes in the GLI3 gene can change the development of many tissues and organs." +"Trigeminal neuralgia is caused by compression of trigeminal nerve root and it leads to demyelination gradually. It was almost idiopathic and occurred unexpected. The upper cervical spinal cord contains the spinal trigeminal tract and nucleus. Fibers with cell bodies in the trigeminal ganglion enter in the upper pons and descend caudally to C2 level. We experienced a rare patient with facial pain, which was paroxysmal attack with severe pain after a clear event, cervical spinal injury (C2). So, this case reminds us of a possible cause of trigeminal neuralgia after a trauma of the head and neck.","Trigeminal nerve pain (neuralgia) is caused by pressure on the trigeminal (meaning ""threefold"", for the three branches of the nerve) nerve. The pressure leads to gradual loss of the protecting layer that covers the nerve. It arises spontaneously and unexpected. The spinal cord is the bundle of nerve tissues that connects the brain with the body. In the upper neck region, it contains parts of the trigeminal nerve. The trigeminal nerve cells and fibers enter the brainstem, the bottom part of the brain connected to the spinal cord, and go down to the second vertebrae at the top of the cervical spine. A rare patient had severe repeated bouts of facial pain after an injury to the second vertebrae at the top of the neck region. This patient reminds us that trigeminal neuralgia may be caused by injuries to the head and neck. " +"Objective: To report a novel wireless neuromodulation system for treatment of refractory craniofacial pain. Background: Previous studies utilizing peripheral nerve stimulation (PNS) of the occipital and trigeminal nerves reported positive outcomes for alleviating neuropathic pain localized to the craniofacial and occipital areas. However several technological limitations and cosmetic concerns inhibited a more widespread acceptance and use of neuromodulation. Also, a relatively high incidence of adverse events like electrode erosions, dislocation, wire fracture and/or infection at the surgical site mandates a change in our approach to neuromodulation technology and implant techniques in the craniofacial region. Methods: We report a novel approach for the management of craniofacial pain with a wirelessly powered, minimally invasive PNS system. The system is percutaneously implanted and placed subcutaneously adjacent to affected facial nerves via visual guidance by the clinician. In this feasibility study, pilot evidence was gathered in a cohort of ten subjects suffering from a combination of chronic headaches, facial pain for at least 15 days per month and for at least 4h/day. Results: At four weeks post-implant follow up, all patients reported sustained pain relief of the primary pain area. Electrode location and total number of electrodes used per subject varied across the cohort. The average pain reduction using the visual analog scale was ?82%. The procedure had no adverse events or side effects. Conclusion: Percutaneous placement of a wireless neurostimulation device directly adjacent to affected craniofacial nerve(s) is a minimally invasive and reversible method of pain control in patients with craniofacial pain refractory to conventional medical managements. Preliminary results are encouraging and further larger scale studies are required for improved applications.","This study presents a new wireless nerve stimulation system for treatment of uncontrollable pain of the head and face. Previous studies reported that stimulation of the nerves called trigeminal (meaning ""threefold"", for the three branches of the nerve) and occipital (relating to the back of the head) reduces pain in the head and face. Due to the shortcomings of the devices and concerns about the appearance, the nerve stimulation systems are not used widely. The relatively common complications are worn and broken wires, devices moving from the original placement, and infection around the device. To avoid these complications, we need to change the nerve stimulation systems and the way they are implanted (placed) in the head and face. We describe a new peripheral nerve stimulation (PNS) system for treatment of pain in the head and neck. The system is wireless and is placed using small cuts and few stitches. The doctors place the system under the skin, next to the damaged facial nerves This study included ten patients who experienced chronic headaches and facial pain for four or more hours a day and at least 15 days a month. Four weeks after the systems were implanted, all patients felt continuing ain relief. The patients had different numbers of wires and implant locations. On average, patients felt five times less pain after treatment. There were no complications Placing a wireless nerve stimulation device under the skin next to the damaged nerves in the head and neck reduces pain that is hard to control otherwise. This treatment is gentle and can be reversed. " +"Traumatic injury to the peripheral nerves often results in persistent discomfort. Substance P has been implicated as a mediator of pain, and depletion of this neurotransmitter has been shown to reduce pain. Subjects suffering from traumatic dysesthesia of the trigeminal nerve were treated with capsaicin, a substance P depleter with significant long-term effects. This form of therapy may be used individually or in combination with other pharmacologic interventions in the treatment of traumatic trigeminal dysesthesia.","After peripheral nerves (the parts of the nervous system outside the brain and spinal cord) are injured, people often feel discomfort for a long time. A chemical called Substance P is involved in the process of feeling pain. Lowering the amount of this chemical involved in the transmission of nerve signals lessens pain. Capsaicin was a good long-term treatment for people who experienced an unpleasant abnormal sensation after injury to the trigeminal nerve. Trigeminal nerve is a large, three-part nerve in the head that provides sensation. Capsaicin is a chemical that lowers the amount of Substance P in the body. Drugs that lower the amount of Substance P in the body may be used alone or together with other medications to treat traumatic trigeminal dysesthesia (an unpleasant abnormal sensation after injury to the trigeminal nerve.)" +"The current understanding of ON is that it causes neuropathic pain in the distribution of the greater occipital nerve, the lesser occipital nerve, the third occipital nerve or a combination of the 3. It is currently a subset of headaches although there is some debate if ON should be its own condition. Occipital neuralgia causes chronic, sharp, stabbing pain in the upper neck, back of the head, and behind the ears that can radiate to the front of the head. Diagnosis is typically clinical and patients present with intermittent, painful episodes associated with the occipital region and the nerves described above. Most cases are unilateral pain, however bilateral pain can be present and the pain can radiate to the frontal region and face. Physical examination is the first step in management of this disease and patients may demonstrate tenderness over the greater occipital and lesser occipital nerves. Anesthetics like 1% to 2% lidocaine or 0.25% to 0.5% bupivacaine can be used to block these nerves and anti-inflammatory drugs like corticosteroids can be used in combination to prevent compressive symptoms. Other treatments like botulinum toxin and radiofrequency ablation have shown promise and require more research. Surgical decompression through resection of the obliquus capitis inferior is the definitive treatment however there are significant risks associated with this procedure.","Occipital Neuralgia is the pain in the occipital nerves, the nerves that run from the top of the spinal cord up in the back of the head. It is considered a type of headaches, but some doctors suggest pain in the nerves in the back of the head is a different problem. Occipital neuralgia is a continuing, sharp, stabbing pain in the upper neck, back of the head, and behind the ears. It can also extend to the front of the head. The doctors decide the patients have the disease if the pain in the back of the patients' heads comes and goes. Most patients have pain on one side of their head, but the pain could also be on both sides and extend to the front of the head and face. When the doctors examine the patients, the patients' skin over the nerves in the back of the head may be tender. Drugs like lidocaine can block the feeling of pain in these nerves. Drugs that reduce inflammation, such as steroids may be added to keep the signs from happening. Other treatments like botulinum toxin that blocks the nerve signals and radiofrequency ablation that uses radio waves to shrink tissues may be promising but need to be studied more. Surgeons may permanently relieve the pressure on the nerve by removing a small muscle between the neck vertebra at the base of the head, but this treatment is risky. " +"Post-traumatic trigeminal neuralgia (PTTN), also known as anesthesia dolorosa, is at times a debilitating affliction, but remains a condition with minimal research and without definitive treatment, specifically in the periorbital and malar regions. Below we present a case of PTTN in a patient with historic facial trauma who has successfully achieved resolution of pain. We describe diagnostic and therapeutic anesthesia blocks and ablative procedures targeting the zygomaticofacial and zygomaticotemporal nerves. We promote awareness for the procedures and the potential large impact on the oral and maxillofacial surgery community when treating those suffering from facial pain. Finally, we present an algorithm that can aid surgeons in diagnosing and treating patients with PTTN.","Post-traumatic trigeminal neuralgia (PTTN), also known as anesthesia dolorosa, refers to the pain in the trigeminal nerve, a three-part nerve in the head that provides sensation. PTTN is a crippling pain that has no established treatments, specifically for the pain around the eyes and back teeth. We describe how trigeminal nerve pain was treated in a patient who had it due to an old injury to his face. We describe surgery and treatment that blocked sensation in the facial nerves around the temples and cheek bones. This treatment could be used by dental surgeons who treat patients with facial pain. We also describe a decision support tool for recognizing and treating PTTN." +"Introduction: Facial pain (FP) is a type of neuropathic pain which recognizes both central and peripheral causes. It can be difficult to treat because it can often become resistant to pharmacological treatments. Motor Cortex Stimulation (MCS) has been used in selected cases, but the correct indications of MCS in FP have not been fully established. Here we systematically reviewed the literature regarding MCS in FP analysing the results of this technique and studying the possible role of different factors in the prognosis of these patients. Methods: A literature search was performed through different databases (PubMed, Scopus, and Embase) according to PRISMA guidelines using the following terms in any possible combination: ""facial pain"" or ""trigeminal"" or ""anaesthesia dolorosa"" and ""motor cortex stimulation."" Results: 111 articles were reviewed, and 12 studies were included in the present analysis for a total of 108 patients. Overall, at latest follow-up (FU), 70.83% of patients responded to MCS. The preoperative VAS significantly decreased at the latest FU (8.83 � 1.17 and 4.31 � 2.05, respectively; p < 0.0001). Younger age (p = 0.0478) and a peripheral FP syndrome (p = 0.0006) positively affected the definitive implantation rate on univariate analysis. Younger age emerged as a factor strongly associated to a higher probability to go to a definitive MCS implant on multivariate analysis (p = 0.0415). Conclusion: Our results evidenced the effectiveness of MCS in treating FP. Moreover, the younger age emerged as a positive prognostic factor for definitive implantation. Further studies with longer FU are needed to better evaluate the long-term results of MCS.","Facial pain is nerve pain caused by nerves in the spinal cord and outside the spinal cord and brain. It can be difficult to treat because pain relieve drugs may stop working. Motor Cortex Stimulation (MCS), surgical stimulation of the nerves, is sometimes used, but it is not known yet when to use it for facial pain. We review what is known about treating patients with facial pain using MCS and the outcomes of the treatment. We found information about 108 patients. MCS helped almost three quarters of the patients. The patients felt their pain was reduced almost to half of the pain they felt before surgery. The treatment was more effective in younger patients and those with pain on the side of the face. Younger patients were more likely to get MCS implanted devices MCS is an effective treatment for facial pain. Younger patients were more likely to get permanent implanted devices. " +"Background: Neuropathic facial pain occurs due to pathologic dysfunctions of a nerve responsible for mediating sensory fibers to the head. Surgical interventions, in cases of failed medical therapy, include microvascular decompression, radiofrequency (RF) ablation, percutaneous balloon decompression, and stereotactic radiosurgery. In this review, we focused on RF ablation as a treatment for chronic facial pain. Objectives: The objective of this review was to summarize available evidence behind RF ablation for facial pain, including pain outcome measures, secondary outcomes, and complications. Study design: Systematic review. Setting: This systematic review examined studies that applied the use of RF ablation for management of facial pain. Methods: This systematic review was reported following the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers independently scored the methodological quality of the selected studies. Due to heterogeneity of studies, a best-evidence synthesis of the available prognostic factors was provided. Results: We reviewed 44 studies and assessed their short- and long-term pain relief measurements, as well as secondary outcomes including patient satisfaction, quality of life improvements, decrease in oral medication use, and recurrence rates. Maximal pain relief was achieved in treatment groups using combined continuous radiofrequency (CRF) and pulsed radiofrequency (PRF) therapies, followed by CRF therapy alone and finally PRF therapy alone. All treatment regimens improved secondary outcomes. Common complications of treatment included facial numbness, masseter weakness, cheek hematomas, diminished corneal reflex, and dry eyes. Limitations: A large variability in definitions of trigeminal neuralgia, RF technique, and patient selection bias was observed in our selected cohort of studies. In addition, there was a paucity of strong longitudinal randomized controlled trials and prospective studies. Conclusions: This systematic review found evidence that RF ablation is efficient in treating patients with facial pain, as well as in improving quality of life and reducing oral medication use. Maximal pain control is achieved using combined CRF and PRF therapy. Complications are uncommon and include facial numbness, masseter weakness, cheek hematomas, diminished corneal reflex, and dry eyes.","Neural facial pain is caused by the nerves that transmit sensation to the head. If medicines do not help, surgery may be used. Surgeries relieve compressed nerves (microvascular decompression); or shrink tissues using radio waves (radiofrequency (RF) ablation) or local radiation (stereotactic radiosurgery). Other surgeries prevent the nerve from transmitting signals (percutaneous balloon decompression.) We discuss using radio waves (RF ablation) to treat chronic facial pain. We summarize what is known about RF ablation for facial pain, including treatment results and complications. We summarize the pain relief results, patient satisfaction, quality of life, decrease in the drug use, and how often the pain returns. Combining two different types of radio wave treatments (continuous radiofrequency (CRF) and pulsed radiofrequency (PRF))reduced pain the best. CRF treatment was second best, followed by PRF. All treatments improved patient satisfaction and quality of life, and decreased drug use and return of the pain. Common complications of the treatment included facial numbness, weakness of facial muscles, bruised cheeks, failure to blink when the eye is touched, and dry eyes. We conclude that radio wave treatment (RF ablation) is efficient in treating patients with facial pain. It also improves quality of life and reduces drug use. Maximal pain control is achieved using combined CRF and PRF therapy. Complications of the treatment were not frequent and included facial numbness, weakness of facial muscles, bruised cheeks, failure to blink when the eye is touched, and dry eyes." +"Introduction: The complex nature of facial pain conditions creates a diagnostic challenge which may necessitate specialist referral. Aim: To identify the case mix presenting to a specialist tertiary care facial pain clinic. Methods: A retrospective review of 112 patient records was undertaken. Trends in provisional diagnoses from referrers and the correlation to diagnoses made following specialist consultation were reviewed. Results: The most common provisional diagnoses recorded in referral letters were painful temporomandibular disorders, trigeminal neuralgia and persistent idiopathic facial pain (PIFP). Over a quarter of referrals did not include a provisional diagnosis. Following assessment, only one case was not given a definitive diagnosis and no patients were diagnosed with PIFP. A causative factor was identified in all the initially queried PIFP cases, and painful post-traumatic trigeminal neuropathic pain was found in multiple patients. Conclusions: Painful post-traumatic trigeminal neuropathic pain should be considered if pain onset coincides with dental treatment or other traumatic events. PIFP is a rare facial pain diagnosis and may be over-diagnosed by dental and medical practitioners. It is important to systematically exclude other causes before reaching this diagnosis. This will facilitate effective treatment, manage patient expectations and potentially reduce unnecessary referrals.",Facial pain may be hard to recognize and a specialist might need to examine the patient. The study's aim was to identify the mix of patient cases at a specialist facial pain clinic. We reviewed the records of 112 patients who visited the specialists at the facial pain clinic. We compared the reasons for specialist consultation given by the primary doctors to the diagnoses made by the specialists. Most often the primary doctors thought the patients' pain was caused by problems with the temporomandibular joints that connect the lower jaw to the skull; pain in the trigeminal nerve that sends signals about sensations in the face to the brain; and other facial pain. Over a quarter of patients referred to the cliniic had no diagnosis. The specialist could not diagnose only one patient and have not diagnosed any patients with unspecified facial pain. The specialists found causes of all previously unspecified facial pain. Many patients had trigeminal nerve pain following an injury (Painful post-traumatic trigeminal neuropathic pain ). Painful post-traumatic trigeminal neuropathic pain should be considered if pain started after dental treatment or injury. Unspecified facial pain is rare and may be overused by dentists and physicians. All other causes should be excluded before diagnosis of the unspecified facial pain. This will improve treatment and patients' expectations. It may reduce unnecessary referrals. +"Introduction: Trigeminal neuralgia is an exemplary neuropathic pain condition characterized by paroxysmal electric-shock-like pain. However, up to 50% of patients also experiences concomitant continuous pain. In this neuroimaging study, we aimed to identify the specific anatomical features of trigeminal nerve root in patients with concomitant continuous pain. Methods: We enrolled 73 patients with a definitive diagnosis of classical and idiopathic trigeminal neuralgia and 40 healthy participants. The diagnosis of trigeminal neuralgia was independently confirmed by two clinicians. Patients were grouped as patients with purely paroxysmal pain (45 patients) and patients also with concomitant continuous pain (28 patients). All participants underwent a structured clinical examination and a 3T MRI with sequences dedicated to the anatomical study of the trigeminal nerve root, including volumetric study. Images analysis was independently performed by two investigators, blinded to any clinical data. Results: In most patients with concomitant continuous pain, this type of pain, described as burning, throbbing or aching, manifested at the disease onset. Demographic and clinical variables did not differ between the two groups of patients; the frequency of neurovascular compression and nerve dislocation were similar. Conversely, trigeminal nerve root atrophy was more severe in patients with concomitant continuous pain than in those with purely paroxysmal pain (p = 0.006). Conclusions: Our clinical and neuroimaging study found that in patients with trigeminal neuralgia, concomitant continuous pain was associated with trigeminal nerve root atrophy, therefore suggesting that this type of pain is likely related to axonal loss and abnormal activity in denervated trigeminal second-order neurons.","Neuralgia is pain in the nerves that feels as bursts of electric-shock-like pain. Up tp half of the patients also experience continuous pain. We study the specific anatomical features of trigeminal nerve root (a part of the nerve that helps the face recognize pain, touch, heat and cold sensations, as well as chewing. We studied patients with continuous pain. We studied 73 patients with trigeminal neuralgia (nerve pain) and 40 healthy participants. The diagnosis of trigeminal neuralgia was independently confirmed by two clinicians. 45 patients had only Burts of pain and 28 patients had continuous pain along with the bursts. All patients had clinical examination and MRI. Two specialists studied the images without losing at the clinical data. In most patients with continuous pain it started as burning, throbbing or aching sensation. The patients in the two groups and the frequency and location of the nerve damage signs in these patients were similar On the contrary, patients with both the bursts and continuous pain had more atrophy ((decrease in size) of the trigeminal nerve than the patients with bursts only. Clinical examination of patients with trigeminal nerve pain and their medical images show that patients who experienced continuous pain along with pain bursts lost some nerve tissues. This type of pain is related to wrong signaling in the nerve that lost tissues. " +"Orofacial pain syndromes encompass several clinically defined and classified entities. The focus here is on the role of clinical neurophysiologic and psychophysical tests in the diagnosis, differential diagnosis, and pathophysiological mechanisms of definite trigeminal neuropathic pain and other chronic orofacial pain conditions (excluding headache and temporomandibular disorders). The International Classification of Headache Disorders 2018 classifies these facial pain disorders under the heading Painful cranial neuropathies and other facial pains. In addition to unambiguous painful posttraumatic or postherpetic trigeminal neuropathies, burning mouth syndrome, persistent idiopathic facial and dental pain, and trigeminal neuralgia have also been identified with neurophysiologic and quantitative sensory testing to involve the nervous system. Despite normal clinical examination, these all include clusters of patients with evidence for either peripheral or central nervous system pathology compatible with the subclinical end of a continuum of trigeminal neuropathic pain conditions. Useful tests in the diagnostic process include electroneuromyography with specific needle, neurography techniques for the inferior alveolar and infraorbital nerves, brain stem reflex recordings (blink reflex with stimulation of the supraorbital, infraorbital, mental, and lingual nerves; jaw jerk; masseter silent period), evoked potential recordings, and quantitative sensory testing. Habituation of the blink reflex and evoked potential responses to repeated stimuli evaluate top-down inhibition, and navigated transcranial magnetic stimulation allows the mapping of reorganization within the motor cortex in chronic neuropathic pain. With systematic use of neurophysiologic and quantitative sensory testing, many of the current ambiguities in the diagnosis, classification, and understanding of chronic orofacial syndromes can be clarified for clinical practice and future research.","Orofacial pain syndromes are diseases known to cause pain in the face and mouth. We discuss clinical examinations of the neural system that help identifying trigeminal nerve pain and other chronic facial pain conditions, but not headaches and problems with TMJ. The International Classification of Headache Disorders 2018 classifies these facial pain disorders under the heading Painful cranial neuropathies and other facial pains. Clinical examinations of the nervous system help identifying painful conditions of the trigeminal nerve, which carries sensation from the face to the brain. These conditions may start after an injury (posttraumatic trigeminal neuropathy) or herpes infection (postherpetic trigeminal neuropathy). Other related conditions are burning mouth syndrome (a burning, scalding, or tingling feeling in the mouth) and persistent idiopathic facial and dental pain, which is described as continuing pain in the face and teeth of unknown cause. Even patients who appear normal on clinical examination have damage to their nervous system that can cause trigeminal nerve pain. Diagnostic tests include recording electrical signals in the muscles (electroneuromyography), MRI of the nerves around the eyes, blink reflexes and jaw jerk when different nerves are stimulated, recording electrical signals after the nerves are stimulated, and tests for pain sensation. Responsiveness of the blink reflex and records of the electrical signals after repeated nerve stimulation show if the response is suppressed. Medical imaging called navigated transcranial magnetic stimulation shows the areas of the brain that change due to chronic nerve pain. Consistent use of the above tests will help understanding the chronic facial pain conditions. " +"Background: Although the three vaccines against coronavirus disease 2019 (Covid-19) that have received emergency use authorization in the United States are highly effective, breakthrough infections are occurring. Data are needed on the serial use of homologous boosters (same as the primary vaccine) and heterologous boosters (different from the primary vaccine) in fully vaccinated recipients. Methods: In this phase 1-2, open-label clinical trial conducted at 10 sites in the United States, adults who had completed a Covid-19 vaccine regimen at least 12 weeks earlier and had no reported history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection received a booster injection with one of three vaccines: mRNA-1273 (Moderna) at a dose of 100 ?g, Ad26.COV2.S (Johnson & Johnson-Janssen) at a dose of 5�1010 virus particles, or BNT162b2 (Pfizer-BioNTech) at a dose of 30 ?g. The primary end points were safety, reactogenicity, and humoral immunogenicity on trial days 15 and 29. Results: Of the 458 participants who were enrolled in the trial, 154 received mRNA-1273, 150 received Ad26.COV2.S, and 153 received BNT162b2 as booster vaccines; 1 participant did not receive the assigned vaccine. Reactogenicity was similar to that reported for the primary series. More than half the recipients reported having injection-site pain, malaise, headache, or myalgia. For all combinations, antibody neutralizing titers against a SARS-CoV-2 D614 G pseudovirus increased by a factor of 4 to 73, and binding titers increased by a factor of 5 to 55. Homologous boosters increased neutralizing antibody titers by a factor of 4 to 20, whereas heterologous boosters increased titers by a factor of 6 to 73. Spike-specific T-cell responses increased in all but the homologous Ad26.COV2.S-boosted subgroup. CD8+ T-cell levels were more durable in the Ad26.COV2.S-primed recipients, and heterologous boosting with the Ad26.COV2.S vaccine substantially increased spike-specific CD8+ T cells in the mRNA vaccine recipients. Conclusions: Homologous and heterologous booster vaccines had an acceptable safety profile and were immunogenic in adults who had completed a primary Covid-19 vaccine regimen at least 12 weeks earlier.","The three vaccines against coronavirus disease 2019 (Covid-19) work well and fewer vaccinated people get sick. Breakthrough infections still sometimes happen, which means vaccinated people may get sick. We need data on the use of the same booster and boosters that are different from the primary vaccine in fully vaccinated people. In this clinical trial, fully vaccinated adults with no reported history of COVID-19 infection got a booster injection at least 12 weeks after the primary vaccination. They got one of the three vaccines: Moderna, Johnson & Johnson-Janssen, or Pfizer. On trial days 15 and 29 they were checked for booster safety, signs of the body�s response to the vaccine, and ability to build up protection against the COVID-19 virus. 458 people participated in the trial. 154 got Moderna, 150 got Johnson & Johnson, and 153 got Pfizer. Signs of the body�s response to the booster were similar to the primary vaccine. More than half had injection-site pain, general discomfort, headache, or muscle aches. All boosters increased the body's ability to protect itself against the SARS-CoV-2 virus from 4-fold to over 70-fold. The numbers of the antibodies that protect against COVID-19 increased from 5-fold to over 50-fold. Using the same vaccine for the boosters increased the protection up to 20-fold, but using a different vaccine increased the protection more. All boosters, except for Johnson & Johnson, increased the body's ability to protect itself agains the spike that the virus uses to get into the body cells. The Johnson & Johnson booster increased the number of cells that block the virus spike in people who were vaccinated with Moderna or Pfizer. All boosters were safe and increased protection against Covid-19 in adults who were fully vaccinated at least 12 weeks earlier." +"Background: The humoral immune response after primary immunisation with a SARS-CoV-2 vector vaccine (AstraZeneca AZD1222, ChAdOx1 nCoV-19, Vaxzevria) followed by an mRNA vaccine boost (Pfizer/BioNTech, BNT162b2; Moderna, m-1273) was examined and compared with the antibody response after homologous vaccination schemes (AZD1222/AZD1222 or BNT162b2/BNT162b2). Methods: Sera from 59 vaccinees were tested for anti-SARS-CoV-2 immunoglobulin G (IgG) and virus-neutralising antibodies (VNA) with three IgG assays based on (parts of) the SARS-CoV-2 spike (S)-protein as antigen, an IgG immunoblot (additionally contains the SARS-CoV-2 nucleoprotein (NP) as an antigen), a surrogate neutralisation test (sVNT), and a Vero-cell-based virus-neutralisation test (cVNT) with the B.1.1.7 variant of concern (VOC; alpha) as antigen. Investigation was done before and after heterologous (n = 30 and 42) or homologous booster vaccination (AZD1222/AZD1222, n = 8/9; BNT162b2/BNT162b2, n = 8/8). After the second immunisation, a subgroup of 26 age- and gender-matched sera (AZD1222/mRNA, n = 9; AZD1222/AZD1222, n = 9; BNT162b2/BNT162b2, n = 8) was also tested for VNA against VOC B.1.617.2 (delta) in the cVNT. The strength of IgG binding to separate SARS-CoV-2 antigens was measured by avidity. Results: After the first vaccination, the prevalence of IgG directed against the (trimeric) SARS-CoV-2 S-protein and its receptor binding domain (RBD) varied from 55-95% (AZD1222) to 100% (BNT162b2), depending on the vaccine regimen and the SARS-CoV-2 antigen used. The booster vaccination resulted in 100% seroconversion and the occurrence of highly avid IgG, which is directed against the S-protein subunit 1 and the RBD, as well as VNA against VOC B.1.1.7, while anti-NP IgGs were not detected. The results of the three anti-SARS-CoV-2 IgG tests showed an excellent correlation to the VNA titres against this VOC. The agreement of cVNT and sVNT results was good. However, the sVNT seems to overestimate non- and weak B.1.1.7-neutralising titres. The anti-SARS-CoV-2 IgG concentrations and the B.1.1.7-neutralising titres were significantly higher after heterologous vaccination compared to the homologous AZD1222 scheme. If VOC B.1.617.2 was used as antigen, significantly lower VNA titres were measured in the cVNT, and three (33.3%) vector vaccine recipients had a VNA titre < 1:10. Conclusions: Heterologous SARS-CoV-2 vaccination leads to a strong antibody response with anti-SARS-CoV-2 IgG concentrations and VNA titres at a level comparable to that of a homologous BNT162b2 vaccination scheme. Irrespective of the chosen immunisation regime, highly avid IgG antibodies can be detected just 2 weeks after the second vaccine dose indicating the development of a robust humoral immunity. The reduction in the VNA titre against VOC B.1.617.2 observed in the subgroup of 26 individuals is remarkable and confirms the immune escape of the delta variant.","We studied how the immune system responds to Pfizer or Moderna booster after AstraZeneca COVID-19 vaccination. We compared these cross-vaccine boosters to using the same boosters as the original vaccine: AstraZeneca or Pfizer. We tested the blood of 59 vaccinated people for its ability to neutralize the SARS-CoV-2 virus and for the chemicals the body produced to fight the virus. The blood was tested before and after the booster vaccine was given. After the first vaccine, chemicals against the parts of the virus that damage human cells ranged from 55-95% for AstraZeneca to 100% for Pfizer. After the boosters, the blood developed highly effective chemicals that block the parts of the virus that damage human cells. Vaccination with different boosters caused the blood to produce more anti-COVID-19 chemicals that boosting with the same AstraZeneca vaccine. Boosting with different vaccines strongly protects against COVID-19 at about the same level as boosting with the same original Pfizer vaccine. All vaccines caused the blood to develop strong protection 2 weeks after the second vaccine dose. The protection against the delta variant of COVID-19 was not as strong in the 26 people in whom it was measured." +"Rationale for review: Heterologous prime-boost doses of COVID-19 vaccines ('mix-and-match' approach) are being studied to test for the effectiveness of Oxford (AZD1222), Pfizer (BNT162b2), Moderna (mRNA-1273) and Novavax (NVX-CoV2373) vaccines for COVID in 'Com-Cov2 trial' in UK, and that of Oxford and Pfizer vaccines in 'CombivacS trial' in Spain. Later, other heterologous combinatios of CoronaVac (DB15806), Janssen (JNJ-78436735), CanSino (AD5-nCOV), and other were also being trialed to explore their effectiveness. Previously, such a strategy was deployed for HIV, Ebola virus, malaria, tuberculosis, influenza, and hepatitis B to develop the artificial acquired active immunity. The present review explores the science behind such an approach for candidate COVID-19 vaccines developed using eleven different platforms approved by the World Health Organization. Key findings: The candidate vaccines' pharmaceutical parameters (e.g. platforms, number needed to vaccinate and intervals, adjuvanted status, excipients and preservatives added, efficacy and effectiveness, vaccine adverse events, and boosters), and clinical aspects must be analysed for the mix-and-match approach. Heterologous prime-boost trials showed safety, effectiveness, higher systemic reactogenicity, well tolerability with improved immunogenicity, and flexibility profiles for future vaccinations, especially during acute and global shortages, compared to the homologous counterparts. Conclusions/recommendations. Still, large controlled trials are warranted to address challenging variants of concerns including Omicron and other, and to generalize the effectiveness of the approach in regular as well as emergency use during vaccine scarcity.","�Mix-and-match� boosters against COVID-19 are being studied in UK and Spain using Oxford, Pfizer, Moderna and Novavax vaccines. Other combinations of CoronaVac, Janssen, and CanSino are also being tested. The �mix-and-match� strategy has been used before to develop body protection against other diseases. We will try to understand why this approach might work for COVID-19. To study the mix-and-match approach, we look at how the different vaccines work, the chemicals in the vaccines and their side effects. The mix-and-match strategy is safe, improves body protection and allows to deal with vaccine shortages. " +"Background: Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer-BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax). Methods: Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8-12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0�63 for the one-sided 98�75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311. Findings: Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9�4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10�2 (one-sided 98�75% CI 8�4 to ?) for ChAd/m1273 and 2�8 (2�2 to ?) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1�3 (one-sided 98�75% CI 1�1 to ?) for BNT/m1273 and 0�5 (0�4 to ?) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation. Interpretation: Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification.","It is important to have flexibility in using different COVID-19 vaccines for additional doses. We studied mixing AstraZeneca, Pfizer, Moderna and Novavax, which work differently. In this clinical trial, adults aged 50 years and older who received the first dose of AstraZeneca or Pfizer vaccine got a second dose of the same vaccine or Moderna or Novavax 8-12 weeks after the first dose. 28 days after the second dose, chemicals the body produces to protect itself against COVID-19 were measured in the blood. These people did not have these chemicals before the study. We also studied safety of the vaccines. 1072 people participated in the study 9.4 weeks after getting the first vaccine. 540 people got the first dose of AstraZeneca and 532 got Pfizer. There were somewhat more men than women in both groups. 28 days after the boosters, all people who had the first AstraZeneca vaccine had an increased number of chemicals against COVID-19 in their blood for all boosters. In people who had the Pfizer vaccine first, getting a Pfizer or Moderna booster increased the chemicals the most. Novavax also increased the amount of anti-COVID-19 chemicals, but not as much as the other boosters. 15 people had serious problems, but the problems were not caused by the vaccine. Getting a Moderna dose after AstraZeneca or Pfizer first vaccines temporarily increased protection against COVID-19 more than getting the same second vaccine. Novavax did not work the same way. Many vaccines can be used as the second dose after getting the first dose of AstraZeneca or Pfizer. This should help distributing vaccines around the world. " +"Background: While Coronavirus disease 2019 (Covid-19) vaccines are highly effective, breakthrough infections are occurring. Booster vaccinations have recently received emergency use authorization (EUA) for certain populations but are restricted to homologous mRNA vaccines. We evaluated homologous and heterologous booster vaccination in persons who had received an EUA Covid-19 vaccine regimen. Methods: In this phase 1/2 open-label clinical trial conducted at ten U.S. sites, adults who received one of three EUA Covid-19 vaccines at least 12 weeks prior to enrollment and had no reported history of SARS-CoV-2 infection received a booster injection with one of three vaccines (Moderna mRNA-1273 100-?g, Janssen Ad26.COV2.S 5�10 10 virus particles, or Pfizer-BioNTech BNT162b2 30-?g; nine combinations). The primary outcomes were safety, reactogenicity, and humoral immunogenicity on study days 15 and 29. Results: 458 individuals were enrolled: 154 received mRNA-1273, 150 received Ad26.CoV2.S, and 153 received BNT162b2 booster vaccines. Reactogenicity was similar to that reported for the primary series. Injection site pain, malaise, headache, and myalgia occurred in more than half the participants. Booster vaccines increased the neutralizing activity against a D614G pseudovirus (4.2-76-fold) and binding antibody titers (4.6-56-fold) for all combinations; homologous boost increased neutralizing antibody titers 4.2-20-fold whereas heterologous boost increased titers 6.2-76-fold. Day 15 neutralizing and binding antibody titers varied by 28.7-fold and 20.9-fold, respectively, across the nine prime-boost combinations. Conclusion: Homologous and heterologous booster vaccinations were well-tolerated and immunogenic in adults who completed a primary Covid-19 vaccine regimen at least 12 weeks earlier.","Coronavirus disease 2019 vaccines protect against Covid-19 well, but some vaccinated people may get sick, which is called breakthrough infections. Boosters with the same Pfizer or Moderna vaccines are approved as an emergency measure for some people. We evaluated boosters with the same and different vaccines in people who got the emergency Covid-19 vaccination. In this clinical trial, adults in ten U.S. locations got Moderna, Janssen or Pfizer boosters at least 12 weeks after getting the first vaccine. We evaluated the vaccine safety and protection against COVID-19 on study days 15 and 29. Out of 458 people, 154 got Moderna, 150 got Janssen and 153 got Pfizer boosters. Adverse reactions to the booster were similar to those reported for the first vaccine. More than half of the participants had pain at the injection site, overall weakness, headache, and muscle pains. Boosters with the same and different vaccines increased protection against the virus. The increase in protection after a different booster was higher. Boosters with the same and different vaccines were well-tolerated and increased protection against COVID-19 in adults who had the first vaccine at least 12 weeks earlier." +"Background: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer-BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. Methods: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97�5% CI of the GMR of these comparisons was greater than 0�63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. Findings: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57�8 years (SD 4�7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9�2 (one-sided 97�5% CI 7�5 to ?). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0�51 (one-sided 97�5% CI 0�43 to ?). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. Interpretation: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines.","Boosters that are not of the same type as the first COVID-19 vaccine can make global COVID-19 immunization easier. However, we know that getting AstraZeneca and Pfizer 4 weeks apart causes more side effects than getting the same vaccine. We report the safety and protective strength of different ways to combine AstraZeneca and Pfizer vaccines. Healthy adults aged 50 years and older that did not have COVID-19 participated in a clinical trial. Most participants got two doses of AstraZeneca or Pfizer or a combination of Pfizer/AstraZeneca or AstraZeneca/Pfizer 28 or 84 days apart. 100 of the participants that had the vaccines 28 days apart was checked for the protective chemicals in the blood more often. Participants did not know which vaccines they got. 28 days after boost, chemicals that fight the SARS-CoV-2 virus were measured in patients' blood. Different-vaccine boosters were considered to be as good as the same-vaccine if the increase in the protective chemicals after the booster was the same or higher for the different vaccines. Protection against COVID-19 was measured in all participants. Safety of the vaccine was measured among participants that had at least one dose of the vaccine. For 463 participants with 28 days between the first vaccine and the booster, the results are reported here. The participants were 54 to 65 years old. About half (212) were women and a quarter (117) were from ethnic minorities. 28 days after the booster, in people who got boosted with Pfizer after AstraZeneca, protection against the SARS-CoV-2 virus was not worse than in those who got the same AstraZeneca booster. Boosting with AstraZeneca after Pfizer was not as good as getting the second dose of the same Pfizer vaccine. Four people had serious health problems during the trial. The problems were not related to getting the vaccines. Although getting AstraZeneca after Pfizer was not as good as getting only Pfizer or Pfizer after AstraZeneca, there were still more protective chemicals against SARS-CoV-2 in the blood compared to getting only AstraZeneca. Getting only AstraZeneca is known to protect against COVID-19 and hospitalization. This trial supports using boosters that are not the same as the first COVID-19 vaccine." +"Reports of waning antibody levels and breakthrough infections among vaccinated individuals1 have prompted the recommendation for vaccine boosters to prevent SARS-CoV-2 infections. Despite more than 80% of the population in Singapore having received 2 doses of a COVID-19 vaccine, cases surged in September 2021 with the relaxation of social distancing and quarantine measures. In response, adults 60 years and older who completed their primary vaccination series at least 6 months prior were invited to receive a booster injection and given a choice of either 30-?g BNT162b2 (Pfizer-BioNTech) or 50-?g mRNA-1273 (Moderna). We estimated SARS-CoV-2 infections and disease severity with the receipt of a booster and by type of booster. Methods: This study was carried out under the Infectious Diseases Act for policy decision-making and exempted from ethical review and informed consent by the Singapore Ministry of Health. Rates and severity of SARS-CoV-2 infections between September 15 and October 31, 2021, among those eligible to receive vaccine boosters between September 15 and October 15, 2021, were analyzed based on official data reported to the Singapore Ministry of Health. Cases were identified through testing of symptomatic individuals and nonsymptomatic high-risk workers and close contacts. Outcomes included polymerase chain reaction�confirmed infections and severe disease (requiring oxygen supplementation, intensive care admission, or death due to COVID-19). Individuals were classified under the booster group 12 days after receiving a vaccine booster and under the nonbooster group otherwise to account for time required for antibody levels to rise. Person-days at risk were reported because individuals could contribute observations to both the nonbooster and booster groups. Using a Poisson regression, we estimated the incidence rate ratio (IRR) of confirmed infections and severe disease between booster and nonbooster groups by type of vaccine received for the primary series (BNT162b2 or mRNA-1273). Covariates included sex, race (4 official racial categories reported in Singapore are Chinese, Malay, Indian, and others and registered at birth according to the child�s parents� race), housing type as a marker of socioeconomic status, age group, date of second vaccine dose to account for possible waning of immunity, and individual dummy variables for calendar date to adjust for the varying force of infection over the study period (eMethods in the Supplement). We obtained IRRs for individuals receiving the same vaccine as a booster (homologous boosted) and those receiving a different vaccine (heterologous boosted). Data analysis was carried out in Stata version 17.0 (StataCorp LLC) and a 2-sided P value less than .05 was considered statistically significant. Results: Among 703?209 eligible individuals during the study period, 576?132 received boosters. The study included 22?643?521 and 9?339?981 person-days among the nonbooster and booster groups, respectively. By person-days, 59% were 60 to 69 years, 29% were 70 to 79 years, and 11% were aged 80 years and older, with 53% being female. Among individuals who received BNT162b2 for their primary series, the incidences (per million person-days) of confirmed and severe infections were 227.9 and 1.4 for the homologous boosted compared with 600.4 and 20.5 for the nonboosted. The IRRs were 0.272 (95% CI, 0.258-0.286) for the confirmed cases among the homologous-boosted individuals and 0.047 (95% CI, 0.026-0.084) for severe cases (Table). For the heterologous-boosted individuals, the incidences of confirmed and severe infections were 147.9 and 2.3 cases per million person-days, respectively, with IRRs of 0.177 (95% CI, 0.138-0.227) and 0.078 (95% CI, 0.011-0.560). For individuals who received mRNA-1273 for their primary series, the incidence of confirmed infections for the homologous boosted was 133.9 cases per million person-years (IRR, 0.198 [95% CI, 0.144-0.271]). For heterologous-boosted individuals, the incidence of confirmed infections was 100.6 per million person-days (IRR, 0.140 [95% CI, 0.052-0.376]). The number of severe infections among individuals receiving mRNA-1273 for their primary series was too small to assess IRRs. Discussion: Heterologous boosting was associated with lower SARS-CoV-2 incidence rates than homologous boosting. Severe infections were lower among those receiving a booster after BNT162b2 as the primary series compared with the nonboosted individuals, regardless of the type of booster. Limitations of the study include potential confounding from unobservable individual characteristics that may influence individuals� choice of booster, a short follow-up period, small numbers of infections after mRNA-1273 administration, and lack of data from younger age groups. The study results support recommendations for vaccine boosters and suggest that heterologous boosting may provide greater protection against COVID-19.","Boosters to prevent SARS-CoV-2 infections in those who had the first vaccines are needed because the amount of body substances that protect against the virus goes down and people get COVID-19, which is called breakthrough infections. Although 80 out of 100 people in Singapore had 2 doses of a COVID-19 vaccine, COVID-19 surged in September 2021 as the social distancing and quarantine rules were relaxed. Adults 60 years and older who got the first vaccine at least 6 months before were invited to get a booster of Pfizer or Moderna. We estimated SARS-CoV-2 infections and disease severity after getting a booster and by type of booster. Rates and severity of SARS-CoV-2 infections between September 15 and October 31, 2021, among those eligible to receive vaccine boosters were studied. COVID-19 patients were found through testing of those with symptoms and high-risk workers and close contacts without symptoms. We measured infections confirmed by tests and severe disease (requiring oxygen support, intensive care admission, or death due to COVID-19). People who got the boosters 12 days before were included in the booster group, and non-booster group otherwise. Depending on the day of observation, a person could be in either group. We estimated getting infected and severe disease between booster and non-booster groups that got the first vaccination with Pfizer or Moderna. We accounted for the patients' sex, race, housing type, age, and the date of second vaccine that may be related to the strength of protection. We observed the rate of infection in those who got the same booster as the first vaccine and a different vaccine as booster. Out of 703,209 people who were allowed to have a booster during the study, 576,132 got boosters. More than half of the people were 60 to 69 years old, a third 70 to 79 years, and a tenth of the people were 0 years and older. Slightly more than half of the people were women. Among those for whom the first vaccine and the booster was Pfizer, about 230 people got COVID-19 and about 2 had severe disease. Among those who had the first Pfizer vaccine but no booster, 600 got COVID-19 and 20 had severe disease. Among those who had a different booster, about 150 people got COVID-19 and about 2 had severe disease. Among those who had Moderna as their first vaccine and booster, about 134 got COVID-19. Among those who first had Moderna and then a Pfizer booster, about 100 had COVID-19. The number of severe infections among those who had Moderna as the first vaccine was too small to count. People who got different boosters had less COVID-19 infections than those boosted with the same vaccine as the first. People who first had Pfizer and then any booster had less severe disease than those who did not have boosters. This study has limitations, such as not knowing why people decided for or against boosters, short time between the booster and the study, and no data from younger age groups. The study supports having vaccine boosters. Boosting with different vaccines may provide greater protection against COVID-19." +"Background: Heterologous vaccinations against SARS-CoV-2 with ChAdOx1 nCoV-19 and a second dose of an mRNA-based vaccine have been shown to be more immunogenic than homologous ChAdOx1 nCoV-19. In the current study, we examined the kinetics of the antibody response to the second dose of three different vaccination regimens (homologous ChAdOx1 nCoV-19 vs. ChAdOx1 nCoV-19 + BNT162b2 or mRNA-1273) against SARS-CoV-2 in a longitudinal manner; whether there are differences in latency or amplitude of the early response and which markers are most suitable to detect these responses. Methods: We performed assays for anti-S1 IgG and IgA, anti-NCP IgG and a surrogate neutralization assay on serum samples collected from 57 participants on the day of the second vaccination as well as the following seven days. Results: All examined vaccination regimens induced detectable antibody responses within the examined time frame. Both heterologous regimens induced responses earlier and with a higher amplitude than homologous ChAdOx1 nCoV-19. Between the heterologous regimens, amplitudes were somewhat higher for ChAdOx1 nCoV-19 + mRNA-1273. There was no difference in latency between the IgG and IgA responses. Increases in the surrogate neutralization assay were the first changes to be detectable for all regimens and the only significant change seen for homologous ChAdOx1 nCoV-19. Discussion: Both examined heterologous vaccination regimens are superior in immunogenicity, including the latency of the response, to homologous ChAdOx1 nCoV-19. While the IgA response has a shorter latency than the IgG response after the first dose, no such difference was found after the second dose, implying that both responses are driven by separate plasma cell populations. Early and steep increases in surrogate neutralization levels suggest that this might be a more sensitive marker for antibody responses after vaccination against SARS-CoV-2 than absolute levels of anti-S1 IgG.",Getting a Pfizer or Moderna booster after the AstraZeneca vaccine protects against COVID-19 better than getting the same AstraZeneca booster. We studied how a booster with the same AstraZeneca or a different Pfizer or Moderna vaccine protects against COVID-19 over time. We analyzed chemicals that protect against COVID-19 in the blood of 57 people on the day of the second vaccination and the following seven days. All boosters increased the protective chemicals in the blood. Different boosters had earlier and stronger protection than boosting with the same AstraZeneca vaccine. People who had Moderna booster after the first AstraZeneca vaccine had more protective chemicals than those who got Pfizer. The body produced different protective chemicals at the same time. The different boosters were more protective than the same AstraZeneca booster. +"Introduction: The vital renal replacement therapy makes it impossible for dialysis patients to distance themselves socially. This results in a high risk of SARS-CoV-2 infection and developing COVID-19 with excess mortality due to disease burden and immunosuppression. We determined the efficacy of a 100 �g booster of mRNA-1273 (Moderna, Inc., Cambridge, Massachusetts, USA) 6 months after two doses of BNT162b2 (BioNTech/Pfizer, Mainz, Germany/New York, NY, USA) in 194 SARS-CoV-2 na�ve dialysis patients. Methods: Anti-SARS-CoV-2-spike antibodies were measured with the Elecsys� Anti-SARS-CoV-2 S assay (Roche Diagnostics GmbH, Germany) 4 and 10-12 weeks after two doses of BNT162b2 as well as 4 weeks after the mRNA-1273 booster. The presence of neutralizing antibodies was measured by the SARS-CoV-2 Surrogate Virus Neutralization Test (GenScript Biotech, USA). Two different cut-offs for positivity were used, one according to the manufacturer's specifications and one correlating with positivity in a plaque reduction neutralization test (PRNT). ROC analyses were performed to match the anti-SARS-CoV-2-spike antibody cut-offs with the cut-offs in the surrogate neutralization assay accordingly. Results: Any level of immunoreactivity determined by anti-SARS-CoV-2-spike antibody assay was found in 87.3% (n = 144/165) and 90.6% (n = 164/181) 4 and 10-12 weeks after two doses of BNT162b2. This was reduced to 68.5% or 60.6% 4 weeks and 51.7% or 35.4% 10-12 weeks, respectively, when using the ROC revealed cut-offs for neutralizing antibodies in the surrogate neutralization test (manufacturer given cut-off ? 103 U/ml and cut-off correlating with PRNT ? 196 U/ml). Four weeks after the mRNA-1273 booster, the concentration of anti-SARS-CoV-2-spike antibodies increased to 23 119.9 U/ml and consecutively to 97.3% for both cut-offs of neutralizing antibodies. Conclusion: Two doses of BNT162b2 followed by one dose of mRNA-1273 within 6 months in patients receiving maintenance dialysis resulted in significant titers of SARS-CoV-2-S-Ab. While two doses of mRNA vaccine only achieved adequate humoral immunity in a minority, the third vaccination boosts the development of virus-neutralizing quantities of SARS-CoV-2 spike antibodies (against wild type SARS-CoV-2) in almost all patients.","Dialysis patients cannot distance themselves socially. They are at high risk of developing COVID-19 with high mortality. We studied Moderna boosters 6 months after two doses of Pfizer in 194 dialysis patients who did not have SARS-CoV-2 infection. We measured the chemicals that protect against the COVID-19 virus 4 weeks after Pfizer and Moderna boosters, and also 10-12 weeks after Pfizer Protective chemicals were found in about 9 out of 10 people 4 and 10-12 weeks after two doses of Pfizer. Looking at different protective thresholds, protection was reduced to 7 out of 10 after 4 weeks and around half after 10-12 weeks. For Moderna, almost all people had strong protection after 4 weeks. People on dialysis who were vaccinated with Pfizer and got Moderna booster within the next 6 month had significant protection against the COVID-19 virus. While the first two doses of Moderna or Pfizer vaccine gave adequate protection to some patients, the booster increased protection against the COVID-19 virus in almost all patients." +"In Spain, 1.5 million essential < 60-year-old workers were vaccinated with a first AstraZeneca vaccine dose. After assessing the cases of thrombosis with thrombocytopenia associated to this vaccine, the European Medicines Agency (EMA) supported the administration of 2 doses of the AstraZeneca vaccine with no age restrictions. Nevertheless, Spain decided not to administer the second dose of this vaccine to < 60-year-olds. The government sponsored a clinical trial (CombiVacS) to assess the immunogenicity response to a Pfizer/BioNTech vaccine dose in adults primed with the AstraZeneca vaccine. The positive results backed the Public Health Commission and the Spanish Ministry of Health to offer the Pfizer/BioNTech vaccine as the booster. Nevertheless, regional public health authorities-responsible for administering vaccines-believed that, following the EMA's decision, an AstraZeneca booster dose should be given. The public confrontation of these 2 positions forced the Spanish Health Ministry to request the signature of an informed consent form to those individuals willing to receive the AstraZeneca vaccine booster and rejecting the Pfizer/BioNTech vaccine dose. Eventually, it was decided that these essential workers could choose the vaccine but signing an informed consent form. All relevant information was posted on the Ministry of Health and regional health authorities' websites and provided to potential vaccine recipients at vaccination sites. Most individuals (? 75%) chose the AstraZeneca vaccine: perhaps because they likely trusted the EMA more than the CombiVacS results. This unprecedented and massive exercise of individual autonomy about the choice of COVID-19 vaccines from 2 different platforms has shown that adequately informed persons can autonomously weigh their options, regardless of government decisions. Exercising individual autonomy may contribute to the success of future COVID-19 booster vaccination campaigns.","In Spain, 1.5 million essential workers under 60 years of age got a first AstraZeneca vaccine dose. Although this vaccine was associated with blood clots and reduction in blood cells, the European Medicines Agency recommended two doses of AstraZeneca for all ages. Spain decided not to give the second dose of this vaccine to people under 60 years old. The government sponsored a clinical trial to evaluate if a dose of Pfizer vaccine works in adults who first got the AstraZeneca vaccine. The positive results supported giving the Pfizer vaccine as the booster. Some local authorities decided to follow the recommendation that an AstraZeneca booster should be given. Because of these contradictions, the Spanish Health Ministry requested those who decide to get the AstraZeneca booster and decline Pfizer should sign an informed consent form. Later these essential workers could choose the vaccine but still sign an informed consent form. Relevant information was posted on the web and given to people at vaccination sites. Three quarters of people getting the vaccine chose AstraZeneca; maybe because they trusted the European Medicines Agency more. Giving people a choice may make future COVID-19 boosters more successful." +"We experienced a 72-year-old man who developed laboratory-confirmed human coronavirus HKU1 pneumonia. PCR testing for SARS-CoV-2 from a nasopharyngeal specimen was negative twice, and rapid immunochromatographic antibody test (RIAT) using a commercially available kit for IgM and IgG against SARS-CoV-2 showed him turning positive for IgG against SARS-CoV-2. We then performed RIAT in stored serum samples from other patients who suffered laboratory-confirmed human common cold coronaviruses (n = 6) and viruses other than coronavirus (influenza virus, n = 3; rhinovirus, n = 3; metapneumovirus, n = 1; adenovirus, n = 1) admitted until January 2019. Including the present case, four of 7 (57%) showed false-positive RIAT results due to human common cold coronaviruses infection. Two of the 4 patients showed initial negative to subsequent positive RIAT results, indicating seroconversion. RIAT was positive for IgG and IgM in viruses other than coronavirus in 2 (25.0%) and 1 (12.5%) patient. Because of high incidence of false positive RIAT results, cross antigenicity between human common cold coronaviruses and SARS-CoV-2 can be considered. Results of RIAT should be interpreted in light of epidemics of human common cold coronaviruses infection. Prevalence of past SARS-CoV-2 infection may be overestimated due to high incidence of false-positive RIAT results.","A 72-year-old man has a confirmed human coronavirus HKU1 pneumonia. His nasal swab test for COVID-19 virus was negative twice, but his antibody (chemicals the body produces to fight the virus) test was positive. We then did the antibody test on the stored blood of other patients who had confirmed viral infections, such as flu and common cold, before January 2019. Including the present case, four of 7 antibody test results were falsely positive for COVID-19. The high rate of the falsely positive antibody test results might be due to similarities between the human common cold coronaviruses and the SARS-CoV-2 virus that causes COVID-19. The results of the antibody tests may depend on epidemics of human common cold coronavirus infection. The spread of the past SARS-CoV-2 infections may be overestimated because of the falsely positive antibody test results." +"Background: Combating the COVID-19 pandemic is a major challenge for health systems, citizens and policy makers worldwide. Early detection of affected patients within the large and heterogeneous group of patients with common cold symptoms is an important element of this effort, but often hindered by limited testing resources, false-negative test results and the lack of pathognomonic symptoms in COVID-19. Therefore, we aimed to identify anamnestic items with an increased/decreased odds ratio for a positive SARS-CoV-2 PCR (CovPCR) result in a primary care setting. Methods: We performed a multi-center cross-sectional cohort study on predictive clinical characteristics for a positive CovPCR over a period of 4 weeks in primary care patients in Germany. Results: In total, 374 patients in 14 primary care centers received CovPCR and were included in this analysis. The median age was 44.0 (IQR: 31.0-59.0) and a fraction of 10.7% (n = 40) tested positive for COVID-19. Patients who reported anosmia had a higher odds ratio (OR: 4.54; 95%-CI: 1.51-13.67) for a positive test result while patients with a sore throat had a lower OR (OR: 0.33; 95%-CI: 0.11-0.97). Furthermore, patients who had a first grade contact with an infected persons and showed symptoms themselves also had an increased OR for positive testing (OR: 5.16; 95% CI: 1.72-15.51). This correlation was also present when they themselves were still asymptomatic (OR: 12.55; 95% CI: 3.97-39.67). Conclusions: Several anamnestic criteria may be helpful to assess pre-test probability of COVID-19 in patients with common cold symptoms."," It is hard to detect COVID-19 patients in a group of patients with common cold symptoms because there are no COVID-specific symptoms, there are not enough test supplies, and test results can be falsely negative in patients with COVID-19. We aim to find some strong signs in the COVID test results that show SARS-CoV-2 infection. We studied 374 patients who got rapid COVID tests. Patients were 31 to 59 years old, and one tenth of them had positive COVID-19 test results. Patients who lost their sense pf smell had a higher chance to test positive for COVID-19. Patients with a sore throat had a lower chance to test positive for COVID-19. Patients who had contact with an infected persons and had symptoms themselves also had an increased chance to test positive. Even if they did not have symptoms, these patients had higher chances to test positive. " +"Antigen-detecting rapid diagnostic tests (Ag-RDTs) can complement molecular diagnostics for COVID-19. The recommended temperature for storage of SARS-CoV-2 Ag-RDTs ranges between 2-30 �C. In the global South, mean temperatures can exceed 30 �C. In the global North, Ag-RDTs are often used in external testing facilities at low ambient temperatures. We assessed analytical sensitivity and specificity of eleven commercially-available SARS-CoV-2 Ag-RDTs using different storage and operational temperatures, including short- or long-term storage and operation at recommended temperatures or at either 2-4 �C or at 37 �C. The limits of detection of SARS-CoV-2 Ag-RDTs under recommended conditions ranged from 1.0�106- 5.5�107 genome copies/mL of infectious SARS-CoV-2 cell culture supernatant. Despite long-term storage at recommended conditions, 10 min pre-incubation of Ag-RDTs and testing at 37 �C resulted in about ten-fold reduced sensitivity for five out of 11 SARS-CoV-2 Ag-RDTs, including both Ag-RDTs currently listed for emergency use by the World Health Organization. After 3 weeks of storage at 37 �C, eight of the 11 SARS-CoV-2 Ag-RDTs exhibited about ten-fold reduced sensitivity. Specificity of SARS-CoV-2 Ag-RDTs using cell culture supernatant from common respiratory viruses was not affected by storage and testing at 37 �C, whereas false-positive results occurred at outside temperatures of 2-4 �C for two out of six tested Ag-RDTs, again including an Ag-RDT recommended by the WHO. In summary, elevated temperatures impair sensitivity, whereas low temperatures impair specificity of SARS-CoV-2 Ag-RDTs. Consequences may include false-negative test results at clinically relevant virus concentrations compatible with transmission and false-positive results entailing unwarranted quarantine assignments. Storage and operation of SARS-CoV-2 Ag-RDTs at recommended conditions is essential for successful usage during the pandemic.","Rapid diagnostic tests can support other COVID-q9 tests. Rapid covid tests could be refrigerated or stored at room temperature under 30 degrees C (86 Fahrenheit) We tested the accuracy of eleven rapid COVID tests that were stored and used at different temperatures. The tests were stored for a short or long time at recommended temperatures or at either 2-4 degrees C (35-39 Fahrenheit) or at 37 degrees C (98-99 Fahrenheit). The tests were stored for a long-term at recommended temperatures and then at the high temperature (37C) for 10 minutes. For five out of 11 rapid tests, the accuracy was reduced ten-fold. After 3 weeks of storage at high temperature (37 C), eight of the 11 rapid tests were ten-fold less accurate. Two out of six rapid tests had false positive results at low temperatures (2-4 degrees C). In summary, high temperatures reduced how well the test identified people who had COVID-19 and low temperatures caused false positive results, showing people who did not have COVID-19 as having it. The false negative test results allow people who have the virus transmit it to others. Due to the false-positive results healthy people will be quarantined. Storing the rapid tests at recommended temperatures is important during the pandemic." +"Background: COVID-19 is an ongoing public health pandemic regardless of the countless efforts made by various actors. Quality diagnostic tests are important for early detection and control. Notably, several commercially available one step RT-PCR based assays have been recommended by the WHO. Yet, their analytic and diagnostic performances have not been well documented in resource-limited settings. Hence, this study aimed to evaluate the diagnostic sensitivities and specificities of three commercially available one step reverse transcriptase-polymerase chain reaction (RT-PCR) assays in Ethiopia in clinical setting. Methods: A cross-sectional study was conducted from April to June, 2021 on 279 respiratory swabs originating from community surveillance, contact cases and suspect cases. RNA was extracted using manual extraction method. Master-mix preparation, amplification and result interpretation was done as per the respective manufacturer. Agreements between RT-PCRs were analyzed using kappa values. Bayesian latent class models (BLCM) were fitted to obtain reliable estimates of diagnostic sensitivities, specificities of the three assays and prevalence in the absence of a true gold standard. Results: Among the 279 respiratory samples, 50(18%), 59(21.2%), and 69(24.7%) were tested positive by TIB, Da An, and BGI assays, respectively. Moderate to substantial level of agreement was reported among the three assays with kappa value between 0 .55 and 0.72. Based on the BLCM relatively high specificities (95% CI) of 0.991(0.973-1.000), 0.961(0.930-0.991) and 0.916(0.875-0.952) and considerably lower sensitivities with 0.813(0.658-0.938), 0.836(0.712-0.940) and 0.810(0.687-0.920) for TIB MOLBIOL, Da An and BGI respectively were found. Conclusions: While all the three RT-PCR assays displayed comparable sensitivities, the specificities of TIB MOLBIOL and Da An were considerably higher than BGI. These results help adjust the apparent prevalence determined by the three RT-PCRs and thus support public health decisions in resource limited settings and consider alternatives as per their prioritization matrix.","COVID-19 is an ongoing public health pandemic. Quality diagnostic tests are important for early detection and control. The World Health Organization (WHO) recommends some tests that detect COVID-19 virus. But we do not know how accurate these tests are. This study estimates accuracy of three commercial rapid tests in a clinical setting in Ethiopia From April to June 2021 we got 279 nasal swabs from community testing, contact cases and suspected cases. Among the 279 respiratory samples, 50, 59, and 69 tested positive by the three tests. The tests agreed ranging from moderate to strong agreement. The tests accurately recognized people that did not have COVID (91 to 99 out of 100), but had more mistakes identifying people who had COVID, only 81 to 83 out of 100 sick people were found. All three tests were almost equal in identifying people with COVID-19, but one test was worse than the other two in identifying people without the disease. " +"To investigate endogenous interference factors of the detection results of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM/IgG. Enzyme-linked immunosorbent assay (ELISA) was used to detect SARS-CoV-2 IgM/IgG in sera of 200 patients without COVID-19 infection, including rheumatoid factor (RF) positive group, antinuclear antibody (ANA) positive group, pregnant women group, and normal senior group, with 50 in each group and 100 normal controls. The level of SARS-CoV-2 IgG in pregnant women was significantly higher than that in the normal control group (p = 0.000), but there was no significant difference between other groups. The levels of SARS-CoV-2 IgM in the pregnant women group, normal senior group, ANA positive group, and RF positive group were significantly higher than that in the normal control group (p < 0.05), with significant higher false-positive rates in these groups (p = 0.036, p = 0.004, p = 0.000, vs. normal control group). Serum RF caused SARS-CoV-2 IgM false-positive in a concentration-dependent manner, especially when its concentration was higher than 110.25 IU/L, and the urea dissociation test can turn the false positive to negative. ANA, normal seniors, pregnant women, and RF can lead to false-positive reactivity of SARS-CoV-2 IgM and/or IgG detected using ELISA. These factors should be considered when SARS-CoV-2 IgM or IgG detection is positive, false positive samples caused by RF positive can be used for urea dissociation test.","Our aim is to find what could cause wrong COVID-19 test results. Blood of 200 patients without COVID-19 infection was tested for proteins that protect against COVID-19 virus. 100 of the patients were healthy, the others had proteins that could attack their own bodies or proteins associated with pregnancy, 50 each. Pregnant women had more of the common anti-COVID protein, but all other groups had the same amounts. There was more anti-COVID protein the body makes when it fights a new infection in pregnant women, normal seniors, and people with proteins that attack their own body. These groups had significantly more false positive COVID test results. Some of the false positive tests caused by the protein that attack your own body can be turned into true negative by adding a chemical called urea to the test. False positive test results could be caused by pregnancy, old age and proteins that attack your own body. " +"At the start of the COVID-19 pandemic, the Centers for Disease Control and Prevention (CDC) designed, manufactured, and distributed the CDC 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel for SARS-CoV-2 detection. The diagnostic panel targeted three viral nucleocapsid gene loci (N1, N2, and N3 primers and probes) to maximize sensitivity and to provide redundancy for virus detection if mutations occurred. After the first distribution of the diagnostic panel, state public health laboratories reported fluorescent signal in the absence of viral template (false-positive reactivity) for the N3 component and to a lesser extent for N1. This report describes the findings of an internal investigation conducted by the CDC to identify the cause(s) of the N1 and N3 false-positive reactivity. For N1, results demonstrate that contamination with a synthetic template, that occurred while the ""bulk"" manufactured materials were located in a research lab for quality assessment, was the cause of false reactivity in the first lot. Base pairing between the 3' end of the N3 probe and the 3' end of the N3 reverse primer led to amplification of duplex and larger molecules resulting in false reactivity in the N3 assay component. We conclude that flaws in both assay design and handling of the ""bulk"" material, caused the problems with the first lot of the 2019-nCoV Real-Time RT-PCR Diagnostic Panel. In addition, within this study, we found that the age of the examined diagnostic panel reagents increases the frequency of false positive results for N3. We discuss these findings in the context of improvements to quality control, quality assurance, and assay validation practices that have since been improved at the CDC.","At the start of the COVID-19 pandemic, the Centers for Disease Control and Prevention (CDC) designed, provides rapid test for detecting SARS-CoV-2 virus that causes the disease. The tests target different parts of the virus in case some parts of the virus change (mutate). Parts of the test that target two specific parts of the virus may show false positive results -- identify people that do not have the virus as having it. We report the results of the CDC analysis of the false positive tests.. One part of the test that targeted one part of the virus was tainted with the material similar to that part when the test was produced, which caused false positive results. In another component of the test, some chemicals interacted with each other and caused false positive results. We conclude that the first batch of CDC rapid tests had problems with the design of the test and manufacturing. We found that the tests that were stored longer gave more false positive results. After our study, CDC improved quality control and procedures for checking accuracy of the tests. " +"The aim was to determine the accuracy of anterior nasal swab in rapid antigen (Ag) tests in a low SARS-CoV-2 prevalence and massive screened community. Individuals, aged 18 years or older, who self-booked an appointment for real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test in March 2021 at a public test center in Copenhagen, Denmark were included. An oropharyngeal swab was collected for RT-PCR testing, followed by a swab from the anterior parts of the nose examined by Ag test (SD Biosensor). Accuracy of the Ag test was calculated with RT-PCR as reference. We included 7074 paired conclusive tests (n = 3461, female: 50.7%). The median age was 48 years (IQR: 36-57 years). The prevalence was 0.9%, that is, 66 tests were positive on RT-PCR. Thirty-two had a paired positive Ag test. The sensitivity was 48.5% and the specificity was 100%. This study conducted in a low prevalence setting in a massive screening set-up showed that the Ag test had a sensitivity of 48.5% and a specificity of 100%, that is, no false positive tests. The lower sensitivity is a challenge especially if Ag testing is not repeated frequently allowing this scalable test to be a robust supplement to RT-PCR testing in an ambitious public SARS-CoV-2 screening.","We aim to find out how accurate the nasal swabs for rapid COVID-19 tests are in a large community with low rates of disease. Study participants were 18 years and older. They had an appointment for COVID-19 test in March 2021 in Copenhagen, Denmark. The swabs from their throat and nose were tested. We compared the accuracy of the rapid test using a nose swab to the throat test that used a tradiional testing method. We had 7074 paired reliable tests of which about half was for females. The age ranged from 36 to 57 years. 66 traditional throat tests (less than 1 percent) were positive. For 32 of these, the rapid nasal test was also positive. We did not have any false positive tests. Overlooking more than half of the patients with the disease is a problem. " +"Antigen-based rapid diagnostics tests (Ag-RDTs) are useful tools for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection. However, misleading demonstrations of the Abbott Panbio coronavirus disease 2019 (COVID-19) Ag-RDT on social media claimed that SARS-CoV-2 antigen could be detected in municipal water and food products. To offer a scientific rebuttal to pandemic misinformation and disinformation, this study explored the impact of using the Panbio SARS-CoV-2 assay with conditions falling outside manufacturer recommendations. Using Panbio, various water and food products, laboratory buffers, and SARS-CoV-2-negative clinical specimens were tested with and without manufacturer buffer. Additional experiments were conducted to assess the role of each Panbio buffer component (tricine, NaCl, pH, and Tween 20) as well as the impact of temperature (4�C, 20�C, and 45�C) and humidity (90%) on assay performance. Direct sample testing (without the kit buffer) resulted in false-positive signals resembling those obtained with SARS-CoV-2 positive controls tested under proper conditions. The likely explanation of these artifacts is nonspecific interactions between the SARS-CoV-2-specific conjugated and capture antibodies, as proteinase K treatment abrogated this phenomenon, and thermal shift assays showed pH-induced conformational changes under conditions promoting artifact formation. Omitting, altering, and reverse engineering the kit buffer all supported the importance of maintaining buffering capacity, ionic strength, and pH for accurate kit function. Interestingly, the Panbio assay could tolerate some extremes of temperature and humidity outside manufacturer claims. Our data support strict adherence to manufacturer instructions to avoid false-positive SARS-CoV-2 Ag-RDT reactions, otherwise resulting in anxiety, overuse of public health resources, and dissemination of misinformation. IMPORTANCE: With the Panbio severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen test being deployed in over 120 countries worldwide, understanding conditions required for its ideal performance is critical. Recently on social media, this kit was shown to generate false positives when manufacturer recommendations were not followed. While erroneous results from improper use of a test may not be surprising to some health care professionals, understanding why false positives occur can help reduce the propagation of misinformation and provide a scientific rebuttal for these aberrant findings. This study demonstrated that the kit buffer's pH, ionic strength, and buffering capacity were critical components to ensure proper kit function and avoid generation of false-positive results. Typically, false positives arise from cross-reacting or interfering substances; however, this study demonstrated a mechanism where false positives were generated under conditions favoring nonspecific interactions between the two antibodies designed for SARS-CoV-2 antigen detection. Following the manufacturer instructions is critical for accurate test results.","Rapid diagnostics tests are useful for detecting COVID-19 virus. Misleading demos of the rapid test on social media showed it can find COVID-19 virus in the tap water and food. To fight misleading information, we studied the results of the rapid tests that did not follow testing rules. We did the test in a wrong way on water, food, other liquids and samples without the COVID-19 virus. We also studied how different temperatures and humidity change test results. Doing the test wrong caused false positive results saying there is COVID-19 virus in the materials that did not have it. False results may happen because the parts of the test change if the test is done wrong. The test changed less in extremes of temperature and humidity. Our study supports strictly following the test instructions to reduce false positive results of COVID-19 rapid test. False positive results increase anxiety, overuse of public health resources, and spread of rumors. The Panbio rapid COVID-19 test that we studied is used in over 120 countries worldwide. It is very important to understand how to get accurate test results. Recently on social media, this kit was shown to generate false positives when manufacturer recommendations were not followed. Health professionals know that not doing the tests right causes errors in the results. Knowing what causes the errors will help them explain the errors and stop rumors. Many different parts of the test need to work properly to avoid mistakes. In many cases, test errors are caused by the chemicals our bodies have to fight other infections or some other chemicals that accidentally got into the test. Our study shows how the parts of the test can cause errors if the test is not done right. Following the manufacturer instructions is critical for accurate test results." +"Positive retests of COVID-19 represent a public health concern because of the increased risk of transmission. This study explored whether factors other than the nucleic acid amplification test (NAAT) contribute to positive retest results. Patients with COVID-19 admitted to the Guanggu district of the Hubei Maternal and Child Health Hospital between February 17 and March 28, 2020, were retrospectively included. The patients were grouped into the negative (n = 133) and positive (n = 51) retest groups. The results showed that the proportion of patients presenting with cough was higher (P < 0.001) and the proportion of patients with dyspnea was lower (P = 0.018) in the positive than in the negative retest group. The positive retest group showed shorter durations between symptom onset and hospitalization (P < 0.001) and symptom onset and the first positive NAAT (P = 0.033). The positive retest group had higher basophil counts (P = 0.023) and direct bilirubin (P = 0.032) and chlorine concentrations (P = 0.023) but lower potassium concentrations (P = 0.001) than the negative retest group. Multivariable regression analysis showed that coughing (OR = 7.59, 95% CI 2.28-25.32, P = 0.001) and serum chloride concentrations (OR = 1.38, 95% CI 1.08-1.77, P = 0.010) were independently associated with a positive retest result. Coughing and serum chloride concentrations were independent risk factors for positive NAAT retest results. Patients with a hospital stay of < 2 weeks or a short incubation period should stay in isolation and be monitored to reduce transmission. These results could help identify patients who require closer surveillance.","Repeated positive COVID-19 tests show that the risk of new people getting the disease is growing. We studied what causes positive test results. We studied children with COVID-19 who were at the hospital in February - March 2020. 133 children had negative rpeated COVID-19 test results and 51 had positive results. Among patients with repeated positive tests, there were more with cough and fewer with shortness of breath, compared to patients with the negative test. Patients who had symptoms and repeated positive tests were admitted to the hospital and had positive test results earlier. People who had repeated positive tests also had different blood test results compared to the people with negative tests. Coughing and a certain blood test result were each associated with a positive retest result. Patients who stayed at the hospital for less than 2 weeks or had symptoms shortly after getting COVID-19 should be quarantined. These results could help identify patients who require closer surveillance." +"Prompt and accurate detection of SARS-CoV-2, the virus that causes COVID-19, has been important during public health responses for containing the spread of COVID-19, including in hospital settings (1-3). In vitro diagnostic nucleic acid amplification tests (NAAT), such as real-time reverse transcription-polymerase chain reaction (RT-PCR) can be expensive, have relatively long turnaround times, and require experienced laboratory personnel.* Antigen detection tests can be rapidly and more easily performed and are less expensive. The performance� of antigen detection tests, compared with that of NAATs, is an area of interest for the rapid diagnosis of SARS-CoV-2 infection. The Quidel Sofia 2 SARS Antigen Fluorescent Immunoassay (FIA) (Quidel Corporation) received Food and Drug Administration Emergency Use Authorization for use in symptomatic patients within 5 days of symptom onset (4). The reported test positive percentage agreement� between this test and an RT-PCR test result is 96.7% (95% confidence interval [CI] = 83.3%-99.4%), and the negative percentage agreement is 100.0% (95% CI = 97.9%-100.0%) in symptomatic patients.� However, performance in asymptomatic persons in a university setting has shown lower sensitivity (5); assessment of performance in a clinical setting is ongoing. Data collected during June 30-August 31, 2020, were analyzed to compare antigen test performance with that of RT-PCR in a hospital setting. Among 1,732 paired samples from asymptomatic patients, the antigen test sensitivity was 60.5%, and specificity was 99.5% when compared with RT-PCR. Among 307 symptomatic persons, sensitivity and specificity were 72.1% and 98.7%, respectively. Health care providers must remain aware of the lower sensitivity of this test among asymptomatic and symptomatic persons and consider confirmatory NAAT testing in high-prevalence settings because a false-negative result might lead to failures in infection control and prevention practices and cause delays in diagnosis, isolation, and treatment.","Fast and accurate COVID-19 tests help reduce the spread of the disease, including in hospitals. Some of the known tests are expensive, take a long time and need training to do the test. Other tests are fast and easy to do without training. Accuracy of the easier and faster tests compared to the traditional tests is an area of interest. The Quidel rapid test was approved for emergency use in patients within the first 5 days of COVID-19 symptoms. These tests agreed with the traditional test for 83 to 99 out of 100 patients with positive results and 97 to all 100 patients with negative results. For the COVID-19 patients that did not have symptoms, the tests were not as accurate as the traditional test. We compared test results at a hospital in June - August 2020. Among 1,732 patients that had no symptoms the rapid test agreed with the traditional test on about 60 out of 100 positive tests, and on almost all negative tests. Among 307 patients that had symptoms the rapid test agreed with the traditional test on over 70 out of 100 positive tests, and on almost all negative tests. As rapid test misses many COVID-19 cases, traditional tests might be needed when the disease is on the rise. False negative test results cause delays in quarantine and treatment of COVID-19." +"A double-blind crossover study of inhibition of histamine-induced pruritus by three commonly prescribed antihistamines was conducted on 28 normal subjects. Drugs used included diphenhydramine HCl (Benadryl), cyproheptadine (Periactin), hydroxyzine HCl (Atarax), and a lactose placebo in identical capsules. Intradermal histamine dose-response thresholds of pruritus were obtained before and after pretreatment with the three antihistamines and placebo in each subject. Analysis of data revealed a fivefold increase above baseline of the histamine dose required to produce pruritus following both cyproheptadine and placebo. This compared to a tenfold increase following diphenhydramine and a 750-fold increase following hydroxyzine HCl. The most common side effect was drowsiness, which occurred with all three drugs.","Three commonly prescribed drugs (antihistamines) for itching caused by histamine, a chemical the body releases during allergic reactions, were studied on 28 healthy people. The drugs in identical capsules included Benadryl, Periactin, Atarax, and a placebo (a pill that contains no drug). The thresholds of itching due to histamine were measured before and after taking the drugs. For Periactin and placebo, the dose of histamine that caused itching increased fivefold. For Benadryl, the dose had to be 10 times higher, and for Atarax 750 times higher. The most common side effect was drowsiness, which occurred with all three drugs." +"Background: This study aimed to measure the association of various H1-antihistamines (H1A) with Torsade de Pointes (TdP), and present a comprehensive overview of H1A-induced TdP cases reported to the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: All H1A-induced TdP cases (n = 406) were retrieved from the FAERS database using the preferred term 'Torsade de Pointes' of MedDRA version-22 from 1990 to 2019. Four data-mining algorithms were used for disproportionality analysis: Reporting Odds Ratio (ROR); Proportional Reporting Ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and Information Content (IC). H1A with >3 TdP cases were included. Results: A total of 12 signals (Astemizole, cetirizine, chlorpheniramine, clemastine, desloratadine, diphenhydramine, hydroxyzine, loratadine, meclizine, promethazine, terfenadine, and trimeprazine) were identified including six new signals (cetirizine, chlorpheniramine, clemastine, desloratadine, loratadine, and meclizine). The number of risk factors (p = 0.031) and concomitant QT-prolonging drugs (p = <0.001) were significantly lower among new signals vs old signals. Moreover, new signals were strongly associated with QT-prolongation, cardiac reactions, and electrolyte abnormalities as compared with old signals. Conclusions: Our study found the increased torsadogenic potential of new signals compared with previously known old signals, hence necessitating clinical studies to determine the actual torsadogenic potential of newly identified signals.",We studied relations between antihistamines (drugs for treating allergies) and Torsade de Pointes (very fast heart rhythm) as reported to the FDA. We found 406 reports on Torsade de Pointes and antihistamines. We used four different statistical methods to study the cases. Antihistamines that had more than three reports of torsade de pointes were included in the analysis. We found 12 drugs associated with torsade de pointes. Six of the drugs were not known before to cause torsade de pointes. Getting antihistamines with other drugs that cause heart complications was lower than for the known antihistamines. The new antihistamines were associated with heart complications stronger than the known ones. The new antihistamines were associated with torsade de pointes stronger. +"Several noncardiac drugs have been linked to cardiac safety concerns, highlighting the importance of post-marketing surveillance and continued evaluation of the benefit-risk of long-established drugs. Here, we examine the risk of QT prolongation and/or torsade de pointes (TdP) associated with the use of hydroxyzine, a first generation sedating antihistamine. We have used a combined methodological approach to re-evaluate the cardiac safety profile of hydroxyzine, including: (1) a full review of the sponsor pharmacovigilance safety database to examine real-world data on the risk of QT prolongation and/or TdP associated with hydroxyzine use and (2) nonclinical electrophysiological studies to examine concentration-dependent effects of hydroxyzine on a range of human cardiac ion channels. Based on a review of pharmacovigilance data between 14th December 1955 and 1st August 2016, we identified 59 reports of QT prolongation and/or TdP potentially linked to hydroxyzine use. Aside from intentional overdose, all cases involved underlying medical conditions or concomitant medications that constituted at least 1 additional risk factor for such events. The combination of cardiovascular disorders plus concomitant treatment of drugs known to induce arrhythmia was identified as the greatest combined risk factor. Parallel patch-clamp studies demonstrated hydroxyzine concentration-dependent inhibition of several human cardiac ion channels, including the ether-a-go-go-related gene (hERG) potassium ion channels. Results from this analysis support the listing of hydroxyzine as a drug with ""conditional risk of TdP"" and are in line with recommendations to limit hydroxyzine use in patients with known underlying risk factors for QT prolongation and/or TdP.","Several drugs can cause heart problems. It is important to monitor and evaluate risks of traditional drugs. We study if taking hydroxyzine, a drug that relieves anxiety and also itch caused by allergies, is associated with fast, chaotic heartbeats. We reviewed data from a drug safety database and the basic studies of hydroxyzine interactions with human cells. The drug safety data had 59 reports between December 1955 and August 2016 that linked fast chaotic heartbeats to hydroxyzine use. Some people took too much of the drug (overdose). All other cases had medical problems or were taking other drugs along with hydroxyzine. People who have heart problems and take drugs that can cause irregular heartbeat are at the greatest risk of complications due to hydroxyzine. Studies show hydroxyzine can effect some heart functions. Hydroxyzine should be listed as drug with ""conditional risk of torsade de pointes"". Hydroxyzine use in patients who are at risk for heart problems should be limited." +"First-generation antihistamines have potency, pharmacokinetic, and cost advantages compared with nonsedating second-generation antihistamines. Bedtime dosing of hydroxyzine was investigated as a dosing strategy to minimize reaction time degradation and adverse subjective symptoms previously documented for hydroxyzine in divided doses. Hydroxyzine, 50 mg qhs, was compared with terfenadine, 60 mg bid, in this double-blind, placebo-controlled crossover study of 15 healthy, asymptomatic adults. Computer-based eye-hand reaction time tests of simple reaction time (SRT) and choice reaction time (CRT) were not statistically different among the three drugs. Drowsiness, dry mouth, and irritability were significant for hydroxyzine (P = .0001, .001 and .02, respectively) compared with terfenadine or placebo, but less than seen in a previous study of hydroxyzine, 25 mg bid. Symptom scores with terfenadine were comparable to placebo. Histamine skin test wheal and flare were both significantly and comparably suppressed by hydroxyzine and terfenadine (P = .0001). While wheal suppression by hydroxyzine was universal, four of the 15 subjects showed little or no suppression with terfenadine (P = .03). Although bedtime dosing of hydroxyzine did not eliminate subjective symptoms, it maintained skin H1-receptor antagonism the following morning and alleviated the prolongation of reaction times previously reported with hydroxyzine in divided doses. The significant adverse subjective symptoms and psychomotor performance degradations caused by first-generation antihistamines can be mitigated by creative dosing schedules.","First-generation antihistamines (allergy drugs that cause drowsiness) are more powerful and cheaper than the second-generation antihistamines that do not cause drowsiness. Hydroxyzine is an antihistamine that is used to relieve itching caused by allergies. We studied if taking hydroxyzine at bedtime reduces the side effects known to be caused by taking this drug divided in small doses. 15 healthy adults took hydroxyzine every night at bedtime or another antihistamine terfenadine or a pill that contained no drugs two times a day. Hydroxyzine caused drowsiness, dry mouth and moodiness more than terfenadine or placebo, but less than taking hydroxyzine twice a day. Symptoms caused by terfenadine and placebo were about the same. Both hydroxyzine and terfenadine lessened allergic reactions. Hydroxyzine lessened allergic reactions in all people, but terfenadine failed to lessen the reaction in four of the 15 people. Taking hydroxyzine at bedtime somewhat lessened the symptoms and relieved skin itching the next morning. The side effects lasted not as long as with taking the drug twice daily. The side effects and sluggish movements caused by the first-generation antihistamines can be lessened by changing when the drug is taken." +"Although older, potentially sedating, ""first-generation"" antihistamines (H1-receptor antagonists) are commonly used in childhood, their central nervous system (CNS) effects have not been well-documented in young subjects. We hypothesized that diphenhydramine and hydroxyzine would affect CNS function adversely in this population. Our objective was to evaluate the effects of these medications on central and peripheral histamine H1-receptors in children. Fifteen subjects with allergic rhinitis were tested before and 2-2.5 h after administration of diphenhydramine, hydroxyzine, or placebo in a double-blind, single-dose, three-way crossover study. Impairment of cognitive processing was assessed objectively by the latency of the P300 event-related potential (P300). Somnolence was assessed subjectively by a visual analog scale. Peripheral H1-blockade was assessed by suppression of the histamine-induced wheals and flares. At the central (Cz) and frontal (Fz) electrodes, diphenhydramine and hydroxyzine increased the P300 latency significantly (P < 0.05) compared to baseline. Hydroxyzine increased somnolence, as recorded on the visual analog scale, significantly compared to baseline (P < 0.05), with a similar trend for diphenhydramine (P = 0.07). Both antihistamines reduced histamine-induced wheals and flares significantly compared to baseline and compared to placebo. In children, diphenhydramine and hydroxyzine are effective H1-receptor antagonists, but both these medications cause CNS dysfunction, as evidenced by increased P300 latency, a measure of cognitive function, and by increased subjective somnolence.","First generation antihistamines, drugs that stop allergies due to the body chemical histamine, may cause drowsiness. They are often given to children, but it is not known how they effect the children's brains We believe that first generation antihistamines diphenhydramine and hydroxyzine may disturb children's brain function. We evaluated how these drugs effect body cells in children. Fifteen children with seasonal allergy (hay fever) had tests before and after they took diphenhydramine, hydroxyzine, or placebo (a pill that contains no drugs.) Their brain functions were evaluated by measuring the delays in response to events. They were also asked to evaluate how sleepy they felt. Diphenhydramine and hydroxyzine significantly increased the time it took to respond to the events. Hydroxyzine and diphenhydramine also increased sleepiness. Both antihistamines also reduced the allergies. In children, diphenhydramine and hydroxyzine help against allergies, but interfere with brain functions. These drugs cause longer response times, increase sleepiness and disturb mental processes." +"First-generation histamine H1-receptor antagonists, such as diphenhydramine, triprolidine, hydroxyzine or chlorpheniramine (chlorphenamine), frequently cause somnolence or other CNS adverse effects. Second-generation H1-antagonists, such as terfenadine, astemizole, loratadine and cetirizine, represent a true advance in therapeutics. In manufacturers' recommended doses, they have a more favourable benefit/risk ratio than their predecessors with regard to lack of CNS effects, and do not exacerbate the adverse CNS effects of alcohol or other CNS-active chemicals. Rarely, some of the newer H1-antagonists may cause cardiac dysrhythmias after overdose or under other specific conditions. The concept of a risk-free H1-antagonist is proving to be an oversimplification. An H1-antagonist absolutely free from adverse effects under all circumstances is not yet available for use. The magnitude of the beneficial effects of each H1-antagonist should be related to the magnitude of the unwanted effects, especially in the CNS and cardiovascular system, and a benefit-risk ratio or therapeutic index should be developed for each medication in this class.","First-generation antihistamines, drugs that help with allergies caused by histamine, a chemical profited by our bodies, often cause sleepiness and disturb brain functions in other ways. These drugs include diphenhydramine, triprolidine, hydroxyzine and chlorpheniramine (chlorphenamine). Second-generation antihistamines, such as terfenadine, astemizole, loratadine and cetirizine, are better. These drugs do not disturb brain functions when taken alone, and do not strengthen the disturbances caused by alcohol or other chemicals. Not often, the new antihistamines may cause heart rhythm disturbances; if a person takes too much of the drug or has other specific conditions. Taking any antihistamines includes some risks. When taking antihistamines, people should consider the benefits and the risks carefully. " +"Objective: Antihistamines often have sedative side effects. This was the first study to measure regional cerebral glucose (energy) consumption and hemodynamic responses in young adults during cognitive tests after antihistamine administration. Methods: In this double-blind, placebo-controlled, three-way crossover study, 18 healthy young Japanese men received single doses of levocetirizine 5 mg and diphenhydramine 50 mg at intervals of at least six days. Subjective feeling, task performances, and brain activity were evaluated during three cognitive tests (word fluency, two-back, and Stroop). Regional cerebral glucose consumption changes were measured using positron emission tomography with [18 F]fluorodeoxyglucose. Regional hemodynamic responses were measured using near-infrared spectroscopy. Results: Energy consumption in prefrontal regions was significantly increased after antihistamine administration, especially diphenhydramine, whereas prefrontal hemodynamic responses, evaluated with oxygenated hemoglobin levels, were significantly lower with diphenhydramine treatment. Stroop test accuracy was significantly impaired by diphenhydramine, but not by levocetirizine. There was no significant difference in subjective sleepiness. Conclusions: Physiological ""coupling"" between metabolism and perfusion in the healthy human brain may not be maintained under pharmacological influence due to antihistamines. This uncoupling may be caused by a combination of increased energy demands in the prefrontal regions and suppression of vascular permeability in brain capillaries after antihistamine treatment. Further research is needed to validate this hypothesis.","Antihistamines, drugs that help with allergies, often cause drowsiness. We studied young adults' brains during tests of mental processes after taking antihistamines. 18 healthy young Japanese men took antihistamines levocetirizine and diphenhydramine at least six days apart. Their well-being, task performances, and brain activity were measured while checking their mental functions. After diphenhydramine, the brains consumed more energy but responded slower. Diphenhydramine, but not levocetirizine, lowered the accuracy of mental processes. There was no difference in sleepiness. Antihistamines may effect human brain. " +"Study objective: To evaluate the efficacy of a 4-day ""burst"" course of prednisone added to standard treatment with H1 antihistamines for the management of acute urticaria in outpatients. Design: Prospective, randomized, double-blinded, clinical trial. Setting: Emergency department of an urban tertiary care teaching hospital. Participants: Adult patients with urticarial rash of no more than 24 hours' duration, regardless of cause. Patients were excluded if they manifested wheezing, stridor, or angioedema or if they had taken antihistamines or glucocorticoids within 5 days of arrival at the ED. Patients also were excluded if there was a history of diabetes or active peptic ulcer disease. Interventions: All patients were asked to evaluate the severity of pruritus (""itch score"") on a 10-cm visual analog scale. Patients were then given diphenhydramine, 50 mg intramuscularly, and discharged home on a regimen of hydroxyzine, 25 mg orally, every 4 to 8 hours for pruritus, plus either prednisone, 20 mg, or placebo orally every 12 hours for 4 days. Patients' conditions were reassessed clinically, with itch score calculated again 2 days later, and again at 5 days by telephone. Results: Forty-three patients were enrolled; 24 received prednisone and 19 received placebo. The two groups had similar itch scores at enrollment (prednisone, 8.1 +/- 1.7; placebo, 7.4 +/- 2.1, P = .25 [ANOVA]), but at 2- and 5-day follow-up the prednisone group had significantly lower itch scores (1.3 +/- 1.3 and .0 +/- .0 versus 4.4 +/- 2.2 and 1.6 +/- 1.0, respectively; P < .0001 [ANCOVA] at each interval) and greater clinical improvement in rash. Response did not correlate with age, sex, or identification of an allergen. No adverse effects were noted in either group. Conclusion: The addition of a prednisone burst improves the symptomatic and clinical response of acute urticaria to antihistamines. Patients' conditions improved more quickly and more completely when prednisone was administered, without any apparent adverse effects.","This study added hormone prednisone to antihistamines, the drugs that are usually used to treat hives (itchy skin rash). Adults with the rash that started no more than 24 hours ago participated in the study. Patients with wheezing, raspy breathing, swelling or those who took antihistamines or hormones within 5 days before coming to the emergency room were not included in the study. Diabetics and people with ulcers (open sores in the stomach) were not included too. All patients were asked to give their itch an ""itch score"" on a scale. Patients then got a shot of an antihistamine diphenhydramine and were sent home. They took an antihistamine hydroxyzine every 4 to 8 hours for their itch. Patients also took another pill every 12 hours for 4 days. For some that pill was the hormone prednisone, and for some it was a placebo (did not contain any drug). Patients came back to evaluate their each score 2 days later. 5 days later the score was evaluated by phone. Out of f43 patients, 24 got prednisone and 19 placebo. All had similar each scores at the beginning. After 2 and 5 days, those who had prednisone had lower itch scores and less rash. Patients' age, sex, and substances that caused allergies did not effect the itch score. No patients had adverse reactions. Adding prednisone improves antihistamine treatment of hives. When prednisone was added, the skin cleared faster and more completely. There were no side effects. " +"This article reviews clinical pharmacokinetic data on the H1-receptor antagonists, commonly referred to as the antihistamines. Despite their widespread use over an extended period, relatively little pharmacokinetic data are available for many of these drugs. A number of H1-receptor antagonists have been assayed mainly using radioimmunoassay methods. These have also generally measured metabolites to greater or lesser extents. Thus, the interpretation of such data is complex. After oral administration of H1-receptor antagonists as syrup or tablet formulations, peak plasma concentrations are usually observed after 2 to 3 hours. Bioavailability has not been extensively studied, but is about 0.34 for chlorpheniramine, 0.40 to 0.60 for diphenhydramine, and about 0.25 for promethazine. Most of these drugs are metabolised in the liver, this being very extensive in some instances (e.g. cyproheptadine and terfenadine). Total body clearance in adults is generally in the range of 5 to 12 ml/min/kg (for astemizole, brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, promethazine and triprolidine), while their elimination half-lives range from about 3 hours to about 18 days [cinnarizine about 3 hours; diphenhydramine about 4 hours; promethazine 10 to 14 hours; chlorpheniramine 14 to 25 hours; hydroxyzine about 20 hours; brompheniramine about 25 hours; astemizole and its active metabolites about 7 to 20 days (after long term administration); flunarizine about 18 to 20 days]. They also have relatively large apparent volumes of distribution in excess of 4 L/kg. In children, the elimination half-lives of chlorpheniramine and hydroxyzine are shorter than in adults. In patients with alcohol-related liver disease, the elimination half-life of diphenhydramine was increased from 9 to 15 hours, while in patients with chronic renal disease that of chlorpheniramine was very greatly prolonged. Little, if any, published information is available on the pharmacokinetics of these drugs in neonates, pregnancy or during lactation. The relatively long half-lives of a number of the older H1-receptor antagonists such as brompheniramine, chlorpheniramine and hydroxyzine suggest that they can be administered to adults once daily.","This is a review of the drugs called antihistamines because they help with allergies caused by the body chemical histamine. These drugs are used widely, but little is known about their interactions with human body. The max amount of antihistamines gets into the blood 2 to 3 hours after taking a pill or syrup. The amounts of the drug that made it into the blood were about a third of the taken pill for chlorpheniramine, about half for diphenhydramine, and about a quarter for promethazine. Most of these drugs are processed in the body by the liver. These drugs are usually removed from the body at a rate of 5 to 12 milliliters per minute for each kilogram of body weight. Half of the total amount of the drug is taken out of the body from about 3 hours to about 20 days. For cinnarizine it's about 3 hours; diphenhydramine about 4 hours; promethazine 10 to 14 hours; chlorpheniramine 14 to 25 hours; hydroxyzine about 20 hours; brompheniramine about 25 hours; astemizole about 7 to 20 days, when taken for a long time; and for flunarizine about 18 to 20 days. These drugs tend to go from the blood into the body tissues, meaning that a higher dose of a drug is needed to keep its levels in the blood. In children, chlorpheniramine and hydroxyzine go to half of the amount in the body faster than in adults. In patients with liver disease due to alcohol, time to get half of the diphenhydramine out lengthens from 9 to 15 hours. In patients with kidney disease, time to get out chlorpheniramine was very greatly prolonged. Almost nothing is known about these drugs in the bodies of newborns, and pregnant or breastfeeding women. Because half of the drug stays in the body longer for the older antihistamines such as brompheniramine, chlorpheniramine and hydroxyzine, they can be given to adults once daily." +"Objectives: To determine the national rate and trend of inappropriate medication administration to elderly emergency department (ED) patients. Secondary objectives were to identify risk factors for receiving an inappropriate medication and to determine whether administration is sometimes justified based on diagnosis. Design: Retrospective analysis of ED visits in the 1992-2000 National Hospital Ambulatory Medical Care Survey. Inappropriate medications identified using Beers' 1997 explicit criteria. Setting: EDs of U.S. noninstitutionalized general and short-stay hospitals. Participants: ED survey patients aged 65 and older. Measurements: Magnitude and rate of administration of 36 medications. Results: Inappropriate medications were administered in an estimated 16.1 million (95% confidence interval (CI)=14.9-17.3 million) or 12.6% (95% CI=11.6-13.5%) of elderly ED visits from 1992 to 2000. The rate of inappropriate administration was unchanged throughout the study period (P=.40). Six drugs accounted for 70.8% of inappropriate administration: promethazine (22.2%), meperidine (18.0%), propoxyphene (17.2%), hydroxyzine (10.3%), diphenhydramine (7.1%), and diazepam (6.0%). In multivariate analysis, number of ED medications was the strongest predictor, with an odds ratio for two to three medications of 6.0 (95% CI=5.3-6.7) and for four to six medications of 8.1 (95% CI=7.2-9.2). Diagnoses indicating potentially appropriate uses of these medications were rarely present. For example, only 42.4% of patients receiving diphenhydramine and 7.4% receiving hydroxyzine were diagnosed with an allergic process. Conclusion: Elderly ED patients are frequently administered inappropriate medications. Potentially appropriate uses of generally inappropriate drugs cannot account for such administrations. Inappropriate administration rates remain unchanged despite the 1997 publication of explicit criteria.","We studied inappropriate use of drugs in elderly patients in the emergency departments. We also find out what causes inappropriate use of drugs and if it is sometimes done for a good reason. We studied visits to emergency departments in 1992-2000. Drugs that are dangerous for elderly and should be used with caution were listed by Dr. Beers in 1997. Drugs from the Beers' list were given about 16 million times (over a tenth of emergency visits by elderly) from 1992 to 2000. Six drugs accounted for the majority of inappropriate use: promethazine, meperidine, propoxyphene, hydroxyzine, diphenhydramine, and diazepam. There were almost no indications that the use of these drugs was potentially appropriate. For example, less than half of patients that got diphenhydramine and less than 10th that got hydroxyzine had allergies. Elderly patients often get inappropriate drugs in the emergency room. Potentially appropriate uses do not account for the given drugs. Although the list of inappropriate drugs was published in 1997, it has not changed how the drugs are given. " +"The objective of this study was to examine the associations between aromatase inhibitor therapy and hair loss or hair thinning among female breast cancer survivors. Data were analyzed from 851 female breast cancer survivors who responded to a hospital registry-based survey. Data on hair loss, hair thinning, demographic characteristics, and health habits were based on self-report; data on aromatase inhibitor therapy were collected on the survey and verified using medical record review. Logistic regression was used to estimate the odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between aromatase inhibitor therapy and the hair outcome variables adjusted for potential confounders, including age and chemotherapy treatment. The results showed that 22.4 % of the breast cancer survivors reported hair loss and 31.8 % reported hair thinning. In the confounder-adjusted analyses, breast cancer survivors who were within 2 years of starting aromatase inhibitor treatment at the time of survey completion were approximately two and a half times more likely to report reporting hair loss (OR 2.55; 95 % CI 1.19-5.45) or hair thinning (OR 2.33; 95 % CI 1.10-4.93) within the past 4 weeks compared to those who were never treated with an aromatase inhibitor. Current aromatase inhibitor use for two or more years at the time of the survey and prior use were significantly associated with hair thinning (current users, ?2 years: OR 1.86; prior users: OR 1.62), but not hair loss. Findings from this study suggest that aromatase inhibitor use is associated with an increased risk of hair loss and hair thinning independent of chemotherapy and age; these side effects are likely due to the substantial decrease in estrogen concentrations resulting from treatment with this drug. Future research should focus on examining these associations in a prospective manner using more detailed and objective measures of hair loss and thinning.","This study examines the links between aromatase inhibitor therapy (drugs commonly used to treat breast cancer) and hair loss or hair thinning among female breast cancer survivors. We analyzed data from 851 female breast cancer survivors who responded to a hospital survey. Data on hair loss, hair thinning, background information, and health habits were self-reported. Data on aromatase inhibitor therapy were collected by the survey and verified with medical records. The relationship between aromatase inhibitor therapy and hair outcome was mathematically estimated and adjusted for possible misleading variables, like age and chemotherapy treatment. 22.4% of the breast cancer survivors reported hair loss. 31.8% reported hair thinning. Breast cancer survivors who were within 2 years of starting aromatase inhibitor treatment at the time of the survey were around two and a half times more likely to report hair loss or thinning in the past 4 weeks compared to those never treated with an aromatase inhibitor. Current aromatase inhibitor use for 2 or more years at the time of the survey and past use were linked with hair thinning but not hair loss. Findings from the study suggest that aromatase inhibitor use is linked with an increased risk of hair loss and thinning regardless of chemotherapy and age. These side effects are likely from the reduction in estrogen (a female sex hormone) from the drug treatment. Future research should examine the links in a future-oriented manner with more detailed and measurable measures of hair loss and thinning." +"Importance: Endocrine therapy-induced alopecia (EIA) has been anecdotally reported but not systematically described. Objective: To characterize EIA in patients with breast cancer. Design, setting, and participants: Retrospective cohort study of 112 patients with breast cancer, diagnosed with EIA from January 1, 2009, to December 31, 2016, the patients were examined at the dermatology service in a large tertiary care hospital and comprehensive cancer center. Main outcomes and measures: The clinical features, alopecia-related quality of life (QoL), and response to minoxidil of EIA in patients with breast cancer were assessed. Data from the Hairdex Questionnaire was used to assess the impact of the alopecia on patients QoL. Higher score indicates lower QoL (0-100 score). Efficacy of minoxidil was measured at 3 or 6 months by a single-blinded investigator through standardized clinical photographs of the scalp. Results: A total of 112 female patients with breast cancer were included (median [range] age, 60 [34-90] years). A total of 104 patients (93%) had standardized clinical photographs; of these, 59 patients (53%) had trichoscopy images available at baseline, and 46 patients (41%) were assessed for response to minoxidil. Alopecia was attributed to aromatase inhibitors in 75 patients (67%) and tamoxifen in 37 (33%). Severity was grade 1 in 96 of 104 patients (92%), and the pattern was similar to androgenetic alopecia. The predominant trichoscopic feature at baseline was the presence of vellus hairs and intermediate- and thick-diameter terminal hair shafts. A negative impact on QoL was reported, with a higher effect in the emotion domain according to the Hairdex score (mean [SD], 41.8 [21.3]; P < .001). After treatment with topical minoxidil, moderate or significant improvement in alopecia was observed in 37 of 46 patients (80%). Conclusions and relevance: Endocrine therapies are associated with a pattern alopecia similar to androgenetic-type, consistent with the mechanism of action of causal agents. A significant negative impact on QoL was reported by patients, despite mostly mild alopecia severity.","The study's importance is based on the fact that endocrine therapy-induced alopecia (EIA) (hair loss or thinning from hormonal therapy) has been mentioned but not measured. The study's objective is to describe EIA thoroughly in patients with breast cancer. The study's design is a study of 112 patients with breast cancer, diagnosed with EIA from January 1, 2009 to December 31, 2016. The patients were examined at a skin center in a large, specialized hospital and professional cancer center. The study's main variables included common hospital measures, hair-loss- or hair-thinning-related quality of life (QoL), and reaction to minoxidil (hair regrowth medication) of EIA in patients with breast cancer. We used data from the Hairdex Questionnaire (a questionnaire for disease-specific quality of life measurements) to measure the impact of hair loss or thinning (alopecia) on patients QoL. Higher scores indicate lower QoL (0-100 score). The success of minoxidil was measured at 3 or 6 months by an investigator unaware of the treatment groups through standard photographs of the scalp. 112 female patients with breast cancer were included. Their median age was 60 years with a range from 34-90 years. 104 patients (93%) had standard photographs. Of these, 59 patients (53%) had images from special hair and scalp evaluations at the start. 46 patients (41%) were measured for response to minoxidil. Alopecia was linked to aromatase inhibitors in 75 patients (67%) and tamoxifen (estrogen-influencing medication) in 37 (33%). Severity was low in 96 of 104 patients (92%). The pattern was similar to common, receding hair loss. The most common scalp and hair-related feature at the start were peach fuzz and mid- and thick, long hairs on the scalp. QoL was negatively reported, especially in the emotional part of life. After treatment with minoxidil on the skin, medium or noticeable improvement in hair loss and thinning was seen in 37 of 46 patients (80%). In conclusion, hormonal therapies are linked with commonly-seen hair loss and thinning, similar to agents that actively cause alopecia. Despite mostly mild alopecia, QoL was negatively impacted for patients." +"Endocrine therapy-induced hair loss (ETIHL) associated with aromatase inhibitors and tamoxifen treatment is currently mostly reported but remained an unresolved therapeutic issue in patients with breast cancer (BC) since the number of studies regarding the management is limited in literature. Herein we investigated the possible causes of this clinical problem and its relation with endocrine therapies widely used for BC survivors and made some modest practical recommendations in light of the literature review in order to provide an optimal management. On the basis of literature findings, common causes of hair loss apart from endocrine therapies should be investigated with an initial evaluation workup and then should be corrected, if observed. Treatment with topical 5-alpha reductase inhibitors and supplementation of Vitamin C and omega-3 fatty acids are likely appeared to be the most appropriate treatment agents for ETIHL without causing an adverse effect on BC prognosis. However, more prospective, randomised, placebo-controlled studied are required in order to confirm our results and also identify the clinical effects of this problem on patients with BC.","Endocrine therapy-induced hair loss (ETIHL) (hair loss from hormonal therapy) linked with aromatase inhibitors (drugs used to treat breast cancer) and tamoxifen (estrogen-influencing medication) is reported but remains unsolved in patients with breast cancer (BC). This is largely because the number of studies regarding this hair loss management is limited. We checked the possible causes of this medical problem and its link to hormonal therapies used for BC survivors. We also made practical recommendations based on relevant medical studies to provide optimal management. Based on medical papers, common causes of hair loss besdies hormonal therapies should be checked with a starting evaluation workup and then corrected if found. Treatment with 5-alpha reductase inhibitors (drugs for treating hair loss) applied on skin and Vitamin C and omega-3 fatty acid supplements may be the best treatment for ETIHL without causing serious side effects on BC recovery. However, more in-depth studies are needed to confirm our results and identify the effects of this problem on BC patients." +"We report five cases of pattern alopecia in female patients who are undergoing hormonal anticancer therapy for the prevention of recurrence of breast cancer after surgery. Three patients demonstrated male pattern alopecia with receding frontal hairlines, and two patients demonstrated female pattern alopecia without receding hairlines. The detailed clinical history showed that the pattern alopecia of the patients developed after the full recovery of global hair loss of the entire scalp due to previous cytotoxic chemotherapy. All of the adjuvant hormonal anticancer drugs that were used in the patients are antiestrogenic agents, either aromatase inhibitors or selective estrogen receptor modulators. Considering androgen effect on the hair follicles of the fronto-parietal scalp, the androgen-estrogen imbalance caused by the drugs was thought to be the reason for the onset of pattern alopecia in the patients. In general, alopecia that develops during cytotoxic chemotherapy is well known to both physicians and patients; however, the diagnosis of pattern alopecia during hormonal anticancer therapy in breast cancer patients seems to be overlooked.","We report 5 cases of common alopecia (hair loss or thinning) in female patients undergoing hormonal anticancer therapy to prevent reoccuring breast cancer after surgery. Three patients showed alopecia common to males with receding hairlines in the front. Two patients showed alopecia common to females without receding hairlines. The patient history showed that common alopecia of the patients developed after full recovery of complete hair loss of the scalp due to prior, severe chemotherapy (cancer treatment). All of the secondary hormonal anticancer drugs used in patients are antiestrogenic agents (which influence levels of estrogen, a female sex hormone). These agents include aromatase inhibitors or selective estrogen receptor modulators. Considering the effect of hormones on hair follicles in the front scalp, the estrogen-hormone imbalance caused by the drugs was thought to be the reason for visible alopecia in patients. In general, alopecia that develops during severe chemotherapy (cancer therapy) is known to physicians and patients. However, the identification of alopecia during hormonal anticancer therapy in breast cancer patients seems to be overlooked." +"Background and objective: Anastrozole is a well-established active pharmaceutical ingredient (API) used for the treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, treatment with the only available oral formulation is often associated with concentration-dependent serious side effects such as hot flashes, fatigue, muscle and joint pain, nausea, diarrhea, headache, and others. In contrast, a sustained-release system for the local application of anastrozole should minimize these serious adverse drug reactions. Methods: Anastrozole-in-adhesive transdermal drug delivery systems (TDDS) were developed offering efficient loading, avoidance of inhomogeneity or crystallization of the drug, the desired controlled release kinetics, storage stability, easy handling, mechanical stability, and sufficient stickiness on the skin. In vitro continuous anastrozole release profiles were studied in Franz diffusion cells. In vivo, consecutive drug plasma kinetics from the final anastrozole transdermal system was tested in beagle dogs. For drug analysis, a specific validated liquid chromatography- mass spectrometry method using fragment ion detection was developed and validated. Results: After efficient drug loading, a linear and sustained 65% drug release from the TDDS over 48 h was obtained. In vivo data showed a favorable anastrozole plasma concentration-time course, avoiding side effect-associated peak concentrations as obtained after oral administration but matching therapeutic plasma levels up to 72 h. Conclusion: These results provide the basis for establishing the transdermal application of anastrozole with improved pharmacokinetics and drug safety as novel therapeutic approach and promising option to treat human BC by decreasing the high burden of unwanted side effects.","For background, anastrozole is an important drug ingredient for treatment of hormone-sensitive breast cancer (BC) in women who have finished their last period. However, treatment with the only available drug taken by mouth is linked with serious side effects that worsen with greater doses. These side effects include hot flashes, fatigue, muscle and joint pain, nausea, diarrhea, headache, and others. In contrast, a steady release of anastrozole could minimize these serious side effects from the drug. Anastrozole administered by a patch on the skin was created for efficient administration, avoiding drug crystals in the body, desired drug release, storage ease, easy handling, stability, and stickiness on the skin. Continuous anastrozole treatment was studied in cells designed to measure the success of oils, creams, and gels. Drug reactions in blood from the final anastrozole treatment on skin was tested in beagle dogs. To analyze the drug, a specific filtration method was created and verified. After enough drug exposure, a sustained 65% drug release from the skin treatment over 48 hours was obtained. Data in living animals showed good anastrozole blood concentration overtime, avoiding the worst of side effects linked with treatment by mouth but matching its helpful blood levels up to 72 hours. In conclusion, applying anastrozole by skin shows improved drug reactions and safety. The treatment is a promising option to treat human BC by reducing unwanted side effects." +"Previous studies have demonstrated that both anastrozole and letrozole are well tolerated. Letrozole suppresses estrogen to a greater degree than anastrozole in the serum and breast tumor. Concerns have been raised that greater potency may adversely affect patients' quality of life (QOL). One hundred eighty-one postmenopausal women with invasive estrogen receptor-positive breast cancers were randomized to receive either 12 weeks of letrozole followed by 12 weeks of anastrozole or the reverse sequence. One hundred and six received immediate adjuvant aromatase inhibitors (AIs) following surgery, and 75 received extended adjuvant therapy. The Functional Assessment of Cancer Therapy Endocrine Subscale (FACT-B-ES) QOL questionnaires were completed to assess QOL on each drug. Additional side-effect profiles were collected. Each patient completed a patient preference form. Twenty-one patients withdrew before study end, 10/179 (5.6%) while taking letrozole and 4/173 (2.3%) while taking anastrozole (P = 0.12). Tamoxifen-na�ve patients had a higher mean ES (endocrine symptoms subscale) score at entry versus those having extended therapy (66.0 vs. 61.9; P = 0.001). There was no significant change in FACT-B-ES (overall) scores or ES scores while patients were taking anastrozole or letrozole and no significant differences between drugs. Nearly 80% of patients reported one or more side effects with either agent. No differences in frequency, grade, or range of side effects were seen between drugs. Of 160 patients, 49 (30.6%) preferred letrozole, 57 (35.6%) preferred anastrozole, and 54 (33.8%) had no preference (P = 0.26, Pearson's Chi-squared test). In conclusion, both AIs are equally well tolerated. There were no significant differences in QOL scores between the two drugs.","Previous studies showed that both anastrozole and letrozole (drugs to treat breast cancer) are well tolerated. Letrozole reduces estrogen (a female sex hormone) more than anastrozole in the blood and breast tumor. There are concerns that its greater strength may harm patients' quality of life (QOL). One hundred eighty-one women who have finished their last period and with harmful estrogen-related breast cancers received either 12 weeks of letrozole followed by 12 weeks of anastrozole or the reverse. One hundred and six received immediate, secondary aromatase inhibitors (Ais) (drugs used to treat breast cancer) after surgery. 75 received extended secondary therapy. Hormonal-cancer-therapy-specific questionnaires were completed to measure QOL on each drug. Descriptions of side effects were collected. Each patient completed a patient preference form. Twenty-one patients quit before the study's end. 10/179 (5.6%) quit while taking letrozole, and 4/173 (2.3%) quit while taking anastrozole. Pateints treated with tamoxifen (an estrogen-influencing medication) had a higher hormonal symptom score at the start versus those with long-term therapy. There was no change in hormonal therapy scores while patients were taking anastrozole or letrozole. There was also no significant differences between drugs. Almost 80% of patients mentioned one or more side effects with either agent. No difference in frequency, severity, or range of side effects were seen between drugs. Of 160 patients, 49 (30.6%) preferred letrozole, 57 (35.6%) preferred anastrozole, and 54 (33.8%) had no preference. In conclusion, both Ais are equally tolerated. There were no differences in QOL scores between the two drugs." +"Background: Whereas the frequency of alopecia to cytotoxic chemotherapies has been well described, the incidence of alopecia during endocrine therapies (i.e., anti-estrogens, aromatase inhibitors) has not been investigated. Endocrine agents are widely used in the treatment and prevention of many solid tumors, principally those of the breast and prostate. Adherence to these therapies is suboptimal, in part because of toxicities. We performed a systematic analysis of the literature to ascertain the incidence and risk for alopecia in patients receiving endocrine therapies. Results: Data from 19,430 patients in 35 clinical trials were available for analysis. Of these, 13,415 patients had received endocrine treatments and 6,015 patients served as controls. The incidence of all-grade alopecia ranged from 0% to 25%, with an overall incidence of 4.4% (95% confidence interval: 3.3%-5.9%). The highest incidence of all-grade alopecia was observed in patients treated with tamoxifen in a phase II trial (25.4%); similarly, the overall incidence of grade 2 alopecia by meta-analysis was highest with tamoxifen (6.4%). The overall relative risk of alopecia in comparison with placebo was 12.88 (p < .001), with selective estrogen receptor modulators having the highest risk. Conclusion: Alopecia is a common yet underreported adverse event of endocrine-based cancer therapies. Their long-term use heightens the importance of this condition on patients' quality of life. These findings are critical for pretherapy counseling, the identification of risk factors, and the development of interventions that could enhance adherence and mitigate this psychosocially difficult event.","For the study's background, while the frequency of alopecia (hair loss or thinning) to powerful chemotherapies (cancer-treating treatments) has been well described, the frequency of alopecia during hormonal therapies (i.e., anti-estrogens, aromatase inhibitors used to treat breast cancer) has not been described. Hormonal agents are widely used in the treatment and prevention of many solid tumors, mainly those of the breast and prostrate. Sticking to these therapies is not the best, In part due to toxicities. We analyzed scientific papers to measure the frequency and risk for alopecia in patients receiving hormonal therapies. Data from 19,430 patients in 35 clinical trials were available for analysis. Of these, 13,415 patients got hormonal treatments. 6,015 did not. The frequency of any alopecia ranged from 0% to 25%, with an overall frequency of 4.4%. The highest frequency of any alopecia was seen in patients treated with tamoxifen (an estrogen-influencing drug) in a clinical trial (25.4%). Similarly, the overall frequency of severe alopecia in the analysis was highest with tamoxifen (6.4%). The overall risk of alopecia compared with sham treatment was 12.88, with specific estrogen-receptor influencers having the highest risk. In conclusion, alopecia is a common yet rarely-mentioned side effect of hormonal cancer therapies. Their long-term use increases the importance of this condition on patients' quality of life. These findings are important for pre-therapy counseling, identifying risk factors, and creating treatments that could improve sticking to the plan and lowering this emotionally difficult event." +"Background: Aromatase inhibitors (AIs) are standard hormone therapy (HT) for the adjuvant treatment of postmenopausal endocrine-sensitive early breast cancer. Treatment discontinuation due to toxicity is an important issue that may help clinicians identify effective clinical interventions to allow adequate treatment duration. We reviewed the main reasons for interruption of AIs at our institution from 2006 to 2009. Methods: 236 patients treated with adjuvant AIs were eligible for analysis. Median age was 64 years (35-89), median follow-up 53 months (6-60). Prior adjuvant chemotherapy was taxane based in 47 patients and anthracycline based in 43 patients. 118 patients had received letrozole, 101 anastrozole, and 17 exemestane. Results: Twenty-four patients (10%) needed discontinuation of the first AI assigned as a result of toxicity. Grade 2/3 arthralgia was the main reason for discontinuation in 13/24 patients. No differences in the incidence of arthralgia were noted in patients who had received taxanes or anthracyclines. Headache, alopecia, itching, diffuse skin reaction, allergic reaction with hypertensive crisis, xerostomia and xerophthalmia, insomnia and somnolence were the other reasons for discontinuation. In multivariate logistic regression analysis, age (65 years) and HT were independent factors associated with the onset of arthralgia (p = 0.006 and p = 0.008, respectively; OR 2.65, 95% CI 1.32-5.31). Alternative HT (AI or tamoxifen) was offered to patients who wanted or needed to permanently interrupt the ongoing drug. Conclusions: In our analysis, 10% of patients discontinued the first AI assigned because of toxicity. Median time course of all adverse events leading to HT discontinuation was 155 days and 135 days for arthralgia. A switch to alternative HT with toxicity monitoring is a recommended option for avoiding premature and permanent interruption of an effective treatment.","For the study's background, aromatase inhibitors (Ais) are common hormone therapy (HT) for the secondary treatment of postmenopausal hormone-sensitive early breast cancer. Treatment stoppage due to toxicitiy is an important issue that may help clinicians find effective clinical treatments to allow proper treatment duration. We reviewed the main reasors for interruption of Ais at our center from 2006 to 2009. For the study's methods, 236 patients treated with secondary Ais were analyzed. Average age was 64 years (ranging from 35 to 89 years). Average treatment follow-up was 53 months (ranging from 6 to 60). Prior secondary chemotherapy (cancer-specific drugs) was taxane for 47 patients and anthracycline for 43 patients. 118 patients received letrozole, 101 anastrozole, and 17 exemestane (breast cancer-treating drugs). Twenty-four patients (10%) needed stoppage of the first AI assigned due to toxicity. Severe arthralgia (joint stiffness) was the main reason for stoppage in 13/24 patients. No differences in the frequency of arthralgia were noted in patients who received taxanes or anthracyclines. Headache, alopecia (hair loss or thinning), itching, skin reactions, allergic reactions with high-blood-pressure events, xerostomia (dry mouth), xerophthalmia (eye dryness), lack of sleep, and sleepiness were other reasons for stopping treatment. With mathematical analysis, age (65 years) and HT were linked with the start of arthralgia. Alternative HT (AI or tamoxifen - an estrogen-influencing drug) was offered to patients who wanted or needed to permanently stop the ongoing drug. In conclusion, 10% of patients stopped the first AI assigned because of toxicity. Average time course of all side effects leading to HT stoppage was 155 days and 135 days for arthralgia. A switch to another HT with toxicity monitoring is recommended for avoiding premature and permanent stoppage of an effective treatment." +"Hair loss and thinning are possible complications in those undergoing endocrine therapies with aromatase inhibitors. Alopecia in pediatric patients undergoing endocrine therapy has not been previously reported. We describe two adolescents, 14 and 16 years of age, who developed androgenetic alopecia following treatment with anastrozole for idiopathic short stature. Accordingly, the possible adverse event of alopecia should be considered in the pediatric population undergoing treatment with aromatase inhibitors.","Hair loss and thinning are possible side effects in those undergoing hormonal therapies with aromatase inhibitors (drugs commonly used to treat breast cancer). Alopecia (hair loss and thinning) in young patients undergoing hormonal therapy has not been previously studied. We describe two adolescents, 14 and 16 years of age, who got androgenetic alopecia (common hair loss or thinning) after receiving treatment with anastrozole (a durg usually used to treat breast cancer) for unusally short height. Therefore, the possible side effect of alopecia should be considered in the young population undergoing treatment with aromatase inhibitors." +"Purpose: Increased epidermal growth factor receptor (EGFR) expression may promote breast cancer resistance to endocrine therapy. We have therefore investigated whether neoadjuvant gefitinib, an EGFR inhibitor, might overcome biologic and clinical resistance to neoadjuvant anastrozole in a phase II placebo-controlled trial. Patients and methods: Postmenopausal women with stage I to IIIB hormone receptor-positive early breast cancer received anastrozole 1 mg daily for 16 weeks and were randomly assigned at a ratio of 2:5:5 to receive, in addition, gefitinib 250 mg/d orally for 16 weeks: placebo 1 tablet/d orally for 2 weeks and then gefitinib for 14 weeks or placebo for 16 weeks. The primary end point was biologic change in proliferation as measured by Ki67 at 2 and 16 weeks; the main secondary end point was overall objective response (OR). Results: Two hundred six women were randomly assigned. Mean changes in Ki67 with anastrozole and gefitinib versus anastrozole alone were -77.4% and -83.6%, respectively, between baseline and 16 weeks (geometric mean ratio = 1.37; 95% CI, 0.79 to 2.39; P = .26), -80.1% and -71.3% between baseline and 2 weeks (geometric mean ratio = 0.70; 95% CI, 0.39 to 1.25; P = .22) and -19.3% and -43% (geometric mean ratio = 1.42; 95% CI, 0.86 to 2.35; P = .16) between 2 and 16 weeks. ORs in the combination and anastrozole alone groups were 48% and 61% (estimated difference = -13.1%; 95% CI, -27.3% to 1.2%), respectively, with a nonsignificant trend against the combination (P = .08) and 48% versus 72% (estimated difference = -24.1%; 95% CI, -45.3% to -2.9%) in the progesterone-receptor-positive subgroup, which was significant (P = .03) and consistent with Ki67 changes. Common treatment-related adverse events included diarrhea, rash, alopecia, dry skin, and nausea. There was no evidence of a pharmacokinetic interaction. Conclusion: Addition of gefitinib to neoadjuvant anastrozole had no additional clinical or biologic effect, failing to support our original hypothesis.","For the study's purpose, increased skin-related or epidermal growth factor receptor (EGFR) expression may promote breast cancer resistance to hormonal therapy. We have studied if giving gefitinib, an EGFR blocker, first might overcome biologic and medical resistance to pre-treatment anastrozole (a drug commonly used for breast cancer) in a medical trial. The study included postmenopausal women (women who had their last period) with hormone receptor-specific, early breast cancer received anastrozole 1 mg daily for 16 weeks. Then, they were randomly assigned at a ratio of 2:5:5 to also receive (1) gefitinib 250 mg/d by mouth for 16 weeks, (2) dummy treatment 1 tablet/d by mouth for 2 weeks and then gefitinib for 14 weeks, or (3) dummy treatment for 16 weeks. The main measure was biologic change in cancer cell growth at 2 and 16 weeks. The main secondary measure was overall health improvement or objective response (OR). For the study's results, two hundred six women were randomly assigned. Average changes in cancer cell growth with anastrozole and gefitinib versus anastrozole alone were -77.4% and -83.6%, respectively, between start and 16 weeks, -80.1% and -71.3% between start and 2 weeks, and -19.3% and -43% between 2 and 16 weeks. ORs in the 2-drug-group and anastrozole alone group were 48% and 61%, respectively, and 48% versus 72% in the female-sex-hormone-specific subgroup, which was consistent with cancer cell growth changes. Common treatment-related side effects included diarrhea, rash, alopecia (hair loss or thinning), dry skin, and nausea. There was no evidence of a drug interaction. In conclusion, adding gefitinib to pre-treatment anastrozole had no additional clinical or biologic effect, failing to support our original theory." +"Background and objectives: Pathogenic variants in the neuronal sodium-channel α1-subunit gene (SCN1A) are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum including the severe childhood epilepsy, Dravet syndrome, characterized by drug-resistant seizures, intellectual disability and high mortality, and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome versus GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of SCN1A-related epilepsies. Methods: Retrospective multicenter cohort study comprising data from SCN1A-positive Dravet syndrome and GEFS+ patients consecutively referred for genetic testing (March 2001-June 2020) including age of seizure onset and a newly-developed SCN1A genetic score. A training cohort was used to develop multiple prediction models that were validated using two independent blinded cohorts. Primary outcome was the discriminative accuracy of the model predicting Dravet syndrome versus other GEFS+ phenotypes. Results: 1018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training cohort, 147/203 (72%) in validation cohort 1 and 60/72 (83%) in validation cohort 2. A high SCN1A genetic score 133.4 (SD, 78.5) versus 52.0 (SD, 57.5; p < 0.001) and young age of onset 6.0 (SD, 3.0) months versus 14.8 (SD, 11.8; p < 0.001) months, were each associated with Dravet syndrome versus GEFS+. A combined 'SCN1A genetic score and seizure onset' model separated Dravet syndrome from GEFS+ more effectively (area under the curve [AUC], 0.89 [95% CI, 0.86-0.92]) and outperformed all other models (AUC, 0.79-0.85; p < 0.001). Model performance was replicated in both validation cohorts 1 (AUC, 0.94 [95% CI, 0.91-0.97]) and 2 (AUC, 0.92 [95% CI, 0.82-1.00]). Discussion: The prediction model allows objective estimation at disease onset whether a child will develop Dravet syndrome versus GEFS+, assisting clinicians with prognostic counseling and decisions on early institution of precision therapies (http://scn1a-prediction-model.broadinstitute.org/). Classification of evidence: This study provides Class II evidence that a combined 'SCN1A genetic score and seizure onset' model distinguishes Dravet syndrome from other GEFS+ phenotypes.","For the study's background, we studied disease-causing types of the brain-located gene called SCN1A, which is the most frequent cause of epileptic seizures or epilepsy. Physical attributes make up a wide spectrum including the severe childhood epilepsy, Dravet syndrome, epilepsy characterized by drug-resistant seizures, lower intelligence, and high death risk, and the milder genetic epilepsy with fever-like seizures plus (GEFS+), characterized by normal intelligence. Early identification of a child's risk for developing Dravet syndrome versus GEFS+ is key for giving disease-modifying treatments when available before intelligence impairment come up. Our objective was to develop and verify a disease prediction model using medical and genetic biomarkers for early identification of SCN1A-related epilepsies. For the study's methods, it was a multicenter group study comprising data from previous SCN1A-positive Dravet syndrome and GEFS+ patients consistently treated with genetic testing (March 2001-June 2020). Data includes age of seizure start and a newly-developed SCN1A genetic score. A training group was used to develop multiple disease prediction models that were verified using two independent groups. The main measure was the accuracy of the model predicting Dravet syndrome versus other GEFS+ phenotypes. 1018 participants were included. The frequency of Dravet syndrome was 616/743 (83%) in the training group, 147/203 (72%) in test group 1 and 60/72 (83%) in test group 2. A high SCN1A genetic score - 133.4 versus 52.0 - and young age of start - 6.0 months versus 14.8 months - were each linked with Dravet syndrome versus GEFS+. A combined 'SCN1A genetic score and seizure onset' model separated Dravet syndrome from GEFS+ more effectively and outperformed all other models. Model performance was replicated in both test group 1 and 2. In short, the prediction model allows measurable estimation at disease start whether a child will develop Dravet syndrome versus GEFS+, helping clinicians with treatment counseling and decisions on early use of specific treatments. This study provides strong evidence that a combined 'SCN1A genetic score and seizure onset' model identifies Dravet syndrome from other GEFS+ phenotypes." +"Background: The EPIGENE network was created in 2014 by four multidisciplinary teams composed of geneticists, pediatric neurologists and neurologists specialized in epileptology and neurophysiology. The ambition of the network was to harmonize and improve the diagnostic strategy of Mendelian epileptic disorders using next-generation sequencing, in France. Over the years, five additional centers have joined EPIGENE and the network has been working in close collaboration, since 2018, with the French reference center for rare epilepsies (CRéER). Results: Since 2014, biannual meetings have led to the design of four successive versions of a monogenic epilepsy gene panel (PAGEM), increasing from 68 to 144 genes. A total of 4035 index cases with epileptic disorders have been analyzed with a diagnostic yield of 31% (n = 1265/4035). The top 10 genes, SCN1A, KCNQ2, STXBP1, SCN2A, SCN8A, PRRT2, PCDH19, KCNT1, SYNGAP1, and GRIN2A, account for one-sixth of patients and half of the diagnoses provided by the PAGEM. Conclusion: These results suggest that a gene-panel approach is an efficient first-tier test for the genetic diagnosis of Mendelian epileptic disorders. In a near future, French patients with ""drug-resistant epilepsies with seizure-onset in the first two-years of life"" can benefit from whole-genome sequencing (WGS), as a second line genetic screening with the implementation of the 2025 French Genomic Medicine Plan. The EPIGENE network has also promoted scientific collaborations on genetic epilepsies within CRéER.","As the article's background, the EPIGENE network was created in 2014 by four multi-specialty teams made up of geneticists, neurologists treating young children and neurologists specialized in epileptic seizures (or epilepsy) and brain make-up. The goal of the network was to group together and improve the identification strategy of genetic epileptic disorders using state-of-the-art gene tagging, in France. Over the years, five additional centers have joined EPIGENE. The network has been working closely, since 2018, with the French reference center for rare epilepsies (CRéER). Since 2014, biannual meetings have created four successive versions of a single-gene epilepsy gene panel (PAGEM), increasing from 68 to 144 genes. A total of 4035 patient cases with epileptic disorders have been analyzed with an identification accuracy of 31% (n = 1265/4035). The top 10 epileptic-related genes, SCN1A, KCNQ2, STXBP1, SCN2A, SCN8A, PRRT2, PCDH19, KCNT1, SYNGAP1, and GRIN2A, account for one-sixth of patients and half of the identifications provided by the PAGEM. In conclusion, these results suggest that a gene-panel approach is an efficient, gold-standard test for the genetic identification of genetic epileptic disorders. In a near future, French patients with ""drug-resistant epilepsies with seizure-onset in the first two-years of life"" can benefit from tagging their entire genome, as a secondary genetic screening with the use of the 2025 French Genomic Medicine Plan. The EPIGENE network has also promoted scientific partnerships on genetic epilepsies within CRéER." +"Background and purpose: In childhood epilepsy, genetic etiology is increasingly recognized in recent years with the advent of next generation sequencing. This has broadened the scope of precision medicine in intractable epilepsy, particularly epileptic encephalopathy (EE). Developmental disorder (DD) is an integral part of childhood uncontrolled epilepsy. This study was performed to investigate the genetic etiology of childhood epilepsy and DD. Methods: In this study, 40 children with epilepsy and DD with positive genetic mutation were included retrospectively. It was done in a tertiary care referral hospital of Bangladesh from January 2019 to December 2020. Genetic study was done by next generation sequencing. In all cases electroencephalography, neuroimaging was done and reviewed. Results: In total, 40 children were enrolled and the average age was 41.4±35.850 months with a male predominance (67.5%). Generalized seizure was the predominant type of seizure. Regarding the association, intellectual disability and attention deficit hyperactivity disorder was common. Seventeen cases had genetically identified early infantile EE and common mutations observed were SCN1A (3), SCN8A (2), SLC1A2 (2), KCNT1 (2), and etc. Five patients of progressive myoclonic epilepsy were diagnosed and the mutations identified were in KCTD7, MFSD8, and CLN6 genes. Three cases had mitochondrial gene mutation (MT-ND5, MT-CYB). Some rare syndromes like Gibbs syndrome, Kohlschütter-Tönz syndrome, Cockayne syndrome, Pitt-Hopkins syndrome and cerebral creatine deficiency were diagnosed. Conclusions: This is the first study from Bangladesh on genetics of epilepsy and DD. This will help to improve the understanding of genetics epilepsy of this region as well as contribute in administering precision medicine in these patients.","For the study's background, in childhood epilepsy, genetic causes are increasingly recognized in recent years with the use of gene labeling or sequencing. This has increased the scope of individualized medicine in unmanageable epileptic seizures or epilepsy, particularly epileptic encephalopathy (EE) (epilepsy that damages the brain). Developmental disorder (DD) (impairments in a child's growth) is an important part of childhood uncontrolled epilepsy. This study was performed to measure the genetic causes of childhood epilepsy and DD. In this study, 40 children with epilepsy and DD with genetic mutations were included via prior records. It was done in a specialized care hospital of Bangladesh from January 2019 to December 2020. Genetic study was done by state-of-the-art gene labeling or sequencing. In all cases electroencephalography (measuring electrical acitvity of the brain) and neuroimaging (imaging the brain) was done and reviewed. In total, 40 children were enrolled. The average age was 41.4±35.850 months with a male majority (67.5%). Generalized seizure was the main type of seizure. Regarding the links, reduced intelligence and attention deficit hyperactivity disorder or ADHD was common. Seventeen cases had genetically identified EE developed during infancy. Common gene mutations observed were SCN1A (3), SCN8A (2), SLC1A2 (2), KCNT1 (2), and etc (genes linked with epilepsy). Five patients of worsening, muscle-jerk-related epilepsy were identified. The mutations identified were in KCTD7, MFSD8, and CLN6 genes. Three cases had mitochondrial gene mutation (MT-ND5, MT-CYB) (genes that affect the mitochondria or the powerhouse of the cell). Some rare diseases like Gibbs syndrome (brain disorder with weak muscle tone), Kohlschütter-Tönz syndrome (genetic disorder with seizures), Cockayne syndrome (delayed development disorder), Pitt-Hopkins syndrome (child development disorder) and cerebral creatine deficiency (creatine-metabolizing disorder) were identified. In conclusion, this is the first study from Bangladesh on genetics of epilepsy and DD. This will help to improve the understanding of genetics epilepsy of this region and contribute in giving individualized medicine in these patients." +"Background: Glucose-transporter-1 deficiency syndrome (GLUT1-DS), due to SLC2A1 gene mutation, is characterized by early-onset seizures, which are often drug-resistant, developmental delay, and hypotonia. Hemiplegic migraine (HM) is a rare form of migraine, defined by headache associated with transient hemiplegia, and can be caused by mutations in either CACNA1A, ATP1A2, or SCN1A. Paroxysmal movements, other transient neurological disorders, or hemiplegic events can occur in GLUT1-DS patients with a mild phenotype. Case: We report on a girl with GLUT1-DS, due to SLC2A1 mutation, with a mild phenotype. In early childhood, she developed epilepsy and mild cognitive impairment, balance disorders, and clumsiness. At the age of 9, the patient reported a first hemiplegic episode, which regressed spontaneously. Over the next 3 years, two similar episodes occurred, accompanied by headache. Therefore, in the hypothesis of HM, genetic testing was performed and CACNA1A mutation was identified. The treatment with Lamotrigine avoided the recurrence of HM episodes. Discussion: To our knowledge, among the several cases of GLUT1-DS with HM symptoms described in the literature, genetic testing was only performed in two of them, which eventually proved to be negative. In all other cases, no other genes except for SLC2A1 were examined. Consequently, our patient would be the first description of GLUT1-DS with HM due to CACNA1A mutation. We would emphasize the importance of performing specific genetic testing in patients with GLUT1-DS with symptoms evocative of HM, which may allow clinicians to use specific pharmacotherapy.","Background: Glucose-transporter-1 deficiency syndrome (GLUT1-DS), an inability to transport sugar in the blood due to a change in the specific gene SLC2A1, is characterized by early-onset seizures, which are often drug-resistant, delay proper growth, and reduce muscle tone. Hemiplegic migraine (HM) is a rare form of migraine, defined by headache linked with temporary paralysis on one side of the body (hemiplegia). It can be caused by mutations in either CACNA1A, ATP1A2, or SCN1A, specific genes. Paroxysmal movements (or suddent fits), other temporary brain-related disorders, or hemiplegic events can occur in GLUT1-DS patients with mild effects. We describe a girl with GLUT1-DS, due to SLC2A1 mutation, with mild effects. In early childhood, she developed epilepsy and mild intelligence impairment, balance disorders, and clumsiness. At the age of 9, the patient reported a first hemiplegic episode, which healed randomly. Over the next 3 years, two similar episodes occurred, followed by headache. Therefore, in the theory of HM, genetic testing was performed and a specific CACNA1A gene mutation was found. The treatment with Lamotrigine (anti-seizure medication) avoided the reapparance of HM episodes. To our knowledge, among the several cases of GLUT1-DS with HM symptoms in the medical studies, genetic testing was only performed in two of them, which eventually found nothing. In all other cases, no other genes except for SLC2A1 were examined. Thus, our patient would be the first description of GLUT1-DS with HM due to the CACNA1A gene mutation. We would highlihgt the importance of performing specific genetic testing in patients with GLUT1-DS with symptoms similar to HM, which may allow clinicians to use specific drugs." +"Neurodevelopmental diseases are increasingly recognized to be caused by ""de novo"" variants with the expanding use of next-generation sequencing. The apparent de novo variants may actually be low-level hereditary parental mosaic variants, which could increase the recurrence risk of disease by >50% and is thought to be an underappreciated cause of neurodevelopmental diseases. Our study aimed to investigate the frequency of parental mosaicism in ""de novo"" neurodevelopmental diseases. A total of 237 patients (and parents) with neurodevelopmental diseases carrying apparent de novo pathogenic or likely pathogenic variants were recruited consecutively. Deep next-generation sequencing was performed on parental samples to identify parental mosaicism. Fourteen parental disease-causing mosaicism variants (3.0%) in 11 genes were detected with alternate allele frequency (AAF) 0.22%-34%. Three parents showed milder clinical phenotypes than their offspring with relatively high AAF (23.33%, 25%, 34% separately). One recurrent variant was identified prenatally. A review of cohort study on parental mosaicism in neurodevelopmental diseases was performed. Our study highlights that identifying the parental mosaic disease-causing variants especially the low-level mosaicism will contribute to improving the accuracy of genetic counseling and prenatal diagnosis for reproductive risks.","Brain-related development (neurodevelopment) diseases are increasingly recognized to be caused by new gene mutations (de novo variants) with the use of state-of-the-art gene labeling. These de novo variants may actually be inherited, which could increase the reapparance risk of disease by >50% and is thought to be an underappreciated cause of neurodevelopment diseases. Our study aimed to find the amount of inheritance in ""de novo"" neurodevelopmental diseases. A total of 237 patients (and parents) with neurodevelopmental diseases carrying apparent de novo disease-causing (pathogenic) or likely pathogenic variants were included. Gene labeling was performed on parental samples to identify parental gene make-up. Fourteen parental disease-causing gene types (3.0%) in 11 genes were detected with the amount of gene types ranging from 0.22%-34%. Three parents showed milder disease-related physical attributes than their offspring with relatively high amounts of gene types (23.33%, 25%, 34% separately). One reoccuring gene type was identified before birth. A review of group study on gene inheritance in neurodevelopmental diseases was performed. Our study highlights that identifying the inherited disease-causing gene types will contribute to improving the accuracy of genetic treatment and before-birth diagnosis for reproductive risks." +"Background: Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families. Methods: Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants. Results: We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified pathogenic variants in ASXL3 and STAC3 expanding the phenotypes associated with these genes. The most frequent cause of AMC was a primary involvement of skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is autosomal recessive (66.3% of patients). In sporadic patients born to non-consanguineous parents (n=60), de novo dominant autosomal or X linked variants were observed in 30 of them (50%). Conclusion: New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.","Background: Arthrogryposis multiplex congenita (AMC) is characterised by deforemed, rigid joints at birth in two or more body areas. AMC exhibits wide physical attributes and genetic types. Our goals were to improve the genetic identification rates of AMC, to test the added value of whole gene labeling compared with targeted gene labeling and to identify new genes in 315 unrelated undiagnosed AMC families. Several gene-related tools were used including gene mapping of disease-related genes in various groups, first in targeted gene labeling and then whole gene labeling. Gene sequencing was performed to identify or verify gene variants. We achieved disease gene identification in 52.7% of AMC patients including nine recently identified genes (CNTNAP1, MAGEL2, ADGRG6, ADCY6, GLDN, LGI4, LMOD3, UNC50 and SCN1A). Moreover, we identified disease-causing variants in ASXL3 and STAC3, expanding the physical attributes linked with these genes. The most frequent cause of AMC was linked to skeletal muscle (40%) followed by brain (22%). The most frequent mode of inheritance is from both parents (66.3% of patients). In irregular patients born to non-related parents (n=60), new, inherited or sex chromosome linked types were observed in 30 of them (50%). In conclusion, new genes recently identified in AMC represent 21% of causing genes in our group. A high amount of new gene types were observed, indicating that genes plays a prominent part in this developmental disease. Our data showed the added value of whole gene labeling when compared with targeted gene labeling due to the larger medical variance of some disease genes than expected and the identification of new genes." +"Objective: To describe the spectrum of being detected gene mutations in patients with epilepsy in clinical practice of neurologists specializing in epilepsy with an analysis of diagnosed epileptic syndromes, the characteristics of seizures, the timing of a genetic diagnosis, options and treatment effectiveness. Patients and methods: The study included 100 patients (40 boys, 60 girls) with epilepsy and/or epileptic encephalopathy and a gene mutation identified. The average age was 6.9±5.1 years. Through remote access, epilepsy specialists filled out a specially designed unified table containing information from outpatient case history. Results and discussion: There are patients with a wide range of gene mutations, the leading of which is a mutation in the SCN1A gene (15%). The main method (85%) of detection remains the sequencing of the last generation in the «Hereditary Epilepsy» panel. Years pass from the onset of the disease to the genetic diagnosis (Me - 3 years). In most cases, patients with severe (52% have epileptic encephalopathy, 88% have developmental disorders) and pharmacoresistant (mean amount of anti-epileptic drugs - 3.8±2.2, multitherapy - 70%) syndromes have undergone genetic testing. In the treatment of these patients epileptologists are increasingly (52%) use alternative methods: steroids, ketogenic diet and others. The absence of seizures was observed only in 46% of patients. Conclusion: Thus, in the outpatient practice of epileptologists, patients with a wide range of gene mutations are found. As a rule, these are patients with severe, therapy-resistant epileptic syndromes.","We aim to describe the spectrum of detected gene mutations in patients with epilepsy (brain disorder with seizures) in clinical practice of brain physicians specializing in epilepsy with an analysis of identified epileptic diseases, the characteristics of seizures, the timing of a genetic diagnosis, options and treatment effectiveness. The study included 100 patients (40 boys, 60 girls) with epilepsy and/or epileptic encephalopathy (epilepsy that leads to brain damage) and a gene mutation identified. The average age was 6.9±5.1 years. Through remote access, epilepsy specialists filled out a specially designed data table containing information from patient history. The results show there are patients with a wide range of gene mutations, the leading of which is a mutation in the specific gene called SCN1A (15%). The main method (85%) of detection remains the gene labeling of the last group in the «Hereditary Epilepsy� panel, groups of genes linked with epilepsy. Years pass from the start of the disease to the genetic diagnosis (average number is 3 years). In most cases, patients with severe (52% have epileptic encephalopathy, 88% have growth disorders) and drug-resistant (average amount of anti-epileptic drugs - 3.8±2.2, multi-treatment - 70%) diseases have undergone genetic testing. In the treatment of these patients, epilepsy specialists are increasingly (52%) using alternative methods: steroids, ketogenic (low-carb) diet and others. The lack of seizures was observed only in 46% of patients. In conclusion, in the practice of epilepsy specialists, patients with a wide range of gene mutations are found. As a rule, these are patients with severe, treatment-resistant epileptic diseases." +"Pathogenic variants in the voltage-gated sodium channel gene (SCN1A) are amongst the most common genetic causes of childhood epilepsies. There is considerable heterogeneity in both the types of causative variants and associated phenotypes; a recent expansion of the phenotypic spectrum of SCN1A associated epilepsies now includes an early onset severe developmental and epileptic encephalopathy with regression and a hyperkinetic movement disorder. Herein, we report a female with a developmental and degenerative epileptic-dyskinetic encephalopathy, distinct and more severe than classic Dravet syndrome. Clinical diagnostics indicated a paternally inherited c.5053G>T; p. A1685S variant of uncertain significance in SCN1A. Whole-exome sequencing detected a second de novo mosaic (18%) c.2345G>A; p. T782 I likely pathogenic variant in SCN1A (maternal allele). Biophysical characterization of both mutant channels in a heterologous expression system identified gain-of-function effects in both, with a milder shift in fast inactivation of the p. A1685S channels; and a more severe persistent sodium current in the p. T782I. Using computational models, we show that large persistent sodium currents induce hyper-excitability in individual cortical neurons, thus relating the severe phenotype to the empirically quantified sodium channel dysfunction. These findings further broaden the phenotypic spectrum of SCN1A associated epilepsies and highlight the importance of testing for mosaicism in epileptic encephalopathies. Detailed biophysical evaluation and computational modelling further highlight the role of gain-of-function variants in the pathophysiology of the most severe phenotypes associated with SCN1A.","Disease-causing variants in the sodium transporter gene (SCN1A) are amongst the most common genetic causes of childhood epilepsies (a brain disorder leading to seizures). There is considerable variation in both the types of causative gene types and associated physical effects. A recent increase of the physical effects of SCN1A-related epilepsies now includes an early severe growth and epileptic encephalopathy (epilepsy leading to brain damage) with reduction in growth and a abnormal movement disorder. We report a female with a growth-related and worsening epileptic-movement-related encephalopathy, distinct and more severe than classic Dravet syndrome (lifelong epilepsy). Medical diagnostics indicated a inherited gene type of SCN1A. Whole-body gene labeling found a second inherited, likely disease-causing gene type of SCN1A. Biophysical measurements of both mutant gene types found gain-of-function effects in both SCN1A products; and a more severe persistent physical effect from the second gene type. Using mathematical analysis, we show that large persistent electrical activity from sodium in the body causes hyper-excitability in brain neurons, thus linking the severe physical effects to the sodium current dysfunction. These findings further broaden the spectrum of physical effects of SCN1A linked epilepsies and highlight the importance of testing for inheritance in epileptic encephalopathies. Detailed biophysical tests and mathematical analysis further highlight the role of gain-of-function gene types in the disease-causing attributes of the most severe physical effects linked with SCN1A." +"Background: SCN1 A is one of the most important epilepsy-related genes, with pathogenic variants leading to a range of phenotypes with varying disease severity. Different modifying factors have been hypothesized to influence SCN1A-related phenotypes. We investigate the presence of rare and more common variants in epilepsy-related genes as potential modifiers of SCN1A-related disease severity. Methods: 87 patients with SCN1A-related epilepsy were investigated. Whole-exome sequencing was performed by the Beijing Genomics Institute (BGI). Functional variants in 422 genes associated with epilepsy and/or neuronal excitability were investigated. Differences in proportions of variants between the epilepsy genes and four control gene sets were calculated, and compared to the proportions of variants in the same genes in the ExAC database. Results: Statistically significant excesses of variants in epilepsy genes were observed in the complete cohort and in the combined group of mildly and severely affected patients, particularly for variants with minor allele frequencies of <0.05. Patients with extreme phenotypes showed much greater excesses of epilepsy gene variants than patients with intermediate phenotypes. Conclusion: Our results indicate that relatively common variants in epilepsy genes, which would not necessarily be classified as pathogenic, may play a large role in modulating SCN1A phenotypes. They may modify the phenotypes of both severely and mildly affected patients. Our results may be a first step toward meaningful testing of modifier gene variants in regular diagnostics for individual patients, to provide a better estimation of disease severity for newly diagnosed patients.","Background: SCN1 A is one of the most important epilepsy-related genes, with disease-causing variants leading to a range of physical effects with varying disease severity. Different attributes have been hypothesized to influence SCN1A-related physical effects. We investigate the presence of rare and more common gene types in epilepsy-related genes as possible influencers of SCN1A-related disease severity. In the study's methods, 87 patients with SCN1A-related epilepsy were investigated. Whole-body gene labeling was performed by the Beijing Genomics Institute (BGI). Functional gene types in 422 genes linked with epilepsy and/or brain excitability were checked. Differences in amounts of gene types between the epilepsy genes and four unrelated gene sets were calculated and compared to the amounts of gene types in the same genes in a specific gene database. The study results show that excesses of gene types in epilepsy genes were observed in the complete group and in the combined group of mildly and severely affected patients, espeically for gene types with minor gene frequencies of <0.05. Patients with severe physical effects showed much greater excesses of epilepsy gene types than patients with medium physical effects. In conclusion, our results show that relatively common gene types in epilepsy genes, which would not necessarily be classified as disease-causing, may play a large role in influencing SCN1A physical effects. They may influence the physical effects of both severely and mildly affected patients. Our results may be a first step toward meaningful testing of influencing gene types in regular diagnostics for individual patients, to provide a better estimation of disease severity for newly identified patients." +"Purpose: The vast majority of mutations responsible for epilepsy syndromes such as genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome (DS) occur in the gene encoding the type 1 alpha subunit of neuronal voltage-gated sodium channel (SCN1A). Methods: 63 individuals presenting with either DS or GEFS + syndrome phenotype were screened for SCN1A gene mutation using Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Results: Our research study identified 15 novel pathogen mutations in the SCN1A gene of which 12 appeared to be missense mutations with addition of two frameshift-deletions and one in-frame deletion. The distribution of clinical phenotypes in patients carrying SCN1A mutations was as follows: twelve patients had classical DS, three patients had GEFS + syndrome and two relatives of DS patients were suffering from febrile seizures. Conclusions: Our study highlights the phenotypic and genotypic heterogeneities of DS and GEFS + with the important aim of gaining a deeper understanding of SCN1A-related disorders. This study also represents the first genetic analysis of the SCN1A gene in a Hungarian cohort with the DS and GEFS + syndrome phenotype.","For the study's purpose, the vast majority of mutations for epilepsy (a brain disease causing seizures) syndromes such as genetic epilepsy with fever-related seizures plus (GEFS+) and Dravet syndrome (DS) (lifelong epilepsy) occur in the specific gene SCN1A. For the study's methods, 63 individuals with either DS or GEFS + syndrome were tested for SCN1A gene mutation using gene labeling techniques. Our research study found 15 new disease-cuasing mutations in the SCN1A gene, of which 12 appeared to be mutations with three deletions, two of which shifted the entire gene. The distribution of clinical physical effects in patients carrying SCN1A mutations was as follows: twelve patients had classical DS, three patients had GEFS + syndrome and two relatives of DS patients were suffering from fever-related seizures. In conclusion, our study highlights the physical effects and gene-related differences of DS and GEFS + with the important aim of gaining a deeper understanding of SCN1A-related disorders. This study also represents the first genetic analysis of the SCN1A gene in a Hungarian group with the DS and GEFS + syndrome physical make-up." +"Elevated inflammatory cytokines and chronic pain are associated with shorter leukocyte telomere length (LTL), a measure of cellular aging. Micronutrients, such as 25-hydroxyvitamin D (vitamin D) and omega 3, have anti-inflammatory properties. Little is known regarding the relationships between vitamin D, omega 6:3 ratio, LTL, inflammation, and chronic pain. We investigate associations between vitamin D, omega 6:3 ratio, LTL, and C-reactive protein (CRP) in people living with/without chronic pain overall and stratified by chronic pain status. A cross-sectional analysis of 402 individuals (63% women, 79.5% with chronic pain) was completed. Demographic and health information was collected. Chronic pain was assessed as pain experienced for at least three months. LTL was measured in genomic DNA isolated from blood leukocytes, and micronutrients and CRP were measured in serum samples. Data were analyzed with general linear regression. Although an association between the continuous micronutrients and LTL was not observed, a positive association between omega 6:3 ratio and CRP was detected. In individuals with chronic pain, based on clinical categories, significant associations between vitamin D, omega 6:3 ratio, and CRP were observed. Findings highlight the complex relationships between anti-inflammatory micronutrients, inflammation, cellular aging, and chronic pain.","Increased infection-fighting (inflammatory) molecules and lasting (chronic) pain are associated with shorter white blood cell gene end or telomere length (LTL), a measure of cellular aging. Micronutrients, such as 25-hydroxyvitamin D (vitamin D) and omega 3, have anti-inflammatory properties. Little is known about the relationships between vitamin D, omega 6:3 ratio, LTL, inflammation, and chronic pain. We investigate links between vitamin D, omega 6:3 ratio, LTL, and C-reactive protein (CRP, a marker of imflammation) in people living with/without chronic pain overall and grouped by chronic pain status. An analysis of 402 individuals (63% women, 79.5% with chronic pain) was done. Basic and health information was collected. Chronic pain was measured as pain experienced for at least three months. LTL was measured in gene DNA isolated from blood white blood cells, and micronutrients and CRP were measured in blood samples. Data were analyzed with general mathematical analysis. Although a link between the continuous micronutrients and LTL was not found, a positive link between omega 6:3 ratio and CRP was detected. In individuals with chronic pain, based on medical categories, significant links between vitamin D, omega 6:3 ratio, and CRP were observed. Findings show the complex relationships between anti-inflammatory micronutrients, inflammation, cellular aging, and chronic pain." +"Polyunsaturated fatty acids (PUFAs) are involved both in immune system regulation and inflammation. In particular, within the PUFAs category, omega-3 (?-3) may reduce inflammation, whereas omega-6 (?-6) PUFAs are generally considered to have a proinflammatory effect. Recent evidence highlights an imbalance in the ?-3:?-6 ratio with an increased intake of ?-6, as a consequence of the shift towards a westernized diet. In critical age groups such as infants, toddlers and young children, as well as pregnant and lactating women or fish allergic patients, ?-3 intake may be inadequate. This review aims to discuss the potential beneficial effects of PUFAs on pediatric food allergy prevention and treatment, both at prenatal and postnatal ages. Data from preclinical studies with PUFAs supplementation show encouraging effects in suppressing allergic response. Clinical studies results are still conflicting about the best timing and dosages of supplementation and which individuals are most likely to benefit; therefore, it is still not possible to draw firm conclusions. With regard to food-allergic children, it is still debated whether PUFAs could slow disease progression or not, since consistent data are lacking. In conclusion, more data on the effects of ?-3 PUFAs supplementation alone or in combination with other nutrients are warranted, both in the general and food allergic population.","Polyunsaturated fatty acids (PUFAs) are involved both in immune system monitoring or regulation and infection-fighting processes such as inflammation. In particular, within the PUFAs category, omega-3 (?-3) may reduce inflammation, whereas omega-6 (?-6) PUFAs are generally considered to have an inflammatory effect. Recent evidence shows an imbalance in the ?-3:?-6 ratio with an increased intake of ?-6, as a result of the shift towards a westernized diet. In important age groups such as infants, toddlers and young children, as well as pregnant and milk-giving women or fish allergic patients, ?-3 intake may be improper. This article aims to discuss the potential beneficial effects of PUFAs on child-related food allergy prevention and treatment, both at pre-birth and post-birth ages. Data from preclinical studies with PUFAs supplementation show encouraging effects in reducing allergic response. Medical study results are still conflicting about the best timing and amounts of supplementation and which individuals are most likely to benefit. Therefore, it is still not possible to draw firm conclusions. Regarding food-allergic children, it is still argued whether PUFAs could slow disease worsening or not, since consistent data are lacking. In conclusion, more data on the effects of ?-3 PUFAs supplementation alone or in combination with other nutrients are needed, both in the general and food allergic population." +"Background/aim: Breast cancer is the most common type of cancer among women around the world and the leading cause of cancer-related death among women. The knowledge about modifiable risk factors, such as diet, can be an acceptable, cheap and non-pharmacological prevention tool. The aim of this study was to investigate the association between dietary fat, dietary fatty acids, fish intake, and breast cancer in women. Patients and methods: A case-control study was designed. A total of 201 consecutive, newly diagnosed, polish female cancer patients (mean age: 58 years) and 201 one-to-one age-matched controls were enrolled. A standardized questionnaire assessing various socio-demographic, clinical, lifestyle, and dietary characteristics was applied via face-to-face interviews. Detailed dietary intake information was assessed using a validated Food Frequency Questionnaire. Odds ratios (OR) and 95% confidence intervals (95%CI) were obtained using multiple unconditional logistic regression models controlling for non-dietary and dietary potential confounders. Results: Consumption of polyunsaturated fats (PUFA) over 10% of total energy intake was associated with a significantly lower risk of breast cancer compared to low intake of PUFA (OR=0.4, 95%CI=0.19-0.85). Low (<0.2) omega-3/ omega-6 ratio (OR=2.04, 95%CI=0.996-4.17), fish consumption less than once every six months (OR=3.37, 95%CI=1.57-7.23) and being overweight (OR=2.07, 95%CI=1.3-3.3) were associated with increased risk of breast cancer. Residents of rural areas had a significantly higher risk compared to women from urban areas (OR=1.8, 95%CI=1.06-3.03). Conclusion: High intake of PUFA can decrease the risk of breast cancer, while the low omega-3/omega-6 ratio increases the risk. In addition, overweight state, eliminating fish from the diet and living in rural areas can also increase the risk of breast cancer.","For this study's background, breast cancer is the most common type of cancer among women around the world and the leading cause of cancer-related death among women. The knowledge about changeable risk factors, such as diet, can be an acceptable, cheap and non-drug prevention tool. The aim of this study was to check the link between dietary fat, dietary fatty acids, fish intake, and breast cancer in women. A patient study was designed. A total of 201 newly diagnosed, polish female cancer patients (average age: 58 years) and 201 age-matched patients without cancer were included. A standard questionnaire measuring various socio-demographic, clinical, lifestyle, and dietary characteristics was applied via face-to-face interviews. Detailed dietary intake information was measured using a verified diet questionnaire. Results were obtained using statistical models controlling for non-dietary and dietary potential confounders. Consumption of polyunsaturated fats (PUFA) over 10% of total energy intake was linked with a significantly lower risk of breast cancer compared to low intake of PUFA. Low (<0.2) omega-3/ omega-6 ratio, fish consumption less than once every six months and being overweight were linked with increased risk of breast cancer. Residents of rural areas had a much higher risk compared to women from urban areas. In conclusion, high intake of PUFA can decrease the risk of breast cancer, while the low omega-3/omega-6 ratio increases the risk. In addition, being overweight, eliminating fish from the diet and living in rural areas can also increase the risk of breast cancer." +"There is evidence that alteration in plasma fatty acid composition may play a role in certain neurological disorders. This case control study was conducted to evaluate the association between plasma fatty acid levels and mental retardation in Korean children. Plasma phospholipid fatty acids, plasma lipids, dietary fatty acids and selected nutrients were measured in 31 mentally retarded boys (mean age 9.93 +/-1.5 yrs) and matched controls. Total plasma omega-3 fatty acids (Sigmaw3), docosahexaenoic acid (DHA) and high density lipoprotein (HDL) concentrations were significantly lower and the Sigmaomega-6/Sigmaomega-3 ratio was significantly higher in cases than in controls. The odds in favor of mental retardation increased by 69 % for each unit increase in the Sigmaomega-6/ Sigmaomega-3 ratio (adjusted odds ratio = 1.69, 95% CI = 1.25-2.29). Significant variation in plasma Sigmaomega-3 and the Sigmaomega-6/ Sigmaomega-3 ratio was explained by mental retardation and plasma HDL concentrations (45% and 37 % respectively). There was a significant inverse association between plasma DHA and mental retardation. For each unit increase in plasma DHA, odds of mental retardation decreased by 74 %. There was no significant difference in either total dietary fat or fatty acids intakes between cases and controls. The energy intake of cases was significantly higher than the controls. These results suggest that proportion of plasma Sigmaomega-3 fatty acids, particularly, DHA, and the Sigmaomega-6/ Sigmaomega-3 ratio are associated with mental retardation in children in this study.","There is evidence that changes in blood fatty acid make-up may play a role in certain brain disorders. This patient study was conducted to test the link between blood fatty acid levels and mental retardation in Korean children. Blood fatty acids, blood fat levels, dietary fatty acids and selected nutrients were measured in 31 mentally retarded boys (average age 9.93 +/-1.5 yrs) and normal boys. Total blood omega-3 fatty acids (Sigmaw3), docosahexaenoic acid (DHA; specific omega-3 fatty acids) and high density lipoprotein (HDL - good cholesterol) concentrations were much lower. The Sigmaomega-6/Sigmaomega-3 ratio was much higher in affectedpatients than in normal patients. The odds in favor of mental retardation increased by 69 % for each unit increase in the Sigmaomega-6/ Sigmaomega-3 ratio. Significant variation in blood Sigmaomega-3 and the Sigmaomega-6/ Sigmaomega-3 ratio was explained by mental retardation and blood HDL concentrations (45% and 37 % respectively). There was a significant opposite link between blood DHA and mental retardation. As one goes up, the other goes down. For each unit increase in blood DHA, odds of mental retardation decreased by 74 %. There was no significant difference in either total dietary fat or fatty acids intakes between affected patients and normal patients. The energy intake of affected patients was significantly higher than the healthy patients. These results suggest that amount of plasma Sigmaomega-3 fatty acids, particularly, DHA, and the Sigmaomega-6/ Sigmaomega-3 ratio are linked with mental retardation in children in this study." +"Sickle cell disease (SCD) is a hematologic disorder with complex pathophysiology that includes chronic hemolysis, vaso-occlusion and inflammation. Increased leukocyte-erythrocyte-endothelial interactions, due to upregulated expression of adhesion molecules and activated endothelium, are thought to play a primary role in initiation and progression of SCD vaso-occlusive crisis and end-organ damage. Several new pathophysiology-based therapeutic options for SCD are being developed, chiefly targeting the inflammatory pathways. Omega-3 fatty acids are polyunsaturated fatty acids that are known to have effects on diverse physiological processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the principal biologically active omega-3 fatty acids. The therapeutic effects of DHA and EPA on chronic inflammatory disorders and cardiovascular diseases are well recognized. The therapeutic effects of omega-3 fatty acids are attributed to their anti-inflammatory and anti-thrombotic eicosanoids, and the novel class of EPA and DHA derived lipid mediators: resolvins, protectins and maresins. Blood cell membranes of patients with SCD have abnormal fatty acids composition characterized by high ratio of pro-inflammatory arachidonic acid (AA) to anti-inflammatory DHA and EPA (high omega-6/omega-3 ratio). In addition, experimental and clinical studies provide evidence that treatment with DHA does confer improvement in rheological properties of sickle RBC, inflammation and hemolysis. The clinical studies have shown improvements in VOC rate, markers of inflammation, adhesion, and hemolysis. In toto, the results of studies on the therapeutic effects of omega-3 fatty acids in SCD provide good body of evidence that omega-3 fatty acids could be a safe and effective treatment for SCD.","Sickle cell disease (SCD) is a blood disorder with complex disease effects that includes lasting (chronic) hemolysis (red blood cell destruction), vaso-occlusion (blood flow blockage) and inflammation (infection-fighting processes). Increased white blood cell-red blood cell-boundary cell interactions, due to increases expression of sticking molecules and activated boundary cells, are thought to play a main role in starting and developing of SCD vaso-occlusive events and organ damage. Several new disease effect-based treatments for SCD are being developed, chiefly targeting the inflammatory pathways. Omega-3 fatty acids are polyunsaturated fatty acids that are known to have effects on many biological processes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the main biologically active omega-3 fatty acids. The helpful effects of DHA and EPA on chronic inflammatory disorders and heart-related or cardiovascular diseases are well recognized. The helpful effects of omega-3 fatty acids are linked to their anti-inflammatory and anti-thrombotic (blood clotting) eicosanoids (signaling molecules), and the new class of EPA and DHA derived fat level influencers: resolvins, protectins and maresins (other fatty-acid-related molecules). Blood cell membranes or boundaries of patients with SCD have abnormal fatty acids composition characterized by high ratio of pro-inflammatory arachidonic acid (AA) to anti-inflammatory DHA and EPA (high omega-6/omega-3 ratio). Also, experimental and clinical studies provide evidence that treatment with DHA does lead to improvement in blood cell deforming properties of sickle RBC, inflammation and hemolysis. The clinical studies have shown improvements in vaso-occlusion crisis (VOC) rate, markers of inflammation, sticking molecules, and hemolysis. In total, the results of studies on the helpful effects of omega-3 fatty acids in SCD provide a good body of evidence that omega-3 fatty acids could be a safe and effective treatment for SCD." +"Background: Atopic dermatitis is a common childhood disease, potentially influenced by prenatal nutritional exposures such as polyunsaturated fatty acids (PUFAs). Objective: In a racially diverse cohort, we hypothesized that childhood atopic dermatitis would be associated with higher prenatal omega-6 (n-6) and lower omega-3 (n-3) PUFAs. Methods: We included mother-child dyads, births 2006 to 2011, enrolled in the University of Tennessee Health Sciences Center Conditions Affecting Neurocognitive Development in Early Childhood cohort. Primary exposures included second trimester plasma n-3 and n-6 PUFA status and the ratio of the two (n-6:n-3). We assessed child current atopic dermatitis symptoms in the previous 12 months at age approximately 4 to 6 years. We investigated the association between PUFA exposures and atopic dermatitis using multivariable logistic regression, adjusting for potential confounders. We assessed for effect modification by maternal prenatal smoking, atopic disease history, and child sex. Results: Among 1131 women, 67% were African American and 42% had an atopic disease history; 17% of children had atopic dermatitis. Higher prenatal n-6 PUFAs were associated with increased relative odds of child atopic dermatitis (adjusted odds ratio: 1.25; confidence interval: 1.01-1.54 per interquartile range difference), and interaction models demonstrated that this association was seen in dyads in which the women had a history of atopic disease. Neither prenatal n-3 PUFAs nor n-6:n-3 were associated with child atopic dermatitis. Conclusion: In this racially diverse cohort, higher second trimester n-6 PUFAs were associated with atopic dermatitis in children of women with atopy. PUFAs may represent a modifiable risk factor for atopic dermatitis, particularly in individuals with a familial predisposition.","As background for this study, atopic dermatitis (eczema) is a common childhood disease, potentially influenced by pre-birth nutritional exposures such as polyunsaturated fatty acids (PUFAs). As the objective for this study, in a racially diverse group, we hypothesized that childhood atopic dermatitis would be linked with higher pre-birth omega-6 (n-6) and lower omega-3 (n-3) PUFAs. We included mother-child groups, births 2006 to 2011, enrolled in the University of Tennessee Health Sciences Center Conditions Affecting Neurocognitive (brain-related intelligence) Development in Early Childhood group. Main events included second trimester blood n-3 and n-6 PUFA status and the ratio of the two (n-6:n-3). We measured child current atopic dermatitis symptoms in the previous 12 months of age approximately 4 to 6 years. We investigated the link between PUFA exposures and atopic dermatitis using mathematical analysis. We measured for effect modification by maternal pre-birth smoking, atopic (allergy-related) disease history, and child sex. The results include among 1131 women, 67% were African American and 42% had an atopic disease history; 17% of children had atopic dermatitis. Higher pre-birth n-6 PUFAs were linked with increased relative odds of child atopic dermatitis, and statistical models show that this link was seen in two-member groups in which the women had a history of atopic disease. Neither pre-birth n-3 PUFAs nor n-6:n-3 were linked with child atopic dermatitis. In conclusion, in this racially diverse cohort, higher second trimester n-6 PUFAs were linked with atopic dermatitis in children of women with atopy. PUFAs may represent a modifiable risk factor for atopic dermatitis, especially in individuals with an inherited risk factor." +"Evidence for a relationship between omega-6/omega-3 (n-6/n-3) polyunsaturated fatty acid (PUFA) ratio and obesity in humans is inconsistent, perhaps due to differences in dietary intake or metabolism of PUFAs between different subsets of the population. Since chronic inflammation is central to obesity and inflammatory pathways are regulated by PUFAs, the objective of this study was to examine whether variants in the NFKB1 gene, an upstream regulator of the inflammatory response, modify the association between the n-6/n-3 ratio (from diet and plasma) and anthropometric traits in a multiethnic/multiracial population of young adults. Participants' (n = 898) dietary PUFA intake was assessed using a food frequency questionnaire and plasma PUFA concentrations by gas chromatography. Nine tag single nucleotide polymorphisms (SNP) in NFKB1 were genotyped. Significant interactions were found between racial/ethnic groups and plasma n-6/n-3 ratio for body mass index (BMI) (p = 0.02) and waist circumference (WC) (p = 0.007). Significant interactions were also observed between racial/ethnic groups and three NFKB1 genotypes (rs11722146, rs1609798, and rs230511) for BMI and WC (all p ? 0.04). Significant interactions were found between two NFKB1 genotypes and plasma n-6/n-3 ratio for BMI and WC (rs4648090 p = 0.02 and 0.03; rs4648022 p = 0.06 and 0.04, respectively). Our findings suggest that anthropometric traits may be influenced by a unique combination of n-6/n-3 ratio, racial/ethnic background, and NFKB1 genotypes.","Evidence for a link between omega-6/omega-3 (n-6/n-3) polyunsaturated fatty acid (PUFA) ratio and obesity in humans is inconsistent, likely due to differences in diet or metabolism of PUFAs between different groups. Since chronic (long-lasting) inflammation (infection-fighting processes) is central to obesity and inflammatory pathways are regulated by PUFAs, the objective of this study was to examine whether gene types in the NFKB1 gene, a regulator of the inflammatory response, modify the link between the n-6/n-3 ratio (from diet and blood) and anthropometric traits (human body proportions) in a multiethnic/multiracial group of young adults. Participants' (n = 898) diet PUFA intake was measured using a food frequency questionnaire and blood PUFA levels. Nine gene mutations in NFKB1 were found. Significant links were found between racial/ethnic groups and plasma n-6/n-3 ratio for body mass index (BMI) and waist circumference (WC). Significant links were also found between racial/ethnic groups and three NFKB1 gene types for BMI and WC. Significant link were found between two NFKB1 genotypes and blood n-6/n-3 ratio for BMI and WC. Our findings suggest that anthropometric traits may be influenced by a special combination of n-6/n-3 ratio, racial/ethnic background, and NFKB1 gene ty[es." +"Maternal obesity is associated with adverse offspring outcomes. Inflammation and deficiency of anti-inflammatory nutrients like omega(n)-3 polyunsaturated fatty acids (PUFA) may contribute to these associations. Fetal supply of n-3 PUFA is dependent on maternal levels and studies have suggested that improved offspring outcomes are associated with higher maternal intake. However, little is known about how maternal obesity affects the response to n-3 supplementation during pregnancy. We sought to determine (1) the associations of obesity with PUFA concentrations and (2) if the systemic response to n-3 supplementation differs by body mass index (BMI). This was a secondary analysis of 556 participants (46% lean, 28% obese) in the Maternal-Fetal Medicine Units Network trial of n-3 (Docosahexaenoic acid (DHA) + Eicosapentaenoic acid (EPA)) supplementation, in which participants had 2g/day of n-3 (n = 278) or placebo (n = 278) from 19 to 22 weeks until delivery. At baseline, obese women had higher plasma n-6 arachidonic acid concentrations (?: 0.96% total fatty acids; 95% Confidence Interval (CI): 0.13, 1.79) and n-6/n-3 ratio (?: 0.26 unit; 95% CI: 0.05, 0.48) compared to lean women. In the adjusted analysis, women in all BMI groups had higher n-3 concentrations following supplementation, although obese women had attenuated changes (? = -2.04%, CI: -3.19, -0.90, interaction p = 0.000) compared to lean women, resulting in a 50% difference in the effect size. Similarly, obese women also had an attenuated reduction (? = 0.94 units, CI: 0.40, 1.47, interaction p = 0.046) in the n-6/n-3 ratio (marker of inflammatory status), which was 65% lower compared to lean women. Obesity is associated with higher inflammation and with an attenuated response to n-3 supplementation in pregnancy.","Maternal obesity is linked with harmful offspring outcomes. Inflammation (infection-fighting processes) and lack of anti-inflammatory nutrients like omega(n)-3 polyunsaturated fatty acids (PUFA) may contribute to these links. Fetal supply of n-3 PUFA is dependent on maternal levels. Studies have suggested that improved offspring results are linked with higher maternal intake. However, little is known about how maternal obesity affects the response to n-3 supplementation during pregnancy. We sought to determine (1) the links of obesity with PUFA concentrations and (2) if the full-body response to n-3 supplementation differs by body mass index (BMI). This was a secondary analysis of 556 participants (46% lean, 28% obese) in the Maternal-Fetal Medicine Units Network trial of n-3 (Docosahexaenoic acid (DHA) + Eicosapentaenoic acid (EPA) - specific omega-3 fatty acids) supplementation, in which participants had 2g/day of n-3 or sham treatment from 19 to 22 weeks until delivery. At start, obese women had higher blood n-6 arachidonic acid (specific omega-6 fatty acid) concentrations and n-6/n-3 ratio compared to lean women. In the adjusted analysis, women in all BMI groups had higher n-3 concentrations following supplementation, although obese women had reduced changes compared to lean women, resulting in a 50% difference. Similarly, obese women also had a smaller reduction in the n-6/n-3 ratio (marker of inflammatory status), which was 65% lower compared to lean women. Obesity is linked with higher inflammation and with a weakened response to n-3 supplementation in pregnancy." +"Background: Attention deficit hyperactivity disorder (ADHD) is a debilitating behavioural disorder affecting daily ability to function, learn, and interact with peers. This publication assesses the role of omega-3/6 fatty acids in the treatment and management of ADHD. Methods: A systematic review of 16 randomised controlled trials was undertaken. Trials included a total of 1,514 children and young people with ADHD who were allocated to take an omega-3/6 intervention, or a placebo. Results: Of the studies identified, 13 reported favourable benefits on ADHD symptoms including improvements in hyperactivity, impulsivity, attention, visual learning, word reading, and working/short-term memory. Four studies used supplements containing a 9 : 3 : 1 ratio of eicosapentaenoic acid : docosahexaenoic acid : gamma linolenic acid which appeared effective at improving erythrocyte levels. Supplementation with this ratio of fatty acids also showed promise as an adjunctive therapy to traditional medications, lowering the dose and improving the compliance with medications such as methylphenidate. Conclusion: ADHD is a frequent and debilitating childhood condition. Given disparaging feelings towards psychostimulant medications, omega-3/6 fatty acids offer great promise as a suitable adjunctive therapy for ADHD.","As the study's background, attention deficit hyperactivity disorder (ADHD) is a harmful behavioural disorder affecting daily ability to function, learn, and interact with peers. This publication measures the role of omega-3/6 fatty acids in the treatment and management of ADHD. A review of 16 randomised controlled trials was done. Trials included a total of 1,514 children and young people with ADHD who were given either an omega-3/6 treatment or a dummy treatment. Of the studies identified, 13 reported helpful benefits on ADHD symptoms including improvements in hyperactivity, impulsivity, attention, visual learning, word reading, and working/short-term memory. Four studies used supplements containing a 9 : 3 : 1 ratio of eicosapentaenoic acid (omega-3) : docosahexaenoic acid (omega-3) : gamma linolenic acid (omega-6) which appeared effective at improving red blood cell levels. Supplementation with this ratio of fatty acids also showed promise as a secondary therapy to traditional medications, lowering the dose and improving the compliance with medications such as methylphenidate (stimulant to treat ADHD). In conclusion, ADHD is a frequent and harmful childhood condition. Given negative feelings towards psychostimulant medications, omega-3/6 fatty acids offer great promise as a suitable secondary therapy for ADHD." +"Background: The ?-6 (n-6) to ?-3 (n-3) fatty acid (FA) ratio (n-6:n-3 ratio) was previously shown to be a predictor of executive function performance in children aged 7-9 y. Objective: We aimed to replicate and extend previous findings by exploring the role of the n-6:n-3 ratio in executive function performance. We hypothesized that there would be an interaction between n-3 and the n-6:n-3 ratio, with children with low n-3 performing best with a low ratio, and those with high n-3 performing best with a high ratio. Design: Children were recruited on the basis of their consumption of n-6 and n-3 FAs. The executive function performance of 78 children aged 7-12 y was tested with the use of the Cambridge Neuropsychological Test Automated Battery and a planning task. Participants provided blood for plasma FA quantification, and the caregiver completed demographic and activity questionnaires. We investigated the role of the n-6:n-3 ratio in the entire sample and separately in children aged 7-9 y (n = 41) and 10-12 y (n = 37). Results: Dietary and plasma n-6:n-3 ratio and n-3 predicted performance on working memory and planning tasks in children 7-12 y old. The interaction between dietary n-6:n-3 ratio and n-3 predicted the number of moves required to solve the most difficult planning problems in children aged 7-9 y and those aged 10-12 y, similar to results from the previous study. There was also an interaction between the plasma n-6:n-3 ratio and n-3 predicting time spent thinking through the difficult 5-move planning problems. The n-6:n-3 ratio and n-3 predicted executive function performance differently in children aged 7-9 y and in those aged 10-12 y, indicating different optimal FA balances across development. Conclusions: The n-6:n-3 ratio is an important consideration in the role of FAs in cognitive function, and the optimal balance of n-6 and n-3 FAs depends on the cognitive function and developmental period studied.","As the study's background, the ?-6 (n-6) to ?-3 (n-3) fatty acid (FA) ratio (n-6:n-3 ratio) was previously shown to be a predictor of brain function performance in children aged 7-9 y. For the objective, we aimed to replicate and extend previous findings by exploring the role of the n-6:n-3 ratio in brain function performance. We hypothesized that there would be an link between n-3 and the n-6:n-3 ratio, with children with low n-3 performing best with a low ratio, and those with high n-3 performing best with a high ratio. For the study design, children were recruited on the basis of their consumption of n-6 and n-3 FAs. The brain function performance of 78 children aged 7-12 y was tested with the use of specific brain health tests and a planning task. Participants provided blood for FA quantification, and the caregiver completed basic background and activity questionnaires. We investigated the role of the n-6:n-3 ratio in the entire sample and separately in children aged 7-9 y and 10-12 y. For the study results, diet and blood n-6:n-3 ratio and n-3 predicted performance on short-term memory and planning tasks in children 7-12 y old. The link between dietary n-6:n-3 ratio and n-3 predicted the number of moves required to solve the most difficult planning problems in children aged 7-9 y and those aged 10-12 y, similar to results from the previous study. There was also a link between the blood n-6:n-3 ratio and n-3 predicting time spent thinking through the difficult 5-move planning problems. The n-6:n-3 ratio and n-3 predicted brain function performance differently in children aged 7-9 y and in those aged 10-12 y, indicating different optimal FA balances across age. In conclusion, the n-6:n-3 ratio is an important factor in the role of FAs in brain function. The optimal balance of n-6 and n-3 FAs depends on the brain function and age period studied." +"Total knee arthroplasty (TKA) is among the most common elective procedures performed worldwide. Recent efforts have been made to significantly improve patient outcomes, specifically with postoperative rehabilitation. Despite the many rehabilitation modalities available, the optimal rehabilitation strategy has yet to be determined. Therefore, this systematic review focuses on evaluating existing postoperative rehabilitation protocols. Specifically, this review analyses the study designs, rehabilitation methods, and outcome measures of postoperative rehabilitation protocols for TKA recipients in the past five years. The PubMed, EMBASE, and Cochrane Library databases were queried for studies evaluating rehabilitation protocols following primary TKA. Of the 11,013 studies identified within the last five years, 70 met the inclusion and exclusion criteria. After assessing for relevance and removing duplicates, a final count of 20 studies remained for analysis. Level-of-evidence was determined by the American Academy of Orthopaedic Surgeons (AAOS) classification system. Our findings demonstrated that continuous passive motion and inpatient rehabilitation may not provide additional benefit to the patient or healthcare system. However, early rehabilitation, telerehabilitation, outpatient therapy, high intensity, and high velocity exercise may be successful forms of rehabilitation. Additionally, weight-bearing biofeedback, neuromuscular electrical stimulation, and balance control appear to be beneficial adjuncts to conventional rehabilitation. Postoperative rehabilitation following TKA facilitates patient recovery and improves quality of life. This systematic review analyzed the existing rehabilitation protocols from the past five years. Some studies did not accurately describe the conventional rehabilitation protocols, the duration of therapy sessions, and the timing of these sessions. As such, future studies should explicitly describe their methodology. This will allow high-quality assessments and the conception of standardized protocols.","Knee replacement is one of the most common types of surgery that people choose to have worldwide. Recently, doctors have tried to make big improvements in outcomes, especially during the rehab process. Even though there are lots of ways to do rehab, doctors have not figured out the best strategy. Because of this, we will focus on rating different rehab strategies that are in published papers. Specifically, we will look at how studies were done, which rehab methods they used, and what the measured outcomes were. We will do this for rehab strategies for people that had knee replacement in the last 5 years. We searched several databases of biomedical literature for studies that looked at rehab strategies after knee replacement. Out of more than 11,000 from our search, 70 met our criteria for including them. After considering relevance and removing duplicates, we were left with 20 studies. We found that Continuous Passive Motion (CPM), where a device moves the leg for the patient, and inpatient rehab may not provide any benefit to the patient or the healthcare system. However, early rehab, tele-rehab, where providers interact with patients remotely using the internet, and outpatient therapy may be successful types of rehab. Exercise at high intensity and high speeds may also be successful types of rehab. One method that seems to help as a supplement is �weight-bearing biofeedback,� where the patient puts some weight on the joint while wearing sensors to ensure it is not too much. Electrical stimulation of the muscles and balancing exercises also appear to be helpful supplements to typical rehab methods. Rehab after knee replacement surgery helps patients recover and improves their quality of life. This article looked at published rehab strategies used in the last 5 years. Some studies did not accurately describe standard rehab methods, duration of therapy sessions, and the timing of these sessions. Studies done in the future should be more explicit about their methods. This will let doctors know what the methods are and evaluate them." +"Objective: The objective of this health technology policy analysis was to determine, where, how, and when physiotherapy services are best delivered to optimize functional outcomes for patients after they undergo primary (first-time) total hip replacement or total knee replacement, and to determine the Ontario-specific economic impact of the best delivery strategy. The objectives of the systematic review were as follows: To determine the effectiveness of inpatient physiotherapy after discharge from an acute care hospital compared with outpatient physiotherapy delivered in either a clinic-based or home-based setting for primary total joint replacement patients. To determine the effectiveness of outpatient physiotherapy delivered by a physiotherapist in either a clinic-based or home-based setting in addition to a home exercise program compared with a home exercise program alone for primary total joint replacement patients. To determine the effectiveness of preoperative exercise for people who are scheduled to receive primary total knee or hip replacement surgery. Conclusions: Based on the evidence, the Medical Advisory Secretariat reached the following conclusions with respect to physiotherapy rehabilitation and physical functioning 1 year after primary TKR or THR surgery: There is high-quality evidence from 1 large RCT to support the use of home-based physiotherapy instead of inpatient physiotherapy after primary THR or TKR surgery. There is low-to-moderate quality evidence from 1 large RCT to support the conclusion that receiving a monitoring phone call from a physiotherapist and practicing home exercises is comparable to receiving clinic-based physiotherapy and practicing home exercises for people who have had primary TKR surgery. However, results may not be generalizable to those who have had THR surgery. There is moderate evidence to suggest that an exercise program beginning 4 to 6 weeks before primary TKR surgery is not effective.","The goal of this health technology policy analysis was to figure out, where, how, and when physiotherapy (PT) can best help patients after knee or hip replacement. We also hope to figure out the financial impact of the best PT strategies for Ontario. Specifically, we wanted to figure out how inpatient PT (during a stay at a care facility) compared with outpatient PT, either at a clinic or at home, for patients that had joint replacements. We also wanted to see how effective outpatient PT with a therapist was, either at a clinic or at home, compared with just a home exercise program for patients that had joint replacements. Finally, we aimed to figure out how effective it is to exercise before surgery for people who are scheduled for knee or hip replacement. Based on the evidence, the Medical Advisory Secretariat concluded that there is good evidence to support using home-based PT instead of inpatient PT after hip or knee replacement. This was concluded with regard to function a year after the surgery. There is some evidence from one large study that getting phone call from a physiotherapist and practicing home exercises is comparable to having PT at a clinic and practicing home exercises for people who have had knee replacement. However, the same might not apply to those who have hip replacement. There is decent evidence that an exercise program beginning 4 to 6 weeks before knee replacement surgery is not effective." +"This study evaluated the use of telerehabilitation during the postoperative period for patients who underwent total knee arthroplasty (TKA) or unicompartmental knee arthroplasty (UKA). Specifically, this study evaluated the following: (1) patient compliance and adherence to the program, (2) time spent performing physical therapy exercises, (3) the usability of the virtual rehabilitation platform, and (4) clinical outcome scores in a selected primary knee arthroplasty cohort. A total of 157 consecutive patients underwent TKA (n = 18) or UKA (n = 139). These patients used a telerehabilitation system with an instructional avatar, three-dimensional motion measurement and analysis software, and real-time televisit capability designed for arthroplasty patients. Compliance was determined by how many times the patients followed prescribed repetitions of exercises. The total time spent performing exercises for each patient was collected. The usability of the virtual rehabilitation platform (on the patient's end) was evaluated using the system usability scale (SUS) questionnaire. The number of in-person and televisits was recorded for each patient. Patient-reported outcomes were collected through the patient and clinician interfaces and included the Knee Society Score (KSS) for pain and functions, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Boston University Activity Measure for Post-Acute Care (AM-PAC) score. Patients spent an average of 29.5 days partaking in the therapy. TKA and UKA patients had a mean of 3.5 and 3.2 outpatient follow-up visits, each, for in-office therapy with a physical therapist, respectively. This figure exceeded the mean number of real-time virtual patient-clinician visits by 0.8 visits per patient in the TKA cohort and by 1 visit per patient in the UKA cohort. Patients spent on average 26.5 minutes per day conducting an average of 13.5 exercises. By the end of rehabilitation, patients had spent an average of 10.8 hours performing exercises, and of all the exercises performed, approximately 21 exercises were uniquely designed. Mean SUS score in the cohort was 93 points, which was interpreted as being above the 50th percentile point of the scale. Following therapy, KSS pain and function scores improved markedly and the improvements were measured at 368% for TKA and 350% for UKA (pain) and 27% for UKA and 33% for TKA (function). In addition, WOMAC scores improved by 57% and 66% for UKA and TKA patients while the improvement in AM-PAC scores was at 22% and 24%. This telerehabilitation platform encouraged clinician-patient interaction beyond the hospital setting and offers the advantage of cost savings, convenience, at-home monitoring, and coordination of care, all of which are geared to improve adherence and overall patient satisfaction. Additionally, the biometric data can be used to develop custom physical therapy regimens to assure proper rehabilitation, which is lacking in other telerehabilitation applications that use noninteractive videos that can be watched on mobile devices and tablets.","This study looked at using tele-rehab (where providers interact with patients remotely using the internet) after complete or partial knee replacement surgery. Specifically, the study looked at: (1) how well patients kept up with the program, (2) time spent performing physical therapy exercises, (3) how easy it was to use the virtual rehab software, and (4) outcomes for a certain group of patients that had knee replacement surgery. A total of 157 patients in a row had complete (18) or partial (139) knee replacement. These patients used a tele-rehab system with an instructional avatar, three-dimensional motion measurement and analysis software, and real-time tele-visit capability designed for joint surgery patients. We measured how well patients kept up with the program by how many times the patients followed the recommended repetitions of exercises. We collected the total each patient time spent performing exercises. We evaluated how easy it was for patients to use the virtual rehab software using a questionnaire. We also recorded the number of in-person and virtual visits for each patient. We collected patient-reported outcomes through patient/doctor portals. Measurements included were the Knee Society Score (KSS) for pain and functions, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Boston University Activity Measure for Post-Acute Care (AM-PAC) score. Patients spent an average of about 30 days participating in the therapy. Complete knee replacement patients, on average, had 3.5 outpatient follow-up visits each for in-office therapy with a physical therapist. Partial knee replacement patients had, on average, 3.2 of these visits. For complete knee replacement patients, this was on average 0.8 more visits than for real-time virtual patient-clinician. For partial hip replacement patients, it was 1 more visit. Patients spent, on average, 26.5 minutes per day doing an average of 13.5 exercises. By the end of rehab, patients had spent an average of 10.8 hours doing exercises, and of all the exercises performed, around 21 were uniquely designed. After therapy, KSS pain and function scores improved notably. The scores for pain improved by 368% for complete knee replacement and 350% for partial. The scores for function improved by 33% for complete knee replacement 27% for partial. Additionally, WOMAC scores improved by 57% for partial knee replacement and 66% for compete knee replacement. The improvement in AM-PAC scores was at 22% for partial and 24% for complete. This tele-rehab platform encouraged interaction between doctors and patients beyond the hospital setting. It offers the advantage of cost savings, convenience, at-home monitoring, and coordination of care. All of these are geared to improve how well patients keep up and overall patient satisfaction. Additionally, the data from the platform can be used to make custom physical therapy regimens to assure proper rehabilitation. This is lacking in other tele-rehab applications that use non-interactive videos that can be watched on mobile devices and tablets." +"Physical therapy is routinely delivered to patients after discharge from the hospital following knee arthroplasty. Posthospitalization physical therapy is thought to be beneficial, particularly for those patients most at risk of poor outcome, the subgroup with persistent function-limiting pain, despite an apparently successful surgery. Research teams have undertaken 3 large-scale multicenter Phase 3 randomized clinical trials designed specifically for patients at risk of poor outcome following knee arthroplasty. All 3 trials screened for poor outcome risk using different methods and investigated different physical therapist interventions delivered in different ways. Despite the variety of types of physical therapy and mode of delivery, all trials found no effects of the enhanced treatment compared with usual care. In all cases, usual care required a lower dosage of physical therapy compared with the enhanced interventions. This Perspective compares and contrasts the 3 trials, speculates on factors that could explain the no-effect findings, and proposes areas for future study designed to benefit the poor outcome phenotype.","Physical therapy (PT) is often given to patients that had knee replacement after after leaving the hospital. PT after leaving the hospital is thought to be helpful, especially for patients with high risk of bad outcomes. These are patients with persistent pain that impairs function, even though the surgery seemed to go well. Research teams have done 3 large-scale trials across different health care facilities, designed specifically for patients at risk of poor outcome following knee replacement. All 3 trials checked for poor outcome risk using different methods and looked at different ways for physical therapists to try to help. Despite the variety of types of physical therapy and how they were given, all trials found no effects of the enhanced treatment compared with usual care. In all cases, usual care required a lower amount of physical therapy compared with the enhanced interventions. This article expresses our opinions on recent research. It compares and contrasts the 3 trials, guesses what could explain the findings that there were no effects, and proposes areas for future studies that could help the people at high risk of bad outcomes." +"Objective: Although total knee replacement (TKR) surgery is highly prevalent and generally successful, functional outcomes post-TKR vary widely. Most patients receive some physical therapy (PT) following TKR, but PT practice is variable and associations between specific content and dose of PT interventions and functional outcomes are unknown. Research has identified exercise interventions associated with better outcomes but studies have not assessed whether such evidence has been translated into clinical practice. We characterized the content, dose, and progression of usual post-acute PT services following TKR, and examined associations of specific details of post-acute PT with patients' 6-month functional outcomes. Methods: Post-acute PT data were collected from patients who were undergoing primary unilateral TKR and participating in a clinical trial of a phone-based coaching intervention. PT records from the terminal episode of care were reviewed and utilization and exercise content data were extracted. Descriptive statistics and linear regression models characterized PT treatment factors and identified associations with 6-month outcomes. Results: We analyzed 112 records from 30 PT sites. Content and dose of specific exercises and incidence of progression varied widely. Open chain exercises were utilized more frequently than closed chain (median 21 [interquartile range (IQR) 4-49] versus median 13 [IQR 4-28.5]). Median (IQR) occurrence of progression of closed and open chain exercise was 0 (0-2) and 1 (0-3), respectively. Shorter timed stair climb was associated with greater total number of PT interventions and use and progression of closed chain exercises. Discussion: Data suggest that evidence-based interventions are underutilized and dose may be insufficient to obtain optimal outcomes.","Although knee replacement surgery is very common and usually turns out well, amount of function after varies widely. Most patients have some physical therapy (PT) after knee replacement, but PT practice varies. We don�t know which amounts and kinds of PT are associated with which outcomes. Research has shown that exercise is associated with better outcomes, but studies have not looked at whether this has made its way into clinical practice. We looked at the content, amount, and progression of usual PT services after knee replacement. We also examined associations of specific details of PT after surgery with how much function patients had after 6 months. We collected PT data from patients who were having knee replacement surgery on one side and participating in a clinical trial of a phone-based coaching program. We reviewed PT records from final sessions to find how much patients used the PT and what exercises were done. We used statistical methods to see which parts of PT treatment were associated with 6-month outcomes. In all, we looked at 112 records from 30 PT sites. The types and amounts of exercises, and how they progressed, varied widely. Exercises that used weights or other resistance were use more than body-weight exercises (on average 21 versus 13). Progression of exercises was used on average 0 times for exercises with resistance and 1 time for exercises that just used body weight. Climbing stairs faster was associated with more PT sessions and the use and progression of body-weight exercises. The evidence suggests that treatments backed by studies are not used as much as they should be and the amount of PT may not be enough to create the best possible outcomes." +"Background: Early ambulation with physical therapy (PT) following total knee arthroplasty (TKA) has demonstrated benefits in the literature. However, the impact of early PT on rehabilitation performance and opioid consumption has not been elucidated. We evaluate the effect of same-day PT on inhospital functional outcomes and opioid consumption. Methods: We retrospectively identified 2 cohorts of primary TKA patients from July 2016 to December 2017: PT0 (n = 295) received PT on the day of surgery, and PT1 (n = 392) received PT on postoperative day (POD) 1. Outcomes studied included number of feet walked on POD0-3, visual analog scale pain scores, morphine equivalents (ME) consumed, length of stay, and discharge disposition. Analysis was conducted using the Student t-test and Fisher exact test. Results: In comparison to the PT1 group, the PT0 group walked significantly more steps on POD1 (347.6 vs 167.4 ft, P < .0001), POD2 (342.1 vs 203.5 ft, P < .0001), and POD3 (190.3 vs 128.9 ft, P = .00028). There was no difference between the 2 groups for visual analog scale. The PT0 group also consumed significantly fewer total ME when compared to the PT1 group (149.0 vs 200.3 mg, P = .0002). The PT0 group had a significantly shorter length of stay when compared to the PT1 group (2.7 vs 3.2 days, P = .00075). More patients were discharged home in the PT0 group (81.7% vs 54.8%, P < .0001). Conclusion: We observed that initiation of PT on POD0 led to better PT performance, reduced ME during hospitalization, and more patients discharged home.","Research has shown that having patients walk early with physical therapy (PT) after knee replacement has benefits. However, the impact of early PT on rehab performance and opioid use is still unclear. We looked at the effect of same-day PT on how well patients functions and opioid use while in the hospital. To do this, we looked at 2 past groups of knee replacement patients from July 2016 to December 2017. The first group had 295 patients and had PT on the day of surgery. The second group had 392 patients and received PT on the day after surgery. The outcomes we looked at included the number of feet walked in the first 3 days after surgery, patient reported pain scores, amount of morphine or similar drugs used, length of stay, and where the patient was sent on discharge. In comparison to the second group (which had PT the day of after surgery), the first group (which had PT the day of the surgery) walked significantly more steps on the first 3 days after surgery. The first group walked, on average, 348 feet the first day after, while the second group walked 167 feet. The second day, the first group walked 342 feet while the second group walked 203. The third day after surgery, the first group walked 190 feet while the second group walked 129 feet. There was no difference between the 2 groups for pain reported. The first group (which had PT the day of the surgery) also used significantly less morphine or similar drugs when compared to the second group (which had PT the day after surgery). The first group also had a significantly shorter length of stay compared to the second group (on average 2.7 days vs 3.2 days). More patients were discharged home in the first group (81.7% vs 54.8%). In conclusion, we observed that starting PT the day of surgery led to better PT performance, reduced drug use during hospitalization, and more patients discharged home." +"Total knee arthroplasty (TKA) is the gold standard treatment for end-stage knee osteoarthritis. Most patients report successful long-term outcomes and reduced pain after TKA, but recovery is variable and the majority of patients continue to demonstrate lower extremity muscle weakness and functional deficits compared to age-matched control subjects. Given the potential positive influence of postoperative rehabilitation and the lack of established standards for prescribing exercise paradigms after TKA, the purpose of this study was to systematically review randomized, controlled studies to determine the effectiveness of postoperative outpatient care on short- and long-term functional recovery. Nineteen studies were identified as highly relevant for the review and four categories of postoperative intervention were discussed: 1) strengthening exercises; 2) aquatic therapy; 3) balance training; and 4) clinical environment. Optimal outpatient physical therapy protocols should include: strengthening and intensive functional exercises given through land-based or aquatic programs, the intensity of which is increased based on patient progress. Due to the highly individualized characteristics of these types of exercises, outpatient physical therapy performed in a clinic under the supervision of a trained physical therapist may provide the best long-term outcomes after the surgery. Supervised or remotely supervised therapy may be effective at reducing some of the impairments following TKA, but several studies without direct oversight produced poor results. Most studies did not accurately describe the ""usual care"" or control groups and information about the dose, frequency, intensity and duration of the rehabilitation protocols were lacking from several studies.","Complete knee replacement surgery is the best known treatment for severe arthritis in the knee. Most patients have successful long-term outcomes and reduced pain after knee replacement. However, recovery varies, and most patients continue to have weakness in the legs and less function compared to peers of the same age. There is a potential positive influence of rehab after surgery and a lack of established standards for prescribing exercise paradigms after knee replacement. With this in mind, our goal in this review article was to look carefully at studies to determine how effective outpatient care is for regaining function short-term and long-term. We found 19 studies that we deemed very relevant for the review. We discussed four categories of treatment after surgery: 1) strengthening exercises; 2) aquatic therapy; 3) balance training; and 4) clinical environment. The best outpatient physical therapy strategies should include strengthening and intensive functional exercises, either normal or in water. The intensity of these should increase based on patient progress. Since these exercises are very individualized, outpatient physical therapy done in a clinic under with a trained physical therapist may provide the best long-term outcomes after the surgery. Supervised or remotely supervised therapy may be effective at reducing some of the impairments following knee replacement, but several studies without direct oversight had poor results. Most studies did not accurately describe what �usual care� was used to compare against the programs they were testing. Information about the amount, frequency, intensity and duration of the rehab protocols was also missing from several studies." +"Background: Total knee arthroplasty (TKA) alleviates pain, but muscle strength and function is reduced for a long period postoperatively. Aim: To investigate whether maximal strength training (MST) is more effective in improving muscle strength than standard rehabilitation (SR) after TKA. Design: A randomized, controlled study. Setting: Community physical therapy centers and University hospital research department. Population: Forty-one adults <75 years with primary, unilateral osteoarthritis of the knee scheduled for TKA. Methods: Participants were randomized to supervised MST of the lower extremities 3 times/week for 8 weeks and physiotherapy session1/week (N.=21) or to SR, including physiotherapy sessions/telephone contact 1/week and writing home exercise logs (N.=20). Maximal strength in leg press and knee extension, 6-minute walk test, patient-reported functional outcome score and pain were assessed preoperatively, 7 days, 10 weeks and 12 months postoperatively. Results: The MST group exceeded preoperative levels of muscle strength in leg press and knee extension by 37% and 43%, respectively at 10 weeks' follow-up, and the increase was higher than in the SR group (P?0.001). Strength differences persisted up to 12-months follow-up. At 12 months, both groups recovered to normative levels in the 6-Minute Walk Test, with no statistically significantly difference between the groups. Conclusions: Participants undergoing MST experienced superior increases in leg press and knee extension muscle strength compared with those managed with SR from 7-day to 10-week follow-up. The difference in muscle strength was maintained at 12-month follow-up. No differences in functional performance were found at any time-point. Clinical rehabilitation impact: Exercises after TKA should be performed with high intensity and target the operated leg specifically.","Complete knee replacement surgery alleviates pain, but muscle strength and function is reduced for a long period after the operation. Our aim was to investigate whether Maximal Strength Training (MST) is more effective in improving muscle strength than standard rehab knee replacement. This study involved two groups who randomly got either the standard care or the experimental care. It was done in community physical therapy centers and a university hospital research department. The study included 41 adults under 75 with arthritis in one knee and who were scheduled for knee replacement surgery. Participants randomly got either supervised MST for the legs 3 times a week for 8 weeks and one physiotherapy session per week or the standard rehab, including physiotherapy sessions and/or telephone contact once a week and writing home exercise logs. The MST group had 21 patients, while the standard rehab group had 20 patients. We measured maximum strength in leg press and knee extension, 6-minute walk test, patient-reported functional outcome score and pain. We looked at these 7 days after the operation, 10 weeks after, and 12 months after. The MST group had 37% more strength in leg press and 43% more strength in knee extension at 10 weeks. These increases were higher than for the group that had standard rehab. Strength differences continued up to the 12-month follow-ups. At 12 months, both groups recovered to normal levels in the 6-Minute Walk Test, with no significant difference between the groups. In conclusion, participants getting Maximal Strength Training (MST) had better increases in leg press and knee extension muscle strength compared to those who had standard rehab, as measured at 7-day to 10-week follow-ups after surgery. The difference in muscle strength was maintained at 12-month follow-up. No differences in functional performance were found at any point. The impact of this on clinical rehab is that exercises after knee replacement should be done with high intensity and should target the operated leg specifically." +"Background: Rehabilitation, with an emphasis on physiotherapy and exercise, is widely promoted after total knee replacement. However, provision of services varies in content and duration. The aim of this study is to update the review of Minns Lowe and colleagues 2007 using systematic review and meta-analysis to evaluate the effectiveness of post-discharge physiotherapy exercise in patients with primary total knee replacement. Methods: We searched MEDLINE, Embase, PsycInfo, CINAHL and Cochrane CENTRAL to October 4(th) 2013 for randomised evaluations of physiotherapy exercise in adults with recent primary knee replacement. Outcomes were: patient-reported pain and function, knee range of motion, and functional performance. Authors were contacted for missing data and outcomes. Risk of bias and heterogeneity were assessed. Data was combined using random effects meta-analysis and reported as standardised mean differences (SMD) or mean differences (MD). Results: Searches identified 18 randomised trials including 1,739 patients with total knee replacement. Interventions compared: physiotherapy exercise and no provision; home and outpatient provision; pool and gym-based provision; walking skills and more general physiotherapy; and general physiotherapy exercise with and without additional balance exercises or ergometer cycling. Compared with controls receiving minimal physiotherapy, patients receiving physiotherapy exercise had improved physical function at 3-4 months, SMD -0.37 (95% CI -0.62, -0.12), and pain, SMD -0.45 (95% CI -0.85, -0.06). Benefit up to 6 months was apparent when considering only higher quality studies. There were no differences for outpatient physiotherapy exercise compared with home-based provision in physical function or pain outcomes. There was a short-term benefit favouring home-based physiotherapy exercise for range of motion flexion. There were no differences in outcomes when the comparator was hydrotherapy, or when additional balancing or cycling components were included. In one study, a walking skills intervention was associated with a long-term improvement in walking performance. However, for all these evaluations studies were under-powered individually and in combination. Conclusion: After recent primary total knee replacement, interventions including physiotherapy and exercise show short-term improvements in physical function. However this conclusion is based on meta-analysis of a few small studies and no long-term benefits of physiotherapy exercise interventions were identified. Future research should target improvements to long-term function, pain and performance outcomes in appropriately powered trials.","Rehab, with an emphasis on physiotherapy and exercise, is widely promoted after total knee replacement. However, how services are given varies in content and duration. The aim of this study is to provide an updated summary of the research to evaluate how effective physiotherapy (PT) exercise is for patients that had knee replacements. We searched several medical literature databases, up to October 4th, 2013, for studies of PT exercise in adults that had knee replacements. The outcomes we looked at were: patient-reported pain and function, knee range of motion, and functional performance. We contacted the researchers for missing data and outcomes. We also looked at whether the study results could be misleading. Our searches found 18 studies including 1,739 patients with total knee replacement. The treatments that were compared were: PT exercise without care; home and outpatient care; pool and gym-based care; walking skills and more general PT; and general PT exercise with and without additional balance exercises or a stationary bike. Compared with people with little or no PT, patients that got PT exercise had improved physical function at 3-4 months. When considering only higher quality studies, there was a clear benefit up to 6 months. There were no differences for outpatient PT exercise compared with home-based care in physical function or pain outcomes. There was a short-term benefit in favor of home-based PT exercise for range of motion. There were no differences in outcomes for pool-based care, or when additional balancing or cycling components were included. In one study, a walking skills treatment plan was associated with a long-term improvement in walking performance. However, for all these evaluations, studies did not have enough patients to be sure of their significance, even taken altogether. In conclusion, after recently having knee replacement, care including PT and exercise improve physical function short-term. However, this conclusion is based on a few small studies, and we found no long-term benefits of PT exercise. Future research should focus on improving long-term function, pain and performance with larger studies." +"Purpose: The aim of the present study was to evaluate the efficacy and safety of non-supervised home-based exercise versus individualized and supervised programs delivered in clinic-based settings for the functional recovery immediately after discharge from a primary TKA. Methods: Medline, Embase, Cochrane, and PEDro databases were screened, from inception to April 2015, in search for randomized clinical trials (RCT) of home-based exercise interventions versus individualized and supervised outpatient physical therapy after primary TKA. Target outcomes were: knee range of motion (ROM), patient-reported pain and function, functional performance, and safety. Risk of bias was assessed with the PEDro scale. After assessing homogeneity, data were combined using random effects meta-analysis and reported as standardized mean differences or mean differences. We set a non-inferiority margin of four points in mean differences. Results: The search and selection process identified 11 RCT of moderate quality and small sample sizes. ROM active extension data suitable for meta-analysis was available from seven studies with 707 patients, and ROM active flexion from nine studies with 983 patients. Most studies showed no difference between groups. Pooled differences were within the non-inferiority margin. Most meta-analyses showed significant statistical heterogeneity. Conclusion: Short-term improvements in physical function and knee ROM do not clearly differ between outpatient physiotherapy and home-based exercise regimes in patients after primary TKA; however, this conclusion is based on a meta-analysis with high heterogeneity.","The aim of this study was to see how effective and safe different functional recovery strategies were immediately after discharge from knee replacement surgery. It compared non-supervised, home-based exercise to individualized and supervised programs delivered in clinic-based settings. We searched several medical literature databases for papers published up until April 2015. We were looking for clinical trials of home-based exercise programs versus individualized and supervised outpatient physical therapy (PT) after knee replacement. The outcomes we compared were knee range of motion (ROM), patient-reported pain and function, functional performance, and safety. Our search and selection process found 11 clinical trials of decent quality but that looked at small numbers of patients. Seven studies, with a total of 707 patients, had data on ROM for extending the leg that could be used. Nine studies, with a total of 983 patients, had data on ROM for bending the leg. Most studies showed no difference between groups. Even taken altogether, differences between the treatment types were small enough to be by chance. In conclusion, short-term improvements in physical function and knee ROM are not clearly different between outpatient PT and home-based exercise regimes in patients after knee replacement. However, this conclusion is based on combining studies with many differences." +"Nearly 20% of mothers will experience an episode of major or minor depression within the first 3 months postpartum, making it the most common complication of childbearing. Postpartum depression (PPD) is significantly undertreated, and because prospective mothers are especially motivated for self-care, a focus on the prevention of PPD holds promise of clinical efficacy. This study is a qualitative review of existing approaches to prevent PPD. A PubMed search identified studies of methods of PPD prevention. The search was limited to peer-reviewed, published, English-language, randomized controlled trials (RCTs) of biological, psychological, and psychosocial interventions. Eighty articles were initially identified, and 45 were found to meet inclusion criteria. Eight RCTs of biological interventions were identified and 37 RCTs of psychological or psychosocial interventions. Results were mixed, with 20 studies showing clear positive effects of an intervention and 25 showing no effect. Studies differed widely in screening, population, measurement, and intervention. Among biological studies, anti-depressants and nutrients provided the most evidence of successful intervention. Among psychological and psychosocial studies, 13/17 successful trials targeted an at-risk population, and 4/7 trials using interpersonal therapy demonstrated success of the intervention versus control, with a further two small studies showing trends toward statistical significance. Existing approaches to the prevention of PPD vary widely, and given the current literature, it is not possible to identify one approach that is superior to others. Interpersonal therapy trials and trials that targeted an at-risk population appear to hold the most promise for further study.","Nearly 20% of mothers will experience an episode of major or minor depression within the first 3 months after childbirth (postpartum depression). This shows it is the most common complication of childbearing. Many times postpartum depression (PPD) is not treated adequately. Because people planning to become mothers are especially motivated for self-care, focusing on preventing PPD brings hope for the best outcome. This research reviews the accepted ways to prevent PPD. A search of articles written about ways to prevent PPD was done using the PubMed search engine. The search only included published articles, written in English, that were evaluated by experts in the same field as the authors. These articles were on studies about the psychology, biology (bodily function), and social aspects of PPD. This search found 88 studies. Only 45 of them met the rules to be included in this research. Of the 45 studies that were included, 8 studies were about biological treatments, and 37 were about psychological or social treatments. Of these 45 studies, 20 studies showed good effects from the treatment and 25 studies showed no effect from the treatment. The studies were very different in how they recognized and treated PPD. There were also differences in the people studied and how the findings were measured. Anti-depressants and nutrients showed the best proof of treatment success in the biological studies. Of the psychological and psychosocial studies, 13 out of 17 successful studies focused on mothers at risk for PPD. Interpersonal therapy showed success in 4 out of 7 studies. Two small studies showed a tendency toward success also. Currently,there are many different ways to prevent PPD. Researchers cannot pinpoint one approach that is better than others. Clinical trials (studies in people) that focus on at-risk populations and clinical trials of interpersonal therapy seem to hold the most hope for further study." +"Postpartum depression (PPD) is a major public health problem affecting 10-57% of adolescent mothers which can affect not only adolescent mothers but also their infants. Thus, there is a need for interventions to prevent PPD in adolescent mothers. However, recent systematic reviews have been focused on effective interventions to prevent PPD in adult mothers. These interventions may not necessarily be applicable for adolescent mothers. Therefore, the purpose of this review was to examine the effectiveness of the existing interventions to prevent PPD in adolescent mothers. A systematic search was performed in MEDLINE, CINAHL, and SCOPUS databases between January 2000 and March 2017 with English language and studies involving human subjects. Studies reporting on the outcomes of intervention to prevent PPD particularly in adolescent mothers were selected. Non-comparative studies were excluded. From 2002 identified records, 13 studies were included, reporting on 2236 adolescent pregnant women. The evidence from this systematic review suggests that 6 of 13 studies from both psychological and psychosocial interventions including (1) home-visiting intervention, (2) prenatal antenatal and postnatal educational program, (3) CBT psycho-educational, (4) the REACH program based on interpersonal therapy, and (5) infant massage training is successful in reducing rates of PPD symptoms in adolescent mothers in the intervention group than those mothers in the control group. These interventions might be considered for incorporation in antenatal care interventions for adolescent pregnant women. However, this review did not find evidence identifying the most effective intervention for preventing postpartum depression symptoms in adolescent mothers.","Depression after giving birth, postpartum depression (PPD) is a major public health problem. PPD affects 10-57% of adolescent mothers. It can affect not only adolescent mothers but also their infants. There is a need for treatments to prevent PPD in adolescent mothers. Recent thorough reviews of studies on preventing PPD have been focused on successful treatments in adult mothers. These treatments to prevent PPD may not necessarily apply to adolescent mothers. This research judged the benefit of accepted treatments to prevent PPD in adolescent mothers. A thorough search was performed in MEDLINE, CINAHL, and SCOPUS databases (organized collection of articles including health topics) to find English language articles written between January 2000 and March 2017 on studies involving human subjects. Studies reporting on the outcomes of intervention (treatment) to prevent PPD particularly in adolescent mothers were selected. Researchers did not include studies that were not comparative studies. Of the 2002 articles found, researchers included 13 studies. These 13 studies included information on a total of 2236 adolescent pregnant women. Six out of 13 studies suggests interventions are successful in lowering rates of PPD symptoms in adolescent mothers (compared to the group that did not receive interventions). The research was from the psychological and social intervention studies. The interventions included: home visits; education (before, during, and after pregnancy and childbirth); psychological therapy; interpersonal therapy, and infant massage training. These interventions might be included in maternity care for adolescent pregnant women. This research did not find out the most successful intervention to prevent postpartum depression in adolescent mothers." +"Most interventions to prevent postpartum depression (PPD) focus on the mother rather than the mother-infant dyad. As strong relationships between infant sleep and cry behavior and maternal postpartum mood have been demonstrated by previous research, interventions targeted at the dyad may reduce symptoms of PPD. The goal of the current study was to examine the effectiveness of Practical Resources for Effective Postpartum Parenting (PREPP). PREPP is a new PPD prevention protocol that aims to treat women at risk for PPD by promoting maternally mediated behavioral changes in their infants, while also including mother-focused skills. Results of this randomized control trial (RCT) (n = 54) indicate that this novel, brief intervention was well tolerated and effective in reducing maternal symptoms of anxiety and depression, particularly at 6 weeks postpartum. Additionally, this study found that infants of mothers enrolled in PREPP had fewer bouts of fussing and crying at 6 weeks postpartum than those infants whose mothers were in the Enhanced TAU group. These preliminary results indicate that PREPP has the potential to reduce the incidence of PPD in women at risk and to directly impact the developing mother-child relationship, the mother's view of her child, and child outcomes.","Most treatments to prevent depression after giving birth, postpartum depression (PPD), focus on the mother instead of the total relationship between mother and infant. Research showed strong relationships between infant sleep and cry behavior and mother's mood after childbirth. Interventions focusing on the relationship between mother and infant (mother-infant dyad) may reduce PPD. This study examines the success of the PREPP (Practical Resources for Effective Postpartum Parenting) intervention. PREPP is a new PPD prevention program that treats women at risk for PPD. This intervention teaches skills to help mothers themselves as well as skills to help make changes in their infant's behavior. This study showed that this new and brief intervention was accepted well and successful in reducing maternal symptoms of anxiety and depression, particularly at 6 weeks postpartum (after childbirth). This study found that infants of mothers in the PREPP program had fewer bouts of fussing and crying at 6 weeks postpartum compared to infants whose mothers were in another group, (the Enhanced TAU group). These early results show that PREPP may be able to reduce PPD in women at risk and to directly affect the developing mother-child relationship, the mother's view of her child, and child outcomes." +"Postnatal depression is a major public health problem affecting about one in seven women after childbirth. Depression is also common during pregnancy and throughout the perinatal period it is associated with symptoms of anxiety. Apart from the adverse consequences for women themselves becoming depressed when they are going through demanding physical and social changes, there are additional concerns. There is the possible negative impact of maternal depression on the relationship between mother and child and on the child's emotional, behavioural and cognitive development. Primary prevention and early intervention/secondary prevention strategies are potentially important in view of the frequent contact pregnant women, new mothers and infants have with health services, but the effectiveness of these strategies needs to be tested. In the past year there have been five new studies of antenatal screening for postnatal depression. These studies are consistent with nine earlier studies in showing that there is no evidence to support routine antenatal screening for postnatal depression. Seven new primary prevention/early intervention trials add evidence on a wide range of interventions ranging from practical support to individual interpersonal therapy, but without identifying significant differences in depression as an outcome. Two new trials of secondary prevention, one involving interpersonal therapy and the other including partners in a series of psychoeducational visits, show promise but neither is large enough to form a basis for practice change. Novel interventions, or promising findings, with a strong basis in theory need to be tested in trials which are appropriately sized and which comply with internationally accepted design and reporting guidelines.","Postnatal depression (depression after childbirth) is a major public health problem. It affects about one in seven women after childbirth. Depression is also common during pregnancy and throughout the perinatal period (time of pregnancy and after childbirth ). it is associated with symptoms of anxiety. There are harmful effects for women themselves to become depressed when they are going through demanding physical and social changes. But there are also other concerns. Maternal depression can cause problems with the relationship between mother and child. There can also be problems with the child's emotional, behavioral and cognitive (thinking) development. Prevention and early interventions may be important in view of the frequent contact pregnant women, new mothers and infants have with health services. The effectiveness of these interventions needs to be tested. In the past year there have been five new studies of antenatal (during pregnancy) screening for postnatal depression. These studies agree with nine earlier studies showing that there is no evidence to support routine antenatal screening for postnatal depression. Seven new prevention and early intervention studies add evidence on a wide range of treatments ranging from practical support to individual interpersonal therapy. These studies have not found significant differences in the outcome of depression. Two new studies on the prevention of the recurrence of depression show promise of success. One invention study involves interpersonal therapy and the other includes partners in psychoeducational visits. Neither study is large enough to form a basis for practice change. New interventions, or promising findings, with a strong basis in theory need to be tested in trials (human studies) which are large enough and which meet internationally accepted standards and guidelines." +"Postpartum depression (PPD) is common, disabling, and treatable. The strongest risk factor is a history of mood or anxiety disorder, especially having active symptoms during pregnancy. As PPD is one of the most common complications of childbirth, it is vital to identify best treatments for optimal maternal, infant, and family outcomes. New understanding of PPD pathophysiology and emerging therapeutics offer the potential for new ways to add to current medications, somatic treatments, and evidence-based psychotherapy. The benefits and potential harms of treatment, including during breastfeeding, are presented.","Postpartum depression (PPD) is depression that occurs after childbirth. It is common disorder that is disabling, but it is treatable. The strongest risk factor for PPD is a history of mood or anxiety disorders, especially if women have active symptoms during pregnancy. PPD is one of the most common complications of childbirth. It is very important to discover the most effective treatments in order to have the best outcomes for mothers, infants, and their families. There is new understanding of how PPD changes the body's functions. Also, new treatments offer possible different ways to add to current medications, mind-body treatments, and evidence-based psychotherapy. The benefits and potential harms of treatment, including during breastfeeding, are presented." +"Objective: Postpartum mood disorders represent a serious problem affecting 10-20% of women and support groups offer a promising intervention modality. The current study examined participant satisfaction with and effectiveness of a peer-facilitated postpartum support group. Intervention: The program consists of a free, peer-support group, developed to increase social support and destigmatise postpartum mood symptoms. The weekly group is co-facilitated by former group attendees and maternal health professionals. Setting: The peer-support program is offered in an urban city in the southeastern United States. Design: To address study aims, a community-based participatory research approach was implemented. Participant satisfaction was assessed via mixed methods analyses. Differences in depression scores at follow-up between program attendees and a community sample were examined via weighted linear regression analysis following propensity score analysis. Finally, within-group change in depression scores for program attendees was examined using a repeated measures ANOVA. Participants: Intake program data were provided by the sponsoring organisation (n = 73) and follow-up data were collected via an online survey from program attendees (n = 45). A community sample was recruited to establish a comparison group (n = 152). Measurements and findings: Participant satisfaction was high with overwhelmingly positive perceptions of the program. Postparticipation depression scores were similar to those of the community sample at follow-up (p = .447). Among attendees, pre-post analyses revealed reductions in depression symptoms with significant interactions for time � complications (p ? .001) and time � delivery method (p ? .017). Key conclusions: Overall, findings indicate this peer-support program is not only acceptable to program attendees but also they provide a potential mechanism for improving mental health outcomes; however, further evaluation is needed. Findings also emphasise the importance of integrating evaluation procedures into community-based mental health programming to support effectiveness. Implications for practice: Peer-support groups are an acceptable form of intervention for women experiencing postpartum depression.","Postpartum (after giving birth) mood disorders represent a serious problem affecting 10-20% of women. Support groups offer a promising treatment. This research studied women's satisfaction with and the success of a postpartum support group. This support group was guided by peers (others who had similar experiences). The program consists of a free, peer-support group, developed to increase social support and take away the shame of postpartum mood symptoms. The weekly group is assisted by former group participants and maternal health professionals. The peer-support program is offered in an urban city in the southeastern United States. The research study was done with community participation. The satisfaction of the participants was analyzed Differences in depression measured at follow-up between program participants and a sample of community members that did not take part in the program were analyzed. Changes in depression measured for the participant group (program attendees) was also analyzed. Facts (data) about the participants at the beginning of the program were provided by the organisation backing the support group. The follow-up data was given by the participants through an online questionnaire. A community sample of women who did not participate in the program was enrolled to compare with the participants. Participant satisfaction was high with overwhelmingly positive perceptions of the program. After participation in the program, depression scores were similar to those of the community sample at follow-up. Analyses comparing data of participants both before and after the program showed decreases in depression symptoms. This decrease in depression was significantly associated with time, complications, and delivery method. The research found that this peer-support program is acceptable to program attendees and it provides a possible way to improve mental health outcomes. More research is needed. The research also stress the importance of combining analysis procedures into community-based mental health programs in order to support successful outcomes. Peer-support groups are an acceptable form of treatment for women experiencing postpartum depression." +"Background: Post-partum depression is a serious mood disorder in women that might be triggered by peripartum fluctuations in reproductive hormones. This phase 2 study investigated brexanolone (USAN; formerly SAGE-547 injection), an intravenous formulation of allopregnanolone, a positive allosteric modulator of ?-aminobutyric acid (GABAA) receptors, for the treatment of post-partum depression. Methods: For this double-blind, randomised, placebo-controlled trial, we enrolled self-referred or physician-referred female inpatients (?6 months post partum) with severe post-partum depression (Hamilton Rating Scale for Depression [HAM-D] total score ?26) in four hospitals in the USA. Eligible women were randomly assigned (1:1), via a computer-generated randomisation program, to receive either a single, continuous intravenous dose of brexanolone or placebo for 60 h. Patients and investigators were masked to treatment assignments. The primary efficacy endpoint was the change from baseline in the 17-item HAM-D total score at 60 h, assessed in all randomised patients who started infusion of study drug or placebo and who had a completed baseline HAM-D assessment and at least one post-baseline HAM-D assessment. Patients were followed up until day 30. This trial is registered with ClinicalTrials.gov, number NCT02614547. Findings: This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (n=10) and placebo (n=11) groups. At 60 h, mean reduction in HAM-D total score from baseline was 21�0 points (SE 2�9) in the brexanolone group compared with 8�8 points (SE 2�8) in the placebo group (difference -12�2, 95% CI -20�77 to -3�67; p=0�0075; effect size 1�2). No deaths, serious adverse events, or discontinuations because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and somnolence (two vs none). Moderate treatment-emergent adverse events were reported in two patients in the brexanolone group (sinus tachycardia, n=1; somnolence, n=1) and in two patients in the placebo group (infusion site pain, n=1; tension headache, n=1); one patient in the placebo group had a severe treatment-emergent adverse event (insomnia). Interpretation: In women with severe post-partum depression, infusion of brexanolone resulted in a significant and clinically meaningful reduction in HAM-D total score, compared with placebo. Our results support the rationale for targeting synaptic and extrasynaptic GABAA receptors in the development of therapies for patients with post-partum depression. A pivotal clinical programme for the investigation of brexanolone in patients with post-partum depression is in progress.","Post-partum depression (depression after childbirth) is a serious mood disorder in women that might be triggered by changes in reproductive hormones during the period of time around pregnancy. This research study examined the drug, brexanolone (formerly SAGE-547 injection). Brexanolone is a naturally occurring reproductive steroid hormone that affects receptors in the brain and nervous system. It is used as an IV medicine for the treatment of post-partum depression. Researchers studied female inpatients who gave birth within 6 months of the study with severe post-partum depression (in four hospitals in the USA. The severity of depression was checked by the questionnaire-Hamilton Rating Scale for Depression [HAM-D]. Eligible women received either one, continuous IV dose of brexanolone for 60 hours or a placebo (a procedure that appears like the real treatment but has no treatment value). The women were chosen at random by a computer program to receive the real treatment or the placebo. Both patients and researchers did not know who received the real treatment and who received the placebo. The most important outcome was the change in the HAM-D score between the start of the study and at 60 hours . Patients were followed up until for 30 days. This study (trial) is registered with ClinicalTrials.gov, number NCT02614547. This trial was done between Dec 15, 2015 (first enrolment), and May 19, 2016 (final visit of the last enrolled patient). 21 women were randomly assigned to the brexanolone (10 women) and placebo (11 women) groups. At 60 hours, the average decrease in the depression score by the HAM-D questionnaire was 21 points in the brexanolone group (compared to the score at the start of the study). In the placebo group, the HAM-D score only decreased by an average of 8.8 points. No deaths, serious adverse (harmful) events, or stopping of the procedures because of adverse events were reported in either group. Four of ten patients in the brexanolone group had adverse events compared with eight of 11 in the placebo group. The most frequently reported adverse events in the brexanolone group were dizziness (two patients in the brexanolone group vs three patients in the placebo group) and sleepiness (two vs none). Other adverse events reported in two patients in the brexanolone group were fast heart rate and sleepiness. Two patients in the placebo group had adverse events; pain at the IV site and tension headache. One patient in the placebo group had a severe treatment adverse event (insomnia). In women with severe post-partum depression, brexanolone IV resulted in a significant and clinically meaningful reduction in HAM-D total score of depression, compared with placebo. Our results support the reasons for focusing on GABAA receptors in order to development therapies for patients with post-partum depression. A major clinical program for the study of brexanolone in patients with post-partum depression is in progress." +"Postpartum depression is one of the most prevalent psychopathologies. Its prevalence is estimated to be between 10% and 15%. Despite its multifactorial etiology, it is known that genetics play an important role in the genesis of this disorder. This paper reviews epidemiological evidence supporting the role of genetics in postpartum depression (PPD). The main objectives of this review are to determine which genes and polymorphisms are associated with PPD and discuss how this association may occur. In addition, this paper explores whether these genes are somehow related to or even the same as those linked to Major Depression (MD). To identify gaps in the current knowledge that require investigation, a systematic review was conducted in the electronic databases PubMed, LILACS and SciELO using the index terms ""postpartum depression"" and ""genetics"". Literature searches for articles in peer-reviewed journals were made until April 2014. PPD was indexed 56 times with genetics. The inclusion criteria were articles in Portuguese, Spanish or English that were available by institutional means or sent by authors upon request; this search resulted in 20 papers. Genes and polymorphisms traditionally related to MD, which are those involved in the serotonin, catecholamine, brain-derived neurotrophic factor and tryptophan metabolism, have been the most studied, and some have been related to PPD. The results are conflicting and some depend on epigenetics, which makes the data incipient. Further studies are required to determine the genes that are involved in PPD and establish the nature of the relationship between these genes and PPD.","Postpartum depression (depression after childbirth) is one of the most common mental disorders. Its occurance is estimated to be between 10% and 15%. Even though the origin of postpartum depression has many causes, it is known that genetics play an important role in the onset of this disorder. This research reviews evidence supporting the role of genetics in postpartum depression (PPD). This research will determine which genes and mutations are associated with PPD. The review will discuss how this association may occur. Also, this research studies if these genes are related to (or the same as) genes linked to Major Depression (MD). To seek out gaps in the current knowledge that require more research, a thorough review was done in the electronic databases PubMed, LILACS and SciELO. The search words ""postpartum depression"" and ""genetics"" were used. Literature searches were done for articles in peer-reviewed journals up until April 2014. Peer-reviewed journals use experts in the same field to go over the studies before publishing the articles. During the literature search, the search words ""postpartum depression"" and ""genetics"" were linked 56 times.. The rules for including the articles in this study were articles written in Portuguese, Spanish or English that were available to the institutional or the authors. This search resulted in 20 papers. Genes and mutations related to Major Depression (MD) have been the most studied. These genes are involved in the metabolism of chemicals that effect emotions (such as serotonin, catecholamines, brain-derived neurotrophic factor, and tryptophan. )Some of these genes and mutations have been related to PPD. The results are not all in agreement. Some depend on epigenetics (which can change the way your genes work without changing the DNA itself). The results are in the early stages. Further studies are required to determine the genes that are involved in PPD. More studies are needed to define the relationship between these genes and PPD." +"Objectives: Both antidepressant medications and psychological therapy are common treatments for depression in postpartum women. Antidepressant treatment may have a number of practical disadvantages, including a preference by women to avoid medication while breastfeeding. Consequently, more information about the relative benefits of the two modalities in the perinatal period is helpful. In the treatment of depressive disorders there is some evidence that combination therapies (pharmacological plus psychological treatment) may be more efficacious than either form of mono-therapy in isolation. However, in the treatment of postnatal depression, such evidence is limited. Method: Forty five postpartum women with a DSM-IV diagnosis of depression were randomised to receive either: 1) cognitive behavioural therapy (CBT); 2) sertraline, or 3) a combination of both treatment modalities. Psychometric measures were collected weekly for 12 weeks, with a follow-up at 24 weeks. Results: Symptoms of depression and anxiety were reduced to a significant degree following all three treatments. CBT mono-therapy was found to be superior to both sertraline mono-therapy and combination therapy after 12 weeks. The CBT mono-therapy group appeared to display the most rapid initial gains after treatment commencement. Conclusions: In this sample, a specialised CBT program for postnatal depression was found to be superior as a mono-therapy compared to sertraline, a commonly prescribed SSRI antidepressant. This is in contrast to previous studies which have found no detectable difference in the efficacies of drug and psychological treatment for postnatal depression. Unlike some previous work, this study allowed a statistically independent evaluation of CBT mono-therapy for postnatal depression compared to both antidepressant and combination therapy. In line with previous studies in postpartum women, there was no detectable advantage of combining pharmacological and psychological treatments in the short term.","Both antidepressant medications and psychological therapy are common treatments for depression in women after childbirth (postpartum depression-PPD). Antidepressant treatment may have a number of practical disadvantages. Women may prefer to avoid medication while breastfeeding. More information about the benefits of these two ways of treating PPD in the perinatal period (time around pregnancy and childbirth) is helpful. In treating of depression, there is some evidence that combining both therapies (medications plus psychological treatment) may be more successful than either treatment alone. However, in the treatment of postnatal depression, such evidence is limited. Researchers did a study in 45 postpartum women with depression. The treatments were assigned randomly. They received either cognitive behavioural therapy (CBT), sertraline (an antidepressant drug), or a combination of both. Psychological measurements were collected weekly for 12 weeks, with a follow-up at 24 weeks. Symptoms of depression and anxiety were reduced to a significant degree following all three treatments. CBT alone was found to be superior to both sertraline alone and combination therapy after 12 weeks. The CBT therapy group appeared to show the most rapid initial gains after treatment began. In this study, a special CBT program for postnatal depression was found to be superior as a single therapy when compared to sertraline, a commonly prescribed antidepressant. This is in disagreement with other studies that found no difference noted in the outcomes between the drug and the psychological treatment for postnatal depression. Unlike some previous work, this study had an independent analysis of CBT single therapy for postnatal depression as compared to both antidepressant and combination therapy. Like previous studies in postpartum women, there was no advantage noticed by combining drug and psychological treatments in the short term." +"Postpartum depression (PPD) is a common and serious mental health problem that is associated with maternal suffering and numerous negative consequences for offspring. The first six months after delivery may represent a high-risk time for depression. Estimates of prevalence range from 13% to 19%. Risk factors mirror those typically found with major depression, with the exception of postpartum-specific factors such as sensitivity to hormone changes. Controlled trials of psychological interventions have validated a variety of individual and group interventions. Medication often leads to depression improvement, but in controlled trials there are often no significant differences in outcomes between patients in the medication condition and those in placebo or active control conditions. Reviews converge on recommendations for particular antidepressant medications for use while breastfeeding. Prevention of PPD appears to be feasible and effective. Finally, there is a growing movement to integrate mental health screening into routine primary care for pregnant and postpartum women and to follow up this screening with treatment or referral and with follow-up care. Research and clinical recommendations are made throughout this review.","Postpartum depression (PPD-depression after childbirth) is a common and serious mental health problem. It is associated with maternal suffering and numerous negative consequences for offspring. The first six months after delivery may represent a high-risk time for depression. Estimates of occurrence range from 13% to 19%. Risk factors mirror those typically found with major depression, except the hormone changes found after childbirth. Studies of psychological treatments have proved a variety of individual and group interventions work. Medication often leads to depression improvement. But In research studies, there are often no significant differences in outcomes between patients on medication and those not on medication (placebo or active control groups). Reviews meet up on recommendations for particular antidepressant medications for use while breastfeeding. Prevention of PPD can be done and treatments are effective. There is a growing movement to add mental health screening into routine primary care for pregnant and postpartum women. This screening should be followed-up with treatment or referral and with follow-up care. Research and patient recommendations are made throughout this review." +"Vitamin B6 is one of the central molecules in the cells of living organisms. Water-soluble vitamin B6 is widely present in many foods, including meat, fish, nuts, beans, grains, fruits, and vegetables. Additionally, B6 is present in many multivitamin preparations for adults and children and is added as a supplement to foods, power bars, and powders. There are several active compounds or vitamers which fall under the generic B6. These include pyridoxine alcohol, pyridoxal an aldehyde, pyridoxamine, which differs from the first two with an amine group, and a 2,5' phosphate esters. The major esters are the active coenzyme form and are pyridoxal 5'phosphate (PLP) and pyridoxamine 5'phosphate (PMP). The primary form of B6 in meats are the esters, and the dominant plant source is pyridoxine, which is less bioavailable. Pyridoxine is the most common form found in multivitamins. As a coenzyme, B6 is involved as a co-factor in over 100 enzymatic reactions, including carbohydrate metabolism, amino acid metabolism, particularly homocysteine, gluconeogenesis, glycogenolysis, and lipid metabolism. Vitamin B6 is also involved in the critical functioning of cells. It plays a significant role in transamination, decarboxylation, initial steps of porphyrin synthesis. Pyridoxine has a role in cognitive development through neurotransmitter synthesis, immune function with interleukin-2 (IL-2) production, and hemoglobin formation. Fetal brain development requires adequate B6, and this continues throughout infancy. Vitamin B6 recommendations are made in accordance with age and life stage with pregnancy and breastfeeding, involving the highest recommended daily allowance.","Vitamin B6 is one of the most important molecules in the cells of living organisms. Vitamin B6 dissolves in water. It is widely present in many foods, including meat, fish, nuts, beans, grains, fruits, and vegetables. Vitamin B6 is present in many multivitamins for adults and children. It is added to foods, power bars, and powders. There are several active chemicals (vitamers) which fall under the types of vitamin B6. These vitamin B6 vitamers include pyridoxine alcohol, pyridoxal, and pyridoxamine. Other vitamin B6 vitamers include pyridoxal 5'phosphate (PLP) and pyridoxamine 5'phosphate (PMP). The main vitamers of vitamin B6 are different in meats and plants. The main vitamer in plants, pyridoxine, is less bioavailable (the amount of the substance taken up by the living organism). Pyridoxine is the most common form of vitamin B6 found in multivitamins. Vitamin B6 is involved in over 100 processes in the body including carbohydrate (sugar) metabolism, amino acid (protein) metabolism, , and lipid (fat) metabolism. Vitamin B6 is also involved in the critical functioning of cells. It plays a significant role in many important chemical reactions in the body. Pyridoxine has a role in the development of the brain, immune function, and hemoglobin formation by helping produce important chemicals the body uses. During pregnancy, fetal brain development requires adequate B6, and this continues throughout infancy. The amount of vitamin B6 doctors recommend is made according to age and life stage. The highest recommended daily allowance is during pregnancy and breastfeeding." +"Background: Vitamin B6 is thought to be a most versatile coenzyme that participates in more than 100 biochemical reactions. It is involved in amino acid and homocysteine metabolism, glucose and lipid metabolism, neurotransmitter production and DNA/RNA synthesis. Vitamin B6 can also be a modulator of gene expression. Nowadays, clinically evident vitamin B6 deficiency is not a common disorder, at least in the general population. Nevertheless, a subclinical, undiagnosed deficiency may be present in some subjects, particularly in the elderly. Objective: This review gives a complete overview over the metabolism and interactions of vitamin B6. Further, we show which complications and deficiency symptoms can occur due to a lack of vitamin B6 and possibilities for public health and supplemental interventions. Methods: The database Medline (www.ncvi.nlm.nih.gov) was searched for terms like ""vitamin B6"", ""pyridoxal"", ""cancer"", ""homocysteine"", etc. For a complete understanding, we included studies with early findings from the forties as well as recent results from 2006. These studies were summarised and compared in different chapters. Results and conclusion: In fact, it has been proposed that suboptimal vitamin B6 status is associated with certain diseases that particularly afflict the elderly population: impaired cognitive function, Alzheimer's disease, cardiovascular disease, and different types of cancer. Some of these problems may be related to the elevated homocysteine concentrations associated to vitamin B6 deficiency, but there is also evidence for other mechanisms independent of homocysteine by which a suboptimal vitamin B6 status could increase the risk for these chronic diseases.","Vitamin B6 is thought to be a most versatile chemical that participates in more than 100 biochemical reactions in the body. It is involved in protein and amino acid (building blocks of protein) metabolism, carbohydrate (sugar) and lipid (fat) metabolism. It is also involved in neurotransmitter (chemicals involved in nerve impulses) production and DNA/RNA synthesis. Vitamin B6 can also be a chemical that regulates gene expression. Currently, signs and symptoms of vitamin B6 deficiency is not a common disorder in the general population. But Vitamin B6 deficiency may be present without signs or symptoms especially in the elderly. This research give a complete overview of the actions of vitamin B6 in the body. Researchers show which specific problems can occur due to a lack of vitamin B6. Researchers also discuss possibilities for public health and adding supplements to foods. The database Medline (www.ncvi.nlm.nih.gov) was searched on the computer for terms like ""vitamin B6"", ""pyridoxal"", ""cancer"", ""homocysteine"", etc. Researchers included studies with early findings from the forties as well as recent results from 2006 for a complete understanding. This research was summarised and compared in different chapters. Researchers have proposed that less than adequate (suboptimal) vitamin B6 levels are associated with certain diseases that particularly trouble the elderly population such as: decreased ability to think clearly, Alzheimer's disease, cardiovascular disease, and different types of cancer. Some of these problems may be related to an increased homocysteine (amino acid) levels that is associated with vitamin B6 deficiency. There is also evidence for other ways suboptimal vitamin B6 levels could increase the risk for these chronic diseases." +"The vitamins folic acid, B12 and B6 and B2 are the source of coenzymes which participate in one carbon metabolism. In this metabolism, a carbon unit from serine or glycine is transferred to tetrahydrofolate (THF) to form methylene-THF. This is either used as such for the synthesis of thymidine, which is incorporated into DNA, oxidized to formyl-THF which is used for the synthesis of purines, which are building blocks of RNA and DNA, or it is reduced to methyl-THF which used to methylate homocysteine to form methionine, a reaction which is catalyzed by a B12-containing methyltransferase. Much of the methionine which is formed is converted to S-adenosylmethionine (SAM), a universal donor of methyl groups, including DNA, RNA, hormones, neurotransmitters, membrane lipids, proteins and others. Because of these functions, interest in recent years has been growing particularly in the area of aging and the possibility that certain diseases that afflict the aging population, loss of cognitive function, Alzheimer's disease, cardiovascular disease, cancer and others, may be in part explained by inadequate intake or inadequate status of these vitamins. Homocysteine, a product of methionine metabolism as well as a precursor of methionine synthesis, was shown recently to be a risk factor for cardiovascular disease, stroke and thrombosis when its concentration in plasma is slightly elevated. There are now data which show association between elevated plasma homocysteine levels and loss of neurocognitive function and Alzheimer's disease. These associations could be due to a neurotoxic effect of homocysteine or to decreased availability of SAM which results in hypomethylation in the brain tissue. Hypomethylation is also thought to exacerbate depressive tendency in people, and for (colorectal) cancer DNA hypomethylation is thought to be the link between the observed relationship between inadequate folate status and cancer. There are many factors that contribute to the fact that the status of these vitamins in the elderly is inadequate. These factors are in part physiological such as the achlorhydria which affects vitamin B12 absorption and in part socioeconomic and habitual. We need more studies to confirm that these vitamins have important functions in the etiology of these diseases. We also need to establish if these diseases can be prevented or diminished by proper nutrition starting at a younger age.","There are several B vitamins: folic acid, B12 and B6 and B2. They are important in one carbon metabolism of protein and DNA metabolism. Here, one carbon unit is transferred from an amino acid (building blocks of proteins) by a B vitamin, tetrahydrofolate (THF), to form a new chemical, methylene-THF. Methylene-THF is used in the synthesis of DNA, RNA, or in the metabolism of important amino acids (such as the reaction that changes one amino acid, homocysteine, to another amino acid, methionine). Much of the methionine which is formed is made into S-adenosylmethionine (SAM) and then used in the metabolism of DNA, RNA, hormones, neurotransmitters (nerve impulse chemicals), cell lipids (fats), proteins and others. Because of these functions, interest in recent years has been growing particularly in the area of aging. The possibility that certain diseases associated with aging such as the loss of thinking, Alzheimer's disease, cardiovascular disease, cancer and others, may be in part explained by inadequate intake or inadequate amounts in the body of these vitamins. Homocysteine, an amino acid that is both needed to make methionine as well as made from methionine metabolism was shown recently to be a risk factor for cardiovascular disease, stroke and blood clots when its amount in blood is slightly elevated. Facts now show association between increased blood levels of homocysteine and loss of brain function and Alzheimer's disease. These associations could be due to harmful effects of homocysteine on the nervous system or on the decreased amount of SAM in the brain. Problems with methionine metabolism are also thought to increase depressive tendency in people.These problems with methionine and DNA metabolism are also thought to be the link between the relationship seen between low levels of vitamin B folate and colorectal cancer. Many factors(reasons) contribute to the fact that the amount of these vitamins in the elderly is inadequate. One factor is not having enough acid in the stomach (achlorhydria). This decreases the amount of vitamin B12 your stomach can absorb from food. Other factors include socioeconomic and habits. We need more studies to prove that these vitamins have important functions in the causes of these diseases. We also need to prove iif these diseases can be prevented or lessened by proper nutrition starting at a younger age." +"The immune system is critical in preventing infection and cancer, and malnutrition can weaken different aspects of the immune system to undermine immunity. Previous studies suggested that vitamin B6 deficiency could decrease serum antibody production with concomitant increase in IL4 expression. However, evidence on whether vitamin B6 deficiency would impair immune cell differentiation, cytokines secretion, and signal molecule expression involved in JAK/STAT signaling pathway to regulate immune response remains largely unknown. The aim of this study is to investigate the effects of vitamin B6 deficiency on the immune system through analysis of T lymphocyte differentiation, IL-2, IL-4, and INF-γ secretion, and SOCS-1 and T-bet gene transcription. We generated a vitamin B6-deficient mouse model via vitamin B6-depletion diet. The results showed that vitamin B6 deficiency retards growth, inhibits lymphocyte proliferation, and interferes with its differentiation. After ConA stimulation, vitamin B6 deficiency led to decrease in IL-2 and increase in IL-4 but had no influence on IFN-γ. Real-time PCR analysis showed that vitamin B6 deficiency downregulated T-bet and upregulated SOCS-1 transcription. Meanwhile, the appropriate supplement of vitamin B6 could benefit immunity of the organism.","The immune system is critical in preventing infection and cancer, and malnutrition can weaken different aspects of the immune system to decrease immunity. Previous research suggested that vitamin B6 deficiency could decrease blood antibody production resulting in an increase in IL4 (cytokine-chemical marker of inflammation) production. Facts about whether vitamin B6 deficiency would impair immune cell function, cytokines secretion, and production of chemicals involved in (JAK/STAT signaling) a pathway that helps control the immune response are largely unknown. Researchers study the effects of vitamin B6 deficiency on the immune system by studying T lymphocyte (type of white blood cell) function, the secretion of immune chemicals, and the function of certain genes. We made a vitamin B6-deficient mouse model by supplying a diet without enough vitamin B6. The results showed that vitamin B6 deficiency slows down growth and inhibits lymphocyte cell production and functions. When T lymphocytes were activated, vitamin B6 deficiency influenced the secretion of some immune chemicals. This study showed that vitamin B6 deficiency affected the function of certain genes. The right amount of supplement of vitamin B6 could benefit immunity of the organism." +"Animal and human studies suggest that vitamin B6 deficiency affects both humoral and cell-mediated immune responses. Lymphocyte differentiation and maturation are altered by deficiency, delayed-type hypersensitivity responses are reduced, and antibody production may be indirectly impaired. Although repletion of the vitamin restores these functions, megadoses do not produce benefits beyond those observed with moderate supplementation. Additional human studies indicate that vitamin B6 status may influence tumor growth and disease processes. Deficiency of the vitamin has been associated with immunological changes observed in the elderly, persons infected with human immunodeficiency virus (HIV), and those with uremia or rheumatoid arthritis. Future research efforts should focus on establishing the mechanism underlying the effects of vitamin B6 on immunity and should attempt to establish safe intake levels that optimize immune response.","Animal and human research studies suggest that vitamin B6 deficiency (not enough vitamin B6) affects the immune system. White blood cell function and antibody production are damaged. Delayed allergy reactions are reduced (like the reaction to a tuberculosis (TB) skin test)). Taking enough vitamin B6 to get levels back to normal corrects the immune system problems. Taking very high doses supplements does not cause further improvement. Human research also show that the amount of vitamin B6 in the body may affect tumor growth and disease. Vitamin B6 deficiency (not enough vitamin B6 in the body) has been associated with immune system changes in the elderly.Vitamin B6 deficiency also affects people with HIV infections, kidney disease, and rheumatoid arthritis. Future research studies should focus on explaining exactly how vitamin B6 affects the immune system and the right amount of vitamin B6 to take for the best immune system function." +"We have reported that a subpopulation of patients with schizophrenia have lower levels of vitamin B6 (VB6) in peripheral blood than do healthy controls. In a previous study, we found that VB6 level was inversely proportional to the patient's positive and negative symptom scale (PANSS) score for measuring symptom severity, suggesting that the loss of VB6 might contribute to the development of schizophrenia symptoms. In the present study, to clarify the relationship between VB6 deficiency and schizophrenia, we generated VB6-deficient (VB6(-)) mice through feeding with a VB6-lacking diet as a mouse model for the subpopulation of schizophrenia patients with VB6 deficiency. After feeding for 4 weeks, plasma VB6 level in VB6(-) mice decreased to 3% of that in control mice. The VB6(-) mice showed social deficits and cognitive impairment. Furthermore, the VB6(-) mice showed a marked increase in 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brain, suggesting enhanced noradrenaline (NA) metabolism in VB6(-) mice. We confirmed the increased NA release in the prefrontal cortex (PFC) and the striatum (STR) of VB6(-) mice through in vivo microdialysis. Moreover, inhibiting the excessive NA release by treatment with VB6 supplementation into the brain and α2A adrenoreceptor agonist guanfacine (GFC) suppressed the increased NA metabolism and ameliorated the behavioral deficits. These findings suggest that the behavioral deficits shown in VB6(-) mice are caused by enhancement of the noradrenergic (NAergic) system.","Research has shown that some patients with schizophrenia have lower levels of vitamin B6 in the blood than healthy people. A study showed that lower vitamin B6 levels increased symptoms of schizophrenia. Higher vitamin B6 levels decreased symptoms of schizophrenia.When measuring the symptoms of schizophrenia, the loss of vitamin B6 might help cause the symptom of schizophrenia. To study the relationship between vitamin B6 and schizophrenia, research was done on mice fed a diet without vitamin B6 . This made a mouse model of vitamin B6 deficiency. After 4 weeks of that diet, blood levels of vitamin B6 in these mice decreased to 3% of the healthy mice. The vitamin B6 deficiency mice showed social and thinking (behavior) problems. Also in the vitamin B6 deficiency mouse model, mice showed a high increase in a chemical that suggests increased metabolism of a hormone (noradrenaline (NA)) for flight-or-flight in the brain. We proved that certain parts of the brain released this increased NA in vitamin B6 deficiency mice. Feeding the mice vitamin B6 supplements decreases the excess NA released by the brain. Treating the mice with a specific drug, guanfacine (GFC), decreased the NA metabolism. Doing these things helped to correct the behavior problems in the vitamin B6 deficiency mice. This research suggests that the behavior problems in the vitamin B6 deficiency mice are caused by an increase in the noradrenergic (NAergic) system." +"Pyridoxal-5'-phosphate (PLP), the bioactive form of vitamin B6, reportedly functions as a prosthetic group for >4% of classified enzymatic activities of the cell. It is therefore not surprising that alterations of vitamin B6 metabolism have been associated with multiple human diseases. As a striking example, mutations in the gene coding for antiquitin, an evolutionary old aldehyde dehydrogenase, result in pyridoxine-dependent seizures, owing to the accumulation of a metabolic intermediate that inactivates PLP. In addition, PLP is required for the catabolism of homocysteine by transsulfuration. Hence, reduced circulating levels of B6 vitamers (including PLP as well as its major precursor pyridoxine) are frequently paralleled by hyperhomocysteinemia, a condition that has been associated with an increased risk for multiple cardiovascular diseases. During the past 30 years, an intense wave of clinical investigation has attempted to dissect the putative links between vitamin B6 and cancer. Thus, high circulating levels of vitamin B6, as such or as they reflected reduced amounts of circulating homocysteine, have been associated with improved disease outcome in patients bearing a wide range of hematological and solid neoplasms. More recently, the proficiency of vitamin B6 metabolism has been shown to modulate the adaptive response of tumor cells to a plethora of physical and chemical stress conditions. Moreover, elevated levels of pyridoxal kinase (PDXK), the enzyme that converts pyridoxine and other vitamin B6 precursors into PLP, have been shown to constitute a good, therapy-independent prognostic marker in patients affected by non-small cell lung carcinoma (NSCLC). Here, we will discuss the clinical relevance of vitamin B6 metabolism as a prognostic factor in cancer patients.","Pyridoxal-5'-phosphate (PLP) is the active form of vitamin B6 in the body. PLP is involved in more than 4% of the chemical reactions of proteins in the cell. Changes in vitamin B6 metabolism have been associated with multiple human diseases. For example, mutations in the gene coding for antiquitin, a protein that appeared early in evolution, result in seizures. These seizures are due to an increase in a chemical (made during vitamin B6 metabolism) that stops the function of PLP. PLP is also required for the metabolism of homocysteine (an amino acid involved in vitamin B metabolism).. Lower blood levels of B6 vitamers (active vitamin B6 chemicals-PLP and pyridoxine) are associated with hyperhomocysteinemia (excess blood homocysteine). Hyperhomocysteinemia is associated with a higher risk of many cardiovascular diseases. During the past 30 years, a lot of research has tried to explain links between vitamin B6 and cancer. High blood levels of vitamin B6, or the related lower blood levels of homocysteine, have been associated with improved disease outcome in patients with blood and solid organ neoplasms. Recently, vitamin B6 metabolism has been shown to control tumor cells' ability to adjust to many different types of stress. Also, increased levels of pyridoxal kinase (PDXK-a protein involved in producing PLP), have been shown to predict good outcomes in patients with non-small cell lung carcinoma (NSCLC). This research discusses the importance of vitamin B6 metabolism in the disease outcome of cancer patients." +"There is little evidence regarding the association between serum vitamin B6 concentration and subsequent mortality. We aimed to evaluate the association of serum vitamin B6 concentration with all-cause, cardiovascular disease (CVD), and cancer mortality in the general population using data from the National Health and Nutrition Examination Survey (NHANES). Our study examined 12,190 adults participating in NHANES from 2005 to 2010 in the United States. The mortality status was linked to National Death Index (NDI) records up to 31 December 2015. Pyridoxal 5'-phosphate (PLP) is the biologically active form of vitamin B6. Vitamin B6 status was defined as deficient (PLP < 20 nmol/L), insufficient (PLP ≥ 20.0 and <30.0 nmol/L), and sufficient (PLP ≥ 30.0 nmol/L). We established Cox proportional-hazards models to estimate the associations of categorized vitamin B6 concentration and log-transformed PLP concentration with all-cause and cause-specific mortality by calculating hazard ratios (HRs) and 95% confidence intervals (95%CIs). In our study, serum vitamin B6 was sufficient in 70.6% of participants, while 12.8% of the subjects were deficient in vitamin B6. During follow-up, a total of 1244 deaths were recorded, including 294 cancer deaths and 235 CVD deaths. After multivariate adjustment in Cox regression, participants with higher serum vitamin B6 had a 15% (HR = 0.85, 95% CI = 0.77, 0.93) reduced risk of all-cause mortality and a 19% (HR = 0.81, 95%CI = 0.68, 0.98) reduced risk for CVD mortality for each unit increment in natural log-transformed PLP. A higher log-transformed PLP was not significantly associated with a lower risk for cancer mortality. Compared with sufficient vitamin B6, deficient (HR = 1.37, 95% CI = 1.17, 1.60) and insufficient (HR = 1.19, 95%CI = 1.02, 1.38) vitamin B6 level were significantly associated with a higher risk for all-cause mortality. There was no significant association for cause-specific mortality. Participants with higher levels of vitamin B6 had a lower risk for all-cause mortality. These findings suggest that maintaining a sufficient level of serum vitamin B6 may lower the all-cause mortality risk in the general population.","There is little evidence about the connection beween blood levels of vitamin B6 and later mortality (death rate). Researchers studied the connection between blood levels of vitamin B6 levels and mortality from all causes, cardiovascular disease, and cancer using facts collected from the National Health and Nutrition Examination Survey (NHANES). Our study examined 12,190 adults participating in NHANES from 2005 to 2010 in the United States. Mortality was linked to National Death Index (NDI) records up to 31 December 2015. The chemical, pyridoxal 5'-phosphate (PLP), is the active form of vitamin B6 in the body. Vitamin B6 blood levels were defined as deficient (not enough), insufficient (low), and sufficient (enough) depending on the level of PLP in the blood.. Researchers created a model to accurately estimate the risk of death (Cox model) between blood levels of vitamin B6 and PLP and mortality from all causes and from specific causes. This study showed vitamin B6 was sufficient in 70.6% of participants. But, 12.8% of participants had deficient vitamin B6 blood levels. During follow-up, a total of 1244 deaths were recorded, including 294 cancer deaths and 235 cardiovascular disease deaths. Participants with higher blood vitamin B6 had a 15% lower risk of all-cause mortality and a 19% lower risk of cardiovascular disease mortality for each unit level of PLP (using the Cox model). Higher PLP blood levels were not significantly associated with a lower risk of cancer mortality (using the Cox model). Compared with sufficient vitamin B6 levels, deficient and insufficient vitamin B6 levels were significantly associated with a higher risk for all-cause mortality (Cox model). There was no significant association for cause-specific mortality. Participants with higher levels of vitamin B6 had a lower risk for all-cause mortality. These findings suggest that maintaining a sufficient level of vitamin B6 in the blood may lower the all-cause mortality risk in the general population." +"Background: a large number of studies have linked vitamin B6 to inflammation and cardiovascular disease in the general population. However, it remains uncertain whether vitamin B6 is associated with cardiovascular outcome independent of inflammation. Methods: we measured plasma pyridoxal 5'-phosphate (PLP), as an indicator of vitamin B6 status, at baseline in a population-based prospective cohort of 6249 participants of the Prevention of Renal and Vascular End-stage Disease (PREVEND) study who were free of cardiovascular disease. As indicators of low-grade systemic inflammation, we measured high-sensitivity C-reactive protein and GlycA; Results: median plasma PLP was 37.2 (interquartile range, 25.1-57.0) nmol/L. During median follow-up for 8.3 (interquartile range, 7.8-8.9) years, 409 non-fatal and fatal cardiovascular events (composite outcome) occurred. In the overall cohort, log transformed plasma PLP was associated with the composite outcome, independent of adjustment for age, sex, smoking, alcohol consumption, body mass index (BMI), estimated glomerular filtration rate (eGFR), total cholesterol:high-density lipoprotein (HDL)-cholesterol ratio, and blood pressure (adjusted hazard ratio per increment of log plasma PLP, 0.66; 95% confidence interval (CI), 0.47-0.93). However, adjustment for high-sensitivity C-reactive protein and GlycA increased the hazard ratio by 9% and 12% respectively, to non-significant hazard ratios of 0.72 (95% confidence interval, 0.51-1.01) and 0.74 (95% confidence interval, 0.53-1.05). The association of plasma PLP with cardiovascular risk was modified by gender (adjusted Pinteraction = 0.04). When stratified according to gender, in women the prospective association with cardiovascular outcome was independent of age, smoking, alcohol consumption, high-sensitivity C-reactive protein, and GlycA (adjusted hazard ratio, 0.50, 95% confidence interval, 0.27-0.94), while it was not in men (adjusted hazard, 0.99, 95% confidence interval, 0.65-1.51). Conclusions: in this population-based cohort, plasma PLP was associated with cardiovascular outcome, but this association was confounded by traditional risk factors and parameters of inflammation. Notably, the association of low plasma PLP with high risk of adverse cardiovascular outcome was modified by gender, with a stronger and independent association in women.","A large number of studies have linked vitamin B6 to inflammation and cardiovascular disease in the general population. It is not known if vitamin B6 is linked to future cardiovascular disease without inflammation. Researchers measured the amount of pyridoxal 5'-phosphate (PLP) in the blood at the start of a prevention study in patients without cardiovascular disease. Levels of PLP in blood can show how much vitamin B6 is present in the body. Low-level widespread inflammation in the body was measured by blood levels of high-sensitivity C-reactive protein (hsCRP) and GlyA. The blood level of PLP was about 37.2 nmol/L. These patients were followed up for about 8 years. During this time, 409 cardiovascular diseases events occurred, some were fatal. In these patients, the amount of PLP in the blood was linked to the cardiovascular events that occurred. This link did not depend on other risk factors like age, sex, smoking, drinking alcohol, body weight (BMI), kidney function (eGFR), cholesterol levels, or blood pressure. But, the amount of hsCRP and GlyA in the blood was linked to an increase in the risk of having these cardiovascular events occurring. Also, this link of the amount of PLP in the blood and the risk of getting cardiovascular disease was affected by gender. In women, the link between the amount of PLP in the blood and getting cardiovascular disease did not depend on the other risk factors like age, smoking, drinking alcohol, or blood levels of hsCRP and GlyA. In men, the link was not as independent of these other risk factors. In these patients, the level of PLP in blood was linked to getting cardiovascular disease. This link was affected by the usual risk factors and measures of inflammation. The association of low blood levels of PLP with high risk of harmful cardiovascular outcomes wasaffected by gender. This association was stronger and independent in women." +"Background: Higher plasma concentrations of the vitamin B-6 marker pyridoxal 5'-phosphate (PLP) have been associated with reduced colorectal cancer (CRC) risk. Inflammatory processes, including vitamin B-6 catabolism, could explain such findings. Objective: We investigated 3 biomarkers of vitamin B-6 status in relation to CRC risk. Design: This was a prospective case-control study of 613 CRC cases and 1190 matched controls nested within the Northern Sweden Health and Disease Study (n = 114,679). Participants were followed from 1985 to 2009, and the median follow-up from baseline to CRC diagnosis was 8.2 y. PLP, pyridoxal, pyridoxic acid (PA), 3-hydroxykynurenine, and xanthurenic acids (XAs) were measured in plasma with the use of liquid chromatography-tandem mass spectrometry. We calculated relative and absolute risks of CRC for PLP and the ratios 3-hydroxykynurenine:XA (HK:XA), an inverse marker of functional vitamin B-6 status, and PA:(PLP + pyridoxal) (PAr), a marker of inflammation and oxidative stress and an inverse marker of vitamin B-6 status. Results: Plasma PLP concentrations were associated with a reduced CRC risk for the third compared with the first quartile and for PLP sufficiency compared with deficiency [OR: 0.60 (95% CI: 0.44, 0.81) and OR: 0.55 (95% CI: 0.37, 0.81), respectively]. HK: XA and PAr were both associated with increased CRC risk [OR: 1.48 (95% CI: 1.08, 2.02) and OR: 1.50 (95% CI: 1.10, 2.04), respectively] for the fourth compared with the first quartile. For HK:XA and PAr, the findings were mainly observed in study participants with <10.5 y of follow-up between sampling and diagnosis. Conclusions: Vitamin B-6 deficiency as measured by plasma PLP is associated with a clear increase in CRC risk. Furthermore, our analyses of novel markers of functional vitamin B-6 status and vitamin B-6-associated oxidative stress and inflammation suggest a role in tumor progression rather than initiation.","Higher blood levels of pyridoxal 5'-phosphate (PLP) have been linked to lower risk of colorectal cancer (CRC). The level of PLP in the blood is a sign of the level of vitamin B6 in the blood. This could be explained by Inflammation, including types of vitamin B6 metabolism. Researchers measured chemicals that are signs (biomarkers) of the amount of vitamin B6 in blood. They studied these 3 biomarkers In relation to the risk of CRC. This large study was done in Sweden and compared 613 participants with CRC to people without CRC. The participants were followed from 1985 to 2009. From the start of the study to the time of the CRC diagnosis was about 8 years. The biomarkers measured in the blood were PLP, pyridoxal, pyridoxic acid (PA), 3-hydroxykynurenine (HK), and xanthurenic acids (XAs) Researchers calculated the risks of CRC and biomarkers for vitamin B6 status, inflammation, and oxidative stress. Oxidative stress occurs when the level of free radicals is too high compared to the level of antioxidants in the body. These biomarkers included PLP, HK:XA, and PAr (PA: (PLP + pyridoxal)). Higher blood PLP levels were linked to lower CRC risk for many participants. PLP sufficiency (enough) compared to deficiency (not enough) was also linked to lower CRC risk. The calculated biomarkers, HK: XA and PAr were both associated with an increased risk for getting CRC. For HK:XA and PAr, this risk was mainly seen in participants with less than 10.5 years of follow-up between blood samples taken at the start of the study and the CRC diagnosis. Vitamin B6 deficiency (blood PLP) is associated with a clear increase in CRC risk. The other biomarkers studied (showing vitamin B6 status and vitamin B6-associated oxidative stress and inflammation), may play a role in cancer development rather than starting it." +"Purpose of review: A summary of management and current research in achondroplasia (OMIM 100800). The most common nonlethal skeletal dysplasia, achondroplasia presents a distinct clinical picture evident at birth. Substantial information is available concerning the natural history of this dwarfing disorder. Diagnosis is made by clinical findings and radiographic features. Characteristic features include short limbs, a relatively large head with frontal bossing and midface hypoplasia, trident hands, muscular hypotonia, and thoracolumbar kyphosis. Children commonly have recurrent ear infections, delayed motor milestones, and eventually develop bowed legs and lumbar lordosis. People with achondroplasia are generally of normal intelligence. Recent findings: The genetic cause of achondroplasia was discovered in 1994. Subsequent research efforts are designed to better characterize the underlying possible biochemical mechanisms responsible for the clinical findings of achondroplasia as well as to develop possible new therapies and/or improve intervention. Summary: Establishing a diagnosis of achondroplasia allows families and clinicians to provide anticipatory care for affected children. Although the primary features of achondroplasia affect the skeleton, a multidisciplinary approach to care for children with achondroplasia helps families and clinicians understand the clinical findings and the natural history of achondroplasia in order to improve the outcome for each patient.","The purpose of this review is to summarize current research and care for people with achondoplasia (a form of dwarfism). Achondroplasia is the most common nonlethal bone growth impairment and its characteristics can be seen at birth. A lot of information is available about how achondroplasia progresses over time. Achondroplasia is diagnosed by a medical exam and X-rays. Achondroplasia is characterised by features such as short limbs and a relatively large head. Children commonly have ear infections, delayed walking, and eventually develop bowed legs and a curve in the back. People with achondroplasia are generally of normal intelligence. The genetic cause of achondroplasia was discovered in 1994. Since then, research efforts aim to understand the mechanisms that lead to achondroplasia as well as to develop and improve treatments. Diagnosis for achondroplasia allows families and doctors to plan future care for affected children. Coordinating care between professionals from different disciplines helps each child with achodroplasia get the best treatment." +"Achondroplasia (MIM 100800) is the most common non-lethal skeletal dysplasia. Its incidence is between one in 10,000 and one in 30,000. The phenotype is characterized by rhizomelic disproportionate short stature, enlarged head, midface hypoplasia, short hands and lordotic lumbar spine, associated with normal cognitive development. This autosomal-dominant disorder is caused by a gain-of-function mutation in the gene encoding the type 3 receptor for fibroblast growth factor (FGFR3); in more than 95% of cases, the mutation is G380R. The diagnosis is suspected on physical examination and confirmed by different age-related radiological features. Anticipatory and management care by a multidisciplinary team will prevent and treat complications, including cervical cord compression, conductive hearing loss and thoracolumbar gibbosity. Weight counselling, psychosocial guidance and professional integration programmes play an important role in the global quality of life of these patients and their families.","Achondroplasia is a type of dwarfism and the most common nonlethal bone growth impairment. Achondroplasia affects between one in 10,000 and 30,000 people. Achondroplasia is characterized by short stature, shortened limbs, enlarged head, disproportionate face, curvature in the lower back and is associated with normal cognitive development. A mutation in a gene called type 3 receptor for fibroblast growth factor (FGFR3) causes achondroplasia. Achondroplasia is diagnosed by physical examination and confirmed by X-ray. A person with achondroplasia is cared for by a multidisciplinary team that will prevent and treat complications, including spinal cord squeezing, hearing loss and development of a hump in the back. Weight counselling, psychosocial guidance and professional integration programmes play an important role in the global quality of life of these patients and their families." +"Achondroplasia is a human bone genetic disorder of the growth plate and is the most common form of inherited disproportionate short stature. It is inherited as an autosomal dominant disease with essentially complete penetrance. Of these most have the same point mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) which is a negative regulator of bone growth. The clinical and radiological features of achondroplasia can easily be identified; they include disproportionate short stature with rhizomelic shortening, macrocephaly with frontal bossing, midface hypoplasia, lumbar hyperlordosis, and a trident hand configuration. The majority of achondroplasts have a normal intelligence, but many social and medical complications may compromise a full and productive life. Some of them have serious health consequences related to fluid build up in the brain, head and neck region shortening, or blockage in the upper breathing passage.. In this article, we discuss a number of treatments from the surgical limb lengthening approach and the Recombinant Growth Hormone (rhGH) treatment, to future treatments, which include the Natriuretic Peptide C-type (CNP). The discussion is a comparative study of the complications and drawbacks of various experiments using numerous strategies.","Achondroplasia is a human bone growth impairment and is the most common form of inherited disproportionate short stature. Achondroplasia tends to run in families, an affected parent has a 50% chance of passing it to their child. Most people with achondroplasia have a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. Characteristics of achodroplasia can be easily identified from physical exams and X-rays; they include disproportionate short stature with limb shortening, large head with prominence of forehead, underdevelopment of the middle part of the face and a short stubby hands with a separation betweem the middle and ring fingers. The majority of people with achondroplasia have normal intelligence, but many social and medical complications may compromise a full and productive life. Some of them have serious health consequences related to hydrocephalus, craniocervical junction compression, or upper-airway obstruction. In this article, we discuss a number of treatments from surgical limb lengthening and Growth Hormone treatment, to future treatments, including therapy using a bone formation stimulator called C-type natriuretic peptide. The discussion is a comparative study of the complications and drawbacks of various experiments using numerous strategies." +"This review focuses on the rheumatological features of achondroplasia, which is the most common skeletal dysplasia and the most frequent cause of short-limbed dwarfism. It is inherited in an autosomal dominant manner but results in the majority of cases of de novo mutations. The disease is related to a mutation in the fibroblast growth factor receptor-3 (FGFR3) gene encoding one member of the FGFR subfamily of tyrosine kinase receptors, which results in constitutive activation of the receptor. Biochemical studies of FGFR3 combined with experiments in knock-out mice have demonstrated that FGFR3 is a negative regulator of chondrocytes proliferation and differentiation in growth plate. This mutation induces a disturbance of endochondral bone formation. The diagnosis of achondroplasia is based on typical clinical and radiological features including short stature, macrocephaly with frontal bossing, midface hypoplasia and rhizomelic shortening of the limbs. The most common rheumatological complications of achondroplasia are medullar and radicular compressions due to spinal stenosis and deformities of the lower limbs. Current treatment and future therapies are discussed.","This review focuses on the muscle and bone-related features of achondroplasia, which is the most common bone growth impairment and the most frequent cause of short-limbed dwarfism. The gene that causes achondroplasia affects many members of a family but in the majority of cases is due to a new mutation. The diseases is related to a mutation in the fibroblast growth factor receptor-3 (FGFR3) gene and results in a continuously active receptor. Experiments show that FGFR3 prevents bone growth by preventing cartilage cells in the bone growth region from growing and maturing. The mutation responsible for achondroplasia prevents growth of long bones. The diagnosis of achondroplasia is based on physical and X-ray features including short stature, large head with a prominent forehead, underdevelopment of the middle part of the face and shortening of the limbs. The most common bone-related complications of achondroplasia are shortening of the spine and deformities of the lower limbs. Current treatment and future therapies are discussed." +"Achondroplasia, the most common form of human dwarfism is a rare condition that occurs in approximately 1:20,000 births. The major clinical outcome of Achondroplasia is attenuated growth, rhizomelic shortening of the long bones and craniofacial abnormalities. As of today there is no pharmacological treatment for Achondroplasia. Some improvement in the patients well being and daily function can be achieved by a surgical limb lengthening procedure. Growth hormone treatment seems to have only modest short term success and to lack long term benefits. Achondroplasia results from a single point mutation in Fibroblast Growth Factor Receptor 3 (FGFR3). In 97% of the patients, there is a Glycine to Arginine substitution at position 380 within the FGFR-3 transmembrane domain leading to receptor overactivation. This FGF receptor tyrosine kinase is expressed by chondrocytes in the growth plate of developing long bones and plays a crucial role in bone growth. Genetic disruption of the FGFR-3 gene in mice leads to a remarkable increase in the length of the vertebral column and long bones. This suggests that overaction of FGFR3 signaling may specifically impair chondrocyte function within the epiphyseal growth plates and cause Achondroplasia. Reconstituted normal bone growth may therefore be achieved by attenuation of FGFR3 signaling in the appropriate cells within the growth plate. It is highly conceivable that drug development strategies aimed either towards blocking extracellular ligand binding or towards intracellular checkpoints along the FGF signal transduction cascade, may prove successful in the treatment of Achondroplasia. This review focuses on the possible approaches for developing a drug for Achondroplasia and related skeletal disorders, using chemical, biochemical and molecular strategies.","Achondroplasia, the most common form of human dwarfism is a sporadic autosomal dominant condition that occurs in approximately 1:20,000 births. The major health impact of Achondroplasia is reduced growth, shortening of the long bones and abnormalitiesin the bones of the head and face. As of today there is no drug treatment for Achondroplasia. Some improvement in the patients well being and daily function can be achieved by a surgical limb lengthening procedure. Growth hormone treatment seems to have only modest short term success and to lack long term benefits. Achondroplasia results from a mutation in Fibroblast Growth Factor Receptor 3 (FGFR3). In 97% of the patients, the mutation leads to overactivation of the protein coded for by the FGFR3 gene. This protein is found in cells in the growth area of developing long bones and plays a crucial role in bone growth. Disruption of the FGFR-3 gene in mice leads to a remarkable increase in the length of the vertebral column and long bones. This suggests that overaction of FGFR3 impairs cell function in the growth regions of the bone and causes Achondroplasia. Normal bone growth may therefore be achieved by reducing FGFR3 activity in the appropriate cells within the growth region of the bones. It is highly conceivable that drug development strategies aimed either towards blocking overaction of the FGFR3 and related activities may prove successful in the treatment of Achondroplasia. This review focuses on the possible approaches for developing a drug for Achondroplasia and related bone diseases." +"The most frequent type of rhizomelic dwarfism, achondroplasia (ACH), is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Mutations in FGFR3 result in skeletal dysplasias of variable severity, including mild phenotypic effects in hypochondroplasia (HCH), severe phenotypic effects in thanatophoric dysplasia types I (TDI) and II (TDII), and severe but survivable phenotypic effects in severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). To explore the molecular mechanisms that result in the different phenotypes, we investigated the kinetics of mutated versions of FGFR3. First, we assayed the phosphorylation states of the mutated FGFR3s and found that the level of phosphorylation in TDI-FGFR3 was lower than in ACH-FGFR3, although the other mutants were phosphorylated according to phenotypic severity. Second, we analyzed the duration of the phosphorylation. TDI-FGFR3 was not highly phosphorylated under ligand-free conditions, but the peak phosphorylation levels of TDI-FGFR3 and ACH-FGFR3 were maintained for 30 min after stimulation with FGF-1. Moreover, ligand-dependent phosphorylation of TDI-FGFR3, but not ACH-FGFR3, lasted for more than 8 h after FGF-1 administration. The other mutant proteins showed sustained phosphorylation independent of ligand presence. Third, we investigated the intracellular localization of the mutant proteins. Immunofluorescence analysis showed accumulations of TDII-FGFR3, SADDAN-FGFR3, and a portion of TDI-FGFR3 in the endoplasmic reticulum (ER). Based on these data, we concluded that sustained phosphorylation of FGFR3 causes chondrodysplasia, and the phenotypic severity depends on the proportion of ER-localized mutant FGFR3. In FGFR3 signaling, the transcription factor, signal transducer and activator of transcription 1 (STAT1) inhibit proliferation and induce apoptosis of chondrocytes. Here we reveal that phospholipase C gamma (PLCgamma) mediates FGFR3-induced STAT1 activation. Both PLCgamma and STAT1 were activated by FGFR3 signaling, but a dominant-negative form of PLCgamma (DN-PLCgamma) remarkably reduced STAT1 phosphorylation. Apoptosis assays revealed that the constitutively active forms of FGFR3 (TDII-FGFR3) and STAT1 (STAT1-C) induce apoptosis of chondrogenic ATDC5 cells via caspase activity. DN-PLCgamma reduced the apoptosis of ATDC5 cells expressing TDII-FGFR3, but over-expression of both DN-PLCgamma and STAT1-C induced apoptosis. Therefore, we conclude that a PLCgamma-STAT1 pathway mediates apoptotic signaling by FGFR3.","The most frequent type of dwarfism, achondroplasia (ACH), is caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Mutations in the FGFR3 result in bone growth impairments of variable severity including hypochondroplasia (HCH), thanatophoric dysplasia types I (TDI) and II (TDII and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). To explore the molecular mechanisms that result in the different bone growth impairments and with varying severity, the authors investigated the properties of mutated versions of FGFR3. First, the authors checked for addition of a phosphate group to FGFR3. Attachement of phosphate groups can change the properites of the receptor and where it is located in the cell. They found that different parts of the receptor had phosphate groups depending on the type of mutation. Second, the authors looked for how long the phosphate groups were present in the mutated FGFR3 receptor. _ _ Generally, the mutated proteins showed longer presence of the phosphate group on FGFR3. Third, the authors investigated where in the cell the mutated proteins were located. Image analysis of the cells showed that mutated FGFR3 was in the part of the cell where proteins are made. Based on these data, the authors conclude that sustained presence of the phosphate group of FGFR3 causes bone growth impairment and the severity depends on the proportion of the mutated FGFR3 present in the region of the cell involved in synthesizing proteins. FGFR3 signaling, activates another protein called STAT1 and causes cartilage cells to stop dividing and dying. Phospholipase gamma (PLCgamma) mediates the activation of STAT1 by FGFR3. _ _ _ The authors conclude that a FGFR3 and two proteins, PLCgamma and STAT1 are responsible for cell death of cartiliage cells." +"Fibroblast growth factor receptor 3 (FGFR3) mutations cause dwarfisms, including achondroplasia (ACH) and thanatophoric dysplasia (TD). The constitutive activation of FGFR3 disrupts the normal process of skeletal growth. Bone-growth anomalies have been identified in skeletal ciliopathies, in which primary cilia (PC) function is disrupted. In human ACH and TD, the impact of FGFR3 mutations on PC in growth plate cartilage remains unknown. Here we showed that in chondrocytes from human (ACH, TD) and mouse Fgfr3Y367C/+ cartilage, the constitutively active FGFR3 perturbed PC length and the sorting and trafficking of intraflagellar transport (IFT) 20 to the PC. We demonstrated that inhibiting FGFR3 with FGFR inhibitor, PD173074, rescued both PC length and IFT20 trafficking. We also studied the impact of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) pathway. Interestingly, mTOR inhibition also rescued PC length and IFT20 trafficking. Together, we provide evidence that the growth plate defects ascribed to FGFR3-related dwarfisms are potentially due to loss of PC function, and these dwarfisms may represent a novel type of skeletal disorders with defective ciliogenesis.","Fibroblast growth factor receptor 3 (FGFR3) gain-of-function mutations cause dwarfisms, including achondroplasia (ACH) and thanatophoric dysplasia (TD). The continuously active state of FGFR3 disrupts normal process of bone growth. Bone-growth abnormalities have been identified in which primary cilia (PC) function is disrupted. Primary cilia are long protrusions on cells that act as an antenna and are important during development. In human ACH and TD, the impact of FGFR3 mutations on PC in growth plate cartilage remains unknown. Here, the authors showed that in cartilage cells from ACH and TD patients and mice with Fgfr3 mutation, the FGFR3 is overactive and it perturbed PC length and formation. They demonstrated that inhibiting FGFR3, using a drug inhibitor, rescued both PC length and formation. The authors also studied the impact of a drug inhibitor of a signaling pathway. Interestingly, the drug also rescued PC length and formation. Together, we provide evidence that the growth plate defects ascribed to FGFR3-related dwarfisms are potentially due to loss of PC function, and these dwarfisms may represent a novel type of bone growth disorders with defective cilia formation." +"Cilia project from almost every cell integrating extracellular cues with signaling pathways. Constitutive activation of FGFR3 signaling produces the skeletal disorders achondroplasia (ACH) and thanatophoric dysplasia (TD), but many of the molecular mechanisms underlying these phenotypes remain unresolved. Here, we report in vivo evidence for significantly shortened primary cilia in ACH and TD cartilage growth plates. Using in vivo and in vitro methodologies, our data demonstrate that transient versus sustained activation of FGF signaling correlated with different cilia consequences. Transient FGF pathway activation elongated cilia, while sustained activity shortened cilia. FGF signaling extended primary cilia via ERK MAP kinase and mTORC2 signaling, but not through mTORC1. Employing a GFP-tagged IFT20 construct to measure intraflagellar (IFT) speed in cilia, we showed that FGF signaling affected IFT velocities, as well as modulating cilia-based Hedgehog signaling. Our data integrate primary cilia into canonical FGF signal transduction and uncover a FGF-cilia pathway that needs consideration when elucidating the mechanisms of physiological and pathological FGFR function, or in the development of FGFR therapeutics.","Cilia are projections present in almost every cell. Cilia integrate signals from outside the cells and those within the cells. Continuous activation of FGFR3 signaling produces the bone growth disorders achondroplasia (ACH) and thanatophoric dysplasia (TD), but many of the molecular mechanisms underlying these remain unresolved. Here, the authors report that primary cilia in ACH and TD cartilage growth regions are significantly shorter. Data demonstrate that transient versus continuous activation of fibrblast growth factor (FGF) signaling correlates with size of the cilia. Transient FGF pathway activation elongated cilia, while continuous activity shortened cilia. FGF signaling extended primary cilia via a pathway involving ERK MAP kinase and mTORC2, but not through mTORC1. _ Authors uncover a FGF-cilia pathway that is involved in the mechanisms of FGFR function, and should be considered in the development of therapies for FGFR function." +"Fibroblast growth factors (FGFs) and their receptors (FGFRs) play significant roles in vertebrate organogenesis and morphogenesis. FGFR3 is a negative regulator of chondrogenesis and multiple mutations with constitutive activity of FGFR3 result in achondroplasia, one of the most common dwarfisms in humans, but the molecular mechanism remains elusive. In this study, we found that chondrocyte-specific deletion of BMP type I receptor a (Bmpr1a) rescued the bone overgrowth phenotype observed in Fgfr3 deficient mice by reducing chondrocyte differentiation. Consistently, using in vitro chondrogenic differentiation assay system, we demonstrated that FGFR3 inhibited BMPR1a-mediated chondrogenic differentiation. Furthermore, we showed that FGFR3 hyper-activation resulted in impaired BMP signaling in chondrocytes of mouse growth plates. We also found that FGFR3 inhibited BMP-2- or constitutively activated BMPR1-induced phosphorylation of Smads through a mechanism independent of its tyrosine kinase activity. We found that FGFR3 facilitates BMPR1a to degradation through Smurf1-mediated ubiquitination pathway. We demonstrated that down-regulation of BMP signaling by BMPR1 inhibitor dorsomorphin led to the retardation of chondrogenic differentiation, which mimics the effect of FGF-2 on chondrocytes and BMP-2 treatment partially rescued the retarded growth of cultured bone rudiments from thanatophoric dysplasia type II mice. Our findings reveal that FGFR3 promotes the degradation of BMPR1a, which plays an important role in the pathogenesis of FGFR3-related skeletal dysplasia.","Fibroblast growth factors (FGFs) and their receptors (FGFRs) play significant roles in vertebrate organ development. FGFR3 prevents cartilage formation and some mutations with continuously active FGFR3 result in achondroplasia, a common dwarfism in humans, but the molecular mechanisms remain elusive. In this study, the authors found that removing BMP type I receptor a (Bmpr1a) from cartilage cells rescued the bone overgrowth observed in Fgfr3 deficient mice by reducing differentiation of cartilage cells. Consistently, using a cartilage cell differentiation assay system, the authors demonstrated that FGFR3 inhibited BMPR1a-mediated maturation of cartilage cells. Furthermore, they showed that FGFR3 hyper-activation resulted in impaired BMP signaling in cartilage cells of mouse growth plates. The authors also found that FGFR3 inhibited BMP-2- or constitutively activated BMPR1-induced phosphate group addition of Smads through a mechanism independent of its enzyme activity. They found that FGFR3 facilitates BMPR1a to through a common protein breakdown pathway called the ubiquitination pathway. Smurf1 played a role in this protein breakdown pathway. They demonstrated that decreasing of BMP signaling by BMPR1 inhibitor dorsomorphin led to the retardation of cartilage cell maturation, which mimics the effect of FGF-2 on cartilage cells. BMP-2 treatment partially rescued the retarded growth of cultured bone rudiments from thanatophoric dysplasia type II mice. Their findings reveal that FGFR3 promotes the degradation of BMPR1a, and this plays an important role in the development of FGFR3-related bone growth impairment." +"Autosomal dominant mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review, we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions.","Mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans and related chondrodysplasia syndromes that include hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD). The mutations are passed on nonsex chromosomes and causes the child that inherits the mutation from an affected parent to have a 50% chance to be affected. FGFR3 is expressed in cartilage cells and mature bone-forming cells where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced binding of two receptors to each other, and enhanced enzyme activity of the receptor. Paradoxically, increased FGFR3 signaling profoundly suppresses cell multiplication and maturation of growth plate cartilage cells resulting in decreased growth region size, reduced volume of the ends of long bones, and resulting decreased bone elongation. In this review, authors discuss the molecular mechanisms that regulate growth region cartilage cells, development of Achondroplasia (Ach), and therapeutic approaches that are being evaluated to improve bone growth in people with Ach and related conditions." +"Early detection of many disorders, mainly inherited, is feasible with population-wide analysis of newborn dried blood spot samples. Phenylketonuria was the prototype disorder for newborn screening (NBS) and early dietary treatment has resulted in vastly improved outcomes for this disorder. Testing for primary hypothyroidism and cystic fibrosis (CF) was later added to NBS programs following the development of robust immunoassays and molecular testing. Current CF testing usually relies on a combined immunoreactive trypsin/mutation detection strategy. Multiplex testing for approximately 25 inborn errors of metabolism using tandem mass spectrometry is a relatively recent addition to NBS. The simultaneous introduction of many disorders has caused some re-evaluation of the traditional guidelines for NBS, because very rare disorders or disorders without good treatments can be included with minimal effort. NBS tests for many other disorders have been developed, but these are less uniformly applied or are currently considered developmental. This review focuses on Australasian NBS practices.","Many disorders (but mostly ones that are inherited) can be detected early by looking at dried blood spot samples of newborns across the population. Phenylketonuria is an inherited disorder that can cause many issues with the brain. This disorder was the original example of how newborn screening can result in big improvements for health outcomes. After improved lab tests for hypothyroidism (a gland disorder) and Cystic Fibrosis (CF), an inherited disorder that causes lung infections, these diseases were added to newborn screening programs. Current testing for CF usually relies on a combination of testing for genetic mutations that cause CF and testing for an enzyme that is reduced by CF. Combined testing for about 25 genetic mutations relating to metabolism is a relatively recent addition to newborn screening. The addition of many disorders all at once has led to some reconsideration of the way newborn screening is usually done. This is because it is easy to include tests for disorders that are very rare or don�t have good treatments. Newborn screening for many other disorders have been developed, but these aren�t applied as evenly or are consider to be still under development. This article focuses on newborn screening practices in Australasia." +"The aim of newborn screening is to detect newborns with serious, treatable disorders so as to facilitate appropriate interventions to avoid or ameliorate adverse outcomes. Mass biochemical testing of newborn babies was pioneered in the 1960s with the introduction of screening for phenylketonuria, a rare inborn error of metabolism, tested by using a dried blood spot sample. The next disorder introduced into screening programs was congenital hypothyroidism and a few more much rarer disorders were gradually included. Two recent advances have greatly changed the pace: modification of tandem mass spectrometry and DNA extraction and analysis from newborn screening dried blood spot. These two technologies make the future possibilities of newborn screening seem almost unlimited. Newborn screening tests are usually carried out on a dried blood spot sample, for which there are special analytical considerations. Dried blood spot calibrators and controls, prepared on the same lot number of filter paper, are needed. Methods have a co-efficient of variation of about 10% due to the increased variability of a dried filter paper sample compared with other biochemical samples. The haematocrit is an additional variable not able to be measured. Also of importance is obtaining a balance between the sensitivity and specificity of each assay. Fixing cut-off points for action needs consideration of what is an acceptable percentage of the population to recall for further testing. Few assays are 100% discriminatory. Programs in Australasia currently screen for at least 30 disorders. Detection of these requires not only the assay of a primary marker but often determination of a ratio of that marker with another, or possibly an alternative assay, for example a DNA mutation. The most important disorders screened for are described briefly: phenylketonuria, primary congenital hypothyroidism, cystic fibrosis, the galactosaemias, medium-chain acyl-CoA dehydrogenase deficiency, glutaryl-CoA dehydrogenase deficiency and congenital adrenal hyperplasia, together with several other disorders detectable by tandem mass spectrometry. Newborn screening deals with rare disorders and benefit cannot be shown easily without very large pilot studies. There have been randomised controlled trials of screening for cystic fibrosis, and now several studies are beginning to establish the benefit of tandem mass spectrometry screening for disorders of fatty acid and amino acid metabolism. Two things will influence the new directions for newborn screening: the development of effective treatments for hitherto untreatable disorders, and advancing technology, enabling new testing strategies to be developed. There are novel treatments on the horizon for many discrete disorders. Susceptibility testing has recently been considered for newborn screening application, but is more controversial. Newborn screening has entered a new and exciting phase, with an explosion of new treatments, new technologies, and, possibly in the future, new preventive strategies.","The goal of newborn screening is to detect newborns with serious, treatable disorders. This allows appropriate action to be taken to prevent or lessen bad outcomes. Large-scale lab testing of newborn babies was pioneered in the 1960s with the introduction of screening for phenylketonuria, a rare, inherited metabolic disorder. This testing was done by using dried blood spot samples. The next disorder introduced into screening programs was congenital hypothyroidism, which is an inherited disorder of the thyroid gland, which controls metabolism. A few more much rarer disorders were gradually included. Two recent advances have greatly change the pace. These are modification of tandem mass spectrometry (an advanced chemical detection technique, also known as MS/MS) and DNA analysis from newborn screening dried blood spots. These two technologies make the future possibilities of newborn screening seem almost unlimited. Newborn screening test are usually done with a dried blood spot sample, which needs to be considered when analyzing. Extra dried blood spots need to be prepared on the same filter paper to calibrate the tests. Since dried filter paper samples have more variability than other types of samples, the results of these tests can vary by about 10% or more. Additionally, the amount of red blood cells cannot be measured. It is also important to balance how sensitive the test is (how good it is at finding a problem) with how specific it is (how sure you can be when a problem is found). In deciding how to balance these, we need to consider how many people it is acceptable to bring back for more testing. Not many tests are perfectly accurate. Programs in Australasia currently screen for at least 30 disorders. Detecting these disorders often requires more than just knowing one amount. It can require knowing relative amounts of two different things, or could require an additional alternative test, like a genetic test. In this article we will briefly describe the most important disorders that are screened for. These are phenylketonuria, hypothyroidism, Cystic Fibrosis (CF), galactosaemias, Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency, Glutaryl-CoA Dehydrogenase (GCDH) deficiency and Congenital Adrenal Hyperplasia (CAH), along with several other disorders detectable by MS/MS. Newborn screening deals with rare disorders and it is hard to see the benefit without very large studies. There have been randomised controlled trials of screening for cystic fibrosis. Also, several studies are now beginning to show the benefit of MS/MS screening for disorders relating to fatty acid and amino acid metabolism. Two things will influence the new directions for newborn screening. The first is the development of effective treatments for disorders that don�t currently have them. The second is advancing technology that will enable new testing strategies to be developed. There are new treatments on the horizon for many distinct disorders. Testing for being at risk for disorders has recently been considered for newborn screening, but this is more controversial. Newborn screening has entered a new and exciting phase, with an explosion of new treatments, new technologies, and, possibly in the future, new preventive strategies." +"OBJECTIVES. To establish a database of literature and other evidence on neonatal screening programmes and technologies for inborn errors of metabolism. To undertake a systematic review of the data as a basis for evaluation of newborn screening for inborn errors of metabolism. To prepare an objective summary of the evidence on the appropriateness and need for various existing and possible neonatal screening programmes for inborn errors of metabolism in relation to the natural history of these diseases. To identify gaps in existing knowledge and make recommendations for required primary research. To make recommendations for the future development and organisation of neonatal screening for inborn errors of metabolism in the UK. HOW THE RESEARCH WAS CONDUCTED. There were three parts to the research. A systematic review of the literature on inborn errors of metabolism, neonatal screening programmes, new technologies for screening and economic factors. Inclusion and exclusion criteria were applied, and a working database of relevant papers was established. All selected papers were read by two or three experts and were critically appraised using a standard format. Seven criteria for a screening programme, based on the principles formulated by Wilson and Jungner (WHO, 1968), were used to summarise the evidence. These were as follows. Clinically and biochemically well-defined disorder. Known incidence in populations relevant to the UK. Disorder associated with significant morbidity or mortality. Effective treatment available. Period before onset during which intervention improves outcome. Ethical, safe, simple and robust screening test. Cost-effectiveness of screening. A questionnaire which was sent to all newborn screening laboratories in the UK. Site visits to assess new methodologies for newborn screening. The classical definition of an inborn error of metabolism was used (i.e., a monogenic disease resulting in deficient activity in a single enzyme in a pathway of intermediary metabolism). RESEARCH FINDINGS. INBORN ERRORS OF METABOLISM. Phenylketonuria (PKU) (incidence 1:12,000) fulfilled all the screening criteria and could be used as the 'gold standard' against which to review other disorders despite significant variation in methodologies, sample collection and timing of screening and inadequacies in the infrastructure for notification and continued care of identified patients. Of the many disorders of organic acid and fatty acid metabolism, a case can only be made for the introduction of newborn screening for glutaric aciduria type 1 (GA1; estimated incidence 1:40,000) and medium-chain acyl CoA dehydrogenase (MCAD) deficiency (estimated incidence 1:8000-1:15,000). Therapeutic advances for GA1 offer prevention of neurological damage but further investigation is required into the costs and benefits of screening for this disorder. MCAD deficiency is simply and cheaply treatable, preventing possible early death and neurological handicap. Neonatal screening for these diseases is dependent upon the introduction of tandem mass spectrometry (tandem MS). This screening could however also simultaneously detect some other commonly-encountered disorders of organic acid metabolism with a collective incidence of 1:15,000. Neonatal screening for congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (incidence 1:17,000) has been shown to be beneficial in other countries and similar benefits should accrue in the UK. A national programme of neonatal screening for CAH would be justified, with reassessment after an agreed period. Biotinidase deficiency is of low incidence in the UK (estimated 1:100,000), but this may be outweighed by the simplicity of the screening methodology and the benefits in prevention.","Our first goal in this article was to establish a database of literature and other evidence on newborn screening programmes and technology for genetic disorders related to metabolism. We also aimed to rigorously review data to evaluate newborn screening for genetic disorders related to metabolism. We aimed to summarize the evidence for whether various newborn screening programs for genetic disorders related to metabolism are appropriate and necessary. We aimed to make this summary in relation to the natural history of these diseases, and for both existing and possible programs. We further aimed to identify gaps in knowledge and make recommendations for further research that is needed. Finally, we aimed to make recommendations for the future development and organisation of newborn screening for genetic disorders related to metabolism in the UK. There were three parts to this research. We rigorously reviewed research papers on genetic disorders related to metabolism, newborn screening programs, new technologies for screening, and economic factors. We decided how we would include or exclude papers, and made a working database of relevant papers. All the papers we selected were read by two or three experts and were critically assessed using a standard format. Seven criteria for a screening programme, based on the principles formulated by Wilson and Jungner (WHO, 1968), were used to summarise the evidence. These were the following: The disorder is well defined by signs and symptoms. The disease occurs in populations relevant to the UK. The disorder is associated with serious health problems or death. Effective treatment is available for the disease. The disorder can be helped by addressing it in the time before it appears. There is an ethical, safe, simple and robust screening test for the disorder. Screening for the disorder is cost-effective. A questionnaire was sent to all newborn screening laboratories in the UK. There are site visits to assess new methodologies for newborn screening. We used the traditional way of defining a genetic disorder related to metabolism. This was that the disorder was caused by a single mutated gene that affected a single type of enzyme needed for metabolism. We found that phenylketonuria matched all the criteria. This disorder could be used as a gold standard when comparing other disorders, even though the screening process can vary and systems for notifying patients are not good enough. Of the many disorders of metabolism of organic and fatty acids, we can only make the case for newborn screening of Glutaric Aciduria type 1 (GA1) and Medium-Chain Acy-CoA Dehydrogenase (MCAD deficiency). Advancements in therapy for GA1 can prevent damage to the brain and nerves but more research into the costs and benefits of screening for this disorder is needed. MCAD deficiency can be treated simply and cheaply, preventing possible early death and brain handicap. Newborn screening for these diseases depends on the introduction of tandem Mass Spectrometry (tandem MS) technology. But, this screening could also detect some other disorders at the same time. These other disorders are related to organic acid metabolism and happen to one in 15,000 people. Newborn screening for congenital adrenal hyperplasia (CAH) has worked well in other countries and the UK should see similar benefits. This disease occurs in one in 17,000 people. A national programme of newborn screening for CAH would be justified, and could be looked at again after an agreed period of time. Another disorder, biotinidase deficiency, is rare in the UK (estimated at one in 100,000), but that may be outweighed by how simple the screening process is and the benefits of preventing the disease." +"Newborn screening is important for the early detection of many congenital genetic and metabolic disorders, aimed at the earliest possible recognition and management of affected newborns, to prevent the morbidity, mortality, and disabilities associated with an inherited metabolic disorder. This comprehensive system includes; testing, education, follow up, diagnosis, treatment, management, and evaluation. There are major differences among many of the disorders being considered for inclusion in newborn screening programs. In recent times, advances in laboratory technology such as tandem mass spectrometry (MS/MS), which is more specific, sensitive, reliable, and comprehensive than traditional assays, has increased the number of genetic conditions that can be diagnosed through neonatal screening programs at birth. With a single dried filter paper blood spot, MS/MS can identify more than 30 inherited metabolic disorders in around two to three minutes. Advances in the diagnosis and treatment and an increased understanding of the natural history of inborn errors of metabolism have produced pressure to implement expanded newborn screening programs in many countries. Even as many countries throughout the world have made newborn screening mandatory, in Iran, nationwide newborn screening for inherited metabolic disorders other than hypothyroidism has not been initiated, hence, there is little information about these diseases. This article aims to review the recent advances in newborn metabolic screening and its situation in Iran and other countries.","Newborn screening is important for the early detection of many hereditary and metabolic disorders. It is aimed at the earliest possible recognition and management of affected newborns, to prevent the health problems, deaths, and disabilities associated with an inherited metabolic disorder. This comprehensive system includes; testing, education, follow up, diagnosis, treatment, management, and evaluation. There are major differences among many of the disorders being considered for inclusion in newborn screening programs. In recent times, advances in laboratory technology such as tandem mass spectrometry (MS/MS), has increased the number of genetic conditions that can be diagnosed through newborn screening programs at birth. With a single dried filter paper blood spot, MS/MS can identify more than 30 inherited metabolic disorders in around two to three minutes. Advances have been made in the diagnosis and treatment of genetic disorders related to metabolism. Our understanding of the natural history of these disorders has also increased. Both these improvements have produced pressure to implement expanded newborn screening programs in many countries. Even as many countries throughout the world have made newborn screening mandatory, in Iran, nationwide newborn screening for inherited metabolic disorders has not been started, except for hypothyroidism. Because of this, there is not much information about these diseases. This article aims to review the recent advances in newborn metabolic screening and its situation in Iran and other countries." +"The aim of newborn screening is to identify presymptomatic healthy infants that will develop significant metabolic or endocrine derangements if left undiagnosed and untreated. The goal of ultimately reducing or eliminating irreversible sequelae is reached by maximizing test sensitivity of the primary newborn screening that measures specific analytes by a number of methodologies. Differentiation of true from false negatives is accomplished by the test specificity. This review discusses disorders for which, in general, there are available therapies and that are detected by routine and expanded newborn screening. Recommendations are presented for evaluation by a primary care physician, with confirmation by a metabolic or endocrinology specialist. Disorders are organized in tabular format by class of pathway or analyte, with attention to typical clinical presentations, confirmatory biochemical and molecular tests, and therapies. There are numerous challenges in clinical follow-up, including diagnosis and appropriate understanding of the consequences of the disorders. The data required to meet these challenges can be acquired only by large scale longitudinal comprehensive studies of outcome in children identified by newborn screening. Only with such data can newborn screening fully serve families.","The aim of newborn screening is to identify healthy infants that will develop significant metabolic or endocrine disorders if left undiagnosed and untreated. Newborn screening measures specific substances in various ways. Using the most sensitive screening tests can ultimately reduce or eliminate permanent consequences. Specificity of a test distinguishes true negative results from false negative results (when the test is negative but the patient actually has the disease). In general, this article discusses disorders that have treatments and that can be detected by routine and expanded newborn screening. We give recommendations for testing by a general practice doctor, with confirmation by a metabolic or endocrine specialist. We organize disorders in a table by the physical process they affect in the body or by the substance that is tested. In doing this we also pay attention to how the disease first appears, lab tests that can confirm the disorders, and treatments available. There are many challenges for following up with patients, including diagnosis and appropriate understanding of the consequences of the disorders. Meeting these challenges will require information. This can only be gained with large-scale studies that follow children identified by newborn screening over time to see their outcomes. Newborn screening can only fully serve families once we have this knowledge." +"Inborn errors of metabolism (IEM) are a phenotypically and genetically heterogeneous group of disorders caused by a defect in a metabolic pathway, leading to malfunctioning metabolism and/or the accumulation of toxic intermediate metabolites. To date, more than 1000 different IEM have been identified. While individually rare, the cumulative incidence has been shown to be upwards of 1 in 800. Clinical presentations are protean, complicating diagnostic pathways. IEM are present in all ethnic groups and across every age. Some IEM are amenable to treatment, with promising outcomes. However, high clinical suspicion alone is not sufficient to reduce morbidities and mortalities. In the last decade, due to the advent of tandem mass spectrometry, expanded newborn screening (NBS) has become a mandatory public health strategy in most developed and developing countries. The technology allows inexpensive simultaneous detection of more than 30 different metabolic disorders in one single blood spot specimen at a cost of about USD 10 per baby, with commendable analytical accuracy and precision. The sensitivity and specificity of this method can be up to 99% and 99.995%, respectively, for most amino acid disorders, organic acidemias, and fatty acid oxidation defects. Cost-effectiveness studies have confirmed that the savings achieved through the use of expanded NBS programs are significantly greater than the costs of implementation. The adverse effects of false positive results are negligible in view of the economic health benefits generated by expanded NBS and these could be minimized through increased education, better communication, and improved technologies. Local screening agencies should be given the autonomy to develop their screening programs in order to keep pace with international advancements. The development of biochemical genetics is closely linked with expanded NBS. With ongoing advancements in nanotechnology and molecular genomics, the field of biochemical genetics is still expanding rapidly. The potential of tandem mass spectrometry is extending to cover more disorders. Indeed, the use of genetic markers in T-cell receptor excision circles for severe combined immunodeficiency is one promising example. NBS represents the highest volume of genetic testing. It is more than a test and it warrants systematic healthcare service delivery across the pre-analytical, analytical, and post-analytical phases. There should be a comprehensive reporting system entailing genetic counselling as well as short-term and long-term follow-up. It is essential to integrate existing clinical IEM services with the expanded NBS program to enable close communication between the laboratory, clinicians, and allied health parties. In this review, we will discuss the history of IEM, its clinical presentations in children and adult patients, and its incidence among different ethnicities; the history and recent expansion of NBS, its cost-effectiveness, associated pros and cons, and the ethical issues that can arise; the analytical aspects of tandem mass spectrometry and post-analytical perspectives regarding result interpretation.","Inborn Errors of Metabolism (IEM) are hereditary diseases that affect how the body processes nutrients. They vary both in how they appear in a patient and in they underlying genetic causes. To date, more than 1000 different IEM have been identified. Though each individual disease is rare, taken altogether the rate has been shown to be upwards of 1 in 800. The way the diseases appear in patients can vary. This makes it difficult it diagnose them. IEM are present in all ethnic groups and across every age. Some IEM can be treated, with promising outcomes. However, doctors suspecting these diseases from patient exams is not enough alone to reduce health problems and death. In the last decade, expanded newborn screening has become a mandatory public health strategy in most developed and developing countries. This is due to the advent of a chemical detection technology called tandem mass spectrometry. This technology allows more than 30 different metabolic disorders to be detected at low cost in one single blood spot specimen. The cost is about 10 dollars per baby, and the tests are highly accurate. Studies of cost-effectiveness have confirmed that the savings from expanded newborn screening programs are much greater than the costs of running them. The side effects of false positives (when the test is positive but the patient does not have the disease) are not significant in light of the economic and health benefits produced by expanded newborn screening. Further, these side effects could be lessened with more education, better communication, and improved technology. Local screening agencies should be given the freedom to create their own screening programs so they can keep up with international advancements. Improvements in knowledge of genes and how they affect the body are closely linked with expanded newborn screening. This knowledge is growing because of advancements in nanotechnology (working with things at the microscopic level) and molecular genomics (the study of how changes DNA drive hereditary outcomes). The potential of tandem mass spectrometry is extending to cover more disorders. In fact, one promising example is the use of genetic markers for Severe Combined Immunodeficiency (SCID), a disease that makes people extremely vulnerable to germs. Newborn screening represents the highest volume of genetic testing. It is more than a test and it calls for providing organized healthcare before, during, and after the test. There should be a comprehensive reporting system requiring genetic counselling as well as short-term and long-term follow-up. It is essential to integrate existing clinical IEM services with the expanded newborn screening program. This is to enable close communication between the laboratory, clinicians, and allied health parties. In this article reviewing the topic, we will discuss the history of IEM, how it appears in children and adults, and its rate among different ethnicities. We will also discuss the history and recent expansion of newborn screening, its cost-effectiveness, associated pros and cons, and the ethical issues that can arise. Finally, we will discuss the technical aspects of tandem mass spectrometry and considerations for interpreting results." +"Newborn screening (NBS) of inborn errors of metabolism (IEM) is a coordinated comprehensive system consisting of education, screening, follow-up of abnormal test results, confirmatory testing, diagnosis, treatment, and evaluation of periodic outcome and efficiency. The ultimate goal of NBS and follow-up programs is to reduce morbidity and mortality from the disorders. Over the past decade, tandem mass spectrometry (MS/MS) has become a key technology in the field of NBS. It has replaced classic screening techniques of one-analysis, one-metabolite, one-disease with one analysis, many-metabolites, and many-diseases. The development of electrospray ionization (ESI), automation of sample handling and data manipulation have allowed the introduction of expanded NBS for the identification of numerous conditions on a single sample and new conditions to be added to the list of disorders being screened for using MS/MS. In the case of a screened positive result, a follow-up analytical test should be performed for confirmation of the primary result. The most common confirmatory follow-up tests are amino acids and acylcarnitine analysis in plasma and organic acid analysis in urine. NBS should be integrated with follow-up and clinical management. Recent improvements in therapy have caused some disorders to be considered as potential candidates for NBS. This review covers some of the basic theory of expanded MS/MS and follow-up confirmatory tests applied for NBS of IEM.","Inborn Errors of Metabolism (IEM) are hereditary diseases that affect how the body processes nutrients. Newborn screening of IEM is a coordinated, comprehensive system. It is made up of education, screening, follow-up of abnormal test results, confirmatory testing, diagnosis, treatment, and evaluation of outcome and efficiency. The ultimate goal of newborn screening and follow-up programs is to reduce poor health and death from the disorders. Over the past decade, tandem mass spectrometry (MS/MS) has become a key technology in the field of newborn screening. It has replaced classic screening techniques, which screen for one disease per lab test, with lab tests that screen for many diseases at once. Several factors have allowed expanded newborn screening for identifying many conditions with a single sample. These factors are the development of Electrospray Ionization (ESI), automation of sample handling, and data manipulation. These factors have also allowed new conditions to be added to the list of disorders being screened for using MS/MS. In the case of a positive result from a screen, a follow-up lab test should be done to confirm the first result. The most common follow-up tests for confirmation are blood tests for amino acids (building blocks of protein) and acylcarnitine (a chemical in the body important for metabolism), and urine tests for certain acids. Newborn screening should be integrated with follow-up and clinical management. Recent improvements in therapy have caused some disorders to be considered as potential candidates for newborn screening. This article reviewing newborn screening covers some of the basic theory of expanded MS/MS. It also covers follow-up tests for confirmation used for newborn screening of IEM." +"Newborn dried blood spot screening (NBS) is a core public health service and is the largest application of genetic testing in the United States. NBS is conducted by state public health departments to identify infants with certain genetic, metabolic, and endocrine disorders. Screening is performed in the first few days of life through blood testing. Several drops of blood are taken from the baby's heel and placed on a filter paper card. The dried blood, on the filter cards, is sent from the newborn nursery to the state health department laboratory, or a commercial partner, where the blood is analyzed. Scientific and technological advances have lead to a significant expansion in the number of tests-from an average of 6 to more than 50--and there is a national trend to further expand the NBS program. This rapid expansion has created significant ethical, legal, and social challenges for the health care system and opportunity for scholarly inquiry to address these issues. The purpose of this chapter is to provide an overview of the NBS programs and to provide an in-depth examination of two significant concerns raised from expanded newborn screening, specifically false-positives and lack of information for parents. Implications for nursing research in managing these ethical dilemmas are discussed.","Newborn dried blood spot screening (or simply �newborn screening�) is an essential public health service and is the largest application of genetic testing in the United States. Newborn screening is done by state public health departments to identify infants with certain genetic, metabolic, and endocrine disorders. Screening is done in the first few days of life through blood testing. Several drops of blood are taken from the baby's heel and placed on a filter paper card. The dried blood, on the filter cards, is sent from the newborn nursery to the state health department laboratory, or a commercial partner, where the blood is analyzed. Scientific and technological advances have lead to a significant expansion in the number of tests�from an average of 6 to more than 50�and there is a national trend to further expand the newborn screening program. This rapid expansion has created significant ethical, legal, and social challenges for the health care system. It has also created opportunity for research to address these issues. The purpose of this chapter is to provide an overview of the newborn screening programs and to provide an in-depth examination of two significant concerns raised from expanded newborn screening. Specifically, these concerns are false positives (when the test is positive but the person does not actually have the disease) and lack of information for parents. We also discuss what newborn screening means for nursing research in managing these ethical dilemmas." +"Each year, 4 to 5 million newborns receive state-mandated screening. Although the Advisory Committee on Heritable Disorders in Newborns and Children has identified 34 core conditions that should be incorporated into screening programs, each state manages, funds, and maintains its own program. State programs encompass screening, as well as the diagnosis and coordination of care for newborns with positive findings. Testing for core disorders is fairly standardized, but more extensive screening varies widely by state, and the rigorous evaluation of new screening panels is ongoing. The core panel includes testing for three main categories of disorders: metabolic disorders (e.g., amino acid and urea cycle, fatty acid oxidation, and organic acid disorders); hemoglobinopathies; and a group of assorted conditions, including congenital hearing loss. Family physicians must be familiar with the expanded newborn screening tests to effectively communicate results to parents and formulate interventions. They must also recognize signs of metabolic disorders that may not be detected by screening tests or that may not be a part of standard newborn screening in their state. For infants with positive screening results leading to diagnosis, long-term follow-up involves ongoing parental education, regular medical examinations, management at a metabolic treatment center, and developmental and neuropsychological testing to detect associated disorders in time for early intervention.","Each year, 4 to 5 million newborns receive state-mandated screening. The Advisory Committee on Heritable Disorders in Newborns and Children has identified 34 main conditions that should be included in screening programs. However, each state manages, funds, and maintains its own program. State programs include screening, as well as the diagnosis and coordination of care for newborns with positive test results. Testing for the main disorders is fairly standardized, but more extensive screening varies widely by state. Additionally, the rigorous evaluation of new screening panels is ongoing. The standard group of tests includes testing for three main categories of disorders: metabolic disorders, problems with hemoglobin (the protein that carries oxygen in the blood) and a group of assorted conditions, including congenital hearing loss. Family doctors need to be familiar with the expanded newborn screening tests to effectively communicate the results to parents, and to create plans of action. These doctors also need to recognize signs of metabolic disorders that may not be detected by screening tests or that may not be a part of standard newborn screening in their state. For infants with positive screening results that lead to a diagnosis, long-term follow-up involves ongoing parental education, regular exams, and management at a metabolic treatment center. Long-term follow-up also involves tests of brain development to detect relevant disorders in time for early action." +"Newborn screening is the largest genetic screening program in the United States with approximately four million newborns screened yearly. It has been available and in continuous development for more than 50 years. Each state manages, funds, and maintains its own individual program, which encompasses newborn screening as well as the diagnosis and coordination of care for affected infants and children. The ideal disorder for screening is one in which newborn intervention prevents later disabilities or death for infants who may appear normal at birth. There are 31 core conditions that are currently recommended for incorporation into state screening programs. To obtain a sample, several drops of blood are collected from the newborn's heel and applied to filter paper. Although testing for core disorders is fairly standardized, more extensive screening varies by state and the rigorous evaluation of new disorders for inclusion in state screening panels is ongoing. As genomic medicine becomes more accessible, screening newborns for chronic diseases that may affect their long-term health will need to be addressed as well as the use of the residual blood spots for research. Obstetric providers should, at some time during pregnancy, review the basic process of newborn screening with parents to prepare them for this testing in the neonatal period. This information can be reviewed as it best suits incorporation in an individual's practice; verbal discussion and the distribution of written materials with resources for further information are encouraged.","Newborn screening is the largest genetic screening program in the United States with approximately four million newborns screened every year. It has been available and continuously being improved for more than 50 years. Each state manages, funds, and maintains its own individual program. This involves newborn screening as well as the diagnosis and coordination of care for affected infants and children. The ideal disorder for screening is one where taking action for newborns that appear normal prevents later disabilities or death. There are 31 main conditions that are currently recommended for inclusion in state screening programs. To get a sample, several drops of blood are collected from the newborn's heel and applied to filter paper. Testing for the main disorders is fairly standardized. However, more extensive screening varies by state. Additionally, new disorders are always being carefully considered for being included in state screening panels. Healthcare based on genetics is becoming more widely available. As this happens we need to think about screening newborns for chronic diseases that may affect their long-term health. We also need to think about the use of the leftover blood spots for research. At some time during pregnancy, obstetricians should review the basic process of newborn screening with parents to prepare them for this testing when the child is born. Reviewing this information can depend on how it fits into each doctor�s individual practice. Talking with patients and giving out of written materials with resources for further information are encouraged." +"Total hip replacement (THR) and, particularly, total knee replacement (TKR), are painful surgical procedures. Effective postoperative pain management leads to a better and earlier functional recovery and prevents chronic pain. Studies on the control of pain during the postoperative rehabilitation period are not common. The aim of this study is to present results of a perioperative anesthetic protocol, and a pain treatment protocol in use in the Orthopaedic and the Rehabilitation intensive units of our Hospital. 100 patients (50 THR and 50 TKR) were retrospectively included in this observational study. Numeric Rating Scale (NRS) for pain at rest registered in the clinical sheet was retrieved for all patients and analyzed with respect to the spinal anaesthesia given for the surgery, local analgesia, analgesia protocol adopted during the postoperative days in the Orthopaedic Unit, the antalgic treatment given during the stay within the Rehabilitation Unit, the postoperative consumption of rescue pain medication, and any collateral effect due to the analgesic therapy. Patients reached standard functional abilities (walking at least 50 meters and climbing/descending stairs) at a mean length of 8 days without medication-related complications. Mean NRS during the time of stay was 1.3 � 0.3 for THR and 1.3 � 0.2 for TKR) and maximum mean NRS was 1.8 � 0.5 for TKR and 1.8 � 0.6 for THR. The use of rescue therapy in the rehabilitation guard was correlated with the mean NRS pain and the maximum NRS pain. A very good control of pain with the perioperative anesthetic protocol and pain treatment protocol in use was obtained.","Total Hip Replacement (THR) and Total Knee Replacement (TKR) are painful surgical procedures, especially TKR. Managing pain well after surgery leads to gaining back function better and earlier and prevents chronic pain. Studies on the control of pain during the rehabilitation period after surgery are not common. The goal of this study is to present results of a protocol for anesthesia at the time of surgery, and a pain treatment protocol in use in the Orthopaedic and the Rehabilitation intensive units of our Hospital. This study looked at outcomes from past procedures without intervening. It included 100 patients, 50 that had THR and 50 that had TKR. From the medical records, we looked at the Numeric Rating Scale (NRS) for pain for all patients. We analyzed this pain measurement with respect to the spinal anaesthesia given for the surgery, local anaesthesia, and the regimen of pain medicine used in the Orthopaedic Unit after the surgery. We also analyzed the pain ratings with respect to pain medicine given while in the Rehabilitation Unit, additional pain medication given as needed because of more intense pain, and any side effects of the pain treatment. Patients reached normal function (walking at least 50 meters and climbing/descending stairs) in 8 days on average without medication-related side effects. How much extra pain medicine was used to address more intense pain during rehabilitation was correlated with how pain was recorded on the NRS. Pain was controlled very well with the protocols for anesthesia at the time of surgery and pain treatment." +"Background: Surgical pain is managed with multi-modal anaesthesia in total hip replacement (THR) and total knee replacement (TKR). It is unclear whether including local anaesthetic infiltration before wound closure provides additional pain control. Methods: We performed a systematic review of randomised controlled trials of local anaesthetic infiltration in patients receiving THR or TKR. We searched MEDLINE, Embase and Cochrane CENTRAL to December 2012. Two reviewers screened abstracts, extracted data, and contacted authors for unpublished outcomes and data. Outcomes collected were post-operative pain at rest and during activity after 24 and 48 hours, opioid requirement, mobilisation, hospital stay and complications. When feasible, we estimated pooled treatment effects using random effects meta-analyses. Results: In 13 studies including 909 patients undergoing THR, patients receiving local anaesthetic infiltration experienced a greater reduction in pain at 24 hours at rest by standardised mean difference (SMD) -0.61 (95% CI -1.05, -0.16; p = 0.008) and by SMD -0.43 (95% CI -0.78 -0.09; p = 0.014) at 48 hours during activity. In TKR, diverse multi-modal regimens were reported. In 23 studies including 1439 patients undergoing TKR, local anaesthetic infiltration reduced pain on average by SMD -0.40 (95% CI -0.58, -0.22; p < 0.001) at 24 hours at rest and by SMD -0.27 (95% CI -0.50, -0.05; p = 0.018) at 48 hours during activity, compared with patients receiving no infiltration or placebo. There was evidence of a larger reduction in studies delivering additional local anaesthetic after wound closure. There was no evidence of pain control additional to that provided by femoral nerve block. Patients receiving local anaesthetic infiltration spent on average an estimated 0.83 (95% CI 1.54, 0.12; p = 0.022) and 0.87 (95% CI 1.62, 0.11; p = 0.025) fewer days in hospital after THR and TKR respectively, had reduced opioid consumption, earlier mobilisation, and lower incidence of vomiting. Few studies reported long-term outcomes. Conclusions: Local anaesthetic infiltration is effective in reducing short-term pain and hospital stay in patients receiving THR and TKR. Studies should assess whether local anaesthetic infiltration can prevent long-term pain. Enhanced pain control with additional analgesia through a catheter should be weighed against a possible infection risk.","In Total Hip Replacement (THR) and Total Knee Replacement (TKR), pain from surgery is managed with multiple types of anaesthesia used together. It is not clear if applying a local anaesthetic directly to the wound before sewing it up provides additional pain control. We systematically reviewed randomised controlled trials of using local anaesthetic in patients having THR or TKR. We searched several medical literature databases up to December 2012. The information we gathered from the studies was: pain after surgery, both at rest and during activity after 24 and 48 hours, whether opioids were needed, when and how much patients walked, hospital stay, and additional problems cause by the surgery. In 13 studies including 909 patients having THR, patients that got local anaesthetic had a bigger reduction in pain at 24 hours at rest and at 48 hours during activity. In TKR, various regimens using multiple types of anesthesia were reported. In 23 studies including 1439 patients having TKR, using local anaesthetic reduced pain at 24 hours at rest and at 48 hours during activity, compared with patients receiving no local anesthetic, or placebo (sham treatment so patients were not biased). In studies where more local anaesthetic was used after closing the wound, there was evidence of a bigger reduction. There was no evidence of pain control on top of what was provided by femoral nerve block, a type of local anesthetic applied directly to a large nerve in the thigh. Patients that got local anaesthetic spent, on average, an estimated 0.83 fewer days in hospital after THR and 0.87 fewer days in hospital after TKR. They also had took fewer opioids, walked earlier, and vomited less. Not many studies reported long-term outcomes. Our first conclusion is that local anaesthesia is effective in reducing short-term pain and hospital stay in patients having THR and TKR. Second, studies should assess whether local anaesthesia can prevent long-term pain. Finally, enhanced pain control with additional medicine through a catheter should be weighed against a possible infection risk." +"Background: We implemented local infiltration analgesia (LIA) as a technique of providing post-operative pain management and early mobilization after arthroplasty surgery and have progressively found patients able to go home earlier. This study compares the national data on hip and knee arthroplasty provided by the Royal Australasian College of Surgeons and Medibank Private with our outcomes using LIA and rapid recovery. Methods: Prospective study of one surgeon including 200 knees, and 165 hips in the two years till June 2016. Variables included in comparison to the two groups were: length of stay, percentage of patients transferred to rehabilitation or intensive care unit (ICU), readmitted within 30 days and average separation cost. Results: Hip replacement median length of stay in our series was two nights versus five nights, inpatient rehabilitation 7% versus 36%, ICU admission zero versus 4%, and readmissions 3.9% versus 6.0%, the average hospital separation cost in our series was $17 813 versus $26 734. Knee replacement median length of stay in our study was one night versus five nights, ICU 0.5% versus 3%, rehabilitation 4.5% versus 43%, and readmission 6% versus 7%, the average hospital separation cost in our group was $16 437 versus $27 505. Conclusion: The comprehensive approach of LIA and rapid recovery enables patients to have shorter hospitalization, lower rehabilitation incidence and a resultant reduction in health expenditure.","Local Infiltration Analgesia (LIA) a method for managing pain and encouraging walking early after joint surgery. It involves injecting several painkillers directly into the surgical wound during and after the procedure. We applied LIA and have found more and more that patients are able to go home earlier. This study uses national data on hip and knee surgery provided by the Royal Australasian College of Surgeons and Medibank Private. It compares the national data with our outcomes using LIA and rapid recovery. This study followed patients over time and was done by one surgeon. It included surgery on knees and 165 hips in the two years leading up to June 2016. We compared the two groups using several factors. These included length of stay, number of patients either transferred to rehabilitation or intensive care unit (ICU) or readmitted within 30 days, and average total cost upon leaving the hospital. We found that the average length of stay for hip replacement in our data was nights, compared to five nights for national data. Inpatient rehabilitation was 7% versus 36%, ICU admission was zero versus 4%, and readmission rate was 4% versus 6%. The average total cost on leaving the hospital was $17,813 for our data, versus $26,734 for national data. For knee replacement, we found that the average length of stay in our study was one night versus five nights for national data. Rate of transfer to ICU was 0.5% versus 3% Rate of transfer to rehabilitation was 4.5% versus 43%. The rate of patient readmission was 6% versus 7%, and the average total cost upon leaving the hospital in our group was $16,437 versus $27,505 for the national data. In conclusion, the comprehensive approach of LIA and rapid recovery allows patients to have shorter hospitalization, lower rates of rehabilitation and, as a result, a reduction in healthcare expenses." +"Introduction: Postoperative pain management options are of great importance for patients undergoing total hip arthroplasty, as joint replacement surgery is reported to be one of the most painful surgical procedures. This study demonstrates pain outcome until 4 weeks postoperatively and evaluates factors influencing pain in the postoperative course after total hip arthroplasty. Materials and methods: A total of 103 patients were included in this prospective cohort trial and underwent total hip arthroplasty. Postoperative pain was described using a numerical rating scale (NRS); demographic data and perioperative parameters were correlated with postoperative pain. Results: Evaluation of pain scores in the postoperative course showed a constant decrease in the first postoperative week (mean NRS 3.1 on day 1 to mean NRS 2.3 on day 8) and, then, a perpetual increase for 3 days (mean NRS 2.6 on day 9 to mean NRS 2.3 on day 12). Afterwards, a continuous pain-level decrease was stated (continuous to a mean NRS 0.9 on day 29). No correlation was found between the potential influencing factors sex, age, body mass index, duration of surgery, ASA score, and postoperative pain levels, but a high significant correlation could be stated for preoperative pain levels and postoperative pain intensity (pain while moving p < 0.02 to p < 0.05 depending on the time period ""week 1 postoperatively"", ""week 2-4"", or ""week 1-4""; pain while resting p < 0.001, in all the measured time intervals, respectively). Conclusion: Increasing pain levels after the first week postoperatively, for 3 days, are most likely to be caused by the change to more extensive mobilization and physiotherapy in the rehabilitation unit. No significant influence or correlation on the intensity of postoperative pain could be found while evaluating potential predictors except preoperative pain levels. Pain management has to take these findings into account in the future to further increase patients' satisfaction in the postoperative course after total hip arthroplasty and to adapt pain management programs.","Options for managing pain after surgery are very important for patients having a hip replacement. This is because joint replacement surgery is reported to be one of the most painful surgical procedures. This study shows pain outcome until 4 weeks after surgery and evaluates factors that influence pain during followup after a hip replacement. This was a study that followed a group of patients over time. It included a total of 103 patients that had a hip replacement. Pain following surgery was described using a Numerical Rating Scale (NRS). Demographic information and ways in which the surgery was done were correlated with the amount of pain after surgery. Looking at pain scores following surgery showed a constant decrease in the first week after surgery (average NRS 3.1 on day 1 to average NRS 2.3 on day 8). After that, there was a continuous increase for 3 days (average NRS 2.6 on day 9 to average NRS 2.3 on day 12). Afterwards, a continuous pain-level decrease was stated (continuous to a mean NRS 0.9 on day 29). No correlation was found between the potential factors of sex, age, body mass index, duration of surgery, ASA score (used to measure fitness for surgery), and pain levels following the operation. However, a there was a significant correlation between pain levels before surgery and after. In conclusion, pain levels increased after the first week following surgery, for 3 days. This is most likely caused by the change to more extensive mobilization and physiotherapy in the rehabilitation unit. We did not find any significant association of several potential predictors with the intensity of pain following surgery. The only exception was the amount of pain before surgery. When managing pain, doctors need to account for these results in the future. This is needed to further increase patients' satisfaction following hip replacement and to adapt pain management programs." +"Introduction: Total hip arthroplasty (THA) is reported to be one of the most painful surgical procedures. Perioperative management and rehabilitation patterns are of great importance for the success of the procedure. The aim of this cohort study was the evaluation of function, mobilization and pain scores during the inpatient stay (6 days postoperatively) and 4 weeks after fast-track THA. Materials and methods: A total of 102 consecutive patients were included in this retrospective cohort trial after minimally invasive cementless total hip arthroplasty under spinal anesthesia in a fast-track setup. The extent of mobilization under full-weight-bearing with crutches (walking distance in meters and necessity of nurse aid) and pain values using a numerical rating scale (NRS) were measured. Function was evaluated measuring the range of motion (ROM) and the ability of sitting on a chair, walking and personal hygiene. Furthermore, circumferences of thighs were measured to evaluate the extent of postoperative swelling. The widespread Harris Hip Score (HHS) was used to compare results pre- and 4 weeks postoperatively. Results: Evaluation of pain scores in the postoperative course showed a constant decrease in the first postoperative week (days 1-6 postoperatively). The pain scores before surgery were significantly higher than surgery (day 6), during mobilization (p < 0.001), at rest (p < 0.001) and at night (p < 0.001). All patients were able to mobilize on the day of surgery. In addition, there was a significant improvement in independent activities within the first 6 days postoperatively: sitting on a chair (p < 0.001), walking (p < 0.001) and personal hygiene (p < 0.001). There was no significant difference between the measured preoperative and postoperative (day 6 after surgery) thigh circumferences above the knee joint. Compared to preoperatively, there was a significant (p < 0.001) improvement of the HHS 4 weeks after surgery. In 100% of the cases, the operation was reported to be successful and all of the treated patients would choose a fast-track setup again. Conclusion: Application of a fast-track scheme is effective regarding function and mobilization of patients. Low pain values and rapid improvement of walking distance confirms the success of the fast-track concept in the immediate postoperative course. Future prospective studies have to confirm the results comparing a conventional and a fast-track pathway.","Total Hip Arthroplasty (THA, or hip replacement) is reported to be one of the most painful surgical procedures. How the patient is cared for and rehabilitated around the time of surgery are very important for the success of the procedure. This was a study of a group of patients that all had fast-track THA. The aim of the study was to evaluate function, ability to walk, and pain scores during the inpatient stay (6 days following surgery) and 4 weeks after the procedure. To perform the study, we included a total of 102 consecutive patients that had previously had minimally invasive cementless THA under spinal anesthesia in a fast-track setup. We measured how far patients could walk under their full weight with crutches, and how much a nurse had to help. We also measured pain using a Numerical Rating Scale (NRS). We looked at function as measured by the range of motion (ROM) and the ability to sit on a chair, to walk and to maintain personal hygiene. On top of that, we measured circumferences of patients� thighs to look at how much swelling there was after surgery. We used the widely used Harris Hip Score (HHS) to compare results before surgery and 4 weeks after surgery. Looking at pain scores following surgery showed a constant decrease in the first week (days 1-6 after surgery). The pain scores before surgery were significantly higher than day 6 after surgery, when attempting to walk, at rest, and at night. All patients were able to walk on the day of surgery. In addition, there was a significant improvement in independent activities within the first 6 days following surgery. These activities were sitting on a chair, walking and personal hygiene. There was no significant difference between the thigh circumferences above the knee joint, measured before surgery and on day 6 after surgery. Compared to before surgery, there was a significant improvement of the HHS 4 weeks after surgery. In 100% of the cases, the operation was reported to be successful and all of the treated patients would choose a fast-track setup again. In conclusion, application of a fast-track program is effective for function and ability of patients to walk. Further, low pain values and fast improvement of walking distance confirms that the fast-track plan immediately after surgery is a success. Finally, future studies that follow patients over time have to confirm the results by comparing a conventional and a fast-track plan." +"Total hip and knee arthroplasty is associated with significant perioperative pain, which can adversely affect recovery by increasing risk of complications, length of stay, and cost. Historically, opioids were the mainstay of perioperative pain control. However, opioids are associated with significant downsides. Preemptive use of a multimodal pain management approach has become the standard of care to manage pain after hip and knee arthroplasty. Multimodal pain management uses oral medicines, peripheral nerve blocks, intra-articular injections, and other tools to reduce the need for opioids. Use of a multimodal approach promises to decrease complications, improve outcomes, and increase patient satisfaction after hip and knee arthroplasty.","Hip and knee replacement surgery is associated with significant pain around the time of the procedure. This can make recovery worse by increasing the risk of additional problems, length of stay, and cost. Historically, opioids were the main way to control pain around the time of surgery. However, opioids are associated with significant downsides. Using several pain treatments at once (called multimodal pain management) before pain starts has become the standard way to manage pain after hip and knee replacement. Multimodal pain management uses drugs taken by mouth, injections into nerves, injections into joints, and other tools to reduce the need for opioids. Using several treatments at once promises to decrease additional problems, improve outcomes, and increase patient satisfaction after hip and knee replacement." +"Background: Pain management after total knee arthroplasty and total hip arthroplasty is pivotal, as it determines the outcome of the recovery process after surgery. Ineffective pain control results in many postoperative complications and hinders successful recovery. In recent years, the transition from opioids to a multimodal pain management approach after total knee and total hip arthroplasty has increasingly become an alternative. This is due to the multitude of adverse effects associated with opioids. As a result, the use of non-opioid interventions such as acetaminophen, nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, gabapentinoids, and ketamine, and techniques such as peripheral nerve block and local infiltration analgesia have become more favorable. Objectives: This paper aims to summarize literature around the effectiveness of non-opioid interventions as part of a multimodal pain management after total knee and total hip arthroplasty. Methods: A literature review was conducted to provide evidence-based information with respect to pain management during the postoperative period in order to enhance the pain recovery process. The literature chosen was extracted through the electronic databases PubMed, CINAHL, and Embase. Twenty-seven eligible articles were identified that met the inclusion and exclusion criteria. Results: Literary evidence shows that non-opioid interventions such as acetaminophen, nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, gabapentinoids, ketamine, peripheral nerve blocks, and local infiltration analgesia benefit patients after total knee and total hip arthroplasty for pain management. However, further quality research trials are necessary for more conclusive evidence-based information. Conclusion: Selective literature supports the use of non-opioid interventions as part of a multimodal analgesics regimen for effective pain management after total knee and total hip arthroplasty.","Taking care of pain after knee replacement and and hip replacement is critical because it determines the how the patient recovers after surgery. Ways of controlling pain that are not effective causes many additional problems after surgery and hinders successful recovery. In recent years, changing from opioids after knee and hip replacement to using multiple pain medicines at once has increasingly become an alternative. This is because of the many side effects of opioids. As a result, the use of non-opioid treatments and techniques such as peripheral nerve block, which directly numbs a large nerve, and local anesthetic have become more favorable. Non-opioid treatments include acetaminophen (Tylenol�), nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase-2 (COX-2) inhibitors, gabapentinoids (such as Lyrica or Neurontin), and ketamine. This paper aims to summarize literature about the effectiveness of non-opioid treatments as part of a multi-pronged pain management plan after knee and hip replacement. We reviewed the scientific research on pain management to improve recovery following surgery. We did this to provide evidence-based information with respect to this pain management. The scientific papers we chose were taken from several electronic databases. We found 27 articles that met our standards for being included in this review. Evidence in scientific literature shows that non-opioid pain treatments such as acetaminophen, NSAIDs, COX-2 inhibitors, gabapentinoids, ketamine, peripheral nerve blocks, and local anesthesia benefit patients after knee and hip replacement. However, further quality research trials are needed to be more sure. In conclusion, certain scientific research papers support the use of non-opioid treatments as part of a multi-pronged pain medication plan for effective pain management after knee and hip replacement." +"Multimodal analgesia has become the standard of care for total joint arthroplasty as it provides superior analgesia with fewer side effects than opioid-only protocols. Systemic medications, including nonsteroidal anti-inflammatory drugs, acetaminophen, corticosteroids, and gabapentinoids, and local anesthetics via local infiltration analgesia and peripheral nerve blocks, are the foundation of multimodal analgesia in total joint arthroplasty. Ideally, multimodal analgesia should begin preoperatively and continue throughout the perioperative period and beyond discharge. There is insufficient evidence to support the routine use of intravenous acetaminophen or liposomal bupivacaine as part of multimodal analgesia protocols.","Using several types of pain treatment at once has become the standard way to care for patients having joint replacement surgery. This is because this approach reduces pain better with fewer side effects than only using opioids. Some pain medicines affect the whole body, including NSAIDs, Tylenol�, corticosteroids, and gabapentinoids (such as Lyrica or Neurontin). These medicines, local anesthetics, and peripheral nerve blocks, are the foundation of the multi-pronged approach for joint replacement surgery. Ideally, this multi-pronged approach should start before the operation and continue throughout the time of surgery and beyond discharge. There is not enough evidence to be in favor of the routine use of IV Tylenol� or liposomal bupivacaine (a type of local anesthetic) as part of multi-pronged pain treatment approaches." +"Background: Opioid addiction is endemic in the United States. We developed a standardized opioid-prescribing schedule (SOPS) after total hip arthroplasty (THA) and total knee arthroplasty (TKA) and evaluated opioid usage alongside Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference scores. We hypothesized that opioid usage would be less than prescribed and reducing prescription would decrease consumption without negatively impacting the PROMIS scores. Methods: A prospective observational study was performed on all patients undergoing primary THA and TKA from April 7, 2018, to August 10, 2019. Opioid consumption and pain interference were determined 2 weeks after discharge via telephone and email surveys. SOPSs were implemented during the study. Outcomes were compared in patients before and after the SOPS. Results: A total of 715 patients met inclusion criteria; 201 patients completed surveys. Before the SOPS, the mean opioid prescription was 81.2 � 15.3 tablets for THA and 82.9 � 10.6 for TKA. The mean usage was 35.1 � 29.4 tablets and 35.4 � 33.4, respectively. After the SOPS, the mean usage decreased to 19.4 � 16.8 (P = .04) and 31.6 � 20.9 (P = .52), respectively. After implementation of a second SOPS for THA, the mean number of tablets consumed was 21.5 � 18.6 (P = .05 compared with pre-SOPS). The PROMIS 6B responses in patients who underwent THA demonstrated no significant changes. PROMIS 6B responses for TKA showed an increase in interference with recreational activities (P = .04) and tasks away from home (P = .04), but otherwise had no significant impact on reported scores. Conclusions: Implementation of the SOPS reduced postoperative opioid prescription and consumption without significantly impacting the reported pain interference, supporting the need to decrease opioid prescription after THA and TKA.","Opioid addiction is commonplace in the United States. We created a standard for prescribing opioids to treat pain after hip and knee replacement. We also studied opioid usage alongside a system of measuring pain as reported by patients. We assumed that people would use opioids less than prescribed. We also assumed that reducing prescriptions of opioids would reduce the amount taken without increasing the amount of pain reported. This study followed patients over time, without intervening. It was done on all patients that had hip and knee replacement from April 7, 2018, to August 10, 2019. We determined the amount of opioids used and how pain interfered with patients� lives 2 weeks after discharge using telephone and email surveys. Standards for prescribing opioids were used during the study. Outcomes were compared in patients before and after following these standards. A total of 715 patients were able to be in the study. Of those, 201 patients completed surveys. Before the standards were followed, the average opioid prescription was about 81 tablets for hip replacement and about 83 tablets for knee replacement. The average number of tablets used for both hip replacement and knee replacement was 35. After the standards were followed, the average number of tables taken dropped to about 19 for hip replacement and about 32 for knee replacement. After following a second standard for hip replacement, the average number of tablets taken was about 22. There was not a significant changed in pain reported by patients that had hip replacement. For knee replacement, there was an increase in patient-reported interference with recreational activities and tasks away from home, but otherwise there was no significant impact. We conclude that following our standards for prescribing opioids reduced the amount of opioids both prescribed and taken, without significantly impacting the reported pain interference. This supports the need to decrease opioid prescription after hip and knee replacement surgery." +"There are multiple available agents and modalities for controlling pain perioperatively during total joint arthroplasty to improve the patient experience, and their unique mechanisms and applications should be considered for use preoperatively, intraoperatively, and postoperatively, keeping in mind that each has differing efficacy and side-effect profiles. Preoperative pain control or preemptive analgesia using anti-inflammatory drugs and opioid analgesics appears to be effective in reducing postoperative pain, although the recommended timing and type of agents are unclear. With regard to intraoperative anesthetic choice and pain control, spinal anesthesia appears to have fewer systemic risks than general anesthesia, and periarticular injections of local anesthetic agents, regardless of technique, and with or without the addition of sympathetic modulators, opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids, have been shown to improve pain scores postoperatively and to overall carry a low risk profile. When considering postoperative pain control, there are several modalities including cryotherapy, peripheral nerve blockade, and parenteral and enteral medication options including acetaminophen, cyclooxygenase inhibitors, neuromodulators, tramadol, ketamine, and opioid patches, but there is no clearly preferred medication regimen and individual patient risk profiles must be considered when choosing appropriate pain management agents. Multimodal pain management can decrease opioid usage, improve pain scores, increase patient satisfaction, and enhance early recovery. The ideal preoperative, intraoperative, and postoperative pain medication regimen remains unclear, and an individualized approach to perioperative pain management is recommended. Despite this, good results are demonstrated with the existing variations in pain management protocols in the literature. Treatment of severe postoperative pain in a multimodal fashion carries the risk for serious side effects, including respiratory depression, mental status changes influencing safe gait mechanics, hypotension, renal and hepatic dysfunction, hematologic variations, gastrointestinal considerations including gastric ulcers, constipation or ileus, nausea or vomiting, infection at injection sites, and peripheral nerve injury with peripheral blockade.","There are many options to control pain during joint replacement surgery to improve the patient experience. Doctors should consider the unique ways that each of these options works when using them before, during, and after surgery. Doctors should also keep in mind that each has different efficacy and side-effects. Pain control before surgery or using anti-inflammatory drugs and opioid painkillers before the pain starts seems to work well to reduce pain after surgery. However, it is not clear what the recommended timing and type of treatment are. Regarding the choice of anesthetic during surgery and pain control, anesthesia applied directly to the spine seems to have fewer general risks to the body than general anesthesia. In addition, injections of local anesthetics around the joint, regardless of technique, have been shown to improve pain scores following surgery and to have low risk overall. This is true whether the injections are used with or without adding other drugs, including those that control the body�s fight-or-flight response, opioids, NSAIDs or corticosteroids. When considering pain control following surgery, there are several methods. These include cold therapy, disabling nerves with injection or electrical stimulation, and medicines take by mouth or otherwise. Options for medicines include Tylenol�, COX inhibitors, drugs that affect the brain, tramadol (sold as Ultram or Zytram), ketamine, and opioid patches. However, there is no clearly preferred treatment, and doctors need to consider individual risks faced by patients when choosing appropriate pain treatments. Using multiple pain treatments at once can decrease opioid usage, improve pain scores, increase patient satisfaction, and enhance early recovery. It is still not clear what the ideal medication plan to use before, during, and after surgery is. We recommend using an individualized approach to pain management around the time of surgery. In spite of this, changes to existing ways of treating pain in the scientific literature have shown good results. Using a multi-pronged approach to treat severe pain following surgery has the risk for serious side effects. These including slow or shallow breathing, changes in mental state that can affect walking, low blood pressure, kidney and liver problems, blood problems, stomach problems, including ulcers, constipation or bowel obstruction. Possible side effects also include nausea or vomiting, infection at injection sites, and nerve injury if nerves are disabled (peripheral blockade)." +"Chronic cough is often attributed to reflux, postnasal drip, or asthma. We present 28 patients who had chronic cough or throat-clearing as a manifestation of sensory neuropathy involving the superior or recurrent laryngeal nerve. They had been identified as having sudden-onset cough, laryngospasm, or throat-clearing after viral illness, surgery, or an unknown trigger. Cough and laryngospasm were the most common complaints. Seventy-one percent of the patients had concomitant superior laryngeal nerve or recurrent laryngeal nerve motor neuropathy documented by laryngeal electromyography or videostroboscopy. After a negative workup for reflux, asthma, or postnasal drip, these patients were treated with gabapentin at 100 to 900 mg/d. Symptomatic relief was achieved in 68% of the patients. Sensory neuropathy of the recurrent laryngeal nerve or superior laryngeal nerve should be considered in the workup for chronic cough or larynx irritability. Symptomatic management of patients with cough and laryngospasm due to a suspected sensory neuropathy may include the use of antiseizure medications such as gabapentin.","Chronic cough is often due to reflux, postnasal drip, or asthma. We studied 28 patients with chronic cough or throat-clearing as a symptom of sensory neuropathy (nerve damage of nerves supplying sensation) to the throat and voice box (larynx). This sensory neuropathy involved the superior or recurrent laryngeal nerves. These patients had sudden-onset cough, muscle spasm of the voice box (laryngospasm), or throat-clearing after viral illness, surgery, or due to an unknown reason. Cough and laryngospasm were the most common complaints. 71% of the patients also had motor neuropathy (nerve damage to the nerves that control the muscles) of the throat. This damage was shown by special tests that measure the function of the larynx and vocal cords. The patients were treated with the drug, gabapentin (a drug used to treat seizures), if the workup did not show reflux, asthma, or postnasal drip. Relief of the symptoms was achieved in 68% of these patients. Sensory neuropathy of the throat and voice box should be considered in the workup for chronic cough or irritation of the larynx. If doctors suspect that cough and laryngospasm may due to a sensory neuropathy, use of antiseizure drugs such as gabapentin may help with these symptoms." +"Objectives: We identify management strategies for the treatment of upper respiratory tract symptoms stemming from dysfunction of the recurrent laryngeal nerve. Methods: We present a retrospective case series of patients who had symptoms of sensory neuropathy, including persistent dysphonia, laryngospasm, and chronic cough. The patients were followed for symptomatic improvement after initiation of treatment with a neuromodulator. Treatment outcome was defined by improvement or resolution of symptoms on a self-reported outcome scale. Results: Of 12 patients identified, 75% exhibited evidence of motor neuropathy on laryngoscopy and 83% had symptoms related to chronic cough treated with neuromodulator therapy over a mean follow-up of 20.4 months. The median dose of amitriptyline hydrochloride was 25 mg daily, and that of gabapentin was 300 mg 3 times daily. The mean time from the initiation of therapy to a complete response was 2 months. Conclusions: Patients with suspected neuropathy of the recurrent laryngeal nerve frequently respond to neuromodulator therapy. The addition of reflux precautions and acid suppression therapy is helpful in cases of chronic and recurrent laryngospasm. Patients with evidence of motor neuropathy appear to have better outcomes with neuromodulator therapy.","Researchers studied ways to treat patients with upper respiratory tract symptoms due to disorder of a nerve supplying sensation (sensory neuropathy) to the throat-the recurrent laryngeal nerve. Researchers studied patients who had symptoms of sensory neuropathy including disorders of speech (dysphonia), spasms of the muscles of the voice box (laryngospasm), and chronic cough. The patients were followed to see if their symptoms improved after starting a neuromodulator (a drug that has an effect on nerves). Patients were asked if the drug improved their symptoms. In 12 patients, tests showed 75% had motor neuropathy (disorder of the nerves controlling the muscles) of the throat. Also, 83% had chronic cough treated with a neuromodulator. They were followed for about 20 months. Two neuromodulator drugs were used in the study, amitriptyline hydrochloride (about 25 mg a day) and gabapentin (about 300 mg three times a day). It took about 2 months for complete symptom improvement after the drugs were first started. These neuromodulator drugs often help the symptoms if doctors suspect neuropathy of the recurrent laryngeal nerve as the cause. In patients with chronic cough and recurrent laryngospasm, doctors may add therapy to prevent reflux and decrease stoamch acid. Patient who have motor neuropathy seem to have better improvement with neuromodulator drugs." +"Chronic throat clearing or a feeling of 'something' at the back of the oropharynx or nasopharynx is a common cause for referral to otorhinolaryngology services. While treatment of an underlying causative condition might be expected to improve these symptoms, in many cases a clear underlying cause is not found. Currently, there is no recognized treatment which is effective against these troublesome symptoms. This observational study investigated the effectiveness of a regime of sipping ice cold carbonated water to try to break the vicious cycle of throat clearing. Seventy-two patients with these symptoms who had previously been advised to use the regime were contacted with a postal questionnaire. Sixty-three per cent of patients documented an improvement in their symptom severity score. The most severely and most frequently affected patients had the greatest benefit. We conclude that the suggested regime can be effective in breaking the vicious cycle of persistent throat-clearing.","Chronic throat clearing or a feeling of 'something' at the back of the throat (or nose) is a common cause for referral to ear, nose, and throat dostors. Treatment of the problem causing these symptoms may help. But in many cases the cause is not found. Currently, there is no accepted treatment which is effective against these symptoms. Researchers studied a plan of sipping ice cold sparkling, fizzy (carbonated) water to help stop the cycle of throat-clearing. A questionnaire was mailed to 72 patients that had been told to use this plan. Improvement was seen in the severity of the symptoms in 63% of these patients The greatest improvement was seen in patients who had the worse symptoms and who had them most often. Doctors advise that sipping ice cold carbonated water can help to break the cycle of throat-clearing." +"Laryngopharyngeal reflux (LPR) is a complex of symptoms caused by the backflow of gastric contents into the larynx, pharynx, nasopharynx, sinuses and even to the middle ear space. The symptomatology of LPR includes: chronic cough, hoarseness, throat clearing, laryngitis,""globus pharyngeus"", swallowing disturbances, postnasal drip, ""fetor ex ore"". In the article, the authors present two boys with chronic cough, in one of them the asthma was suspected and antiasthmatic treatment was administrated; in our patients according to the 24-hour pharyngeal pH-metry LPR was diagnosed. The aim of this study was to emphasise that pediatricians should be able to recognise symptoms of LPR. The appropriate diagnosis and treatment leads the symptoms to subside.","A disorder caused by backflow of stomach contents into the back of the throat, nose, sinuses, and even the middle ear space is called laryngopharyngeal reflux (LPR). The symptoms of LPR include: chronic cough, hoarseness, throat clearing, sore throat, feeling of a lump in throat, problems swallowing, postnasal drip, and bad breath. In this study, two boys with chronic cough are discussed. One boy was thought to have asthma and given medicine for it. The other boy was found to have LPR by a test for acid in the throat. Pediatricians should be able to recognize the symptoms of LPR. The correct diagnosis and treatment results in improvement of the symptoms." +"The aim of the study was to report on the prevalence and severity of laryngopharyngeal symptoms in patients with COPD compared to controls. A total of 27 patients with COPD and 13 controls matched according to age and gender were included. Demographic data included age, gender, history of smoking and history of allergic rhinitis. The Reflux symptom Index described by Belafsky et al. was used. The frequency and average score of each of the laryngopharyngeal symptoms were computed. The mean age of patients was 61.67 ± 11.09 years. Ninety-two percent were smokers and 11.1 % had allergy rhinitis. The mean of Total Reflux Symptom index in patients was significantly higher compared to controls (12.70 ± 7.06 vs. 3.00 ± 2.94). In the COPD group, 18 subjects had a positive Reflux symptom index (>11) compared to one in the control group (p value <0.05). There was also a significant difference between the means of six laryngopharyngeal symptoms in patients vs. Controls: COPD patients had higher degree of hoarseness, throat clearing, excessive throat mucus, cough and sticking sensation in the throat. Laryngopharyngeal reflux is more prevalent in patients vs. Controls: The frequency and severity of laryngopharyngeal symptoms is significantly higher in COPD patients.","This study reports on how often and how severe symptoms of the throat and voice box occur in patients with chronic obstructive pulmonary disease (COPD) compared to those without COPD (controls). A total of 27 patients with COPD and 13 controls were included, comparing their age and gender. Facts about the patients and controls include age, gender, history of smoking, and history of allergic rhinitis (irritation of the nose due to allergies). The severity of reflux symptoms was given a score (Reflux Symptom Index). The Reflux Symptom Index and how often each of the throat and voice box (laryngopharyngeal) symptoms occurred was scored. The average age of patients was 61 years. Ninety-two percent of the patients were smokers . About 11% had allergic rhinitis. The average of Total Reflux Symptom Index in patients was significantly higher compared to controls. In the COPD group, 18 patients had a positive Reflux symptom index compared to one in the control group. There was also a significant difference between the average of 6 laryngopharyngeal symptoms in patients compared to controls. COPD patients had higher amounts of hoarseness, throat-clearing, excesss throat mucus, cough and sticking sensation in the throat. Laryngopharygeal reflux (LPR) is a disorder caused by the backflow of stomach contents into the throat. It is more common in patients compared to controls. LPR occurs a lot more often and it is more severe in COPD patients." +"Background/aim: To investigate the clinical features and underlying etiologies of chronic cough (CC). Materials and methods: Five hundred and ten CC patients were enrolled. The phases, characteristics and associated clinical manifestations of CC among the gastroesophageal reflux cough (GERC), cough-variant asthma (CVA), and upper airway cough syndrome (UACS) groups were compared, and the diagnostic values of each group were evaluated by multiple regression analysis. Results: In the 510 patients, 404 had CC with single etiology-GERC (n = 175), CVA (n = 134), and UACS (n = 95). The characteristic features of GERC included gastric acid backflow symptoms such as sour-tasting regurgitation, heartburn, endoscopic esophagitis, poststimulation cough, frequent throat clearing, daytime mono-cough, and feelings of heaviness and pain in the chest. Patients with CVA typically exhibited sensitivity to smog and other irritants; the cough occurred mostly at night, and was associated with positive bronchodilator and provocation test results. The typical features of UACS included a history and/or symptoms of rhinitis, retropharyngeal postnasal drip, and wet cough occurring mostly during the daytime. The diagnostic specificities of above factors were >70%. Conclusion: The most common causes of CC include GERC, CVA, and UACS, and their diagnosis is based on the characteristics of the underlying disease.","Researchers studied the signs, symptoms and underlying causes of chronic cough (CC). There were 510 patients that took part in the study. The features in patients with different causes of chronic cough (CC) were compared. The different causes were gastroesophageal reflux cough (GERC), cough-variant asthma (CVA), and upper airway cough syndrome (UACS). In the 510 patients, 404 had CC caused by a single disorder. In these patients, CC was caused by GERC in 175 patients, by CVA in 134 patients, and by UACS in 95 patients. GERC patients have stomach acid backflow symptoms such as sour-tasting backflow, heartburn, inflammation of food tube (esophagus) on examination with an instrument (endoscopy), cough when the throat is touched, throat-clearing, daytime cough, and feelings of heaviness and pain in the chest. CVA patients are sensitive to smog and other irritants. They coughed mostly at night and they reacted to drugs that cause the airways to open or close up. UACS patients have a history and symptoms of inflammation of the nose, postnasal drip in the back of the throat, and wet coughing mostly during the daytime. The facts allowed doctors to correctly diagnose the cause more than 70% of the time. The most common causes of CC include GERC, CVA, and UACS. Doctors can diagnose which of these underlying diseases cause CC by their signs and symptoms." +"Objective: To evaluate whether the clinical characteristics of chronic cough were helpful in determining its specific causes. Methods: Patients with chronic cough were evaluated by a validated systematic diagnostic protocol. The patients with identified single cause were divided into 4 groups accordingly: cough-variant asthma (CVA), upper airway cough syndrome (UACS) or post-nasal drip syndrome (PNDS), eosinophilic bronchitis (EB), gastroesophageal reflux related cough (GERC), and the characteristics of the timing, character, onset and associated manifestations of chronic cough in different causes were compared. Results: A total of 196 patients met the inclusion criteria, including 55 with EB, 45 with UACS, 50 with CVA and 46 with GERC. No significant difference was found in age, gender and course among EB, UACS, CVA and GERC. The incidence of nocturnal cough in CVA was 26.0% (13/44), significantly higher than in EB (9.1% (5/55), chi2 = 5.272, P<0.05), UACS (2.2% (1/45), chi2 = 10.657, P<0.01) and GERC (0% (0/46), chi2 = 13.833, P<0.01). The specificity of nocturnal cough for CVA was 95.9%. The sensitivity and specificity of cough associated with meals in GERC was 52.2% (24/46) and 83.3%, and regurgitation associated symptom in GERC were 69.6% (32/46) and 80.0%, which were significantly higher than other groups. The incidence of postnasal drip, rhinitis associated symptom and case history of nasal diseases in UACS were 66.7% (30/45), 88.9% (40/45) and 82.2% (37/45), and the specificity of them were 89.4%, 65.6% and 63.6% respectively. Conclusion: The timing character and some associated symptoms of chronic cough are useful in predicting a single cause.","Researchers studied whether the signs and symptoms associated with chronic cough were helpful in finding out the disease that caused it. Patients with chronic cough were studied by a specific set of rules in order to make a diagnosis. The signs and symptoms of chronic cough caused by a single disease were compared. These patients were divided into 4 groups: cough-variant asthma (CVA), upper airway cough syndrome (UACS), post-nasal drip syndrome (PNDS), eosinophilic bronchitis (EB), and gastroesophageal reflux related cough (GERC). A total 196 patients met the rules: 55 had EB, 45 had UACS, 50 had CVA, and 46 had GERC. No important difference was found in age, gender, and course of disease among EB, UACS, CVA, and GERC. Nighttime cough (nocturnal cough) occurred much more often in CVA than in EB, UACS, and GERC. Nocturnal cough was very highly associated with CVA. Cough associated with meals and backflow of stomach contents was more highly associated with GERC than the other groups. UACS was more associated with postnasal drip, symptoms of nose inflammation , and history of nose diseases. The signs and symptoms of chronic cough are useful in the diagnosis of a single underlying cause." +"Objective: To explore the spectrum and clinical features of causes for chronic cough. Methods: A total of 103 patients with at least 8 weeks of chronic cough and normal chest radiographs were recruited from the outpatient clinic of China-Japan Friendship Hospital Department of Respiratory Diseases between Oct 2005 to Feb 2009. The causes were investigated using a well established protocol according to The Chinese Respiratory Society guidelines for management of cough. The diagnostic protocol included history inquiring and physical examination, pulmonary function tests, induced sputum cell differentials, 24 h esophageal pH monitoring, CT of the paranasal sinuses or chest, fiberoptic rhinoscopy or bronchoscopy. The final diagnosis was made based on clinical manifestations, examination findings and a positive response to therapy. The results were compared with those reported in Guangzhou before. Results: The cause of chronic cough was defined in 95.1% of the patients, of which 83 patients (83.5%) with a single cause, 32 (13.6%) with 2 causes, and 3 (2.9%) with 3 causes.","Researcher studied the range of signs and symptoms to find out the causes of chronic cough. A total of 103 patients with chronic cough for at least 8 weeks and normal chest X-rays were studied from a hospital outpatient clinic in China. The causes of the chronic cough were studied using well established rules and guidelines. The diagnostic tests included: medical history, physical exam, lung function tests, sputum cell counts, esophagus acid test, CAT scan of sinuses or chest, and looking into the nose or lungs with the endoscope. The final diagnosis of the cause of chronic cough was made based on all of these tests plus how patients responded to treatment. The results were compared with patients studied before in another city in China. The cause of chronic cough was found in about 95% of patients. About 83% had one cause, about 13% had 2 causes, and about 3% had 3 causes." +"The most important causes of cough were: cough variant asthma (CVA) (n = 41, 33.3%), rhinitis and/or sinusitis (n = 30, 24.4%), gastroesophageal reflux (GERC) (n = 25, 20.3%), medicine related (n = 7, 5.7%), eosinophilic bronchitis (EB) (n = 6, 4.9%), atopic (n = 4, 3.3%), and idiopathic (n = 6, 4.9%). Other causes included pulmonary interstitial fibrosis (n = 2, 1.6%), left heart insufficiency (n = 1, 0.8%) and bronchiectasis (n = 1, 0.8%). There was more nocturnal cough in CVA (80.9%, 36/41) than in other causes (chi2 = 19.81, P<0.01). In CVA, 63.4% (26/41) was complicated with atopic rhinitis, 68.3% (28/41) showed seasonal variations, and 67.8% (19/28) aggravated in the autumn. GERC manifested more day coughs, with 56.0% (14/25) cough associated with taking food and 68.0% (17/25) with reflux symptoms. There was more productive cough in rhinitis and/or sinusitis (73.3% (22/30) ,chi2 = 24.99, P<0.01). The percentages of CVA and GERC were significantly higher than those reported in Guangzhou (chi2 value were 9.52 and 4.56 respectively, P<0.01), but those of EB and atopic cough were significantly lower (p values were 17.61 and 7.86 respectively, P<0.01). Conclusions: The most common causes of chronic cough in our study were CVA, rhinitis and/or sinusitis, GERC, medicine related cough, EB and atopic cough, which were different from previous reports in other cities such as Guangzhou. The spectrum and clinical features of causes for chronic cough are important in the diagnostic procedure of chronic cough.","The most important causes of chronic cough were (most to least): cough variant asthma (CVA), inflammation of the nose (rhinitis) and/or sinuses (sinusitis), gastroesophageal reflux (GERC), medicine related, inflammation of airways (eosinophilic bronchitis -EB), allergies, and unknown cause. Other lung and heart diseases caused chronic cough in a small number of patients Nighttime cough occurred the most in CVA than the other diseases. CVA was associated with nose allergy (atopic rhinitis) which changed with the seasons and increased in autumn. GERC was associated with daytime cough, cough with eating, and with reflux. Productive cough occurred more in rhinnitis and/or sinusitis. There were more patients with CVA and GERC in this study than in the study before in another city. But there were less patients with EB and allergic cough in this study. The most common causes of chronic cough in this study were CVA, rhinitis and/or sinusitis, GERC, medicine related, EB, and allergy related. This was different from studies done before in other cities. The range of signs and symptoms of chronic cough are important in order to find out the causes." +"Objective: The spectrum and frequency of causes and the diagnostic protocol for chronic cough were explored. Methods: A total of 194 patients with at least 3 weeks of chronic cough and normal chest radiographs were recruited from the outpatient clinic of Guangzhou Institute of Respiratory Diseases between July 2003 to June 2004. The causes were investigated using a well-established protocol. The diagnostic protocol included history inquiring and physical examination, pulmonary function tests, induced sputum cell differentials, 24 h esophageal pH monitoring, CT of the paranasal sinuses or chest, fiberoptic rhinoscopy or bronchoscopy. The final diagnosis was made based on clinical manifestation, examination findings and a positive response to therapy. Results: The cause of chronic cough was defined in 95.4% of the patients, with a single cause found in 153 patients (82.7%), and multiple causes in 32 patients (17.3%). The five most important causes of cough were: eosinophilic bronchitis (n = 51, 22.4%), rhinitis and/or paranasal sinusitis (PNDs, n = 39, 17.1%), cough-variant asthma (n = 31, 13.6%), atopic cough (n = 28, 12.3%), and gastroesophageal reflux (n = 27, 11.8%). Conclusions: The spectrum and frequency of causes of chronic cough in our study is different from the previous reports in western countries. Eosinophilic bronchitis and atopic cough are important causes of chronic cough. A modified diagnostic protocol was established accordingly.","Researchers studied the causes of chronic cough using specific rules for making the diagnosis. A total of 194 patients with chronic cough for at least 3 weeks and normal chest X-rays were included from an outpatient clinic in China. The causes of chronic cough were studied using well established rules. The diagnostic tests included: medical history, physical exam, lung function tests, sputum cell counts, esophagus acid test, CAT scan of sinuses or chest, and looking into the nose or lungs with the endoscope. The final diagnosis of the cause of chronic cough was made based on all of these tests plus how patients responded to treatment. The cause of chronic cough was found in about 95% of patients. About 83% had one cause, about 17% hadmore than one cause. The 5 most important causes of cough were: eosinophilc bronchitis (inflammation of the airways), inflammation of the nose (rhinitis) and/or sinuses (sinusitis), cough variant asthma, allergic cough (atopic cough), and gastroesophageal reflux. In this study in China, the types and amount of occurrences of the causes of chronic cough is different from studies done before in western countries. Eosinophilic bronchitis and atopic cough are important causes of chronic cough. Researchers changed the diagnostic rules for this reason." +"Objective: To explore the spectrum and frequency of causes for chronic cough in Chinese patients. Methods: 86 patients with chronic cough were enrolled in the study. The diagnostic procedure was based on the anatomical protocol for diagnosing chronic cough designed by Irwin, and additional cytological assay was performed for sputum induced by hypertonic saline aerosol inhalation. The efficacy of therapy specific to the diagnosis was evaluated. Results: Definite diagnosis was made in 77 (89.5%) out of the 86 patients with chronic cough. The most common causes included cough variant asthma (CVA) (24/86, 27.9%), postnasal drip syndrome (PNDs) (22/86, 25.6%), eosinophilic bronchitis (EB) (13/86, 15.1%), and gastroesophageal reflux (GER) (12/86, 14.0%). After active management based on the diagnosis, cough improved in 72 patients (93.5%). Conclusions: In addition to CVA, PNDs and GER, eosinophilic bronchitis is also an important cause of chronic cough. A positive response to the specific therapy is essential to a definite diagnosis.","Researchers studied the causes of chronic cough in Chinese patients. This study included 86 patients with chronic cough. The rules for finding the cause of chronic cough included a test to study cells in sputum, as well as other tests. Researchers also studied how well treatments worked according to the cause (diagnosis). The diagnosis was made in about 90% of the patients. The most common causes included: cough variant asthma (CVA), postnasal drip syndrome (PND), eosinophilic bronchitis (inflammation of airways-EB), and gastroesophageal relux (GER). Cough improved in about 94% of patients after treatment based on the cause. Besides CVA, PNDs, and GER, eosinophilic bronchitis (EB) is also an important cause of chronic cough. A good response to treatment based on the cause is very important to making the correct diagnosis." +"Sickle cell disease (SCD) is a monogenetic disorder due to a single base-pair point mutation in the ?-globin gene resulting in the substitution of the amino acid valine for glutamic acid in the ?-globin chain. Phenotypic variation in the clinical presentation and disease outcome is a characteristic feature of the disorder. Understanding the pathogenesis and pathophysiology of the disorder is central to the choice of therapeutic development and intervention. In this special edition for newborn screening for haemoglobin disorders, it is pertinent to describe the genetic, pathologic and clinical presentation of sickle cell disease as a prelude to the justification for screening. Through a systematic review of the literature using search terms relating to SCD up till 2019, we identified relevant descriptive publications for inclusion. The scope of this review is mainly an overview of the clinical features of pain, the cardinal symptom in SCD, which present following the drop in foetal haemoglobin as young as five to six months after birth. The relative impact of haemolysis and small-vessel occlusive pathology remains controversial, a combination of features probably contribute to the different pathologies. We also provide an overview of emerging therapies in SCD.","Sickle Cell Disease (SCD) is a genetic disorder due to a single mutation in the Beta-globin gene. This mutation causes a change in an amino acid in the Beta-hemoglobin protein that decreases the ability of oxygen to be carried out to the body. Patients with Sickle Cell Disease (SCD) may experience a variety of signs, symptoms and disease outcomes from this disorder. Understanding the causes, progression, and functional problems that result in patients with SCD are very important in finding and choosing treatments. In this special paper, doctors discuss the importance of screening newborns for SCD. They also describe the genes, the pathology, and the signs and symptoms of Sickle Cell Disease. This paper is the result of a very thorough research of the literature on SCD. The paper focuses on the pain SCD can cause after the decrease in fetal hemoglobin which occurs in infants as young as five to six months after birth. The features seen in Sickle Cell Disease is probably due to a combination of the red blood cells being destroyed and the small blood vessels being blocked. This paper also discusses new therapies for Sickle Cell Disease." +"Sickle cell disease (SCD) was the first human monogenic disorder to be characterized at the molecular level. It results from the substitution of glutamic acid by valine at position 6 of the ?-chain of hemoglobin. The clinical manifestations of SCD arise from the tendency of sickle hemoglobin (known as HbS or ?2?S2) to polymerize at reduced oxygen tensions and deform red cells into the characteristic rigid sickle cell shape. Such inflexible red cells cannot pass through the microcirculation efficiently, and this results in anemia (due to destruction of the red cells) and intermittent vasoocclusion causing tissue damage and pain. Although all patients with homozygous SCD have exactly the same molecular defect, there is considerable clinical variation, ranging from death in early childhood to a normal life span with few complications. Genetic modifiers of SCD include ?-thalassemia, and it has been known for many years that patients with increased levels of fetal Hb (HbF or ?2?2) often tend to have a relatively mild clinical course because HbF reduces the tendency of HbS to polymerise within the red cell. Increased HbF may result from rare deletions within the ?-globin gene cluster or from point mutations in the promoters of the fetal ?-globin genes (hereditary persistence of fetal hemoglobin, HPFH), but additional loci are known to increase HbF levels in adult life. Identifying such loci has been a painstaking task, but a combination of genome-wide analysis within a large kindred and within twin pairs has identified two quantitative trait loci (QTL) with major influences on fetal hemoglobin levels in adults. A significant proportion of the variation in HbF levels and the frequency of painful crises in patients with SCD is accounted for by five common single-nucleotide polymorphisms (SNPs) at these loci.","Sickle Cell Disease (SCD) was the first human genetic disorder caused by a mutation in a single gene to be described at the chemical level. SCD occurs when a mutation of the Beta-hemoglobin gene causes the amino acid, glutamic acid, to be replaced by valine in the beta chain of the hemoglobin protein. The signs and symptoms in SCD occur because these sickle hemoglobin (HbS) proteins tend to join together where oxygen levels are lower in the body. This causes the red blood cells to change into the typical abnormal rigid sickle cell shape. These rigid red blood cells cannot pass through the smallest blood vessels well.This causes the vessels to be blocked, resulting in tissue damage and pain.These sickle red blood cells are also destroyed, which causes anemia. Patients with the same genetic defect in SCD can have many different outcomes, ranging from death in early childhood to a normal life span with few problems. Alpha-Thalassemia is a genetic disease that can change the outcome of patients with SCD. Also, patients with increased levels of another type of hemoglobin protein, fetal hemoglobin (HbF), tend to have a milder disease. The presence of fetal hemoglobin decreases the tendency of the sickle hemoglobin to join together in the red blood cells. Increased levels of HbF may be due to other mutations in various hemoglobin genes. Identifying these mutations in the hemoglobin genes has been very difficult. But researchers have been able to identify two areas on the genes that have major influences on fetal hemoglobin (HbF) levels in adults. A large part of the different HbF levels and number of painful crises in Sickle Cell Disease patients is due to five common mutations in the hemoglobin gene." +"Sickle cell disease (SCD) is a debilitating monogenic blood disorder with a highly variable phenotype characterized by severe pain crises, acute clinical events, and early mortality. Interindividual variation in fetal hemoglobin (HbF) expression is a known and potentially heritable modifier of SCD severity. High HbF levels are correlated with reduced morbidity and mortality. Common single nucleotide polymorphisms (SNPs) at the BCL11A and HBS1L-MYB loci have been implicated previously in HbF level variation in nonanemic European populations. We recently demonstrated an association between a BCL11A SNP and HbF levels in one SCD cohort [Uda M, et al. (2008) Proc Natl Acad Sci USA 105:1620-1625]. Here, we genotyped additional BCL11A SNPs, HBS1L-MYB SNPs, and an SNP upstream of (G)gamma-globin (HBG2; the XmnI polymorphism), in two independent SCD cohorts: the African American Cooperative Study of Sickle Cell Disease (CSSCD) and an SCD cohort from Brazil. We studied the effect of these SNPs on HbF levels and on a measure of SCD-related morbidity (pain crisis rate). We strongly replicated the association between these SNPs and HbF level variation (in the CSSCD, P values range from 0.04 to 2 x 10(-42)). Together, common SNPs at the BCL11A, HBS1L-MYB, and beta-globin (HBB) loci account for >20% of the variation in HbF levels in SCD patients. We also have shown that HbF-associated SNPs associate with pain crisis rate in SCD patients. These results provide a clear example of inherited common sequence variants modifying the severity of a monogenic disease.","Sickle Cell Disease (SCD) is a disabling genetic blood disorder caused by a single mutation. SCD can have various outcomes,but it can result in severe pain crises, acute symptoms, and early death. The severity of the problems that occur in SCD can vary depending on the amount of fetal hemoglobin (HbF) in the blood. High HbF levels are associated with decreased problems and death in patients with SCD. Common single mutations in two genes, BCL11A and HBS1L-MYB, are thought to cause the changes in HbF levels seen in European populations without anemia. Research has shown a connection between a single BCL11A gene mutation and HbF levels in some SCD patients. In this paper, researchers found more single mutations in the BCL11A, HBS1L-MYB, and HBC2 genes in two other groups of patients (a study in African Americans SCD patients and a study of SCD patients from Brazil). We studied the effect of these single gene mutations on HbF levels and the number of pain crises in SCD. We showed a strong connection between the single mutations in these genes and different HbF levels. Common single mutations in the BCL11A, HBS1L-MYB, beta-globin (HBB) genes explain >20% of the different HbF levels in SCD patients. These mutations, associated with HbF levels, are also associated with the number of pain crises in SCD patients. This shows a clear example that inherited common gene mutations can change the severity of a genetic disease. " +"Sickle cell anemia (SCA) is a disease characterized by abnormal red blood cell rheology. Because of their effects on HbS polymerization and red blood cell deformability, alpha-thalassemia and the residual HbF level are known genetic modifiers of the disease. The aim of our study was to determine if the number of HbF quantitative trait loci (QTL) would also favor a specific sub-phenotype of SCA as it is the case for alpha-thalassemia. Our results confirmed that alpha-thalassemia protected from cerebral vasculopathy but increased the risk for frequent painful vaso-occlusive crises. We also showed that more HbF-QTL may provide an additional and specific protection against cerebral vasculopathy but only for children with alpha-thalassemia (-?/?? or -?/-? genotypes).","Sickle Cell Anemia (SCA) is a genetic blood disease that causes abnormal red blood cell flow through blood vessels. Due to their effects on sickle hemoglobin (HbS) chemistry and red blood cell shape changes, alpha-thalassemia (another genetic blood disease)and HbF (fetal hemoglobin) levels are known to change the course of SCA. The aim of our study was to find out if the number of HbF-QTL, quantitative trait loci (QTL-special sections of DNA) would influence the severity of SCA as seen in alpha-thalassemia. Results showed that alpha-thalassemia protected SCA patients from cerebral vasculopathy (diseases of blood vessels in the brain). But, it increased the risk for more painful crises due to blood vessel blockages. We also showed that more HbF-QTL may protect more against cerebral vasculopathy, but only for children with certain genetic types of alpha-thalassemia." +"Sickle cell disease (SCD) is a monogenic disease characterized by multisystem morbidity and highly variable clinical course. Inter-individual variability in hemoglobin F (HbF) levels is one of the main modifiers that account for the clinical heterogeneity in SCD. HbF levels are affected by, among other factors, single nucleotide polymorphisms (SNPs) at the BCL11A gene and the HBS1L-MYB intergenic region and Xmn1 gene. Our aim was to investigate HbF-enhancer haplotypes at these loci to obtain a first overview of the genetic situation of SCD patients in Egypt and its impact on the severity of the disease. The study included 100 SCD patients and 100 matched controls. Genotyping of BCL11A (rs1886868 C/T), HBS1L-MYB (rs9389268 A/G) and Xmn1 ?G158 (rs7842144 C/T) SNPs showed no statistically significant difference between SCD patients and controls except for the hetero-mutant genotypes of BCL11A which was significantly higher in SCD patients compared with controls. Baseline HbF levels were significantly higher in those with co-inheritance of polymorphic genotypes of BCL11A + HSB1L-MYB and BCL11A + Xmn1. Steady-state HbF levels, used as an indicator of disease severity, were significantly higher in SCD-S? patients having the polymorphic genotypes of HSB1L-MYB. Fold change of HbF in both patient groups did not differ between those harboring the wild and the polymorphic genotypes of the studied SNPs. In conclusion, BCL11A, HSB1L, and Xmn1 genetic polymorphisms had no positive impact on baseline HbF levels solely but had if coexisted. Discovery of the molecular mechanisms controlling HbF production could provide a more effective strategy for HbF induction.","Sickle Cell Disease (SCD) is a genetic blood disease that can affect many areas of the body. The course of the disease can vary between patients. Different levels of fetal hemoglobin (HbF) is a main reason that explains the variation in the course of SCD. HbF levels are affected by single gene mutations in the BCL11A, HBS1L-MYB, and Xmn1 genes. Our research focused on specific areas in these genes that affected HbF and also affected the disease severity in SCD patients in Egypt. The study compared 2 groups, 100 SCD patients and 100 patients without SCD (controls). Generally, closer analysis of the BCL11A, HBS1L-MYB, and Xmn1 genes didn't show important differences between the 2 groups. But certain specific genetic mutations in the BCL11A gene were higher in SCD patients. Baseline HbF levels were significantly higher in those who inherited mutations of both BCL11A + HSB1L-MYB and BCL11A+ Xmn1 genes. Steady HbF levels, (a sign of disease severity) in both groups, were significantly higher in SCD-Sbeta patients having the different genetic mutations of the HSB1L-MYB gene. The protein folding chemistry of HbF in both groups didn�t change between patients with the normal or mutant genes. BCL11A, HSB1L, and Xmn1 gene mutations did not have a positive effect on baseline HbF levels unless the mutations occurred together. If researchers could discover the underlying chemistry of HbF production we might be able to increase it in patients." +"Fetal hemoglobin (HbF) ameliorates clinical severity of sickle cell anemia (SCA). The major loci regulating HbF levels are HBB cluster, BCL11A, and HMIP-2 (HBS1L-MYB). However, the impact of noncoding single-nucleotide polymorphisms (SNPs) in these loci on clinical outcomes and their functional role on regulating HbF levels should be better elucidated. Therefore, we performed comprehensive association analyses of 14 noncoding SNPs in five loci with HbF levels and with clinical outcomes in a cohort of 250 children with SCA from Southeastern Brazil, and further performed functional annotation of these SNPs. We found SNPs independently associated with HbF levels: rs4671393 in BCL11A (?-coefficient = 0.28), rs9399137 in HMIP-2A (?-coefficient = 0.16), and rs4895441 in HMIP-2B (?-coefficient = 0.15). Patients carrying minor (HbF-boosting) alleles for rs1427407, rs93979137, rs4895441, rs9402686, and rs9494145 showed reduced count of reticulocytes (p < 0.01), while those carrying the T allele of rs9494145 showed lower white blood cell count (p = 0.002). Carriers of the minor allele for rs9402686 showed higher peripheral saturation of oxygen (p = 0.002). Patients carrying minor alleles in BCL11A showed lower risk of transfusion incidence rate ratio (IRR ? 1.3; p < 0.0001). This effect was independent of HbF effect (p = 0.005). Carriers of minor alleles for rs9399137 and rs9402686 showed lower risk of acute chest syndrome (IRR > 1.3; p ? 0.01). Carriers of the reference allele for rs4671393 showed lower risk of infections (IRR = 1.16; p = 0.01). In conclusion, patients carrying HbF-boosting alleles of BCL11A and HMIP-2 were associated with milder clinical phenotypes. Higher HbF concentration may underlie this effect.","Fetal hemoglobin (HbF) makes the severity of Sickle Cell Anemia (SCA) better. The major specific genetic areas effecting HbF levels are in the HBB cluster, BCL11A, and HMIP-2 (HBS1L-MYB) genes. Researchers need to know more about how the areas of these genes effect the process of HbF levels and the outcome of disease in SCA. Researchers analyzed the function and relationship of 14 mutations in 5 specific genetic areas of the genes with HbF levels and disease outcomes in 250 children with SCA in Southeastern Brazil. They found single mutations that were linked to HbF levels in BCL11A and HMIP-2A and HMIP-2B genes. Patients who had minor mutations (carriers) that increased HbF levels (HbF-boosting) had reduced white blood cells counts. Carriers of other minor mutations (genetic differences) showed higher levels of oxygen in the blood. Patients carrying still other minor genetic differences in BCL11A showed lower risk of transfusions. These findings were separate from the HbF effect. Carriers of other minor mutations showed lower risk of acute chest syndrome. Carriers of the standard minor genetic change showed lower risk of infection. Patients carrying HBF-boosting minor mutations of BCL11A and HMIP-2 genes had milder disease. Higher HbF levels may be the cause of this effect." +"Background: Our objective was to investigate the combined and differential effects of alpha-thalassemia -3.7 kb deletion and HbF-promoting quantitative trait loci (HbF-QTL) in Senegalese hydroxyurea (HU)-free children and young adults with sickle cell anemia (SCA). Procedure: Steady-state biological parameters and vaso-occlusive crises (VOC) requiring emergency admission were recorded over a 2-year period in 301 children with SCA. The age of the first hospitalized VOC was also recorded. These data were correlated with the alpha-globin and HbF-QTL genotypes. For the latter, three different genetic loci were studied (XmnI, rs7482144; BCL11A, rs1427407; and the HBS1L-MYB region, rs28384513) and a composite score was calculated, ranging from zero (none of these three polymorphisms) to six (all three polymorphisms at the homozygous state). Results: A positive clinical impact of the HbF-QTL score on VOC rate, HbF, leucocytes, and C-reactive protein levels was observed only for patients without alpha-thalassemia deletion. Conversely, combination of homozygous -3.7 kb deletion with three to six HbF-QTL was associated with a higher VOC rate. The age of the first hospitalized VOC was delayed for patients with one or two alpha-thalassemia deletions and at least two HbF-QTL. Conclusion: Alpha-thalassemia -3.7 kb deletion and HbF-QTL are modulating factors of SCA clinical severity that interact with each other. They should be studied and interpreted together and not separately, at least in HU-free children.","Researchers analyzed the effects of an alpha-thalassemia (another genetic blood disease) mutation and fetal hemoglobin-promoting quantitative trait loci (HbF-QTL (special section of DNA)) in Senegalese children and young adults with Sickle Cell Anemia (SCA) who have not received the medicine, hydroxyurea. Steady biological signs and crises from blood vessel blockages (vaso-occlusive crises-VOC) requiring emergency admission were recorded over a 2-year period in 301 children with Sickle Cell Anemia (SCA). The age of the first hospitalized VOC was also recorded. These facts were compared to patients who had alpha-globin and HbF-QTL genes. Three different gene regions on the HbF-QTL gene were studied in detail. A score was given to patients from zero to six depending on the different changes (mutations) at the 3 gene regions. A higher HbF-QTL score resulted in better signs of SCA disease outcome only for patients without the alpha-thalassemia mutation. With the alpha-thalassemia mutation, a higher HbF-QTL score was linked to more VOC (vaso-occlusive crises). The age of the first hospitalization for VOC was older in patients with the alpha-thalassemia mutation and at least 2 HbF-QTL gene region mutations. The alpha-thalassemia mutation and the HbF-QTL gene mutations react with each other and can change the severity of Sickle Cell Anemia. These genes and their mutations should be studied together, not separately, at least in children who have not received hydroxyurea." +"Introduction: Fetal hemoglobin (HbF) is the major modifier for sickle cell disease (SCD) severity. HbF is modulated mainly by three major quantitative trait loci (QTL) on chromosomes 2, 6, and 11. Methods: Five SNPs in the three QTLs (HBG2, rs7482144; BCL11A, rs1427407 and rs10189857; and HBS1L-MYB intergenic region, rs28384513 and rs9399137) were investigated by multiplex PCR and reverse hybridization, and their roles in HbF and clinical phenotype variability in Iraqi Kurds with SCD were assessed. Results: HBG2 rs7482144 with minor allele frequency (MAF) of 0.133 was the most significant contributor to HbF variability, contributing 18.1%, followed by rs1427407 (MAF of 0.266) and rs9399137 (MAF of 0.137) at 14.3% and 8.8%, respectively. The other two SNPs were not significant contributors. Furthermore, when the cumulative numbers of minor alleles in the three contributing SNPs were assessed, HbF% and hemoglobin concentration increased with increasing number of minor alleles (P < 0.0005 and 0.001, respectively), while serum lactic dehydrogenase, reticulocytes, leukocytes, transfusion, and pain frequencies decreased (P = 0.003, 0.004, <0.0005, <0.0005, and 0.017, respectively). Conclusions: It was demonstrated that SNPs in all three major HbF QTLs contribute significantly to HbF and clinical variability in Iraqi Kurds with SCD and that the cumulative number of minor alleles at contributing SNPs may serve as a better predictor of such variability in this population.","Fetal hemoglobin (HbF) is an important protein that affects the severity of Sickle Cell Disease (SCD). HbF is changed mainly by three important quantitative trail loci (QTL-special sections of DNA) on chromosomes 2, 6, and 11. Five single mutations in the three QTLs were studied. The roles of these mutations in HbF were studied. The research evaluated how these mutations affected the variety of characteristics seen in Iraqui Kurds with Sickle Cell Disease (SCD). Three minor single mutations of the HBG2 gene resulted in the most important changes in HbF. The other two single mutations did not contribute significantly. An increase in the number of these minor single mutations resulted in an increase in the amount of HbF and hemoglobin. This also resulted in a decrease in blood lactic dehydrogenase (an enzyme from tissue damage), white blood cells, transfusions, and occurences of pain. Research showed these mutations in all three major HbF QTLs are important to HbF. These mutations also contribute to the variety of disease outcomes in Iraqui Kurds with SCD. The added amount of these minor single mutations may better predict variety of disease outcome in this population." +"Sickle cell anemia (SCA), albeit monogenic, has heterogeneous phenotypic expression, mainly related to the level of hemoglobin F (HbF). No large cohort studies have ever compared biological parameters in patients with major ?-globin haplotypes; ie, Senegal (SEN), Benin (BEN), and Bantu/Central African Republic (CAR). The aim of this study was to evaluate the biological impact of ? genes, ? haplotypes, and glucose-6-phosphate dehydrogenase (G6PD) activity at baseline and with hydroxyurea (HU). Homozygous HbS patients from the Cr�teil pediatric cohort with available ?-gene and ?-haplotype data were included (n = 580; 301 females and 279 males) in this retrospective study. Homozygous ?-haplotype patients represented 74% of cases (37.4% CAR/CAR, 24.3% BEN/BEN, and 12.1% SEN/SEN). HU was given to 168 cohort SCA children. Hematological parameters were recorded when HbF was maximal, and changes (?HU-T0) were calculated. At baseline, CAR-haplotype and ?-gene numbers were independently and negatively correlated with Hb and positively correlated with lactate dehydrogenase. HbF was negatively correlated with CAR-haplotype numbers and positively with BEN- and SEN-haplotype numbers. The BCL11A/rs1427407 ""T"" allele, which is favorable for HbF expression, was positively correlated with BEN- and negatively correlated with CAR-haplotype numbers. With HU treatment, ? and HbF values were positively correlated with the BEN-haplotype number. BEN/BEN patients had higher HbF and Hb levels than CAR/CAR and SEN/SEN patients. In conclusion, we show that BEN/BEN patients have the best response on HU and suggest that this could be related to the higher prevalence of the favorable BCL11A/rs1427407/T/allele for HbF expression in these patients.","Sickle Cell Anemia (SCA) is caused by a single gene mutation. SCA varies in different patients mainly due to the fetal hemoglobin (HbF) level in the blood. No large research studies have ever compared factors seen in patients with the major different beta-globin genetic types; for example, Senegal (SEN), Benin (BEN), and Bantu/Central African Republic (CAR). This research studies the importance of alpha genes, different beta gene types, and glucose-6-phosphate dehydrogenase (G6PD-an enzyme that protects red blood cells from damage) activity in patients before and after treatment with the medicine, hydroxyurea. This study included boys and girls who inherited the sickle hemoglobin (HbS) from both parents (SS -Creteil pediatric group). Facts about the alpha-gene and beta-globin genetic types were known. Children who inherited the major different beta-globin genetic types from both parents made up 74% all patients CAR/CAR, BEN/BEN, and SEN/SEN. Hydroxyurea (HU) was given to 168 children with Sickle Cell Anemia (SCA). Factors in the blood were recorded when HbF was highest. Changes were analyzed after hydroxyurea (HU) was given. Before HU, the CAR beta-globin genetic type and the alpha-gene were separately linked to lower hemoglobin and higher lactate dehydrogenase (an enzyme from tissue damage). Higher HbF was linked to lower CAR genetic type numbers but higher BEN and SEN genetic type numbers. A BCL11A gene mutation is linked to the favorable higher HbF levels. This gene mutation was also linked to higher BEN, but lower CAR genetic type numbers. With HU treatment, positive changes and higher HbF numbers were linked to the BEN genetic type. BEN/BEN patients had higher HbF and hemoglobin (Hb) levelsthan CAR/CAR and SEN/SEN patients. This research shows that children inheriting BEN mutations from both parents (BEN/BEN) have the best response on hydroxyurea. This could be related to the more likely presence of favorable genetic mutations for HbF production in these patients." +"We aimed to investigate the clinical and genetic predictors of painful vaso-occlusive crises (VOC) in sickle cell disease (SCD) in Cameroon. Socio-demographics, clinical variables/events and haematological indices were acquired. Genotyping was performed for 40 variants in 17 pain-related genes, three fetal haemoglobin (HbF)-promoting loci, two kidney dysfunctions-related genes, and HBA1/HBA2 genes. Statistical models using regression frameworks were performed in R� . A total of 436 hydoxycarbamide- and opioid-na�ve patients were studied; median age was 16 years. Female sex, body mass index, Hb/HbF, blood transfusions, leucocytosis and consultation or hospitalisation rates significantly correlated with VOC. Three pain-related genes variants correlated with VOC (CACNA2D3-rs6777055, P = 0�025; DRD2-rs4274224, P = 0�037; KCNS1-rs734784, P = 0�01). Five pain-related genes variants correlated with hospitalisation/consultation rates. (COMT-rs6269, P = 0�027; FAAH-rs4141964, P = 0�003; OPRM1-rs1799971, P = 0�031; ADRB2-rs1042713; P < 0�001; UGT2B7-rs7438135, P = 0�037). The 3�7 kb HBA1/HBA2 deletion correlated with increased VOC (P = 0�002). HbF-promoting loci variants correlated with decreased hospitalisation (BCL11A-rs4671393, P = 0�026; HBS1L-MYB-rs28384513, P = 0�01). APOL1 G1/G2 correlated with increased hospitalisation (P = 0�048). This first study from Africa has provided evidence supporting possible development of genetic risk model for pain in SCD.","This research studies factors that may predict painful blood vessel blockages (VOC-vaso-occlusive crises) in Sickle Cell Disease (SCD) patients in Cameroon. Researchers found out facts about the population, signs and symptoms, and their blood. Genetic testing was done for 40 mutations in 17 pain-relating genes, three fetal hemoglobin areas on genes, two genes related to kidney disease, and the HBA1/HBA2 (alpha-globin)genes. Models were performed to predict outcomes. A total of 436 patients that had not taken hydroxycarbamide or opioids were studied. Half the patients were younger than 16 years old and half were older. Female sex, body mass index, Hb/HbF (hemoglobin/fetal hemoglobin), blood transfusions, higher white blood cell count, and consultations or hospitalisations are significantly linked with blood vessel blockages (vaso-occlusive crises (VOC)). Three pain-related gene variants (mutations) are linked to VOC. Five pain-related gene variants are linked to the amount of hospitalisations/consultations. These gene variants are specific mutations in COMT, FAAH, OPRM1, ADRB2, and UGT2B7 genes. A specific mutation in the HBA1/HBA2 genes are linked to increased VOC. Specific gene variants on the BCL11A gene and the HBS1L-MYB gene increase HbF and are linked to decreased hospitalisation. The APOL1 G1/G2 genes (related to kidney disease) are linked to increased hospitalisation. This first study from an African country has provided evidence supporting the possible development of a genetic risk model for pain in Sickle Cell Disease. " +"Urinary incontinence is the inability to willingly control bladder voiding. Stress urinary incontinence (SUI) is the most frequently occurring type of incontinence in women. No widely accepted or approved drug therapy is yet available for the treatment of stress urinary incontinence. Numerous studies have implicated the neurotransmitters, serotonin and norepinephrine in the central neural control of the lower urinary tract function. The pudendal somatic motor nucleus of the spinal cord is densely innervated by 5HT and NE terminals. Pharmacological studies confirm central modulation of the lower urinary tract activity by 5HT and NE receptor agonists and antagonists. Duloxetine is a combined serotonin/norepinephrine reuptake inhibitor currently under clinical investigation for the treatment of women with stress urinary incontinence. Duloxetine exerts balanced in vivo reuptake inhibition of 5HT and NE and exhibits no appreciable binding affinity for receptors of neurotransmitters. The action of duloxetine in the treatment of stress urinary incontinence is associated with reuptake inhibition of serotonin and norepinephrine at the presynaptic neuron in Onuf's nucleus of the sacral spinal cord. In cats, whose bladder had initially been irritated with acetic acid, a dose-dependent improvement of the bladder capacity (5-fold) and periurethral EMG activity (8-fold) of the striated sphincter muscles was found. In a double blind, randomized, placebo-controlled, clinical trial in women with stress urinary incontinence, there was a significant reduction in urinary incontinence episodes under duloxetine treatment. In summary, the pharmacological effect of duloxetine to increase the activity of the striated urethral sphincter together with clinical results indicate that duloxetine has an interesting therapeutic potential in patients with stress urinary incontinence.","Urinary incontinence is the loss of bladder control. Bladder control loss from stress is the most common type of urinary incontinence in women. No approved drug therapy is available. Chemical messengers, such as serotonin and norepinephrine, in the brain and spinal cord may control function of the bladder area. A portion of the spinal cord receives chemical signals from serotonin and norepinephrine. Drug studies show activity of serotonin and norepinephrine influences bladder area activity. Duloxetine blocks removal of serotonin/norepinephrine and is studied for treating women with bladder control loss from stress. In cats with impaired bladders, the drug improved bladder capacity and control proportionally with dosage. In women with bladder control loss from stress, duloxetine reduced frequency of bladder control loss. In short, duloxetine increases bladder control and may help patients with bladder control loss from stress." +"Urinary incontinence is the inability to willingly control bladder voiding. Stress urinary incontinence (SUI) is the most frequently occurring type of incontinence in women. No widely accepted or approved drug therapy is yet available for the treatment of stress urinary incontinence. Numerous studies have implicated the neurotransmitters, serotonin and norepinephrine in the central neural control of the lower urinary tract function. The pudendal somatic motor nucleus of the spinal cord is densely innervated by 5HT and NE terminals. Pharmacological studies confirm central modulation of the lower urinary tract activity by 5HT and NE receptor agonists and antagonists. Duloxetine is a combined serotonin/norepinephrine reuptake inhibitor currently under clinical investigation for the treatment of women with stress urinary incontinence. Duloxetine exerts balanced in vivo reuptake inhibition of 5HT and NE and exhibits no appreciable binding affinity for receptors of neurotransmitters. The action of duloxetine in the treatment of stress urinary incontinence is associated with reuptake inhibition of serotonin and norepinephrine at the presynaptic neuron in Onuf's nucleus of the sacral spinal cord. In cats, whose bladder had initially been irritated with acetic acid, a dose-dependent improvement of the bladder capacity (5-fold) and periurethral EMG activity (8-fold) of the striated sphincter muscles was found. In a double blind, randomized, placebo-controlled, clinical trial in women with stress urinary incontinence, there was a significant reduction in urinary incontinence episodes under duloxetine treatment. In summary, the pharmacological effect of duloxetine to increase the activity of the striated urethral sphincter together with clinical results indicate that duloxetine has an interesting therapeutic potential in patients with stress urinary incontinence.","Urinary incontinence is the inability to control your bladder. Stress urinary incontinence (SUI) is the most common type of bladder control issue in women. There are no drugs that are available to treat stress urinary incontinence. Many studies have looked at two chemical messengers, serotonin and norepinephrine, for controlling bladder function. The chemical messengers serotonin (5HT) and norepinephrine (NE) go to one particular part of the spinal cord. Drug studies find that drugs which help or block the chemical messengers 5HT and NE affect bladder control. Duloxetine is a drug that increases the amount of 5HT and NE available for use and is being looked at to see if it can treat women with bladder control problems. Duloxetine increases the amount of 5HT and NE available for use while not blocking the ability of the nerves to use the chemical messengers. Duloxetine works for the treatment of bladder problems by increasing the amount of the chemical messengers 5HT and NE for use in one special area of the spinal cord Researchers tested the drug in cats with irritated bladders and found that it improved bladder capacity and muscle control. Duloxetine reduced bladder control problems for women in clincal trials. To sum up, duloxetine may be a treatment option for bladder control problems because of its effect on the bladder and the results from clinical studies." +"In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act. We show two distinct mechanisms by which the selective inhibitor of serotonin and noradrenaline reuptake duloxetine and the tricyclic antidepressant amitriptyline relieve neuropathic allodynia. One of these mechanisms is acute, central, and requires descending noradrenergic inhibitory controls and ?2A adrenoceptors, as well as the mu and delta opioid receptors. The second mechanism is delayed, peripheral, and requires noradrenaline from peripheral sympathetic endings and ?2 adrenoceptors, as well as the delta opioid receptors. We then conducted a transcriptomic analysis in dorsal root ganglia, which suggested that the peripheral component of duloxetine action involves the inhibition of neuroimmune mechanisms accompanying nerve injury, including the downregulation of the TNF-?-NF-?B signaling pathway. Accordingly, immunotherapies against either TNF-? or Toll-like receptor 2 (TLR2) provided allodynia relief. We also compared duloxetine plasma levels in the animal model and in patients and we observed that patients' drug concentrations were compatible with those measured in animals under chronic treatment involving the peripheral mechanism. Our study highlights a peripheral neuroimmune component of antidepressant drugs that is relevant to their delayed therapeutic action against neuropathic pain. SIGNIFICANCE STATEMENT In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. However, the mechanism by which antidepressant drugs can relieve neuropathic pain remained in part elusive. Indeed, preclinical studies led to contradictions concerning the anatomical and molecular substrates of this action. In the present work, we overcame these apparent contradictions by highlighting the existence of two independent mechanisms. One is rapid and centrally mediated by descending controls from the brain to the spinal cord and the other is delayed, peripheral, and relies on the anti-neuroimmune action of chronic antidepressant treatment.","Antidepressant drugs, aside from treating depression, are also an important treatment for pain that comes from sensory nerve disorders. However, we still don't know why antidepressants work for this type of pain. This study examined mice with this type of pain to learn more. We specifically examine the antidepressants duloxetine and amitriptyline. Duloxetine prevents the neurotransmitters serotonin and norepinephrine from being re-absorbed by cells, increasing the amount available. For relieving allodynia (where pain is felt instead of other sensations like touch), we found there are two different ways antidepressants can work. One way is short-term and involves the central nervous system. The other way is long-term and involves the neurotransmitter noradrenalin coming from the sympathetic nervous system (which controls the ""fight or flight"" response) and opioid receptors (which opioid drugs act on). We then studied the gene activation in clusters of nerve cells in the spinal cord. Results suggested that duloxetine acts on the peripheral nervous system by inhibiting the immune response following nerve injury. We also compared the amount of duloxetine in the blood of the mice versus people. We found that the level of the drug in people was similar to the level in the mice being treated long-term. This study shows that the immune system of the peripheral nervous system is important to how antidepressants provide long-term relief of pain that does not come from injury. Antidepressant drugs, aside from treating depression, are also an important treatment for pain that comes from sensory nerve disorders. However, we still don't know why antidepressants work for this type of pain. In fact, studies done before clinical trials seemed to create contradictions in how they acted. This study suggests that these apparent contradictions are actually because there are two different ways the drugs can work. One way is quick and involves the connection of the brain to the spinal cord. The other way is delayed and involves suppression of nerve-related immune response when taking antidepressants long-term." +"In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. Despite the widespread use of these drugs, the mechanism underlying their therapeutic action in this pain context remains partly elusive. The present study combined data collected in male and female mice from a model of neuropathic pain and data from the clinical setting to understand how antidepressant drugs act. We show two distinct mechanisms by which the selective inhibitor of serotonin and noradrenaline reuptake duloxetine and the tricyclic antidepressant amitriptyline relieve neuropathic allodynia. One of these mechanisms is acute, central, and requires descending noradrenergic inhibitory controls and ?2A adrenoceptors, as well as the mu and delta opioid receptors. The second mechanism is delayed, peripheral, and requires noradrenaline from peripheral sympathetic endings and ?2 adrenoceptors, as well as the delta opioid receptors. We then conducted a transcriptomic analysis in dorsal root ganglia, which suggested that the peripheral component of duloxetine action involves the inhibition of neuroimmune mechanisms accompanying nerve injury, including the downregulation of the TNF-?-NF-?B signaling pathway. Accordingly, immunotherapies against either TNF-? or Toll-like receptor 2 (TLR2) provided allodynia relief. We also compared duloxetine plasma levels in the animal model and in patients and we observed that patients' drug concentrations were compatible with those measured in animals under chronic treatment involving the peripheral mechanism. Our study highlights a peripheral neuroimmune component of antidepressant drugs that is relevant to their delayed therapeutic action against neuropathic pain. SIGNIFICANCE STATEMENT In addition to treating depression, antidepressant drugs are also a first-line treatment for neuropathic pain, which is pain secondary to lesion or pathology of the nervous system. However, the mechanism by which antidepressant drugs can relieve neuropathic pain remained in part elusive. Indeed, preclinical studies led to contradictions concerning the anatomical and molecular substrates of this action. In the present work, we overcame these apparent contradictions by highlighting the existence of two independent mechanisms. One is rapid and centrally mediated by descending controls from the brain to the spinal cord and the other is delayed, peripheral, and relies on the anti-neuroimmune action of chronic antidepressant treatment.","In addition to treating depression, antidepressants are used to treat chronic pain. Doctors do not yet understand how exactly these drugs treat chronic pain. This study combines the results of a study done on mice and a study done on humans to try to understand how the antidepressants work on pain. The study shows two different ways that the drugs duloxetine and amitriptyline relieve nerve pain. One way that duloxetine and amitriptyline work is by affecting the nerves quickly and strongly. The other way duloxetine and amitriptyline work is by affecting the nerves in a delayed way using different chemical messengers. The study suggests that duloxetine works by affecting the immune system around the nerve injury. This means that certain treatments that affect the immune system also relieved pain caused by touch. Researchers also found that duloxetine works similiarly in both humans and animals used for testing. This study shows a delayed way that antidepressant drugs use to treat chronic pain. In addition to treating depression, antidepressant drugs can also be used to treat chronic pain. However, researchers still don't understand how antidepressant drugs work to treat chronic pain. Previous animal studies did not give an answer to how antidepressants treat chronic pain. This study shows that there are two different ways antidepressants treat chronic pain. One way the antidepressants work is by affecting the brain and spinal cord quickly. The second way the antidepressants work is slower and affects the inmmune system around the nerves." +"This chapter covers antidepressants that fall into the class of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. That is, they bind to the 5-HT and NE transporters with varying levels of potency and binding affinity ratios. Duloxetine is a more potent 5-HT and NE reuptake inhibitor with a more balanced profile of binding at about 10:1 for 5HT and NE transporter binding. It is also a moderate inhibitor of CYP2D6, so that modest dose reductions and careful monitoring will be needed when prescribing duloxetine in combination with drugs that are preferentially metabolized by CYP2D6. The most common side effects identified in clinical trials are nausea, dry mouth, dizziness, constipation, insomnia, asthenia, and hypertension, consistent with its mechanisms of action. Clinical trials to date have demonstrated rates of response and remission in patients with major depression that are comparable to other marketed antidepressants reviewed in this book. In addition to approval for MDD, duloxetine is approved for diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain. All medications in the class can cause serotonin syndrome when combined with MAOIs.","This work covers antidepressants that block removal of the chemical messengers, serotonin (5-HT) and norepinephrine (NE). These antidepressants bind to 5-HT and NE transporters with varying effect. Duloxetine, an antidepressant, is a stronger, more balanced drug for blocking the removal of 5-HT and NE. Duloxetine suppresses the drug-metabolizing molecule, CYP2D6. Thus, careful dosage changes and monitoring are needed when used with other drugs digested by CYP2D6. The most common side effects are nausea, dry mouth, dizziness, constipation, insomnia, physical weakness, and high blood pressure. The drug works with similar success to other antidepressants. Besides depression, duloxetine also treats nerve damage from diabetes and full-body muscle pain. Similar medications that are used with another class of antidepressant medication can lead to high levels of serotonin." +"This chapter covers antidepressants that fall into the class of serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. That is, they bind to the 5-HT and NE transporters with varying levels of potency and binding affinity ratios. Duloxetine is a more potent 5-HT and NE reuptake inhibitor with a more balanced profile of binding at about 10:1 for 5HT and NE transporter binding. It is also a moderate inhibitor of CYP2D6, so that modest dose reductions and careful monitoring will be needed when prescribing duloxetine in combination with drugs that are preferentially metabolized by CYP2D6. The most common side effects identified in clinical trials are nausea, dry mouth, dizziness, constipation, insomnia, asthenia, and hypertension, consistent with its mechanisms of action. Clinical trials to date have demonstrated rates of response and remission in patients with major depression that are comparable to other marketed antidepressants reviewed in this book. In addition to approval for MDD, duloxetine is approved for diabetic peripheral neuropathic pain, fibromyalgia, and musculoskeletal pain. All medications in the class can cause serotonin syndrome when combined with MAOIs.","This chapter talks about the antidepressant drugs that are called serotonin (5-HT) and norepinephrine (NE) reuptake inhibitors. Duloxetine is a strong version of the 5-HT and NE reuptake inhibitor type. The way that duloxetine works means that doctors will have to watch you closely and may have to adjust your dose if you are taking certain types of other drugs. Duloxetine's side effects include upset stomach, dry mouth, dizzy spells, constipation, high blood pressure, and loss of sleep and energy. Studies show that duloxetine treats depression just as well as other drugs. In addition to treating depression, duloxetine may be given to you to treat pain such as pain caused by diabetes and other body pains. Drugs in the 5-HT and NE reuptake inhibitor class can make you very sick if taken with drugs that are in the MAOI class of antidepressants." +"Background: In antidepressant trials for pediatric patients with depression or anxiety disorders, the risk of suicidal events and other severe psychiatric adverse events such as aggression and agitation is increased with antidepressants relative to placebo. Objective: To examine whether largely mentally healthy adolescents treated for a non-psychiatric condition are also at increased risk of suicidality and other severe psychiatric disorders. Methods: This is a re-analysis of a placebo-controlled duloxetine trial for juvenile fibromyalgia based on the main journal article and additional data published in the online supplementary material and on ClinicalTrials.gov. Both serious adverse events related to psychiatric disorders and adverse events leading to treatment discontinuation were defined as severe treatment-emergent psychiatric adverse events. Results: We found that a significant portion of adolescents had treatment-emergent suicidal ideation and behaviour as well as other severe psychiatric adverse events with duloxetine, but no such events were recorded on placebo. The incidence of severe treatment-emergent psychiatric adverse events was statistically significantly higher with duloxetine as compared to placebo. Conclusions: Antidepressants may put adolescents at risk of suicidality and other severe psychiatric disorders even when the treatment indication is not depression or anxiety.","Studies of antidepressants in minors with depression or anxiety have shown a higher risk of suicide attempts and other severe mental issues, such as aggression and agitation, when taking antidepressants. Our objective was to see if healthy adolescents being treated for a non-mental condition also have a higher risk of suicide attempts and severe mental issues. We took a second look at the results from a published trial of duloxetine (Cymbalta) for treating fibromyalgia (a chronic pain disorder). We used results both from the published article and from supplemental results online and from ClinicalTrials.gov. We found that a significant portion of the adolescents on duloxetine had suicidal tendencies and other serious mental side effects. None of these problems were seen in the participants that weren't taking duloxetine. We concluded that antidepressants may put adolescents at risk of suicidal tendencies and other serious mental problems, even if they are not being treated for depression or anxiety." +"Background: In antidepressant trials for pediatric patients with depression or anxiety disorders, the risk of suicidal events and other severe psychiatric adverse events such as aggression and agitation is increased with antidepressants relative to placebo. Objective: To examine whether largely mentally healthy adolescents treated for a non-psychiatric condition are also at increased risk of suicidality and other severe psychiatric disorders. Methods: This is a re-analysis of a placebo-controlled duloxetine trial for juvenile fibromyalgia based on the main journal article and additional data published in the online supplementary material and on ClinicalTrials.gov. Both serious adverse events related to psychiatric disorders and adverse events leading to treatment discontinuation were defined as severe treatment-emergent psychiatric adverse events. Results: We found that a significant portion of adolescents had treatment-emergent suicidal ideation and behaviour as well as other severe psychiatric adverse events with duloxetine, but no such events were recorded on placebo. The incidence of severe treatment-emergent psychiatric adverse events was statistically significantly higher with duloxetine as compared to placebo. Conclusions: Antidepressants may put adolescents at risk of suicidality and other severe psychiatric disorders even when the treatment indication is not depression or anxiety.",Children with depression or anxiety have a higher risk of suicide and aggressive and anxious behavior when taking antidepressants. This study wants to find out if healthy teens have a higher risk of suicide and other bad thoughts when taking antidepressants for reasons other than depression. This study looks at data from another study where teens with chronic pain known as fibromyalgia were treated with an antidepressant called duloxetine. The study defined severe side effects as suicidal and other bad thoughts and anything that stopped the patient from taking the drug. The study found that a large number of teens in the study had suicidal thoughts and other side effects when treated with duloxetine. Teens that were not taking the drug did not have these side effects. Many more instances of severe side effects occurred for teens taking duloxetine as opposed to those not taking the drug. Teens may be at risk of suicide and other bad thoughts when taking the drug duloxetine even if the drug is not being used to treat depression or anxiety. +"Purpose: Several studies have previously reported the association between dry eye and depression along with the treatment of depression. The aim of this study was to investigate the effects of different antidepressant drugs on tear parameters in patients with major depressive disorder. Methods: We recruited 132 patients who were using different antidepressants and 58 healthy controls. Venlafaxine, duloxetine, escitalopram, and sertraline were used by 34, 28, 36, and 34 patients, respectively. The participants filled out and completed the Beck Depression Scale. We recorded Schirmer test, tear breakup time (TBUT) and corneal staining values of the participants. The Ocular Surface Disease Index was completed by the participants. In addition, we evaluated the tear meniscus parameters by using anterior segment optical coherence tomography. Results: All conventional dry eye tests and tear meniscus parameters were significantly lesser in the depression group than in the control group (Schirmer test, 11.41 � 6.73 mm and 22.53 � 4.98 mm; TBUT, 5.29 � 2.92 seconds and 13.38 � 1.72; Corneal staining, tear meniscus area, 0.026 � 0.012 mm2 and 0.11 � 0.025 mm2; tear meniscus depth, 182.75 � 78.79 ?m and 257.48 � 90.1 ?m; tear meniscus height, 290.3 � 133.63 ?m and 459.78 � 180.26 ?m, in patients and controls, respectively). The tear parameters of the duloxetine group were lowest among the drug groups and Schirmer test, and TBUT of the venlafaxine group was statistically significantly different from the duloxetine group (P = 0.028 and P = 0.017, respectively). Ocular Surface Disease Index score of the depression group was significantly higher than the control group (31.12 � 21.15 and 17.43 � 11.75 in depression and control group, respectively.). Conclusions: We found that the usage of selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors affects the ocular surface by a mechanism other than the anticholinergic system. Besides serotonin blockage, the noradrenaline blockade of serotonin noradrenaline reuptake inhibitors may increase the dry eye findings on the ocular surface.","Dry eye, depression, and treatent of depression may be linked. This study investigates how different antidepressant drugs affects eye tears in patients with depression. We included 132 patients using different antidepressants and 58 healthy people. Different antidepressants were used by groups of size 34, 28, 36, and 34. Participants filled out a questionnaire to measure depression. We recorded different eye and tear measurements. Participants completed an eye measurement test. We also measured other parameters of the tear. The depression group had smaller dry eye and tear volume than the healthy group. The tear measurements of the antidepressant duloxetine group was lowest among the drug groups and notably different than the antidepressant venlafaxine group. Dry eye of the depression group was worse than that of the healthy group. We found that using antidepressants that block removal of the chemical messengers serotonin and noradrenaline affect the eye surface. Besides blocking removal of serotonin, blockage of noradrenaline by these antidepressants may increase dry eye." +"Purpose: Several studies have previously reported the association between dry eye and depression along with the treatment of depression. The aim of this study was to investigate the effects of different antidepressant drugs on tear parameters in patients with major depressive disorder. Methods: We recruited 132 patients who were using different antidepressants and 58 healthy controls. Venlafaxine, duloxetine, escitalopram, and sertraline were used by 34, 28, 36, and 34 patients, respectively. The participants filled out and completed the Beck Depression Scale. We recorded Schirmer test, tear breakup time (TBUT) and corneal staining values of the participants. The Ocular Surface Disease Index was completed by the participants. In addition, we evaluated the tear meniscus parameters by using anterior segment optical coherence tomography. Results: All conventional dry eye tests and tear meniscus parameters were significantly lesser in the depression group than in the control group (Schirmer test, 11.41 � 6.73 mm and 22.53 � 4.98 mm; TBUT, 5.29 � 2.92 seconds and 13.38 � 1.72; Corneal staining, tear meniscus area, 0.026 � 0.012 mm2 and 0.11 � 0.025 mm2; tear meniscus depth, 182.75 � 78.79 ?m and 257.48 � 90.1 ?m; tear meniscus height, 290.3 � 133.63 ?m and 459.78 � 180.26 ?m, in patients and controls, respectively). The tear parameters of the duloxetine group were lowest among the drug groups and Schirmer test, and TBUT of the venlafaxine group was statistically significantly different from the duloxetine group (P = 0.028 and P = 0.017, respectively). Ocular Surface Disease Index score of the depression group was significantly higher than the control group (31.12 � 21.15 and 17.43 � 11.75 in depression and control group, respectively.). Conclusions: We found that the usage of selective serotonin reuptake inhibitors and serotonin noradrenaline reuptake inhibitors affects the ocular surface by a mechanism other than the anticholinergic system. Besides serotonin blockage, the noradrenaline blockade of serotonin noradrenaline reuptake inhibitors may increase the dry eye findings on the ocular surface.","Studies show that there is a link between depression treatment and dry eyes. This study looks at the tears of depressed people when given different types of drugs that treat depression. This study includes 132 people taking antidepressant drugs and 58 people not taking antidepressant drugs for comparison. Patients were taking the antidepressant drugs called venlafaxine, duloxetine, escitalopram, and sertraline. Patients filled our a form to measure their level of depression. The researchers looked at the eyes and tears of the patients. Patients filled out a form to measure the dryness of their eyes. Those people taking antidepressant drugs had drier eyes than those that were not taking antidepressant drugs. The people taking duloxetine had the driest eyes. The people taking antidepressant drugs scored much higher on a test to measure dry eyes. This study finds that certain classes of antidepressant drugs affects the eye ducts but does not because the drugs affect the nerves. Using antidepressants from the drug class called serotonin noradrenaline reuptake inhibitors may lead to dry eyes." +"Duloxetine is a medication used to manage major depressive disorder (MDD), generalized anxiety disorder (GAD), fibromyalgia, diabetic peripheral neuropathy, and chronic musculoskeletal pain. Off-label uses for duloxetine include chemotherapy-induced peripheral neuropathy and stress urinary incontinence. It is in the Serotonin and norepinephrine reuptake inhibitors (SNRIs) class of medications. This activity describes the indications, mechanism of action, and contraindications for duloxetine as a valuable agent in treating multiple health conditions. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant drug-drug interactions) pertinent for members of the interprofessional team in the treatment of patients with major depressive disorder (MDD), generalized anxiety disorder (GAD), fibromyalgia, diabetic peripheral neuropathy, chronic musculoskeletal pain, and related conditions.","Duloxetine is a medication used to treat depression, anxiety, fibromyalgia, diabete nerve damage, and chronic pains in the body. Duloxetine may also be used to treat nerve pain caused by chemotherapy and loss of bladder control caused by physical activity. Duloxetine is in the Serotonin and norepinephrine reuptake inhibitors (SNRIs) class of medications. Duloxetine is valuable because it treats many different health problems. This article describes the uses of the antidepressant, how it works, and medications that should not be used while taking it. This article will highlight things your doctors will need to know when prescribing duloxetine for treatment." +"Duloxetine, a potent reuptake inhibitor of serotonin (5-HT) and norepinephrine, is effective for the treatment of major depressive disorder, diabetic neuropathic pain, stress urinary incontinence, generalized anxiety disorder and fibromyalgia. Duloxetine achieves a maximum plasma concentration (C(max)) of approximately 47 ng/mL (40 mg twice-daily dosing) to 110 ng/mL (80 mg twice-daily dosing) approximately 6 hours after dosing. The elimination half-life of duloxetine is approximately 10-12 hours and the volume of distribution is approximately 1640 L. The goal of this paper is to provide a review of the literature on intrinsic and extrinsic factors that may impact the pharmacokinetics of duloxetine with a focus on concomitant medications and their clinical implications. Patient demographic characteristics found to influence the pharmacokinetics of duloxetine include sex, smoking status, age, ethnicity, cytochrome P450 (CYP) 2D6 genotype, hepatic function and renal function. Of these, only impaired hepatic function or severely impaired renal function warrant specific warnings or dose recommendations. Pharmacokinetic results from drug interaction studies show that activated charcoal decreases duloxetine exposure, and that CYP1A2 inhibition increases duloxetine exposure to a clinically significant degree. Specifically, following oral administration in the presence of fluvoxamine, the area under the plasma concentration-time curve and C(max) of duloxetine significantly increased by 460% (90% CI 359, 584) and 141% (90% CI 93, 200), respectively. In addition, smoking is associated with a 30% decrease in duloxetine concentration. The exposure of duloxetine with CYP2D6 inhibitors or in CYP2D6 poor metabolizers is increased to a lesser extent than that observed with CYP1A2 inhibition and does not require a dose adjustment. In addition, duloxetine increases the exposure of drugs that are metabolized by CYP2D6, but not CYP1A2. Pharmacodynamic study results indicate that duloxetine may enhance the effects of benzodiazepines, but not alcohol or warfarin. An increase in gastric pH produced by histamine H(2)-receptor antagonists or antacids did not impact the absorption of duloxetine. While duloxetine is generally well tolerated, it is important to be knowledgeable about the potential for pharmacokinetic interactions between duloxetine and drugs that inhibit CYP1A2 or drugs that are metabolized by CYP2D6 enzymes.","Duloxetine blocks two chemical messengers from working, called serotonin (5-HT) and norepinephrine. Duloxetine is given to treat things such as depression, diabetic nerve pain, leaky bladder, anxiety, and other chronic pain. The goal of this paper is to look at other studies on duloxetine to see if the drug can be used with other drugs. Things that affect the way that duloxetine works are your sex, age, ethnicity, whether you smoke or not, the condition of your kidney and liver, and your genetics. A doctor will only have warnings against using duloxetine if your liver or kidneys are not in good condition. Studies show that activated charcoal, used to treat certain poisons, makes duloxetine less effective. Taking drugs that affect a certain enzyme with duloxetine could make you sick. Taking the drug fluvoxamine, used to treat depression and OCD, with duloxetine could make you sick. Smoking makes duloxetine less effective. Certain drugs and genetics could affect duloxetine, but not enough to affect how much dulxoetine you would take. There are certain drugs that should not be taken with duloxetine because they can make you sick when taking them normally. Studies show that duloxetine may make tranquilizers like valium and xanax stronger, but does not seem to affect alcohol or the blood thinner warfarin. Antacids and other stomach acid blockers do not affect duloxetine. It is important that your doctors know what drugs you are taking in order to make sure you do not get sick from taking duloxetine." +"Atraumatic trismus can be one of the presentations of medication-induced acute dystonia, particularly by antipsychotics and less commonly antidepressants. A case of an unusual emergency presentation of atraumatic trismus on initiation of duloxetine is reported. The patient was a 40-year-old woman experiencing sudden difficulty in mouth opening and speaking due to a stiffened jaw after taking 5 days of duloxetine prescribed for her fibromyalgia-related chest pain. Assessment of vital signs is prudent to ensure there is no laryngeal involvement. Other physical examinations and her recent investigations were unremarkable. She was treated for acute dystonia and intravenous procyclidine was given together with oral diazepam. Her symptoms improved immediately and her duloxetine was suggested to be stopped. To our knowledge, this is the first case of isolated trismus induced by duloxetine. Clinicians should be aware of this risk, especially considering the limitation of important physiological functions (such as swallowing, eating, etc) associated with this condition.","A stiff jaw is a possible side effect of taking certain medications, such as antidepressant drugs or drugs called antipsychotics. Here is an example of someone who visited the ER with a severely stiff jaw after taking the drug duloxetine. The patient was a 40-year-old woman who was having trouble with opening her mouth and speaking five days after starting the drug duloxetine. The woman's doctors found no other problems that might cause her jaw stiffness. She was treated for muscle spasms with an IV and pills. The woman improved right away and was told to stop taking duloxetine. This is the first time the authors have heard of jaw stiffness being caused by the drug duloxetine. Doctors should be aware of the risk of jaw stiffness since it could lead to very serious problems." +"We present a case of hypertensive urgency in a diabetic patient with painful diabetic neuropathy on duloxetine treatment. The patient's blood pressure was high after taking 1-day dose of duloxetine and the patient was diagnosed with hypertensive urgency. The patient was treated with labetalol, leading to reduction in blood pressure. The patient's medication was switched to telmisartan and metoprolol, which leads to resolution of increased blood pressure. This case report is a possible case of hypertensive urgency after the initiation of duloxetine managed with antihypertensives and resolves with the discontinuation of the duloxetine.","This paper is about a patient with pain caused by diabetes who went to the doctor with very serious high blood pressure. The patient's blood pressure was high after taking a 1-day dose of the antidepressant duloxetine (a drug that also treats diabetic nerve pain). The patient was diagnosed with a high blood pressure emergency. The patient was given labetalol, a drug that lowers blood pressure. The patient was switched to the drugs telmisartan and metoprolol, which treat high blood pressure. This paper reports on a case of high blood pressure caused by the drug duloxetine. It was treated with drugs that treat high blood pressure and went back to normal after the patient stopped taking duloxetine." +"Background: Antidepressants-induced movement disorders are rare and imperfectly known adverse drug reactions. The risk may differ between different antidepressants and antidepressants' classes. The objective of this study was to assess the putative association of each antidepressant and antidepressants' classes with movement disorders. Methods: Using VigiBase�, the WHO Pharmacovigilance database, disproportionality of movement disorders' reporting was assessed among adverse drug reactions related to any antidepressant, from January 1967 to February 2017, through a case/non-case design. The association between nine subtypes of movement disorders (akathisia, bruxism, dystonia, myoclonus, parkinsonism, restless legs syndrome, tardive dyskinesia, tics, tremor) and antidepressants was estimated through the calculation first of crude Reporting Odds Ratio (ROR), then adjusted ROR on four potential confounding factors: age, sex, drugs described as able to induce movement disorders, and drugs used to treat movement disorders. Results: Out of the 14,270,446 reports included in VigiBase�, 1,027,405 (7.2%) contained at least one antidepressant, among whom 29,253 (2.8%) reported movement disorders. The female/male sex ratio was 2.15 and the mean age 50.9 � 18.0 years. We found a significant increased ROR for antidepressants in general for all subtypes of movement disorders, with the highest association with bruxism (ROR 10.37, 95% CI 9.62-11.17) and the lowest with tics (ROR 1.49, 95% CI 1.38-1.60). When comparing each of the classes of antidepressants with the others, a significant association was observed for all subtypes of movement disorders except restless legs syndrome with serotonin reuptake inhibitors (SRIs) only. Among antidepressants, mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan and fluvoxamine were associated with the highest level to movement disorders and citalopram, paroxetine, duloxetine and mirtazapine were the most frequently associated with movement disorders. An association was also found with eight other antidepressants. Conclusions: A potential harmful association was found between movement disorders and use of the antidepressants mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan, fluvoxamine, citalopram, paroxetine, duloxetine, bupropion, clomipramine, escitalopram, fluoxetine, mianserin, sertraline, venlafaxine and vilazodone. Clinicians should beware of these adverse effects and monitor early warning signs carefully. However, this observational study must be interpreted as an exploratory analysis, and these results should be refined by future epidemiological studies.","A rare side effect of taking antidepressant drugs is uncontrollable movement, also called movement disorders. There may be different side effects depending on what antidepressant drugs you take. This study tried to figure out which antidepressant drugs caused which movement disorder side effects. This study looked at reports of antidepressant use from 1967 to 2017 using a computer database. This study used statistics to see if the links between the different antidepressants and movement disorders. There were over 14 million reports in the database. One million of those contained a report of antidepressant use. Almost 30 thousand of the antidepressant reports contained a movement disorder side effect. The patients in the reports ranged from 32-68 years old and contained twice as many women as men. All movement disorders were linked to antidepressant use. Jaw clenching was seen the most often, and involuntary movement called tics were the least seen. The anitdepressant drug class called serotonin reuptake inhibitors (SRIs) were most often linked to movement disorders except for restless leg syndrome. The antidepressants linked to the strongest movement disorders, like Parkinson's or Huntington's disease, were mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan, and fluvoxamine. The antidepressants with the most movement disorder side effects were citalopram, paroxetine, duloxetine, and mirtazapine. Eight other antidepressants were linked to movement disorder side effects. This study found that movement disorder side effects were linked to the antidepressants mirtazapine, vortioxetine, amoxapine, phenelzine, tryptophan, fluvoxamine, citalopram, paroxetine, duloxetine, bupropion, clomipramine, escitalopram, fluoxetine, mianserin, sertraline, venlafaxine, and vilazodone. Doctors should be aware of side effects and watch patients on antidepresants carefully. This study is introductory and should be furthered explored with more studies." +"The European Society for Clinical Microbiology and Infectious Diseases established the Sore Throat Guideline Group to write an updated guideline to diagnose and treat patients with acute sore throat. In diagnosis, Centor clinical scoring system or rapid antigen test can be helpful in targeting antibiotic use. The Centor scoring system can help to identify those patients who have higher likelihood of group A streptococcal infection. In patients with high likelihood of streptococcal infections (e.g. 3-4 Centor criteria) physicians can consider the use of rapid antigen test (RAT). If RAT is performed, throat culture is not necessary after a negative RAT for the diagnosis of group A streptococci. To treat sore throat, either ibuprofen or paracetamol are recommended for relief of acute sore throat symptoms. Zinc gluconate is not recommended to be used in sore throat. There is inconsistent evidence of herbal treatments and acupuncture as treatments for sore throat. Antibiotics should not be used in patients with less severe presentation of sore throat, e.g. 0-2 Centor criteria to relieve symptoms. Modest benefits of antibiotics, which have been observed in patients with 3-4 Centor criteria, have to be weighed against side effects, the effect of antibiotics on microbiota, increased antibacterial resistance, medicalisation and costs. The prevention of suppurative complications is not a specific indication for antibiotic therapy in sore throat. If antibiotics are indicated, penicillin V, twice or three times daily for 10 days is recommended. At the present, there is no evidence enough that indicates shorter treatment length.","A European scientific organization made a Sore Throat Guideline Group to write a new guideline to diagnose and treat people with short-term sore throat. A common sore throat scoring survey or a rapid strep test involving a quick throat swab to find bacterial fragments can be useful in deciding which antibiotic to use. The sore throat scoring survey can help identify people who are more likely to have group A strep, caused by group A strep bacteria. Doctors might use a rapid strep test in people who are highly likely to have strep throat based on the sore throat scoring survey. If the rapid strep test shows no strep infection, a throat swab to find, grow, and test bacteria in the throat that make you sick is not needed. Advil or Tylenol can help short-term sore throat symptoms. Zinc gluconate should not be used in sore throat. It is unclear whether herbal treatments and acupuncture can help sore throat. People with less serious sore throat (low throat scoring survey score, for example) should not use antibiotics to help sore throat. Moderate benefits of antibiotics, seen in people with higher throat survey scores, have to be compared to side effects, effects on small organisms that live in or on the human body, the ability of bacteria to defeat the antibiotics designed to kill them, people more likely to seek medical care for future illness and costs. Preventing pus formation is not a reason for using antibiotics to help sore throat. If using antibiotics, taking penicillin V two to three times a day for 10 days is suggested. Currently, taking antibiotics for fewer than 10 days is not recommended." +"The European Society for Clinical Microbiology and Infectious Diseases established the Sore Throat Guideline Group to write an updated guideline to diagnose and treat patients with acute sore throat. In diagnosis, Centor clinical scoring system or rapid antigen test can be helpful in targeting antibiotic use. The Centor scoring system can help to identify those patients who have higher likelihood of group A streptococcal infection. In patients with high likelihood of streptococcal infections (e.g. 3-4 Centor criteria) physicians can consider the use of rapid antigen test (RAT). If RAT is performed, throat culture is not necessary after a negative RAT for the diagnosis of group A streptococci. To treat sore throat, either ibuprofen or paracetamol are recommended for relief of acute sore throat symptoms. Zinc gluconate is not recommended to be used in sore throat. There is inconsistent evidence of herbal treatments and acupuncture as treatments for sore throat. Antibiotics should not be used in patients with less severe presentation of sore throat, e.g. 0-2 Centor criteria to relieve symptoms. Modest benefits of antibiotics, which have been observed in patients with 3-4 Centor criteria, have to be weighed against side effects, the effect of antibiotics on microbiota, increased antibacterial resistance, medicalisation and costs. The prevention of suppurative complications is not a specific indication for antibiotic therapy in sore throat. If antibiotics are indicated, penicillin V, twice or three times daily for 10 days is recommended. At the present, there is no evidence enough that indicates shorter treatment length.","A European society created a group to update guidelines to identify and treat patients with sore throat. Centor clinical scoring system or rapid antigen, or foreign protein, testing can help target antibiotics (antibacterial medication). The Centor scoring system can help identify those with higher risk of group A streptococcal or strep bacterial infection. In patientis with high risk of streptoccal bacterial infections, physicians may use rapid antigen, or foreign protein, testing (RAT). If rapid antigen testing is used, testing isolated throat cells are not needed for identifying group A strep bacterial infection if no antigens are detected. Either ibuprofen or paracetamol, common pain relievers, can help relieve immediate sore throat symptoms. Zinc gluconate, a dietary supplement, is not recommeded with a sore throat. There is inconsistent evidence that herbal treatments or acupuncture treats sore throat. Patients with less severe sore throats should not use antibiotics to relieve symptoms. Limited benefits of antibiotics, seen in patients with severe sore throat, have to be weighed against antibiotic side effects, its effects on bacteria, medicalisation and costs. Preventing pus is not a sign for antibacterial medication in sore throat. If using antibiotics, penicillin V, two or three times daily for 10 days is recommended. Currently, there is not enough evidence for shorter treatment length." +"In patients with symptoms and signs suggestive of streptococcal pharyngitis a specific diagnosis should be determined by performing a throat culture or a rapid antigen-detection test with a throat culture if the rapid antigen-detection test is negative, at least in children. Penicillin is the preferred treatment, and a first-generation cephalosporin is an acceptable alternative unless there is a history of immediate hypersensitivity to a beta-lactam antibiotic.","Doctors should give patients who are believed to have strep throat a throat culture (a test using a throat swab to find, grow, and test bacteria in the throat that make you sick) or a rapid strep test (a test using a throat swab to find fragments of bacteria in the throat that make you sick) followed by a throat culture if the rapid strep test finds no strep-related bacteria, at least in children. Penicillin is prescribed most commonly. A first-generation cephalosporin, another kind of antibiotic, is another option if no allergies exist." +"Group A beta-hemolytic streptococcal (GABHS) infection causes 15% to 30% of sore throats in children and 5% to 15% in adults, and is more common in the late winter and early spring. The strongest independent predictors of GABHS pharyngitis are patient age of five to 15 years, absence of cough, tender anterior cervical adenopathy, tonsillar exudates, and fever. To diagnose GABHS pharyngitis, a rapid antigen detection test should be ordered in patients with a modified Centor or FeverPAIN score of 2 or 3. First-line treatment for GABHS pharyngitis includes a 10-day course of penicillin or amoxicillin. Patients allergic to penicillin can be treated with firstgeneration cephalosporins, clindamycin, or macrolide antibiotics. Nonsteroidal anti-inflammatory drugs are more effective than acetaminophen and placebo for treatment of fever and pain associated with GABHS pharyngitis; medicated throat lozenges used every two hours are also effective. Corticosteroids provide only a small reduction in the duration of symptoms and should not be used routinely.","Group A strep infection, caused by group A strep bacteria, causes 15% to 30% of sore throats in children and 5% to 15% in adults, and is more common in the late winter and early spring. The most common risk factors of group A strep throat are people under 5 to 15 years old, no cough, tender swollen lymph nodes in the front of the neck, white or yellow spots on the tonsils, and fever. To determine if it is Group A strep throat, a rapid strep test, a test using a throat swab to find bacterial fragments in the throat that make you sick, should be used in people with a medium to high score on common sore throat scoring surveys. Taking antibiotics (penicillin or amoxicillin) for 10 days is the most common treatment for group A strep throat. People allergic to penicillin can be treated with other types of antibiotics like first-generation cephalosporins, clindamycin, or macrolide. antibiotics. Nonsteroidal anti-inflammatory drugs (common over-the-counter drugs like ibuprofen or aspirin) are better than Tylenol or nothing for relief of fever and pain caused by group A strep throat. Taking medicated throat lozenges every two hours also helps with fever and pain. Steroids only make the length of symptoms a little shorter and should not be used regularly." +"Acute pharyngitis/tonsillitis, which is characterized by inflammation of the posterior pharynx and tonsils, is a common disease. Several viruses and bacteria can cause acute pharyngitis; however, Streptococcus pyogenes (also known as Lancefield group A ?-hemolytic streptococci) is the only agent that requires an etiologic diagnosis and specific treatment. S. pyogenes is of major clinical importance because it can trigger post-infection systemic complications, acute rheumatic fever, and post-streptococcal glomerulonephritis. Symptom onset in streptococcal infection is usually abrupt and includes intense sore throat, fever, chills, malaise, headache, tender enlarged anterior cervical lymph nodes, and pharyngeal or tonsillar exudate. Cough, coryza, conjunctivitis, and diarrhea are uncommon, and their presence suggests a viral cause. A diagnosis of pharyngitis is supported by the patient's history and by the physical examination. Throat culture is the gold standard for diagnosing streptococcus pharyngitis. However, it has been underused in public health services because of its low availability and because of the 1- to 2-day delay in obtaining results. Rapid antigen detection tests have been used to detect S. pyogenes directly from throat swabs within minutes. Clinical scoring systems have been developed to predict the risk of S. pyogenes infection. The most commonly used scoring system is the modified Centor score. Acute S. pyogenes pharyngitis is often a self-limiting disease. Penicillins are the first-choice treatment. For patients with penicillin allergy, cephalosporins can be an acceptable alternative, although primary hypersensitivity to cephalosporins can occur. Another drug option is the macrolides. Future perspectives to prevent streptococcal pharyngitis and post-infection systemic complications include the development of an anti-Streptococcus pyogenes vaccine.","Sore throat/tonsillitis, or when the back of the throat or tonsils is inflamed, is common. Many viruses and bacteria can cause short-term sore throat. However, group A strep, caused by Group A strep bacteria, is the only cause that must be identified based on signs and symptoms and treated. Group A strep bacteria are important to identify because they can cause post-strep throat complications throughout the body, acute rheumatic fever (a disease that inflames the body's tissues), and post-strep throat kidney disease. Strep throat symptoms usually happen quickly and include severe sore throat, fever, chills, general discomfort, headache, swollen lymph nodes in the front of the neck, and white or yellow spots on the throat or tonsils. Cough, cold symptoms, pink eye, and diarrhea are not common and might be caused by a virus. Learning the person's history and doing a physical exam are used to diagnose strep throat. A throat swab to find, grow, and test bacteria in the throat that make you sick is the best way to diagnose strep throat. However, it has not been used as much as it should because it is not widely available and takes 1 to 2 days to get results. Rapid strep tests have been used to find fragments of bacteria that cause strep throat from swabs within minutes. Scoring systems have been made to predict the risk of strep throat. The modified Centor score is the most common scoring survey. Short-term strep throat often goes away on its own without treatment. Penicillins, a type of antibiotics, are prescribed most commonly. For people allergic to penicillin, cephalosporins, another type of antibiotics, can be prescribed, although people can be allergic to cephalosporins. Another drug option is macrolides, another type of antibiotics. Making an anti-strep throat vaccine could be one way to prevent strep throat and post-strep throat complications throughout the body in the future." +"Acute pharyngitis/tonsillitis, which is characterized by inflammation of the posterior pharynx and tonsils, is a common disease. Several viruses and bacteria can cause acute pharyngitis; however, Streptococcus pyogenes (also known as Lancefield group A ?-hemolytic streptococci) is the only agent that requires an etiologic diagnosis and specific treatment. S. pyogenes is of major clinical importance because it can trigger post-infection systemic complications, acute rheumatic fever, and post-streptococcal glomerulonephritis. Symptom onset in streptococcal infection is usually abrupt and includes intense sore throat, fever, chills, malaise, headache, tender enlarged anterior cervical lymph nodes, and pharyngeal or tonsillar exudate. Cough, coryza, conjunctivitis, and diarrhea are uncommon, and their presence suggests a viral cause. A diagnosis of pharyngitis is supported by the patient's history and by the physical examination. Throat culture is the gold standard for diagnosing streptococcus pharyngitis. However, it has been underused in public health services because of its low availability and because of the 1- to 2-day delay in obtaining results. Rapid antigen detection tests have been used to detect S. pyogenes directly from throat swabs within minutes. Clinical scoring systems have been developed to predict the risk of S. pyogenes infection. The most commonly used scoring system is the modified Centor score. Acute S. pyogenes pharyngitis is often a self-limiting disease. Penicillins are the first-choice treatment. For patients with penicillin allergy, cephalosporins can be an acceptable alternative, although primary hypersensitivity to cephalosporins can occur. Another drug option is the macrolides. Future perspectives to prevent streptococcal pharyngitis and post-infection systemic complications include the development of an anti-Streptococcus pyogenes vaccine.","Immediate pharyngitis/tonsillitis, characterized by inflammation of the pharynx (an airway in the throat) and tonsils, is a common disease. Many viruses and bacteria can cause immediate pharyngitis (throat inflammation). However, only Streptoccocus pyogenes (a specific bacteria) needs identification and specific treatment. S. pyogenes, a specific bacteria, is important since it can trigger post-infection issues, immediate rheumatic fever, and kidney disease. Symptoms start abruptly in strep bacterial infection and include intense sore throat, fever, chills, fatigue, headache, enlarged neck lymph nodes, and pharyngeal or tonsillar fluid leakage. Cough, nose and eye inflammation, and diarrhea are uncommon. Their presence suggests a viral cause. Identifying pharynx, or throat, inflammation is supported by patient history and physical examination. Testing throat cells are the gold standard for identifying strep throat. However, testing isolated throat cells is underused due to its low availability and 1- to 2-day delay for results. Rapid antigen, or foreign protein, detection tests may detect bacterial S. pyogenes from throat swabs in minutes. Medical scoring systems have been created to predict risk of S. pyogenes bacterial infection. The most common scoring system is the modified Centor score. Immediate strep throat is often a self-resolving disease. Penicillins, or antibacterial drugs, are the first-choice treatment. For patients with penicillin allergy, cephalosporins (another antibacterial) can be an alternative. Although, immediate immune responses to cephalosporins can occur. Another antibiotic option is macrolides. Future options to prevent strep throat and associated issues include developing an anti-Streptococcus pyogenes bacterial vaccine." +"The most common bacterial cause of pharyngitis is infection by Group A ?-hemolytic streptococcus (GABHS), commonly known as strep throat. 5-15% of adults and 15-35% of children in the United States with pharyngitis have a GABHS infection. The symptoms of GABHS overlap with non-GABHS and viral causes of acute pharyngitis, complicating the problem of diagnosis. A careful physical examination and patient history is the starting point for diagnosing GABHS. After a physical examination and patient history is completed, five types of diagnostic methods can be used to ascertain the presence of a GABHS infection: clinical scoring systems, rapid antigen detection tests, throat culture, nucleic acid amplification tests, and machine learning and artificial intelligence. Clinical guidelines developed by professional associations can help medical professionals choose among available techniques to diagnose strep throat. However, guidelines for diagnosing GABHS created by the American and European professional associations vary significantly, and there is substantial evidence that most physicians do not follow any published guidelines. Treatment for GABHS using analgesics, antipyretics, and antibiotics seeks to provide symptom relief, shorten the duration of illness, prevent nonsuppurative and suppurative complications, and decrease the risk of contagion, while minimizing the unnecessary use of antibiotics. There is broad agreement that antibiotics with narrow spectrums of activity are appropriate for treating strep throat. But whether and when patients should be treated with antibiotics for GABHS remains a controversial question. There is no clearly superior management strategy for strep throat, as significant controversy exists regarding the best methods to diagnose GABHS and under what conditions antibiotics should be prescribed.","Strep throat caused by bacteria is most commonly caused by group A strep bacteria. 5-15% of adults and 15-35% children in the United States with strep throat have a group A strep bacteria infection. The symptoms of group A strep bacteria are similar to short-term strep throat caused by viruses and other bacteria, which makes strep throat hard to diagnose. Diagnosing strep throat caused by group A strep bacteria begins with a careful physical exam and patient history. Following a physical exam and patient history, there are five ways to diagnose strep throat caused by group A strep bacteria: scoring systems, rapid antigen tests to find strep bacterial fragments, throat swabs to grow strep bacteria, tests for strep genetic material, and computer predictions. Clinical guidelines written by professional groups can help doctors choose which way to diagnose strep throat. However, guidelines for diagnosing group A strep throat created by professional groups in the United States and Europe differ, and many doctors do not follow any guidelines. Treating group A strep throat with painkillers, fever-reducers, and antibiotics aims to relieve symptoms, shorten illness length, prevent later medical problems with pus or without pus, and decrease the spread, while reducing the use of antibiotics when they are not needed. Experts agree that antibiotics that kill fewer bacteria are best to treat strep throat. Experts do not agree whether and when people with group A strep throat should be given antibiotics. There is no best way to treat strep throat, as experts do not agree on the best way to diagnose group A strep throat and when antibiotics should be given." +"Objective: To compare azithromycin (AZT) and benzathine penicillin (BP) in the treatment of recurrent tonsillitis in children. Methods: The study comprised of 350 children with recurrent streptococcal tonsillitis, 284 of whom completed the study and 162 children received conventional surgical treatment. The rest of the children, 122, were divided randomly into two equal main groups. Group A children received a single intramuscular BP (600,000 IU for children?27kg and 1,200,000IU for ?27kg) every two weeks for six months. Group B children received single oral AZT (250mg for children?25kg and 500mg for ?25kg) once weekly for six months. Results: Both groups showed marked significant reduction in recurrent tonsillitis that is comparable to results of tonsillectomy. There were no statistical differences between group A and B regarding the recurrence of infections and drug safety after six-month follow-up. Group B showed better compliance. Conclusion: AZT proved to be good alternative to BP in the management of recurrent tonsillitis with results similar to those obtained after tonsillectomy.","Our objective is to compare two antibiotics, azithromycin (AZT) and benzathine penicillin (BP), in treating reoccurring inflamed tonsils in children. 284 of 350 children with reoccurring inflamed tonsils caused by strep bacteria participated in the study. 162 children had surgery to treat reoccurring inflamed tonsils. We divided the rest of the children, 122, into two groups. Group A children got a single BP injection (600,000 international units for children weighing 27 kg or less and 1,200,000 international units for children over 27 kg) once a week for six months. Group B children got a single dose of AZT by mouth (250 mg for children weighing 25 kg or less and 500 mg for children over 25 kg). Once a week for six months. Both groups had results similar to getting surgery to remove the tonsils. Drug safety and the reoccurring of inflamed tonsils were similar in both groups. Group B followed doctor instructions better. We concluded that AZT can treat reoccurring inflamed tonsils similar to BP with results similar to getting surgery to remove the tonsils." +"Background: Diagnosing group A streptococcus (Strep A) throat infection by clinical examination is difficult, and misdiagnosis may lead to inappropriate antibiotic use. Most patients with sore throat seek symptom relief rather than antibiotics, therefore, therapies that relieve symptoms should be recommended to patients. We report two clinical trials on the efficacy and safety of flurbiprofen 8.75 mg lozenge in patients with and without streptococcal sore throat. Methods: The studies enrolled adults with moderate-to-severe throat symptoms (sore throat pain, difficulty swallowing and swollen throat) and a diagnosis of pharyngitis. The practitioner assessed the likelihood of Strep A infection based on historical and clinical findings. Patients were randomised to flurbiprofen 8.75 mg or placebo lozenges under double-blind conditions and reported the three throat symptoms at baseline and at regular intervals over 24 h. Results: A total of 402 patients received study medication (n = 203 flurbiprofen, n = 199 placebo). Throat culture identified Strep A in 10.0% of patients and group C streptococcus (Strep C) in a further 14.0%. The practitioners' assessments correctly diagnosed Strep A in 11/40 cases (sensitivity 27.5%, and specificity 79.7%). A single flurbiprofen lozenge provided significantly greater relief than placebo for all three throat symptoms, lasting 3-4 h for patients with and without Strep A/C. Multiple doses of flurbiprofen lozenges over 24 h also led to symptom relief, although not statistically significant in the Strep A/C group. There were no serious adverse events. Conclusions: The results highlight the challenge of identifying Strep A based on clinical features. With the growing problem of antibiotic resistance, non-antibiotic treatments should be considered. As demonstrated here, flurbiprofen 8.75 mg lozenges are an effective therapeutic option, providing immediate and long-lasting symptom relief in patients with and without Strep A/C infection.","Diagnosing group A strep throat (Strep A) by a physical exam is difficult, and diagnosing it incorrectly may lead to use of the wrong antibiotic. Doctors should suggest treatments that improve symptoms to people with sore throat because most do not want antibiotics. We looked at two studies on how well flurbiprofen 8.75 mg lozenge works and how safe it is in people with and without strep throat. We studied adults with moderate-to-severe throat symptoms (sore throat pain, difficulty swallowing and swollen throat) and a diagnosis of strep throat. The doctor determined how likely it was that people have Strep A infection based on the history of the patient and a physical exam. We gave people either flurbiprofen 8.75 mg lozenges or sugar lozenges and they reported three throat symptoms (sore throat pain, difficulty swallowing and swollen throat) at the beginning of the study and regularly over 24 h. We gave 203 people flurbiprofen 8.75 mg and 199 people sugar lozenges, for a total of 402 people. A throat swab to find, grow, and test bacteria in the throat found Strep A in 10% of people and group C strep (Strep C) in 14% of people. The doctors correctly diagnosed Strep A in 11 of 40 cases. People had greater symptom relief with one flurbiprofen lozenge than one sugar lozenge for three throat symptoms (sore throat pain, difficulty swallowing and swollen throat), lasting 3-4 h for people with and without Strep A or C. People with Strep A or C may have some symptom relief with more than one flurbiprofen lozenge over 24 h. There were no serious side effects. We conclude that the studies emphasize the difficulty of identifying Strep A based on signs and symptoms. With the growing problem of bacteria able to defeat the antibiotics designed to kill them, treatments that are not antibiotics should be considered. As shown here, flurbiprofen 8.75 mg lozenges work, giving immediate and long-lasting symptom relief in people with and without Strep A or C infection." +"Background: Diagnosing group A streptococcus (Strep A) throat infection by clinical examination is difficult, and misdiagnosis may lead to inappropriate antibiotic use. Most patients with sore throat seek symptom relief rather than antibiotics, therefore, therapies that relieve symptoms should be recommended to patients. We report two clinical trials on the efficacy and safety of flurbiprofen 8.75 mg lozenge in patients with and without streptococcal sore throat. Methods: The studies enrolled adults with moderate-to-severe throat symptoms (sore throat pain, difficulty swallowing and swollen throat) and a diagnosis of pharyngitis. The practitioner assessed the likelihood of Strep A infection based on historical and clinical findings. Patients were randomised to flurbiprofen 8.75 mg or placebo lozenges under double-blind conditions and reported the three throat symptoms at baseline and at regular intervals over 24 h. Results: A total of 402 patients received study medication (n = 203 flurbiprofen, n = 199 placebo). Throat culture identified Strep A in 10.0% of patients and group C streptococcus (Strep C) in a further 14.0%. The practitioners' assessments correctly diagnosed Strep A in 11/40 cases (sensitivity 27.5%, and specificity 79.7%). A single flurbiprofen lozenge provided significantly greater relief than placebo for all three throat symptoms, lasting 3-4 h for patients with and without Strep A/C. Multiple doses of flurbiprofen lozenges over 24 h also led to symptom relief, although not statistically significant in the Strep A/C group. There were no serious adverse events. Conclusions: The results highlight the challenge of identifying Strep A based on clinical features. With the growing problem of antibiotic resistance, non-antibiotic treatments should be considered. As demonstrated here, flurbiprofen 8.75 mg lozenges are an effective therapeutic option, providing immediate and long-lasting symptom relief in patients with and without Strep A/C infection.","Identifying bacterial group A strep (Strep A) throat infection by examination is difficult. Misidentifying may lead to innappropriate antibacterial antibiotic use. Most with sore throat seek symptom relief rather than antibacterial antibiotics, so therapies that relieve symptoms should be promoted. We show two trials on the success and safety of anti-inflammatory fluriboprofen lozenges in those with and without strep throat. The studies enrolled adults with moderate-to-severe throat symptoms (sore throat pain, difficulty swallowing and swollen throat) and with inflammation of the pharynx (specific throat area). The practitioner measured risk of Strep A bacterial infection by historical and medical findings. Patients were randomised to anti-inflammatory flurbiprofen or inactive treatment. They also reported three throat symptoms at start and regular intervals over 24 hours. 402 patients received treatment (203 with antinflammatory flurbiprofen and 199 with inactive treatment). Testing isolated throat cells identified bacterial Strep A in 10% of patients and group C streptococcus (Strep C) in another 14%. The practitioners correctly identified Strep A in 11/40 cases. A single anti-inflammatory flurbiprofen lozenge gave more relief than the inactive treatment for all three throat symptoms and for 3-4 hours. Multiple doses of flurbiprofen over 24 hours led to mild, negligible symptom relief. There were no serious side effects. It is difficult identifying bacterial Strep A by clinical features. With growing antibiotic resistance, non-antibiotic treatments should be considered. As seen here, anti-inflammatory flurbiprofen lozenges are effective treatment, giving immediate and long-lasting symptom relief." +"Most patients who seek medical attention for sore throat are concerned about streptococcal tonsillopharyngitis, but fewer than 10% of adults and 30% of children actually have a streptococcal infection. Group A beta-hemolytic streptococci (GAS) are most often responsible for bacterial tonsillopharyngitis, although Neisseria gonorrhea, Arcanobacterium haemolyticum (formerly Corynebacterium haemolyticum), Chlamydia pneumoniae (TWAR agent), and Mycoplasma pneumoniae have also been suggested as possible, infrequent, sporadic pathogens. Viruses or idiopathic causes account for the remainder of sore throat complaints. Reliance on clinical impression to diagnose GAS tonsillopharyngitis is problematic; an overestimation of 80% to 95% by experienced clinicians typically occurs for adult patients. Overtreatment promotes bacterial resistance, disturbs natural microbial ecology, and may produce unnecessary side effects. Existing data suggest that rapid GAS antigen testing as an aid to clinical diagnosis can be very useful. When used appropriately, it is sensitive (79% to 88%) in detecting GAS-infected patients and is specific (90% to 96%) and cost-effective. Penicillin has been the treatment of choice for GAS tonsillopharyngitis since the 1950s; 10 days of treatment are necessary for bacterial eradication. A single IM injection of benzathine penicillin is effective and obviates compliance issues. Until the early 1970s, the bacteriologic failure rate for the treatment of GAS tonsillopharyngitis ranged from 2% to 10% and was attributed to chronic GAS carriers. Since the late 1970s, the penicillin failure rate has frequently exceeded 20% in published reports. Explanations for recurrent GAS tonsillopharyngitis include poor patient compliance; reacquisition from a family member or peer, copathogenic colonization by Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, anaerobes that inactivate penicillin with beta-lactamase, or all these organisms; suppression of natural immune response by too-early administration of antibiotics; GAS tolerance to penicillin; antibiotic eradication of normal pharyngeal flora that normally act as natural host defenses; and establishment of a true carrier state. When therapy fails, milder symptoms may occur during the relapse. Several antimicrobials have demonstrated superior efficacy compared with penicillin in eradicating GAS and are administered less frequently to enhance patient compliance. In previously untreated GAS throat infections, cephalosporins produce a 5% to 22% higher bacteriologic cure rate; after a penicillin treatment failure, these differences are greater. Amoxicillin/clavulanate and the extended-spectrum macrolides clarithromycin and azithromycin may also produce enhanced bacteriologic eradication in comparison to penicillin.","Most people who go to a doctor for sore throat are worried they have a strep throat and tonsil infection, but fewer than 10% of adults and 30% of children actually have a strep infection. Group A strep bacteria are the most common cause of bacterial strep throat and tonsil infection, but other bacteria known to cause sexually-transmitted gonorrhea or chlamydia, or head, neck, and lung infections occasionally might cause it. Remaining sore throat issues are caused by viruses and unknown causes. Relying on a doctor's exam to diagnose group A strep throat and tonsil infection causes problems. Experienced doctors over-diagnose 80 to 95% of adult cases. Doctors treating someone more than needed leads to the ability of bacteria to defeat the antibiotics designed to kill them, affects small organisms that live in or on the human body, and may cause side effects that are not needed. Studies show combining a rapid strep testing (using a throat swab to detect bacterial fragments) with a doctor exam can be helpful for diagnosis. When used correctly, a rapid strep test has high accuracy for group A strep throat and tonsil infection detection and does not cost a lot. Penicillin has been the preferred treatment for group A strep throat and tonsil infection since the 1950s. Taking penicillin for 10 days is needed to kill all the group A bacteria. One benzathine penicillin shot works and does not require people following doctor instructions. Until the early 1970s, the rate of group A strep bacteria coming back after treatment was low and thought to be caused by people who had long-term Group A bacteria in their bodies. Since the late 1970s, the rate of group A strep bacteria coming back after treatment more than doubled according to studies. Reasons for reoccurring group A strep throat and tonsil infection are people not following doctor instructions; getting the infection again from a family member or peer; infection caused by group A strep bacteria and other bacteria; taking antibiotics too early in the infection; group A strep bacteria defeating antibiotics used to kill them; antibiotics killing small organisms in the throat that protect it; and people who have the bacteria in their bodies but are not sick. When treatment doesn't work, milder symptoms may happen as symptoms return. Many substances that kill small organisms have worked better than penicillin to kill group A strep bacteria and are given less often to increase the rate at which people follow doctor orders. In group A strep and tonsil infection that is not treated, cephalosporins, another type of antibiotic, kill all group A strep bacteria more often than penicillin. After penicillin is taken and does not cure group A strep throat and tonsil infection, this rate is higher. A combination of amoxicillin and clavulanate, other antibiotics, and clarithromycin and azithromycin, another kind of antibiotics called macrolides that kill more types of bacteria, may also kill more bacteria than penicillin." +"Chronic GAS carrier state is best defined as the prolonged presence of group A ?-haemolytic Streptococcus (GAS) in the pharynx without evidence of infection or inflammation. Chronic GAS carriers have a low risk of immune mediated complications. Persistent pharyngeal carriage often raises management issues. In this study, we review the evidence on the management of persistent GAS carriage in children and propose a management algorithm. Areas covered: Chronic GAS pharyngeal carriage is quite common affecting 10-20% of school-aged children. Pathogenesis of carriage has been related to the pharynx microflora and to special properties of GAS, but several aspects are yet to be elucidated. Management greatly depends on whether the individual child belongs to a 'high-risk' group and might benefit from eradication regimens or not, when observation-only and reassurance are enough. Penicillin plus rifampin and clindamycin monotherapy have been recommended for eradication; limited evidence of effectiveness of azithromycin has been reported. Surgical intervention is not indicated. Expert commentary: GAS infection is a common reason for antibiotic use and abuse in children and asymptomatic carriers constitute the major reservoir of GAS in the community. Several aspects are yet to be elucidated and well-designed studies are needed for firm conclusions to be drawn.","Chronic GAS carrier state is defined as the long-term presence of group A strep (GAS) in the throat with no infection or inflammation. Chronic GAS carriers have a low risk of conditions that result from abnormal functioning of the body's immune system. Long-term GAS in the throat often causes treatment issues. In this study, we review the science on treating long-term GAS in children and suggest a way to treat it using computers. Long-term GAS in the throat is found in 10-20% of school-aged children. Whether or not GAS in the throat causes infection depends on small organisms in the throat and special qualities of GAS, but many things are not clear. Treating long-term GAS depends on whether the child is high-risk and might benefit from killing the bacteria or not, when a doctor looking at it and removing fears and concerns about the illness are enough. Combining antibiotics penicillin with rifampin and clindamycin in one drug has been recommended to kill GAS. There is not much proof that the antibiotic azithromycin works. Surgery is not recommended. Experts comment that GAS infection is a common reason for antibiotic use and overuse in children and people who have GAS without symptoms are the most common carriers in the community. Many things are not clear, and good studies are needed to make decisions." +"We conducted a meta-analysis of 9 randomized controlled trials (involving 2113 patients) comparing cephalosporins with penicillin for treatment of group A beta -hemolytic streptococcal (GABHS) tonsillopharyngitis in adults. The summary odds ratio (OR) for bacteriologic cure rate significantly favored cephalosporins, compared with penicillin (OR,1.83; 95% confidence interval [CI], 1.37-2.44); the bacteriologic failure rate was nearly 2 times higher for penicillin therapy than it was for cephalosporin therapy (P=.00004). The summary OR for clinical cure rate was 2.29 (95% CI, 1.61-3.28), significantly favoring cephalosporins (P<.00001). Sensitivity analyses for bacterial cure significantly favored cephalosporins over penicillin in trials that were double-blinded and of high quality, trials that had a well-defined clinical status, trials that performed GABHS serotyping, trials that eliminated carriers from analysis, and trials that had a test-of-cure culture performed 3-14 days after treatment. This meta-analysis indicates that the likelihood of bacteriologic and clinical failure in the treatment of GABHS tonsillopharyngitis is 2 times higher for oral penicillin than for oral cephalosporins.",We analyzed results from 9 studies (2113 people total) comparing cephalosporins (antibacterial antibiotics) and penicillin (another antibiotic) for treatment of group A strep throat and tonsil infection in adults. Results favored cephalosporins over penicillin. Results favored cephalosporins. Results favored cephalosporins over penicillin. This analysis shows using penicillin to treat group A strep throat and tonsil infection is twice as likely to result in the bacteria and infection coming back as using cephalosporins. +"We conducted a meta-analysis of 9 randomized controlled trials (involving 2113 patients) comparing cephalosporins with penicillin for treatment of group A beta -hemolytic streptococcal (GABHS) tonsillopharyngitis in adults. The summary odds ratio (OR) for bacteriologic cure rate significantly favored cephalosporins, compared with penicillin (OR,1.83; 95% confidence interval [CI], 1.37-2.44); the bacteriologic failure rate was nearly 2 times higher for penicillin therapy than it was for cephalosporin therapy (P=.00004). The summary OR for clinical cure rate was 2.29 (95% CI, 1.61-3.28), significantly favoring cephalosporins (P<.00001). Sensitivity analyses for bacterial cure significantly favored cephalosporins over penicillin in trials that were double-blinded and of high quality, trials that had a well-defined clinical status, trials that performed GABHS serotyping, trials that eliminated carriers from analysis, and trials that had a test-of-cure culture performed 3-14 days after treatment. This meta-analysis indicates that the likelihood of bacteriologic and clinical failure in the treatment of GABHS tonsillopharyngitis is 2 times higher for oral penicillin than for oral cephalosporins.",We reviewed 9 randomized trials (with 2113 patients) comparing cephalosporins (antibacterial antibiotics) with penicillin (another antibiotic) for treating group A beta -hemolytic streptococcal tonsillopharyngitis (a bacterial throat infection) in adults. Results favored cephalosporins over penicillin. Results favored cephalosporins. Results favored cephalosporins over penicillin. The risk of treatment failure for bacterial strep throat is 2 times higher for oral penicillin antibiotics than for cephalosporins antibiotics. +"The normal sleep-wake cycle is characterized by diurnal variations in blood pressure, heart rate, and cardiac events. Sleep apnea disrupts the normal sleep-heart interaction, and the pathophysiology varies for obstructive sleep apnea (OSA) and central sleep apnea (CSA). Associations exist between sleep-disordered breathing (which encompasses both OSA and CSA) and heart failure, atrial fibrillation, stroke, coronary artery disease, and cardiovascular mortality. Treatment options include positive airway pressure as well as adaptive servo-ventilation and phrenic nerve stimulation for CSA. Treatment improves blood pressure, quality of life, and sleepiness, the last particularly in those at risk for cardiovascular disease. Results from clinical trials are not definitive in terms of hard cardiovascular outcomes.","The normal sleep-wake cycle (our-24 hour daily sleep pattern) is characterized by fluctuations in the day and variations at night in blood pressure, heart rate, and cardiac events (reduced blood flow that may damage the heart). Sleep apnea is a sleep disorder where breathing repeatedly stops and starts. Sleep apnea disrupts the normal patterns between sleep and how the heart functions, and the physical changes vary for obstructive sleep apnea (OSA), caused by airflow blockage, and central sleep apnea (CSA), when breathing regularly stops while sleeping because the brain doesn't tell the muscles to take in air. There are associations between sleep-disordered breathing, including OSA and CSA, and heart failure, atrial fibrillation (a fluttery and irregular heartbeat that can lead to blood clots) and other heart problems. Treatment options include positive airway pressure (a machine used to pump air under pressure into the airway of the lungs), adaptive servo-ventilation (a device that tracks and adjusts its pressure to match the breathing pattern of a person with sleep apnea), and phrenic nerve stimulation (treatment that sends electrical stimulation to the patient's phrenic nerve to contract the diaphragm and produce breathing). Treatment improves blood pressure, quality of life, and sleepiness. Results from clinical trials are not definite in how they affected common cardiovascular diseases." +"The normal sleep-wake cycle is characterized by diurnal variations in blood pressure, heart rate, and cardiac events. Sleep apnea disrupts the normal sleep-heart interaction, and the pathophysiology varies for obstructive sleep apnea (OSA) and central sleep apnea (CSA). Associations exist between sleep-disordered breathing (which encompasses both OSA and CSA) and heart failure, atrial fibrillation, stroke, coronary artery disease, and cardiovascular mortality. Treatment options include positive airway pressure as well as adaptive servo-ventilation and phrenic nerve stimulation for CSA. Treatment improves blood pressure, quality of life, and sleepiness, the last particularly in those at risk for cardiovascular disease. Results from clinical trials are not definitive in terms of hard cardiovascular outcomes.","The normal sleep-wake cycle has daily changes in blood pressure, heart rate, and heart-related events. Sleep apnea (a disorder in which breathing is regularly interrupted during sleep) alters the sleep-heart interaction. The disease-related physical effects vary for obstructive and central sleep apnea, sleep apnea by throat blockage and brain dysfunction, respectively. Links exist between sleep-disordered breathing, which includes both types of sleep apnea, heart failure, irregular heart beats, stroke (brain damage from reduced brain blood supply), coronary artery disease, which is plaque buildup blocking blood flow, and cardiovascular death. Machine-based treatments include positive airway pressure and adaptive servo-ventillation, which both involve pumping air into the lungs, and phrenic nerve stimulation, which involves contracting the diaphragm to breathe, for central sleep apnea (sleep apnea by brain dysfunction). Treatment improves blood pressure, quality of life, and sleepiness, the last especially in those at risk for heart- and blood-related disease. Heart-related results from clinical trials are not definitive." +"Objective: Nighttime onset of atrial fibrillation (AF) is sometimes associated with obstructive sleep apnea accompanied by a characteristic heart rate (HR) pattern known as cyclical variation of HR. The aim of this study was to evaluate whether cyclical variation of HR is prevalent in patients with nocturnal AF. Methods: The subjects consisted of 34 patients (68�12 years) with paroxysmal AF, including 14 patients with daytime AF and 20 patients with nighttime AF. Holter electrocardiogram (ECGs) were examined for the presence of cyclical variation in HR and to quantify the HR variability within the 40-minute period preceding each AF episode using a fast Fourier transform (FFT) methods. Results: Cyclical variation in HR was observed in 12 of 20 (60%) nighttime episodes and in only two of 14 (14%) daytime episodes. The prevalence of cyclical variation in HR was significantly greater in the nighttime AF episodes than in the daytime AF episodes (Chi=5.34, p<0.05). The mean frequency of cyclical variation in HR was 0.015�0.003 Hz. The mean power of the VLF (very low frequency) component (0.008-0.04 Hz) before the onset of AF was significantly greater in the nighttime AF episodes than in the daytime AF episodes. Among the nighttime AF episodes, the power of the HF (high frequency), LF (low frequency) and very low frequency (VLF) components increased significantly just before the onset of AF compared with that observed 40 minutes before onset. Conclusion: The high prevalence of cyclical variation in HR observed before nocturnal AF episodes suggests that sleep apnea may play a role in the onset of nighttime AF.","Nighttime onset of atrial fibrillation (a fluttery and irregular heartbeat that can lead to blood clots or stroke) is sometimes associated with obstructive sleep apnea (where muscles in the throat relax, the airway is narrowed or closed, and breathing is momentarily cut off) along with a specific heart rate pattern called cyclical variation. This study determines whether cyclical variation of heart rate is common in patients with nighttime atrial fibrillation (AF). There are 34 patients in the study with paroxysmal AF (when the heart rate returns to normal within 7 days on its own or with treatment), including 14 patients with daytime AF and 20 patients with nighttime AF. The presence of cyclical variation in heart rate is examined, and the heart rate differences are measured and counted 40 minutes before each AF episode. Cyclical variation in heart rate is found in 12 of 20 (60%) nighttime episodes and only in two of 14 (14%) daytime episodes. Cyclical variation in heart rate was much greater in the nighttime AF than in daytime AF episodes. The high presence of cyclical variation in heart rate found before nighttime atrial fibrillation episodes suggests that sleep apnea may play a role in the onset of nighttime atrial fibrillation." +"Background: For patients presenting with atrial fibrillation of only a few weeks duration, the use of transesophageal echocardiography offers the opportunity to markedly abbreviate the duration of atrial fibrillation before cardioversion. We sought to determine if the shorter duration of atrial fibrillation allowed by a transesophageal echocardiography strategy had an impact on the recurrence of atrial fibrillation and prevalence of sinus rhythm during the first year following cardioversion. Methods: Transesophageal echocardiography was attempted in 539 patients (292 men, 247 women; 71.6 +/- 13.0 years.) with atrial fibrillation > or =2 days (66.1% <3 weeks) or of unknown duration before elective cardioversion of atrial fibrillation. Therapeutic anticoagulation at the time of transesophageal echocardiography was present in 94.6% of patients, and 73.4% of subjects were discharged on warfarin. Results: Atrial thrombi were identified in 70 (13.1%) patients. Successful cardioversion in 413 patients without evidence of atrial thrombi was associated with clinical thromboembolism in 1 patient (0.24%, 95% confidence interval: 0.0--0.8%). In patients with atrial fibrillation <3 weeks at the time of cardioversion (a duration incompatible with conventional therapy of 3 to 4 weeks of warfarin before cardioversion), the 1-year atrial fibrillation recurrence rate was lower (41.1% vs. 57.9%, P <0.01), and the prevalence of sinus rhythm at 1 year was increased (65.8% vs. 51.3%, P <0.03). No other clinical or echocardiographic index was associated with recurrence of atrial fibrillation or sinus rhythm at 1 year. Conclusions: Early cardioversion facilitated by transesophageal echocardiography has a favorable safety profile and provides the associated benefit of reduced recurrence of atrial fibrillation for patients in whom the duration of atrial fibrillation is <3 weeks.","Atrial fibrillation is a fluttery and irregular heartbeat that can lead to blood clots or stroke. For patients that had atrial fibrillation for only a few weeks, using a test that produces pictures of the heart called transesophageal echocardiography is an opportunity to shorten the duration of atrial fibrillation before cardioversion, a procedure used to return an irregular or very fast heartbeat to a normal rhythm. Researchers aimed to find out if the shorter time period of atrial fibrillation from using transesophageal echocardiography impacts how often atrial fibrillation returns and the frequency of sinus rhythm in the first year after cardioversion. Sinus rhythm is the pattern of your heartbeat based on the sinus node of your heart which sends out electrical pulses. Transesophageal echocardiography is used in 539 patients who had atrial fibrillation for two or more days (more than half had atrial fibrillation for less than 3 weeks) or for an unknown duration before non-emergency cardioversion of atrial fibrillation. Blood thinners at the time of the transesophageal echocardiography were used in almost all patients, and 73.4% were discharged on warfarin, a blood thinner to prevent blood clots. Heart-related blood clots were found in 70 (13.1%) patients. Among patients who successfully had the cardioversion procedure, 1 patient had clinical thromboembolism, a blood clot in the vein. In the patients who had atrial fibrillation for less than 3 weeks at the time of cardioversion, the return of atrial fibrillation in the first year was lower, and the frequency of sinus rhythm at 1 year increased. No other clincal or heart evaluations are associated with returning atrial fibrillation or sinus rhythm at 1 year. Having the cardioversion procedure earlier by using the transesophageal echocardiography is shown to be a safe method and is associated with reducing the return of atrial fibrillation in patients who have had the heart condition for less than 3 weeks." +"Circadian variation in atrial fibrillation (AF) frequency is explored in this paper by employing recent advances in signal processing. Once the AF frequency has been estimated and tracked by a hidden Markov model approach, the resulting trend is analyzed for the purpose of detecting and characterizing the presence of circadian variation. With cosinor analysis, the results show that the short-term variations in the AF frequency exceed the variation that may be attributed to circadian. Using the autocorrelation method, circadian variation was found in 13 of 18 ambulatory ECG recordings (Holter) acquired from patients with long-standing persistent AF. Using the ensemble correlation method, the highest AF frequency usually occurred during the afternoon, whereas the lowest usually occurred during late night. It is concluded that circadian variation is present in most patients with long-standing persistent AF though the short-term variation in the AF frequency is considerable and should be taken into account.","Circadian variation (a part of the natural, internal process that regulates the sleep�wake cycle) in atrial fibrillation (a fluttery and irregular heartbeat that can lead to blood clots or stroke) frequency is explored in this paper by using recent advances in signal processing, which monitors the heart's electrical activity. When the atrial fibrillation frequency is estimated and tracked by signal processing tools, the information is further reviewed to detect and describe the presence of circadian variation. The results show that the short-term variations in the atrial fibrillation frequency are greater than the variation that may be attributed to circadian. Circadian variation is found in 13 of 18 patients with long-standing and persistent (last longer than 7 days) atrial fibrillation. The highest atrial fibrillation frequency usually occurred during the afternoon, whereas the lowest usually occurred during late night. Circadian variation is present in most patients with long-standing persistent atrial fibrillation, though the short-term variation in the AF frequency is great and should be taken into account." +"Circadian variation in atrial fibrillation (AF) frequency is explored in this paper by employing recent advances in signal processing. Once the AF frequency has been estimated and tracked by a hidden Markov model approach, the resulting trend is analyzed for the purpose of detecting and characterizing the presence of circadian variation. With cosinor analysis, the results show that the short-term variations in the AF frequency exceed the variation that may be attributed to circadian. Using the autocorrelation method, circadian variation was found in 13 of 18 ambulatory ECG recordings (Holter) acquired from patients with long-standing persistent AF. Using the ensemble correlation method, the highest AF frequency usually occurred during the afternoon, whereas the lowest usually occurred during late night. It is concluded that circadian variation is present in most patients with long-standing persistent AF though the short-term variation in the AF frequency is considerable and should be taken into account.","Sleep-wake changes in the frequency of atrial fibrillation (irregular or rapid heart beat) (AF) is explored by using new advances in signal processing. Once the frequency of the irregular heart beat is estimated and tracked by a mathematical technique, the result is measured to detect and characterize sleep-wake changes. With mathematical analysis, the results show that short-term changes in the frequency of the irregular heart beat surpass the changes owing to sleep-wake patterns. With mathematical analysis, sleep-wake changes were found in 13 of 18 ambulatory heart-beat recordings from those with long-lasting frequencies of irregular heart beats. With mathematical analysis, the highest frequency of an irregular heart beat usually came in the afternoon, while the lowest usually came at late night. Thus, sleep-wake changes occur in most with long-lasting AF frequency. However, the short-term changes in AF frequency should be examined." +"Background: Dronedarone is a new multichannel blocker for atrial fibrillation (AF) previously demonstrated to have both rhythm and rate control properties in paroxysmal and persistent AF. The Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation (ERATO) trial assessed the efficacy of dronedarone in the control of ventricular rate in patients with permanent AF, when added to standard therapy. Methods: In this randomized, double-blind, multinational trial, dronedarone, 400 mg twice a day (n = 85), or matching placebo (n = 89) was administered for 6 months to adult patients with permanent AF, in addition to standard therapy. The primary end point was the change in mean ventricular rate between baseline and day 14, as assessed by 24-hour Holter. Ventricular rate was also assessed during submaximal and maximal exercise. Results: Dronedarone significantly decreased mean 24-hour ventricular rate. Compared with placebo, the mean treatment effect at day 14 was a reduction of 11.7 beats per minute (beat/min; P < .0001). Comparable reductions were sustained throughout the 6-month trial. During maximal exercise and compared to placebo, there was a mean reduction of 24.5 beat/min (P < .0001), without any reduction in exercise tolerance as measured by maximal exercise duration. The effects of dronedarone were additive to those of other rate-control agents, including beta-blockers, calcium antagonists, and digoxin. Dronedarone was well tolerated, with no organ toxicities or proarrhythmia. Conclusion: In addition to its reported rhythm-targeting and rate-targeting therapeutic actions in paroxysmal and persistent AF, dronedarone improves ventricular rate control in patients with permanent AF. Dronedarone was well tolerated with no evidence of organ toxicities or proarrhythmias in this short-term study.","Dronedarone is a new drug that can treat atrial fibrillation (a fluttery and irregular heartbeat that can lead to blood clots or stroke) or AF and is found to help control the heart rhythm and heart rate in patients with paroxysmal (when the heart rate returns to normal within 7 days on its own or with treatment) or with persistent (greater than 7 days) atrial fibrillation. A clinical trial called the Efficacy and safety of dRonedArone for The cOntrol of ventricular rate during atrial fibrillation (ERATO) reviewed how well dronedarone worked to control the ventricular rate (heart rate) in patients with permanent AF, when added to other treatments. In this clinical trial of patients with permanent AF, 85 patients receive the dronedarone drug, and 85 receive a placebo (an inactive substance that looks like the treatment drug) for 6 months. A key measure is the average change in ventricular rate between the start of the trial and day 14 of the trial. Ventricular rate is also evaluated during submaximal exercise (any physical activity with increased intensity in which heart rate does not go above 85) and maximal exercise (physical activity increased to come close to fatigue). Dronedarone significantly decreased the average 24-hour ventricular rate. When compared to the placebo group, the average effect of dronedarone on day 14 was a reduction of 11.7 beats per minute. Similar reductions continued throughout the 6-month trial. There was a reduction in heart beats per minute during maximal exercise when compared to the placebo group. The effects of dronedarone were an addition to the effects of other drugs that control heart rate. Dronedarone was well tolerated with few side effects. In addition to its previously demonstrated effects on heart rhythm and rate in short-term and long-term AF, dronedarone improves ventricular rate control in patients with permanent AF. Dronedarone was well tolerated with no evidence of damage to organs or worsening of heart condition in this short-term study." +"Introduction: Sleep apnea-hypopnea syndrome (SAHS) is one of the extracardiac reasons of atrial fibrillation (AF), and the prevalence of AF is high in SAHS-diagnosed patients. Nocturnal hypoxemia is associated with AF, pulmonary hypertension, and nocturnal death. The rate of AF recurrence is high in untreated SAHS-diagnosed patients after cardioversion (CV). In this study, we present a patient whose SAHS was diagnosed with an apnea test performed in the intensive care unit (ICU) and who did not develop recurrent AF after the administration of standard AF treatment and bi-level positive airway pressure (BiPAP). Case presentation: A 57-year-old male hypertensive Caucasian patient who was on medical treatment for 1.5 months for non-organic AF was admitted to the ICU because of high-ventricular response AF (170 per minute), and sinus rhythm was maintained during the CV that was performed two times every second day. The results of the apnea test performed in the ICU on the same night after the second CV were as follows: apnea-hypopnea index (AHI) of 71 per hour, minimum peripheral oxygen saturation (SpO2) of 67%, and desaturation period (SpO2 of less than 90%) of 28 minutes. The patient was discharged with medical treatment and nocturnal BiPAP treatment. The results of the apnea test performed under BiPAP on the sixth month were as follows: AHI of 1 per hour, desaturation period of 1 minute, and minimum SpO2 of 87%. No recurrent AF developed in the patient, and his medical treatment was reduced within 6 months. After gastric bypass surgery on the 12th month, nocturnal hypoxia and AF did not re-occur. Thus, BiPAP and medical treatments were ended. Conclusions: SAHS can be diagnosed by performing an apnea test in the ICU. SAHS should be investigated in patients developing recurrent AF after CV. Recovery of nocturnal hypoxia may increase the success rate of standard AF treatment.","Sleep apnea-hypopnea syndrome (SAHS) (a sleep disorder of recurring episodes of partial or complete upper airway collapse during sleep) is one of the causes of atrial fibrillation (AF) (a fluttery and irregular heartbeat that can lead to blood clots or stroke). The occurrence of AF is high in SAHS-diagnosed patients. Nocturnal hypoxemia (a temporary drop in oxygen while sleeping) is associated with AF, pulmonary hypertension (high blood pressure affecting the arteries in the lungs and heart), and nocturnal death (death in sleep caused by sudden cardiac death). The frequency of AF recurring is high in people with untreated SAHS after cardioversion, a procedure used to return an irregular or very fast heartbeat to a normal rhythm. This study summarizes the case of a patient with SAHS diagnosed by an apnea test (monitoring of breathing and oxygen) and who did not develop recurring (chronic) atrial fibrillation after receiving standard treatment and the bi-level positive airway pressure (BiPAP), a ventilator used to maintain a consistent breathing pattern (often used at night). A 57-year old male patient who was on treatment for 1.5 months for AF was admitted to the hospital because of a high, irregular heart beat. The sinus rhythm (the pattern of your heartbeat based on the sinus node of your heart which sends out electrical pulses) was steady during the cardioversion procedure. Heart and oxygen tests were performed in the hospital after the second cardioversion. The patient was sent home with medical treatment and a nocturnal BiPAP. No recurring atrial fibrillation developed in the patient, and his medical treatment was reduced within 6 months. After gastric bypass surgery on the 12th month, nocturnal hypoxia and atrial fibrillation did not re-occur. Because they did not recur, the BiPAP and medical treatments were ended. In conclusion, SAHS can be diagnosed by performing an apnea test in the hospital. SAHS should be investigated in patients developing recurring atrial fibrillation after a cardioversion procedure. Recovery of nocturnal hypoxia may increase the success of standard atrial fibrillation treatment." +"Background: Sleep-disordered breathing (SDB) and atrial fibrillation (AF) are associated. This study investigated the impact of AF intervention on 6-month home sleep testing data. Methods: Sixty-seven patients (aged 66 to 86, 53% male) with persistent AF were randomized (1:1:1) to direct current cardioversion (DCCV) (22 patients), permanent pacemaker (PPM) + atrioventricular node ablation (AVNA) + DCCV (22 patients) or AF ablation (23 patients). Baseline and 6-month multichannel home sleep tests with the Watch-PAT200 (Itamar Medical Lts., Caesarea, Israel) were recorded. Implantable cardiac monitors (ICMs) (Medtronic Reveal XT, Minneapolis, Minnesota) in the DCCV and AF ablation groups, and PPM Holters in the 'pace and ablate' group were utilized to assess cardiac rhythm beat-to-beat throughout the study period. Results: The prevalence of moderate-to-severe SDB [apnoea-hypopnoea index (AHI) ? 15/h] was 60%. At 6 months there was no change in AHI, Epworth sleepiness scale, sleep time, % REM sleep, respiratory desaturation index or central apnoeic events. Twenty-five patients (15 AF ablation, 9 DCCV and 1 following DCCV post-AVNA) maintained SR at 6 months confirmed on ICMs in these patients. AHI fell from 29.8 � 26.6/h to 22.2 � 20.4/h; P = 0.049. Conclusions: SDB is highly prevalent in patients with persistent AF. Restoration of sinus rhythm, and the associated long-term recovery of haemodynamics, is associated with a significant reduction in AHI. This implicates reversal of fluid shift from the lower limbs to the neck region, a key mechanism in the pathogenesis of SDB.","There are associations between sleep-disordered breathing (SDB), a potentially serious sleep disorder in which breathing repeatedly stops and starts, and atrial fibrillation (AF), an irregular and often very rapid heart rhythm that can lead to blood clots in the heart. This study investigates the impact of AF interventions and treatments on 6-month home sleep testing data. Sixty-seven patients with persistent (lasting longer than 7 days) atrial fibrillation were randomly put in 3 different treatment groups: 1) cardioversion (a procedure used to return an irregular or very fast heartbeat to a normal rhythm), 2) permanent pacemaker (a small device that is inserted under the skin of the chest to help the heart beat normally) with atrioventricular node ablation (heat energy to destroy a small amount of tissue between the upper and lower chambers of your heart) with cardioversion, or 3) AF ablation (using small burns or freezes to cause some scarring on the inside of the heart to help break up the electrical signals that cause irregular heartbeats). Home sleep tests were recorded at the start of the study and at 6 months. Other devices were used to monitor heart rhythm throughout the study period. The occurrence of moderate-to-severe SBD, that measured over 15 for apnoea-hypopnoea index (AHI), the number of breathing pauses or disruptions per hour while asleep, was found in more than half (60%) of patients. At six months there was no change in AHI, sleepiness during the day, sleep time, rapid eye movement (REM) sleep, and other tests that measure sleep and breathing patterns. At 6 months, 25 patients (15 from the AF ablation group) had a steady sinus rhythm, the pattern of your heartbeat based on the sinus node of your heart which sends out electrical pulses. AHI fell from 29.8 � 26.6/h to 22.2 � 20.4/h. In conclusion, sleep-disordered breathing is very common in patients with persistent atrial fibrillation. Restoration of sinus rhythm, and the associated long-term recovery of normal heart function, is associated with a large reduction in AHI. This finding suggests that reversing fluid from the lower limbs to the neck area is a key process in the development of sleep-disordered breathing." +"Background: Sleep-disordered breathing (SDB) and atrial fibrillation (AF) are associated. This study investigated the impact of AF intervention on 6-month home sleep testing data. Methods: Sixty-seven patients (aged 66 to 86, 53% male) with persistent AF were randomized (1:1:1) to direct current cardioversion (DCCV) (22 patients), permanent pacemaker (PPM) + atrioventricular node ablation (AVNA) + DCCV (22 patients) or AF ablation (23 patients). Baseline and 6-month multichannel home sleep tests with the Watch-PAT200 (Itamar Medical Lts., Caesarea, Israel) were recorded. Implantable cardiac monitors (ICMs) (Medtronic Reveal XT, Minneapolis, Minnesota) in the DCCV and AF ablation groups, and PPM Holters in the 'pace and ablate' group were utilized to assess cardiac rhythm beat-to-beat throughout the study period. Results: The prevalence of moderate-to-severe SDB [apnoea-hypopnoea index (AHI) ? 15/h] was 60%. At 6 months there was no change in AHI, Epworth sleepiness scale, sleep time, % REM sleep, respiratory desaturation index or central apnoeic events. Twenty-five patients (15 AF ablation, 9 DCCV and 1 following DCCV post-AVNA) maintained SR at 6 months confirmed on ICMs in these patients. AHI fell from 29.8 � 26.6/h to 22.2 � 20.4/h; P = 0.049. Conclusions: SDB is highly prevalent in patients with persistent AF. Restoration of sinus rhythm, and the associated long-term recovery of haemodynamics, is associated with a significant reduction in AHI. This implicates reversal of fluid shift from the lower limbs to the neck region, a key mechanism in the pathogenesis of SDB.","Sleep-disordered breathing and irregular heart beats are linked. This study examines irregular heart beat treatment on 6-month home sleep testing data. Sixty-seven patients (aged 66 to 86, 53% male) with long-lasting atrial fibrillation (irregular or rapid heart beat) were randomly grouped (1:1:1) to three standard treatments for atrial fibrillation. The presence of moderate-to-severe sleep-disordered breathing [number of breathing interruptions during sleep ? 15/h] was 60%. At 6 months, there was no change in sleep-disordered breathing measurements. Twenty-five patients (with standard treatments for irregular heart beat) maintained sinus rhythm for 6 months confirmed on implanted heart beat monitors in these patients. Number of breathing interruptions during sleep fell from 29.8 � 26.6/h to 22.2 � 20.4/h. Sleep-disordered breathing is very present in patients with lasting irregular heart beats. Recovery of sinus rhythm, and the linked long-term recovery of blood flow, is linked with a noticeable reduction in the number of breathing interruptions during sleep. These fewer breathing interruptions during sleep imply reversal of fluid shift from the lower limbs to the neck region, which is key for causing sleep-disordered breathing." +"Obstructive sleep apnea syndrome (OSA) is associated with different types of cardiac arrhythmias. The original studies, concentrated mostly on nocturnal brady- and tachyarrhythmias. More recent studies documented high prevalence of atrial fibrillation (AF) and its association with obesity and other risk factors for AF. In addition, continuous positive airway pressure (CPAP) prevents recurrence of AF after cardioversion. In, OSA the highest risk for sudden death is at night in comparison to general population most of who die suddenly between six and noon. This observation suggests that hypoxia or other nocturnal abnormality, trigger sudden death. An important recent finding is the beneficial effect of CPAP on sudden death. The role of pacing in OSA remains controversial. In general, pacemaker therapy is not indicated in patients with nocturnal bradyarrhythmias. However, some authors recommend pacing in those with severe nocturnal bradyarrhythmias not tolerating or not responding to CPAP. According to a recent study, 59% of patients with permanent pacemaker have OSA.","Obstructive sleep apnea syndrome (OSA) occurs as muscles in the throat relax and the airway narrows or closes, and breathing is momentarily cut off. OSA is associated with different types of cardiac arrhythmias (irregular heartbeat occuring when electrical impulses in the heart do not work properly). Past studies mostly focus on nighttime heartbeats that are too slow (bradyarrhythmias) or too fast (tachyarrhythmias). Recent studies document very common occurrences of atrial fibrillation (an irregular and often very rapid heart rhythm that can lead to blood clots in the heart) and their association with obesity and other risk factors for atrial fibrillation. In addition, continuous positive airway pressure (CPAP), a device to help people with OSA breathe more easily while sleeping, prevent atrial fibrillation from returning after cardioversion (a procedure used to return an irregular or very fast heartbeat to a normal rhythm). For people with obstructive sleep apnea syndrome, the highest risk for sudden death is at night. This observation suggests that hypoxia (not enough oxygen in the tissues for the body to function properly) or other nighttime abnormalities trigger sudden death. An important recent finding is the beneficial impact of CPAP on sudden death. The role of pacing (controlling the heartbeat) in patients with OSA remains controversial. In general, using a pacemaker (a small device that's placed or implanted in the chest to help control the heartbeat) is not recommended in patients with nighttime heart rate that is too slow (bradyarrhythmias). However, some researchers recommend pacing in people with severe nighttime bradyarrhythmias who are not able to use or are not responding to CPAP. According to a recent study, 59% of patients with a permanent pacemaker have obstructive sleep apnea syndrome (OSA)." +"Background: Paroxysmal atrial fibrillation (AF) can be caused by gain-of-function mutations in genes, encoding the cardiac potassium channel subunits KCNJ2, KCNE1, and KCNH2 that mediate the repolarizing potassium currents Ik1, Iks, and Ikr, respectively. Methods: Linkage analysis, whole-exome sequencing, and Xenopus oocyte electrophysiology studies were used in this study. Results: Through genetic studies, we showed that autosomal dominant early-onset nocturnal paroxysmal AF is caused by p.S447R mutation in KCND2, encoding the pore-forming (?) subunit of the Kv4.2 cardiac potassium channel. Kv4.2, along with Kv4.3, contributes to the cardiac fast transient outward K+ current, Ito. Ito underlies the early phase of repolarization in the cardiac action potential, thereby setting the initial potential of the plateau phase and governing its duration and amplitude. In Xenopus oocytes, the mutation increased the channel's inactivation time constant and affected its regulation: p.S447 resides in a protein kinase C (PKC) phosphorylation site, which normally allows attenuation of Kv4.2 membrane expression. The mutant Kv4.2 exhibited impaired response to PKC; hence, Kv4.2 membrane expression was augmented, enhancing potassium currents. Coexpression of mutant and wild-type channels (recapitulating heterozygosity in affected individuals) showed results similar to the mutant channel alone. Finally, in a hybrid channel composed of Kv4.3 and Kv4.2, simulating the mature endogenous heterotetrameric channel underlying Ito, the p.S447R Kv4.2 mutation exerted a gain-of-function effect on Kv4.3. Conclusions: The mutation alters Kv4.2's kinetic properties, impairs its inhibitory regulation, and exerts gain-of-function effect on both Kv4.2 homotetramers and Kv4.2-Kv4.3 heterotetramers. These effects presumably increase the repolarizing potassium current Ito, thereby abbreviating action potential duration, creating arrhythmogenic substrate for nocturnal AF. Interestingly, Kv4.2 expression was previously shown to demonstrate circadian variation, with peak expression at daytime in murine hearts (human nighttime), with possible relevance to the nocturnal onset of paroxysmal AF symptoms in our patients. The atrial-specific phenotype suggests that targeting Kv4.2 might be effective in the treatment of nocturnal paroxysmal AF, avoiding adverse ventricular effects.","Paroxysmal atrial fibrillation (AF) (an irregular heart rate that returns to normal within 7 days on its own or with treatment) can be caused by mutations in genes. Genetic linkage analysis to trace diseases in families using genes, whole-exome sequencing to find a genetic cause of a disease, and models to study biological processes of cells were used in this study. Through these genetic studies, researchers show that one genetic trait or mutation that is passed down from parent to child causing nighttime paroxysmal atrial fibrillation is caused by a mutation in the KCND2 gene. Kv4.2 and Kv4.3 are potassium channels that release potassium from cells and contribute to the heart-related, temporary, fast, outward potassium (K+) current, Ito. Ito is the base of the early phase of repolarization (when the outward current of ions exceeds the inward current) in the cardiac action potental (where unique properties necessary for function of the electrical conduction system of the heart occur), and creates the initial potential of the plateau phase (the time that allows for longer muscle contraction and allows the heart to contract in a steady, uniform, and forceful manner). In studies that modeled the cell's biology, the mutation increased the potassium channel's inactivation time (the time when the channel no longer allows potassium to be passed through it) and affected its regulation. The mutant Kv4.2 showed an impaired response to protein kinase C (PKC), a protein that regulates cells growth and plays a major role in sending signals to the heart. The gene mutation alters Kv4.2's transfer properties, impairs its regulation process, and exerts gain-of-function effect (changes the activity or function of a protein) in both Kv4.2 and Kv4.2-Kv4.3 potassium channels. These effects possibly increase the repolarizing potassium current Ito, creating arrhythmogenic substrates (factors that can produce or lead to arrhythmia) for nocturnal atrial fibrillation (an irregular and often very rapid heart rhythm occuring at night that can lead to blood clots in the heart). Kv4.2 expression has previously been shown to demonstrate circadian variation (the natural, internal process that regulates the sleep�wake cycle and repeats roughly every 24 hours), with peak expression at daytime, with possible relevance to the nighttime onset of symptoms of paroxysmal atrial fibrillation (an irregular heart rate that returns to normal within 7 days on its own or with treatment) in patients. Targeting Kv4.2 might be effective in the treatment of nocturnal paroxysmal atrial fibrillation." +"In the treatment of arrhythmia, beta-blockers are mainly used to regulate the heart rate. However, beta-blockers are also known as drugs with an antiarrhythmic effect due to the suppression of sympathetic activity. We evaluated the antiarrhythmic effects of a highly selective beta(1)-blocker, bisoprolol, in patients with diurnal paroxysmal atrial fibrillation (P-AF). A total of 136 patients with symptomatic diurnal P-AF were enrolled. Patients were divided into a diurnal-specific P-AF group and a diurnal & nocturnal P-AF group, as well as into a bisoprolol single use group and a combined use group with an antiarrhythmic drug. The effects of bisoprolol were evaluated in 3 categories: subjective symptom improvement, quality of life (QOL) improvement, and elimination of P-AF episode in Holter electrocardiograms (ECGs). For patients with effective treatment, a long-term effect up to 24 months was evaluated. Five patients (3.7%) discontinued bisoprolol due to side effects. Following administration of bisoprolol, 109 patients (80%) experienced subjective symptom improvement, 103 patients (76%) experienced QOL improvement, and elimination of P-AF episodes in ECGs was observed in 84 patients (62%). The elimination rate of P-AF episodes in ECGs was higher in the diurnal P-AF group than in the diurnal & nocturnal P-AF group (P=0.042). There was no significant difference between the bisoprolol single use group and the combined use group. A long-term suppressive effect by bisoprolol was observed in 70 of 83 patients (84%). The results demonstrate that bisoprolol has an antiarrhythmic effect against sympathetic diurnal P-AF, improving subjective symptoms and QOL and eliminating P-AF episodes in ECGs.","In the treatment of arrhythmia (an irregular heartbeat), beta-blockers (medications that reduce blood pressure) are mainly used to regulate the heart rate. However, beta-blockers are also known as drugs with an antiarrhythmic effect (drugs that slow down the electrical impulses of the heart) due to the suppression of sympathetic activity (the part of the nervous system that increases heart rate, blood pressure, and other heart functions). Researchers evaluated how electrical impulses of the heart are slowed down when using a beta-blocker called bisoprolol in patients with diurnal (during the day) paroxysmal atrial fibrillation (an irregular heart rate that returns to normal within 7 days on its own or with treatment). A total of 136 patients with symptomatic daytime paroxysmal atrial fibrillation (P-AF) were included in the study. Patients were divided into a daytime P-AF or a daytime and nighttime P-AF group, as well as into a group that only uses bisoproplol and a group that uses a combination of heart treatment drugs. The effects of bisoprolol are evaluated in 3 categories: symptom improvement, quality of life improvement, and elimination of paroxysmal atrial fibrillation (P-AF) events, which are measured using a portable device called Holter electrocardiograms (ECGs) to record heart rhythms. For patients with effective treatment, a long-term effect up to 24 months was evaluated. Five patients stopped using bisoprolol due to side effects. Following use of bisoprolol, 80% experienced symptom improvement, 76% experienced quality of life improvement, and elimination of P-AF episodes in ECGs was observed in 62%. The elimination rate of paroxysmal atrial fibrillation episodes in ECGs was higher in the daytime group than in the daytime and nighttime group. There was no significant difference between the group that only used bisoprolol and the combined use group. A long-term effect of reducing P-AF using bisoprolol was found in 84% of patients. This study shows that bisoprolol can slow down the electrical impulses of the heart in daytime paroxysmal atrial fibrillation, improve symptoms and quality of life, and eliminate paroxysmal atrial fibrillation episodes in ECGs." +"In the treatment of arrhythmia, beta-blockers are mainly used to regulate the heart rate. However, beta-blockers are also known as drugs with an antiarrhythmic effect due to the suppression of sympathetic activity. We evaluated the antiarrhythmic effects of a highly selective beta(1)-blocker, bisoprolol, in patients with diurnal paroxysmal atrial fibrillation (P-AF). A total of 136 patients with symptomatic diurnal P-AF were enrolled. Patients were divided into a diurnal-specific P-AF group and a diurnal & nocturnal P-AF group, as well as into a bisoprolol single use group and a combined use group with an antiarrhythmic drug. The effects of bisoprolol were evaluated in 3 categories: subjective symptom improvement, quality of life (QOL) improvement, and elimination of P-AF episode in Holter electrocardiograms (ECGs). For patients with effective treatment, a long-term effect up to 24 months was evaluated. Five patients (3.7%) discontinued bisoprolol due to side effects. Following administration of bisoprolol, 109 patients (80%) experienced subjective symptom improvement, 103 patients (76%) experienced QOL improvement, and elimination of P-AF episodes in ECGs was observed in 84 patients (62%). The elimination rate of P-AF episodes in ECGs was higher in the diurnal P-AF group than in the diurnal & nocturnal P-AF group (P=0.042). There was no significant difference between the bisoprolol single use group and the combined use group. A long-term suppressive effect by bisoprolol was observed in 70 of 83 patients (84%). The results demonstrate that bisoprolol has an antiarrhythmic effect against sympathetic diurnal P-AF, improving subjective symptoms and QOL and eliminating P-AF episodes in ECGs.","To treat irregular heart beats, beta-blockers (drugs that reduce blood pressure) are used to regulate heart rate. However, beta-blockers also prevent irregular heart beats due to the reduction of nerve-related, stimulating activity. We measured the irregular-heart-beat-preventing effects of a highly specific drug that reduces blood pressure, bisoprolol, in patients with daily paroxysmal atrial fibrillation (P-AF), which involves sudden occurences of an irregular or rapid heart beat. 136 patients with typical daily P-AF were employed. Patients were divided into a group with daily-specific P-AF and a daily and nightly P-AF group. Patients were also divided into a group with single use of bisoprlol and a combined use group with an drug that prevents an irregular heart beat. For patients with treatment, a long-term effect up to 24 months was measured. Five patients (3.7%) stopped bisoprolol due to side effects. After using a drug that reduces blood pressure, 109 patients (80%) had personal improvement, and 103 pateints (76%) had quality-of-life improvement. Elimination of sudden occurences of an irregular heart beat was measured in 84 patients (62%). The elimination rate of episodes of P-AF was higher in the daily P-AF group than in the daily and nightly P-AF group. There was no difference between the group with single use of bisoprolol and the combined use group. The long-term effect of bisoprolol was seen in 70 of 83 patients (84%). Bisoprolol helps prevent an irregular heart beat against nerve-related, sudden episodes of an irregular heart beat, improving personal symptoms and eliminating episodes." +"180 cases of head trauma were classified according to the degree of impairment of consciousness, clinical and neurological symptoms and EEG patterns. Based on the radiological and clinical findings and blood gas analyses a study was made of the incidence and extent of aspiration of blood, vomit or debris into the tracheo-bronchial tree and of the resultant pulmonary complications. As loss of consciousness became more complete the incidence of aspiration and the amount of material inhaled increased. Clinically and radiologically proven aspiration occurred in 60 per cent of cases of severe head trauma. A comparison of two groups after they had been given first aid and artificial respiration showed that the paO2 values were significantly lower in patients with radiologically proven aspiration and infiltration of the lungs than they were in those with normal chest radiograms. These observations point to the relationship between the quantity of material inhaled and the extent of intra-pulmonary shunting. There was no difference in the incidence of aspiration between persons who had been intubated and those who had not been intubated prior to admission to hospital. Although in many cases of head trauma aspiration of blood immediately after the accident can not be prevented prompt intubation is the only measure that will mitigate the consequences of aspiration and prevent its recurrence. As the latter is a very real risk in the unconscious person intubation in these cases is a ""must"". The study also showed that aspiration of foreign material into the tracheobronchial system and the resultant pulmonary complications can be successfully treated even if the head trauma is very severe. In none of the cases studied was death attributable to these causes. Apart from intubation and bronchial toilet artificial respiration with oxygen-enriched gas mixtures has a decisive influence on the course of the aspiration-induced pulmonary complications.","We divided 180 cases of head injury based on the level of loss of wakefulness and awareness, medical and brain-related symptoms observed by a doctor, and a common brain function test. Based on x-rays, symptoms observed by a doctor, and blood gas tests, we studied how often and how much blood, vomit or debris entered the airways and the lung complications that occurred as a result. As consciousness went away, how often material entered the airways and the amount of material breathed in increased. Material entering the airways happened in 60 percent of cases of severe head injury based on symptoms observed by a doctor and x-rays. A comparison of two groups after they received first aid and artificial aid to breathe showed that the levels of oxygen dissolved in the blood were much lower in patients with x-rays that showed material entered the airways and the lungs than those with normal chest x-rays. These findings suggest a relationship between the amount of material breathed in and how much blood put out by the heart lacks enough oxygen. Persons who had a breathing tube and those who did not before admission to the hospital did not differ in how often material entered the airways. Although often in head injuries blood entering the airways after the accident cannot be prevented quickly, putting in a breathing tube is the only thing that will lessen the consequences of material entering the airways and prevent it from happening again. As the second result is a very real risk in the unconscious person, putting in a breathing tube in these cases is a ""must"". The study also showed that material from outside the body entering the airways and the lung complications that occurred as a result can be successfully treated even if the head injury is very severe. In the cases we looked at, death did not result from any of these causes. Aside from putting in a breathing tube and clearing mucus and secretions from the airways, substituting a person's breathing with gas mixtures with high levels of oxygen plays a big role in lung complications from material entering the airways." +"180 cases of head trauma were classified according to the degree of impairment of consciousness, clinical and neurological symptoms and EEG patterns. Based on the radiological and clinical findings and blood gas analyses a study was made of the incidence and extent of aspiration of blood, vomit or debris into the tracheo-bronchial tree and of the resultant pulmonary complications. As loss of consciousness became more complete the incidence of aspiration and the amount of material inhaled increased. Clinically and radiologically proven aspiration occurred in 60 per cent of cases of severe head trauma. A comparison of two groups after they had been given first aid and artificial respiration showed that the paO2 values were significantly lower in patients with radiologically proven aspiration and infiltration of the lungs than they were in those with normal chest radiograms. These observations point to the relationship between the quantity of material inhaled and the extent of intra-pulmonary shunting. There was no difference in the incidence of aspiration between persons who had been intubated and those who had not been intubated prior to admission to hospital. Although in many cases of head trauma aspiration of blood immediately after the accident can not be prevented prompt intubation is the only measure that will mitigate the consequences of aspiration and prevent its recurrence. As the latter is a very real risk in the unconscious person intubation in these cases is a ""must"". The study also showed that aspiration of foreign material into the tracheobronchial system and the resultant pulmonary complications can be successfully treated even if the head trauma is very severe. In none of the cases studied was death attributable to these causes. Apart from intubation and bronchial toilet artificial respiration with oxygen-enriched gas mixtures has a decisive influence on the course of the aspiration-induced pulmonary complications.","180 cases of head trauma were classified by severity of damage to consciousness, medical and brain-related effects, and brain activity measurements. Based on x-rays, medical findings, and blood analyses, the frequency and extent of breathing in blood, vomit, or debris into the lungs and of its effects were measured. As consciousness decreased, the frequency and extent of breathing in material increased. Medically and x-ray proven breathing in of fluid occured in 60% of reports of severe head trauma. Comparing two groups after both received first aid and artificial breathing showed that oxygen was lower in patients with x-ray proven breathing in of fluids in the lungs than unaffected patients. A relationship exists between the amount inhaled and extent of fluid moved into the lungs. There was no change in the frequency of breathing in fluids between patients with breathing tubes and those without before arriving to the hospital. In many cases, while breathing in of blood cannot be stopped after head trauma, prompt use of breathing tubes is the only way to lessen the effects of breathing in fluids and prevent its return. Breathing in fluids again is a serious risk. For unconscious patients, breathing tubes are a ""must"". The study showed that breathing in foreign material into the lungs and the resulting effects can be treated even with severe head trauma. In no cases studied was death owing to these causes. Besides adding tubes and removing lung waste, artificial breathing in of oxygen-enriched gases greatly influence breathing-related effects." +"The patient who presents with a serious head injury is often very difficult to manage. The airways is of primary concern; adequate ventilation must be provided and aspiration protected against. Recent studies suggest that hyperventilation may be as beneficial as was earlier believed. As the pCO2 level decreases, vasoconstriction occurs. If the level falls too low, cerebral perfusion is restricted, and profound cerebral anoxia may ensue. Current standards call for a ventilatory rate to allow for moderate respiratory alkalosis, in theory to mildly constrict teh vessels but still provide adequate perfusion. Arterial blood gas analysis in the ED is the definitive measurement of airway management in the field. Remember that the anatomy of the meningeal layers places the arteries primarily in the epidural space and the veins in the subdural space. A bleed in the epidural space often presents with a rapid onset of signs and symptoms, as was obvious in this traumatized patient. When a bleed occurs in the subdural space, the onset is usually more insidious, and an accurate history is a key to field diagnosis. As the hemorrhage expands, compression displaces the brain within the cranial vault. This displacement causes pressure to be exerted on the medulla of the brainstem. Cushing's Traid is a result of this pressure on the medulla and is evidence by the pulse slowing while systolic blood pressure rises and respirations become ataxic. Vomiting is often associated, and as the bleed continues, herniation syndrome begins. Decorticate posturing is displayed, followed by decerebrate posturing if relief is not provided. It is important to distinguish between decorticate and decerebrate posturing. It is important to distinguish between decorticate and decerebrate posturing. An easy way to remember the differences is to picture the anatomy of the brain. The cerebral cortex lies above the cerebellum, so when a patient's arms flexed up toward the face , he is pointing to his ""core"" (de-cor-ticate). As the arms extend downward, he is pointing to his cerebellum(de-cere-brate). T o manage the head-injured patient, it is imperative to anticipate potential developments, as well as protect against underlying injuries that may not be fully evaluated until arrival at the ED. Cervical spine often accompany head injuries, and full spinal immobilization is a mandatory precaution in all presentations. With the expanding hematoma found on this patient's neck, vascular damage ws obvious and contributed to the suspicion of spinal injury. As the intracranial pressure rise, vomiting and seizures are common. Placement of an endotracheal tube and having suction equipment ready are the best tools to prevent against aspiration. It is possible to angle the long spine board 10-15 degrees, exercising caution to ensure the patient's spinal alignment is not manipulated during the process. Seizures are usually treated with anticonvulsants like Valium. When a seizure accompanies a head injury, it is a direct result of the increased intracranial pressure and has a generally poor response to Valium, as the underlying cause of the seizure still exists. In this case, the patient had a full neuromuscular blockade, and any seizure would not have been recognized as long as the paralytics were on board. Early notification to the ED is essential, reporting all findings and interventions. This can alert them and give them the opportunity to prepare specialized equipment, such as CT scanners, mechanical ventilators, etc. Also, consider transportation options and the length of time to definitive care, including neurosurgical evaluation. This patient needs to be seen in a trauma center capable of the most thorough evaluation and management. Evacuation by air ambulance may be the most appropriate method of transport.","A person with a serious head injury is often very difficult to treat. The airways are the most important concern; enough air movement must be provided, and material entering the airway or lungs by accident must be avoided. Recent studies suggest that quick breathing or hyperventilation may be as helpful as was thought before. As the amount of carbon dioxide gas dissolved in the blood decreases, blood vessels narrow. If the amount of carbon dioxide gas dissolved in the blood gets too low, blood flow to the brain is limited, and not enough oxygen getting to the brain may follow. Current standards suggest a rate of movement of air into and out of the lungs to allow for a decrease in carbon dioxide gas dissolved in the blood, in theory to narrow the vessels but still allow enough circulation of blood through organs and tissues. Measuring oxygen and carbon dioxide levels in the blood in the emergency department is the best measurement of airway treatment by first responders. Remember that the structure of the brain's protective layers puts the arteries in the space between the outermost layer and the skull (epidural) and the veins in the space between the outermost layer and the brain (subdural). A bleed in the epidural space often has quick signs and symptoms, as was obvious in this injured patient. A bleed in the subdural space usually happens more slowly, and knowing what happened to the person is key to a diagnosis by first responders. As the bleeding spreads, pressure pushing on the brain moves the brain within the skull. This movement of the brain puts pressure on the area of the brain that controls things like heartbeat and breathing (medulla). Pressure on the medulla causes Cushing's Triad, which is a slowing heartbeat while blood pressure increases and breathing becomes abnormal. Vomiting often occurs, and as the bleed continues, something inside the skull produces pressure that moves brain tissues. A person gets stiff with bent arms, clenched fists, and legs held out straight (decorticate posturing), followed by the arms and legs being held straight out, the toes being pointed downward, and the head and neck being arched backward (decerebrate posturing) if relief is not given. It is important to recognize the difference between decorticate and decerebrate posturing. It is important to recognize the differences between decorticate and decerebrate posturing. An easy way to remember the differences is to picture the structure of the brain. One part of the brain, the cerebral cortex, lies above another part of the brain, the cerebellum, so when a patient's arms point toward the face, he is pointing to his ""core"" (de-cor-ticate). As the arms go down to his side, he is pointing to his cerebellum (de-cere-brate). To treat the patient with a head injury, it is important to predict what might happen, and protect against other injuries that may not be realized until the patient gets to the hospital. Neck injuries often happen with head injuries, and making sure the spine cannot move is required in all cases. With the growing bruise on this patient's neck, damage to blood vessels was clear and helped lead to the belief of a spinal injury. As the pressure in the brain rises, vomiting and seizures are common. Putting in a breathing tube and having suction tools ready are the best ways to prevent material entering the airway or lungs by accident. It is possible to angle the rescue board 10-15 degrees, making sure to not change the alignment of the patient's spine. Seizures are usually treated with drugs that prevent convulsions, like Valium. When a seizure happens with a head injury, it is caused by rising pressure in the brain, and Valium does not usually help, as the cause for the seizure is not resolved. In this case, the patient had a full nerve block (paralyzed skeletal muscles). Any seizure would not have been seen while the paralyzing drugs were working. Notifying the emergency department is very important, reporting everything the first responders see and do to treat the patient. This can warn emergency staff and give them the chance to get specialized equipment ready (e.g., CT scanners, mechanical ventilators). Also, think about how to get the patient to the hospital and how much time it will take to best care for the patient, including seeing a brain surgeon. This patient needs to be seen in a trauma center able to do the most complete evaluation and treatment. A medical helicopter may be the best way to get the patient to the hospital." +"The airway obstruction concerns any situation that clogs partially or totally the normal pulmonary ventilation. In this way, it is an absolute emergency which in case of not being solved leads to death in afew minutes. One of the most common airway obstructions is the one that results from an extrinsic cause to the airway--food, blood or vomit. Any solid object can work as a foreign body and cause an airway obstruction--mechanical obstruction. Evaluation and control of the airway are carried out through quick and simple procedures. Initially there is no need for any equipment, being just enough the application of manual techniques for control and disobliteration. Interscapular claps, the Heimlich Manoeuvre and the Thoracic Compressions, are manual techniques used in the disobliteration of the respiratory tract due to a solid body.","The airway blockage has to do with any situation that partially or totally clogs normal breathing. In this way, it is an emergency that if not solved leads to death in a few minutes. One of the most common airway blockages is the one due to an outside cause--food, blood or vomit. Any solid object can be an object that shouldn't be swallowed and block an airway--mechanical obstruction. Assessing and managing the airway are done through quick and simple procedures. At the beginning, there is no need for any equipment, with techniques by hand being enough for managing the airway and removing the blockage. Backslaps, the Heimlich Maneuver and the Thoracic Compressions are techniques done using the hands to remove a solid blockage from the airways." +"The tongue is the most common cause of upper airway obstruction, a situation seen most often in patients who are comatose or who have suffered cardiopulmonary arrest. Other common causes of upper airway obstruction include edema of the oropharynx and larynx, trauma, foreign body, and infection. The management of the patient with upper airway obstruction depends upon the cause of the obstruction, the training and skills of the rescuer, and the availability of adjuncts necessary to perform advanced airway techniques. In most cases, merely positioning the patient or performing one of the three maneuvers designed to elevate the tongue will open the airway of the comatose patient or the victim of cardiac arrest. In patients with suspected foreign body obstruction, abdominal or chest compression should be performed immediately, with digital extraction of the foreign body reserved for those in whom these maneuvers are unsuccessful. Most patients with obstruction secondary to edema, trauma, or infection can be managed initially with orotracheal or nasotracheal intubation. Intubation should be attempted prior to surgical management of the airway in most cases of upper airway obstruction. Occasionally, however, cricothyroidotomy or tracheostomy is necessary to establish an airway. The choice of technique depends primarily on the experience and skills of the rescuing physician or paramedic. In most cases, cricothyroidotomy is technically more simple and more easily performed than tracheotomy, especially for the physician who has not been trained in surgery or otolaryngology and for the nonphysician rescuer. No matter what the method employed in establishing an airway in a patient with upper airway obstruction, it must be performed quickly and a source of ventilation provided for the patient once the airway has been secured.","The tongue is the most common cause of blocked upper airways, seen most often in people in comas or cardiac arrest (abrupt heart stop). Other common causes of blocked upper airways include swelling of the middle part of the throat and voice box, injury, objects that shouldn�t be swallowed, and infection. Treatment of the patient with blocked upper airways depends on the cause of the blockage, the training and skills of the rescuer, and the availability of additional treatments needed for advanced airway methods. In most cases, simply positioning the patient or doing one of the three maneuvers to raise the tongue will open the airway of the patient in a coma or cardiac arrest. In people thought to have swallowed an object that should not be swallowed, stomach or chest compression should be done immediately, with removing the object with the fingers used only when these maneuvers do not work. Most people with blocked airways that occur due to swelling, injury, or infection can be treated first without breathing tubes through the mouth or nose. Breathing tubes should be used before surgery in most instances of blocked upper airways. Sometimes, however, surgery to cut a hole in the neck is needed to open the airway. The experience and skills of the rescuing doctor or paramedic mostly determines the approach. Usually, a surgery to cut a hole in the neck is simpler and easier to do than opening the windpipe, especially for a doctor who does not have surgery training or the rescuer who is not a doctor. Regardless of the method used to open the airway in a patient with blocked upper airways, it must be done quickly, and air must be supplied to the person once the airway is open." +"The tongue is the most common cause of upper airway obstruction, a situation seen most often in patients who are comatose or who have suffered cardiopulmonary arrest. Other common causes of upper airway obstruction include edema of the oropharynx and larynx, trauma, foreign body, and infection. The management of the patient with upper airway obstruction depends upon the cause of the obstruction, the training and skills of the rescuer, and the availability of adjuncts necessary to perform advanced airway techniques. In most cases, merely positioning the patient or performing one of the three maneuvers designed to elevate the tongue will open the airway of the comatose patient or the victim of cardiac arrest. In patients with suspected foreign body obstruction, abdominal or chest compression should be performed immediately, with digital extraction of the foreign body reserved for those in whom these maneuvers are unsuccessful. Most patients with obstruction secondary to edema, trauma, or infection can be managed initially with orotracheal or nasotracheal intubation. Intubation should be attempted prior to surgical management of the airway in most cases of upper airway obstruction. Occasionally, however, cricothyroidotomy or tracheostomy is necessary to establish an airway. The choice of technique depends primarily on the experience and skills of the rescuing physician or paramedic. In most cases, cricothyroidotomy is technically more simple and more easily performed than tracheotomy, especially for the physician who has not been trained in surgery or otolaryngology and for the nonphysician rescuer. No matter what the method employed in establishing an airway in a patient with upper airway obstruction, it must be performed quickly and a source of ventilation provided for the patient once the airway has been secured.","The tongue is the most common cause of airway blockage, especially in comatose patients or those suffering cardiac arrest. Other common causes of airway blockage include swelling from trapped fluid of the airway, trauma, something stuck in the airway, and infection. Treating patients with airway blockage depends on its cause, the training and skills of the rescuer, and available airway devices needed for complex procedures. Mostly, just arranging the patient or using one of three methods to elevate the tongue will open the airway of the comatose patient or person with cardiac arrest. In patients with something stuck in the airway, abdominal or chest squeezing should be done quickly, with removal by fingers when squeezing is unsuccessful. Most with blockage due to swelling from trapped fluid, trauma, or infection can be treated initially with breathing tubes. Breathing tubes should be used before surgery of the airway in most cases of airway blockage. Sometimes, however, airway surgery is needed to create an airway. The chosen procedure depends largely on the experience and skills of the rescuer. Mostly, surgery to add a tube to a specific airway location is simpler and easier than surgery to cut a hole in the windpipe, especially for rescuers and those not specialized or trained in surgery. Despite the method used to create an airway for those with airway blockage, it must be done quickly and fresh air provided for the patient afterward." +"Ensuring free passage of air is the first priority in emergency care of patients. Removing obstruction to softtissue, dislodging obstructing foreign bodies and positioning the patient correctly usually secure open airways and respiration in trauma patients. If respiration has ceased, oroendotracheal intubation is necessary and should be performed by trained personnel. Correct control of airways may reduce morbidity and mortality. The author discusses the practical aspects of control of airways and unobstructed respiration.","The most important thing in the emergency care of patients is making sure air passes freely. Removing blocked tissue, loosening objects that shouldn't be swallowed and putting the patient in the right position usually open airways and allow breathing in injured people. If breathing has stopped, a breathing tube is needed and should be given by a trained professional. Correct control of airways may decrease illness and death. The author discusses control of airways and normal breathing in real life situations." +"Definitive management of the unconscious choking victim, whether in hospital or in the field, should include removal of the foreign body by instrumentation under direct visualization. However, there is debate as to the best management of the conscious victim with an obstructed upper airway and of the unconscious victim for whom such definitive instrumentation is not available. Which artificial-cough maneuver is the most eficacious in clearing the obstructed airway? Which maneuver should be used first? What are the complications of the various techniques? Is any maneuver dangerous or deleterious? To date there is no consensus on any of these issues. There are significant discrepancies in the literature as to which technique produces the highest intrathoracic pressures and airflow rates. Most of the data seem to support the conclusion that blows to the back generate the highest intrathoracic pressure, whereas chest or abdominal thrust produces the highest airflow rate. Clinically, all the maneuvers are somewhat efficacious in clearing the obstructed airway when used alone; however, each maneuver seems to be substantially more efficacious when used in combination with another maneuver. Also, the results appear to be more successful when pressure is applied as a series of jolts rather than applied steadily.","The best treatment for an unconscious person choking, whether in the hospital or by first responders, should include removal of the object that should not be swallowed with a medical tool while clearly seeing the object. However, experts do not agree about the best way to treat a conscious person with partial or complete blockage of the airway and the unconscious person for whom medical tools are not available. Which way to force air out of a person's lungs works the best to clear the blocked airway? Which way should be used first? What are the complications of the different ways? Is any way dangerous or harmful? To date, there is no agreement on any of these issues. Studies disagree as to which way creates the highest pressure in the chest that forces air out of the lungs and highest airflow rates. Most studies support the idea that blows to the back make the highest pressure in the chest that forces air out of the lungs, while stomach thrusts make the highest airflow rate. All the ways work somewhat to clear the blocked airway on their own; however, each way seems to work much better when combined with another way. Also, pressure applied as a series of jolts seems to work better than steadily applied pressure." +"Background: Oral poisoning is a major cause of mortality and disability worldwide, with estimates of over 100,000 deaths due to unintentional poisoning each year and an overrepresentation of children below five years of age. Any effective intervention that laypeople can apply to limit or delay uptake or to evacuate, dilute or neutralize the poison before professional help arrives may limit toxicity and save lives. Objectives: To assess the effects of pre-hospital interventions (alone or in combination) for treating acute oral poisoning, available to and feasible for laypeople before the arrival of professional help. Authors' conclusions: The studies included in this review provided mostly low- or very low-certainty evidence about the use of first aid interventions for acute oral poisoning. A key limitation was the fact that only one included study actually took place in a pre-hospital setting, which undermines our confidence in the applicability of these results to this setting. Thus, the amount of evidence collected was insufficient to draw any conclusions.","Poisoning caused by swallowing a toxic substance is a big cause of death and disability worldwide, with over 100,000 deaths due to accidental poisoning each year largely from children younger than five years. Anything that bystanders can do to reduce or delay how much is swallowed or to make ineffective, make weaker, or remove the poison before professional help arrives may limit the harm and save lives. Our objectives were to measure the effects of pre-hospital treatments (alone or in combination) for treating poisoning caused by swallowing a toxic substance that are available to and doable for bystanders before professional help arrives. We concluded that the studies we looked at had mostly unreliable findings about the use of first aid treatments for poisoning caused by swallowing a toxic substance once or many times over a short period of time. An important limitation was that only one study happened in a pre-hospital setting, which does not make us confident that these results apply to this setting. Therefore, there were not enough results to draw any conclusions." +"Background: Oral poisoning is a major cause of mortality and disability worldwide, with estimates of over 100,000 deaths due to unintentional poisoning each year and an overrepresentation of children below five years of age. Any effective intervention that laypeople can apply to limit or delay uptake or to evacuate, dilute or neutralize the poison before professional help arrives may limit toxicity and save lives. Objectives: To assess the effects of pre-hospital interventions (alone or in combination) for treating acute oral poisoning, available to and feasible for laypeople before the arrival of professional help. Authors' conclusions: The studies included in this review provided mostly low- or very low-certainty evidence about the use of first aid interventions for acute oral poisoning. A key limitation was the fact that only one included study actually took place in a pre-hospital setting, which undermines our confidence in the applicability of these results to this setting. Thus, the amount of evidence collected was insufficient to draw any conclusions.","Oral poisoning is a major cause of death and disability worldwide, with over 100,000 deaths from unintended poisoning yearly and noticeably by chlidren younger than five years. Any useful treatment that anyone can use to prevent intake or control the poison before help arrives may limit the poisoning and save lives. The objective is to measure the effects of pre-hospital treatments (alone or in combination) for immediate oral poisoning, available to anyone before professional help arrives. The studies in this review provided mostly unreliable evidence about using first aid treatments for immediate oral poisoning. An key limitation is that only one study actually occured in a pre-hospital setting, which weakens our faith in the usefulness of these results to this setting. Thus, the evidence is not enough to make any conclusions." +"Introduction: In acute oral poisoning, any first aid intervention that limits or delays the uptake of the ingested substance, and which can be performed by bystanders as first responders, might assist in reducing morbidity if a toxic substance has been ingested. The current recommendation by the International Federation of Red Cross/Red Crescent Societies is to place a victim in the left lateral decubitus position. Conclusions: The identified studies provide evidence of very low certainty. However, based on the evidence that the left lateral decubitus position may be effective in decreasing the absorption of several drugs, the simplicity of the intervention and the generally low perceived risk of this intervention, the recommendation of the first aid guidelines of the International Federation of Red Cross and Red Crescent Societies can remain unchanged.","In poisoning caused by swallowing a toxic substance once or many times over a short period of time, any first aid assistance that reduces or delays how much is swallowed, and which ones bystanders can do, might help in reducing illness. The International Federation of Red Cross/Red Crescent Societies recommends a victim be placed on the person's left side. We conclude that the studies provide unreliable results. However, based on studies that show placing a person on the person's left side may decrease absorption of many drugs, and the ease and low risk of doing so, the recommendation of the International Federation of Red Cross and Red Crescent Societies stands." +"Study objectives: Many factors influence the rate of gastric emptying and therefore the rate of drug absorption in the orally poisoned patient. Limited studies have evaluated the effect of body position on the rate of gastric emptying of radiographically marked foods and contrast media, but effects on drug absorption have not been studied previously. Our hypothesis was that body position would have an effect on the rate of drug absorption in an oral overdose model. Design: A blinded, within-subjects (crossover) design. Participants: Six male and six female healthy, adult volunteer subjects with no concurrent drug use or medications affecting gastrointestinal function. Interventions: Five body positions commonly used in prehospital and emergency department settings were examined: left lateral decubitus, right lateral decubitus, supine, prone, and sitting. All were performed by all subjects in random order with a three-day washout phase between trials. To simulate an acute overdose, fasted subjects ingested 80 mg/kg acetaminophen in the form of 160-mg pediatric tablets. Each subject then remained in the body position for that trial for two hours. Acetaminophen levels were obtained at 15-minute intervals, and a two-hour area under the curve (AUC) was calculated for each subject trial to represent total drug absorption during each study period. Investigators were blinded to all results until all trials were completed. Measurements and main results: All subjects completed the study. Group mean drug absorption as represented by two-hour AUC (mg.L.min) was calculated for each body position. AUC for left lateral decubitus (6,006 +/- 2,614) was lowest but did not significantly differ from that for supine (6,649 +/- 2,761). Both were significantly less than those for prone (7,432 +/- 1,809), right lateral decubitus (8,950 +/- 1,405), and sitting (8,608 +/- 1,725) positions (P less than .05 by one-way analysis of variance and follow-up paired t tests). Conclusion: Initial drug absorption as determined by two-hour AUC was lowest in the left lateral decubitus position. Although the difference between the left lateral decubitus and supine positions did not reach statistical significance, both left lateral decubitus and supine were significantly lower than three other common patient body positions tested. Because the left lateral decubitus position has other advantages (eg, prevention of aspiration) in addition to minimizing drug absorption, we recommend that orally poisoned patients be placed in the left lateral decubitus position for prehospital and initial ED management.","Many things determine how fast the stomach empties and therefore how fast a drug is taken in by the body in a person who swallows a toxic substance. Few studies have rated the effect of body position on how fast the stomach empties via a technique to more easily see stomach contents with x-rays. However, effects on how fast a drug is absorbed have not been studied before. We thought that body position would have an effect on how fast a drug is absorbed in a person who swallows a toxic substance. Participants were six male and six female healthy, adult volunteers not taking any drugs or medicine affecting stomach function. We looked at five body positions often used before hospital and emergency room treatment: left side, right side, back, stomach, and sitting. Participants did every position in random order with a 3-day break between trials. To pretend that participants swallowed a toxic substance, participants did not eat prior to taking 80 mg of Tylenol/kg of body weight in the form of 160-mg children's tablets. Each participant then stayed in the body position for that trial for two hours. We measured Tylenol levels every 15 minutes. We calculated how much Tylenol participants absorbed over 2 hours for each trial. Investigators did not know the results until after the trials were done. All participants finished the study. We calculated average amount of drug absorbed for each body position. The average amount of drug absorbed was lowest for the left side, which was similar to the back position. Absorption for the left side and back were less than for stomach, right side, and sitting positions. We concluded that drug absorption was lowest for the left side position. Although the difference between the left side and back positions did not differ significantly, both the left side and back positions were significantly lower than the three other positions tested. Because the left side position is better for other reasons (e.g., material entering the airway or lungs by accident) than decreasing how much drug is absorbed, we suggest that people who swallow a toxic substance be put in the left side position before going to the hospital and emergency room." +"Abdominal thrusts or the Heimlich maneuver is a first-aid procedure used to treat upper airway obstruction caused by a foreign body. This skill is commonly taught during basic life support (BLS) and advanced cardiac life support (ACLS) classes, but it never receives as much attention as chest compressions and rescue breaths do. The abdominal thrust maneuver can be performed in both children and adults via different techniques. In the 1960s, choking on food, toys, and other objects was the sixth leading cause of accidental death in the United States. Slapping individuals on the back was the main response and was frequently found to be ineffective, at times even lodging the object further down. The Heimlich maneuver was initially introduced in 1974 by Dr. Henry Heimlich after proving his theory that the reserve of air in the lung could serve to dislodge objects from the esophagus by quick upwards thrust under the ribcage. The medical community of the time did not embrace the maneuver right away. The American Red Cross (ARC) and the American Heart Association (AHA) continued to promoted backslaps for ten years after the introduction of the Heimlich maneuver. Today, the Heimlich maneuver is accepted and taught during BLS and ACLS for conscious adults, but backslaps are still a recommendation for infants, and chest compressions are recommended for unconscious patients. Furthermore, different techniques of the maneuver have been developed with conflicting effectiveness results.","Stomach thrusts or the Heimlich maneuver is the first-aid procedure used to treat partial or complete blockage of the upper airway from an object that shouldn't be swallowed. This skill is commonly taught during basic life support and advanced heart life support classes, but it never gets as much attention as chest compressions and rescue breaths do. The stomach thrust maneuver can be done in both children and adults using different ways. In the 1960s, choking on food, toys, and other objects was the sixth leading cause of accidental death in the United States. Slapping a person on the back was the most common response and was often found to not work, sometimes even pushing the object further down. Dr. Henry Heimlich introduced the Heimlich maneuver in 1974 after proving his idea that stored air in the lung could push objects out of the throat by fast upward thrusts under the ribcage. The medical community then did not accept the maneuver right away. The American Red Cross (ARC) and the American Heart Association (AHA) pushed backslaps for 10 years after the Heimlich maneuver was introduced. Today, the Heimlich maneuver is accepted and taught during basic life support and advanced heart life support classes for conscious adults, but backslaps are still recommended for infants. Chest compressions are recommended for unconscious people. Furthermore, people have come up with different ways of doing the maneuver with mixed results." +"Abdominal thrusts or the Heimlich maneuver is a first-aid procedure used to treat upper airway obstruction caused by a foreign body. This skill is commonly taught during basic life support (BLS) and advanced cardiac life support (ACLS) classes, but it never receives as much attention as chest compressions and rescue breaths do. The abdominal thrust maneuver can be performed in both children and adults via different techniques. In the 1960s, choking on food, toys, and other objects was the sixth leading cause of accidental death in the United States. Slapping individuals on the back was the main response and was frequently found to be ineffective, at times even lodging the object further down. The Heimlich maneuver was initially introduced in 1974 by Dr. Henry Heimlich after proving his theory that the reserve of air in the lung could serve to dislodge objects from the esophagus by quick upwards thrust under the ribcage. The medical community of the time did not embrace the maneuver right away. The American Red Cross (ARC) and the American Heart Association (AHA) continued to promoted backslaps for ten years after the introduction of the Heimlich maneuver. Today, the Heimlich maneuver is accepted and taught during BLS and ACLS for conscious adults, but backslaps are still a recommendation for infants, and chest compressions are recommended for unconscious patients. Furthermore, different techniques of the maneuver have been developed with conflicting effectiveness results.","Abdominal thrusts or the Heimlich manuever is a first-aid procedure for airway blockage due to something being stuck in throat. Abdominal thrusts are usually taught during basic life support (BLS) and advanced cardiac, or heart-related, life support (ACLS) classes, but it never gets as much attention as chest squeezes and mouth-to-mouth rescue breaths do. Abdominal thrusts can be used on both children and adults via different ways. In the 1960s, choking on objects was the sixth leading cause of accidental death in the US. Slapping others on the back was the main treatment and found to not be useful, sometimes forcing the object further down. Abdominal thrusts were introduced in 1974 by Dr. Henry Heimlich after proving his theory that air in the lungs could remove objects in the airway by quick upward thrusts under the ribs. The medical groups of the time did not employ the technique right away. The American Red Cross (ARC) and the American Heart Association (AHA) still used backslaps for ten years after the introduction of abdominal thrusts. Today, abdominal thrusts are accepted and taught during basic and advanced cardiac, or heart-related, life support classes. Still, backslaps are approved for infants and chest compressions for unconscious patients. Also, different techniques of abdominal thrusts have been created with conflicting success." +"Background: As a highly contagious disease, coronavirus disease 2019 (COVID-19) is wreaking havoc around the world due to continuous spread among close contacts mainly via droplets, aerosols, contaminated hands or surfaces. Therefore, centralized isolation of close contacts and suspected patients is an important measure to prevent the transmission of COVID-19. At present, the quarantine duration in most countries is 14 d due to the fact that the incubation period of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is usually identified as 1-14 d with median estimate of 4-7.5 d. Since COVID-19 patients in the incubation period are also contagious, cases with an incubation period of more than 14 d need to be evaluated. Case summary: A 70-year-old male patient was admitted to the Department of Respiratory Medicine of The First Affiliated Hospital of Harbin Medical University on April 5 due to a cough with sputum and shortness of breath. On April 10, the patient was transferred to the Fever Clinic for further treatment due to close contact to one confirmed COVID-19 patient in the same room. During the period from April 10 to May 6, nucleic acid and antibodies to SARS-CoV-2 were tested 7 and 4 times, respectively, all of which were negative. On May 7, the patient developed fever with a maximum temperature of 39?, and his respiratory difficulties had deteriorated. The results of nucleic acid and antibody detection of SARS-CoV-2 were positive. On May 8, the nucleic acid and antibody detection of SARS-CoV-2 by Heilongjiang Provincial Center for Disease Control were also positive, and the patient was diagnosed with COVID-19 and reported to the Chinese Center for Disease Control and Prevention. Conclusion: This case highlights the importance of the SARS-CoV-2 incubation period. Further epidemiological investigations and clinical observations are urgently needed to identify the optimal incubation period of SARS-CoV-2 and formulate rational and evidence-based quarantine policies for COVID-19 accordingly.","Coronavirus disease 2019, also known as COVID-19, is a highly contagious, viral, breathing-related disease that has caused world-wide distress. Continual spread of COVID-19 occurs between people in close contact with one another through coughing, sneezing, breathing, talking, and touching dirty hands or surfaces. To prevent further spread of COVID-19, a period of quarantine (isolation) is recommended for those suspected of having COVID-19 and/or those who believe they have come in contact with a COVID-19-infected person. In most countries, the recommended quarantine duration is 14 days. This is because the incubation period, or the time between exposure and the first signs of illness, of respiratory or breathing-related illnesses is normally between 4 to 7.5 days. However, potential COVID-19 patients are still contagious during the incubation period. Cases with incubation periods longer than 14 days need further evaluation by doctors. For example, a 70-year-old man was admitted to the hospital on April 5th, reporting a cough, the spitting up of saliva and mucus, and shortness of breath. On April 10th, the man was transferred to the Fever Clinic within the hospital for additional treatment as he had experienced close contact with a confirmed COVID-19 patient. From April 10th to May 6th, the man was tested for COVID-19 several times. All tests returned negative, detecting no COVID-19. On May 7th, the man developed a severe fever, and his breathing issues become worse. The man was tested again for COVID-19 and was positive, detecting COVID-19. On May 8th, a second COVID-19 test was conducted by the Heilongjiang Provincial Center for Disease Control and was returned positive. The man was diagnosed with COVID-19, and his health status was recorded by the Chinese Center for Disease Control and Prevention. This example shows the importance of the COVID-19 incubation period. Additional research is needed to better define the incubation period of COVID-19 to create quarantine measures that best protect human health." +"Background: A novel human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in China in December 2019. There is limited support for many of its key epidemiologic features, including the incubation period for clinical disease (coronavirus disease 2019 [COVID-19]), which has important implications for surveillance and control activities. Objective: To estimate the length of the incubation period of COVID-19 and describe its public health implications. Design: Pooled analysis of confirmed COVID-19 cases reported between 4 January 2020 and 24 February 2020. Setting: News reports and press releases from 50 provinces, regions, and countries outside Wuhan, Hubei province, China. Participants: Persons with confirmed SARS-CoV-2 infection outside Hubei province, China. Measurements: Patient demographic characteristics and dates and times of possible exposure, symptom onset, fever onset, and hospitalization. Results: There were 181 confirmed cases with identifiable exposure and symptom onset windows to estimate the incubation period of COVID-19. The median incubation period was estimated to be 5.1 days (95% CI, 4.5 to 5.8 days), and 97.5% of those who develop symptoms will do so within 11.5 days (CI, 8.2 to 15.6 days) of infection. These estimates imply that, under conservative assumptions, 101 out of every 10 000 cases (99th percentile, 482) will develop symptoms after 14 days of active monitoring or quarantine. Limitation: Publicly reported cases may overrepresent severe cases, the incubation period for which may differ from that of mild cases. Conclusion: This work provides additional evidence for a median incubation period for COVID-19 of approximately 5 days, similar to SARS. Our results support current proposals for the length of quarantine or active monitoring of persons potentially exposed to SARS-CoV-2, although longer monitoring periods might be justified in extreme cases.","In December 2019, a new human coronavirus that affects the breathing or respiratory system, known as COVID-19, was identified in China. Little is known about how COVID-19 impacts human health, including how long the disease's incubation period (the time between initial exposure and the first signs of illness) lasts. Knowing the incubation period of the disease is important for preventing further spread. The goal of this paper was to estimate the length of the COVID-19 incubation period and how it impacts the public's health. To reach this goal, the authors reviewed confirmed COVID-19 cases that were reported between January 4th to February 24th in 2020. The information was gathered from news reports and press releases from over 50 locations outside of Wuhan city within the Hubei province of China. Only people with confirmed COVID-19 infection outside of the Hubei province of China were of interest for the evaluation. Patient characteristics (e.g. age, ethnicity) and specific health measurements (e.g. dates of exposure, start of symptoms) were reviewed. In total, 181 confirmed COVID-19 cases with definable exposure points and start of symptoms were evaluated for incubation period estimation. The average incubation period was estimated to be 5.1 days. Overall, the majority of people will develop symptoms within 11.5 days after time of infection. These estimates imply that a portion of the population (101 out of every 10,000 COVID-19 patients) will show symptoms after 14 days of quarantine. Because only cases from new outlets and press releases were evaluated, the estimations may be based on more severe COVID-19 cases. Mild cases, which may go unreported, may have a different incubation period. Even though the data for mild COVID-19 cases may differ, this estimate provides support for an average incubation period for COVID-19 of 5 days. This estimation may help in the creation of appropriate quarantine measures for persons potentially exposed to COVID-19." +"Recurrence of positive SARS CoV?2 PCR has been described in patients discharged from hospital after 2 consecutive negative PCR. We discuss possible explanations including false negative, reactivation and re?infection and propose different strategy to solve this issue. Prolonged SARS?CoV?2 RNA shedding and recurrence of viral RNA shedding in asymptomatic patients remain unknown. Transmission of SARS?CoV?2 by asymptomatic carriers had been documented. Considering the significance of this ongoing global public health emergency, it is necessary to carry out large studies to better understand the issue of potential SARS? CoV?2 recurrence in COVID?19 patients.","Patients previously discharged from hospitals with negative (or undetected) COVID-19 tests have been seen to later test positive (detecting COVID-19). This paper aims to explain possible reasons for these events. These reasons include false or incorrect negative test results, the virus transitioning from a sleeping to an active phase within the patient, or a patient being exposed and infected after leaving the hospital. The reasons why people with no COVID-19 related symptoms test positive for the virus are unknown. However, it is known that people with no COVID-19 related symptoms can still spread the virus to others. Due to the large scale impact the COVID-19 pandemic is having on the world, it is important to conduct research to better understand how previous COVID-19 patients can become ill with the virus more than once." +"Recurrence of positive SARS CoV?2 PCR has been described in patients discharged from hospital after 2 consecutive negative PCR. We discuss possible explanations including false negative, reactivation and re?infection and propose different strategy to solve this issue. Prolonged SARS?CoV?2 RNA shedding and recurrence of viral RNA shedding in asymptomatic patients remain unknown. Transmission of SARS?CoV?2 by asymptomatic carriers had been documented. Considering the significance of this ongoing global public health emergency, it is necessary to carry out large studies to better understand the issue of potential SARS? CoV?2 recurrence in COVID?19 patients.","Patients released from a hospital after 2 consecutive test results detecting no SARS-CoV-2 (a viral breathing-related illness) have shown reappearance of SARS CoV-2 in test results. We discuss possible explanations including inaccurate results, reactivation, and re-infection. We also propose a new strategy to solve the issue. Prolonged and recurring virus release and emission from patients without symptoms is unknown. Transmission of SARS-CoV-2 by carriers without symptoms had been documented. Considering this ongoing global public health emergency, large studies are needed to better understand the issue of possible SARS-CoV-2 reapparance in infected patients." +"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), has spread globally in a few short months. Substantial evidence now supports preliminary conclusions about transmission that can inform rational, evidence-based policies and reduce misinformation on this critical topic. This article presents a comprehensive review of the evidence on transmission of this virus. Although several experimental studies have cultured live virus from aerosols and surfaces hours after inoculation, the real-world studies that detect viral RNA in the environment report very low levels, and few have isolated viable virus. Strong evidence from case and cluster reports indicates that respiratory transmission is dominant, with proximity and ventilation being key determinants of transmission risk. In the few cases where direct contact or fomite transmission is presumed, respiratory transmission has not been completely excluded. Infectiousness peaks around a day before symptom onset and declines within a week of symptom onset, and no late linked transmissions (after a patient has had symptoms for about a week) have been documented. The virus has heterogeneous transmission dynamics: Most persons do not transmit virus, whereas some cause many secondary cases in transmission clusters called ""superspreading events."" Evidence-based policies and practices should incorporate the accumulating knowledge about transmission of SARS-CoV-2 to help educate the public and slow the spread of this virus.","Severe acute respiratory syndrome coronavirus 2, also known as SARS-CoV-2, is the cause of coronavirus disease 2019 or COVID-19 (a viral lung infection). Within a short period of time, SARS-CoV-2 has spread around the world. A significant amount of strong scientific evidence now backs up the initial thoughts on how COVID spreads from one person to another. This can improve current policies surrounding COVID-19 health safety rules and prevent the spread of false information. This paper offers a thorough review of the scientific reports concerning the spread of COVID-19. Several laboratory studies have been able to grow live COVID-19 viruses from the air and surfaces, even several hours after the virus was placed there. However, real-world studies that detect COVID-19 genetic material in the environment report very low levels. Few have been able to grow the virus from these samples. Strong evidence from cases and outbreaks shows that COVID-19 mostly spreads through the airways (lungs, throat, nose, and mouth). Distance and ventilation are key factors for risk of spreading COVID-19. Even in the few cases where scientists think the virus spread through contact with people or surfaces, spreading through the airways has not been ruled out. The rate that a person spreads the virus is highest a day before symptoms appear and declines within a week of symptoms appearing. The spread of the COVID-19 virus is different for each person. Most people infected do not spread COVID-19. However, some people infected with COVID-19 can cause many infections in groups, known as ""superspreading events."" Rules and procedures around COVID-19 should include the growing amount of scientific evidence about how it spreads. This will help educate the public and slow the spread of the virus." +"Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over four million people worldwide. There are multiple reports of prolonged viral shedding in people infected with SARS-CoV-2 but the presence of viral RNA on a test does not necessarily correlate with infectivity. The duration of quarantine required after clinical recovery to definitively prevent transmission is therefore uncertain. In addition, asymptomatic and presymptomatic transmission may occur, and infectivity may be highest early after onset of symptoms, meaning that contact tracing, isolation of exposed individuals and social distancing are essential public health measures to prevent further spread. This review aimed to summarise the evidence around viral shedding vs infectivity of SARS-CoV-2.","Since December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causing agent of COVID-19, has infected over four million people around the world. The are several reports of people infected with COVID-19 being active spreaders of the virus for extended periods of time. However, the results of COVID-19 tests do not always correlate to the duration of time a person can spread the virus. Meaning a person can test negative but may be actively giving the virus to others unknowingly. Because of this, the duration of time needed before a previously COVID-19 infected person is no longer able to infect others is not known. People without symptoms can spread the virus. COVID-19 can also be spread before people begin to show symptoms. The spread of the virus may actually occur the most right after symptoms show. This means the tracing of potential exposures, isolation of exposed people, and social distancing are needed to improve public health and reduce virus spread. The goal of this paper was summarize the scientific research around the spreading of COVID-19." +"Defining the duration of infectivity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has major implications for public health and infection control practice in healthcare facilities. Early in the pandemic, most hospitals required 2 negative RT-PCR tests before discontinuing isolation in patients with Covid-19. Many patients, however, have persistently positive RT-PCR tests for weeks to months following clinical recovery, and multiple studies now indicate that these generally do not reflect replication-competent virus. SARS-CoV-2 appears to be most contagious around the time of symptom onset, and infectivity rapidly decreases thereafter to near-zero after about 10 days in mild-moderately ill patients and 15 days in severely-critically ill and immunocompromised patients. The longest interval associated with replication-competent virus thus far is 20 days from symptom onset. This review summarizes evidence-to-date on the duration of infectivity of SARS-CoV-2, and how this has informed evolving public health recommendations on when it is safe to discontinue isolation precautions.","Defining the period of time someone can spread Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), also known as COVID-19, to others can positively impact public health and prevent infection spreading within healthcare facilities. COVID-19 is a harmful, breathing-related, viral disease. Early in the pandemic, most hospitals required two negative (or undetected) COVID-19 tests before COVID-19 infected patients could come out of quarantine (isolation). However, several COVID-19 patients continually test positive (with COVID-19 detected) after clinically recovering from the virus. Based on several reports, this is not believed to be the norm for the replication-competent virus, or a virus that is able to reproduce itself in one person and infect other people. The virus appears to be contagious (easily spread) around the time symptoms first appear. The ability of the virus to spread decreases as symptoms progress. The ability of the virus to spread becomes near-zero around 10 days in mild to moderately ill patients. The ability of the virus to spread becomes near-zero around 15 days in severely to critically ill and immunocompromised (those with decreased immune system function) patients. The longest documented duration between symptom onset and viral spread is 20 days. This review summarizes the most recent evidence on the length of time COVID-19 is able to spread from one patient to another. Additionally, this paper states how this knowledge has helped create improved COVID-19 mandates or rules on quarantine lengths." +"Defining the duration of infectivity of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has major implications for public health and infection control practice in healthcare facilities. Early in the pandemic, most hospitals required 2 negative RT-PCR tests before discontinuing isolation in patients with Covid-19. Many patients, however, have persistently positive RT-PCR tests for weeks to months following clinical recovery, and multiple studies now indicate that these generally do not reflect replication-competent virus. SARS-CoV-2 appears to be most contagious around the time of symptom onset, and infectivity rapidly decreases thereafter to near-zero after about 10 days in mild-moderately ill patients and 15 days in severely-critically ill and immunocompromised patients. The longest interval associated with replication-competent virus thus far is 20 days from symptom onset. This review summarizes evidence-to-date on the duration of infectivity of SARS-CoV-2, and how this has informed evolving public health recommendations on when it is safe to discontinue isolation precautions.","Defining the duration of infectvity of Severe Acute Respiratory Syndrome Coronovirus 2 (SARS-CoV-2), which is a viral breathing-related illness, can influence public health and infection control practice for healthcare. Early in the pandemic, most hospitals needed 2 test results detecting no disease before releasing patients with Covid-19, or SARS-CoV-2. Many patients still have test results detecting the disease for weeks to months after recovery. Studies note that these results generally do not reflect contagious viruses. SARS-CoV-2 seems the most contagious around the time of symptom onset. The infectivity or ability to spread the virus quickly decreases to near-zero after about 10 days in mildly ill patients and 15 days in severely ill and immunocompromised patients. The longest interval for contagious viruses so far is 20 days from symptom onset. This review summarizes current evidence on the duration of infectivity of SARS-CoV-2, and how this affects new public health recommendation for releasing people in isolation." +"Objectives: The distribution of the transmission onset of COVID-19 relative to the symptom onset is a key parameter for infection control. It is often not easy to study the transmission onset time, as it is difficult to know who infected whom exactly when. Methods: We inferred transmission onset time from 72 infector-infectee pairs in South Korea, either with known or inferred contact dates, utilizing the incubation period. Combining this data with known information of the infector's symptom onset, we could generate the transmission onset distribution of COVID-19, using Bayesian methods. Serial interval distribution could be automatically estimated from our data. Results: We estimated the median transmission onset to be 1.31 days (standard deviation, 2.64 days) after symptom onset with a peak at 0.72 days before symptom onset. The pre-symptomatic transmission proportion was 37% (95% credible interval [CI], 16-52%). The median incubation period was estimated to be 2.87 days (95% CI, 2.33-3.50 days), and the median serial interval to be 3.56 days (95% CI, 2.72-4.44 days). Conclusions: Considering that the transmission onset distribution peaked with the symptom onset and the pre-symptomatic transmission proportion is substantial, the usual preventive measures might be too late to prevent SARS-CoV-2 transmission.","Understanding when a potential COVID-19 patient is contagious in relation to when they first show symptoms is important to help reduce the spread of the virus. Is it not easy to determine COVID-19 transmission duration, or how long the virus was spread, as it is difficult to trace who had contact with who. The goal of this paper was to determine COVID-19 transmission by evaluating 72 infector-infected pairs from South Korea, with known or estimated contact dates, by reviewing the pairs' incubation period. The incubation period is a time between the date of exposure and the first day of virus related symptoms. Using this data in comparison with the confirmed date of the infector's first day of symptoms, the authors aim to estimate when an infected person first becomes contagious (able to spread the virus). The time between the date of infection and the time a person is capable of spreading COVID-19 to others could be predicted. The estimated average time of COVID-19 spreading to others after a patient first shows symptoms was 1.31 days. However, the peak of transmissibility was 0.72 days before symptoms appear. The amount of cases that displayed patients who could spread the virus before they started showing symptoms accounted for 37% of the 72 reviewed cases. The average time between COVID-19 entering a person's body (time of exposure) and the onset of symptoms was 2.87 days. This paper has shown that ability of a person to spread COVID-19 was highest at the time symptoms first occurred. Additionally, it has been demonstrated a large portion of the population is able to spread the virus even before symptoms occur. Because of this, the usual measures to prevent the spread of COVID-19 may not be enough to improve public health." +"Objectives: To summarise the evidence on the duration of infectiousness of individuals in whom SARS-CoV-2 ribonucleic acid is detected. Methods: A rapid review was undertaken in PubMed, Europe PubMed Central and EMBASE from 1 January 2020 to 26 August 2020. Results: We identified 15 relevant studies, including 13 virus culture studies and 2 contact tracing studies. For 5 virus culture studies, the last day on which SARS-CoV-2 was isolated occurred within 10 days of symptom onset. For another 5 studies, SARS-CoV-2 was isolated beyond day 10 for approximately 3% of included patients. The remaining 3 virus culture studies included patients with severe or critical disease; SARS-CoV-2 was isolated up to day 32 in one study. Two studies identified immunocompromised patients from whom SARS-CoV-2 was isolated for up to 20 days. Both contact tracing studies, when close contacts were first exposed greater than 5 days after symptom onset in the index case, found no evidence of laboratory-confirmed onward transmission of SARS-CoV-2. Conclusion: COVID-19 patients with mild-to-moderate illness are highly unlikely to be infectious beyond 10 days of symptoms. However, evidence from a limited number of studies indicates that patients with severe-to-critical illness or who are immunocompromised, may shed infectious virus for longer.","The goal of this paper was to summarize scientific reports detailing the amount of time someone positive for (or with) COVID-19 (a viral, breathing-related disease) can infect others. To do this, the authors reviewed papers published in public databases (e.g. PubMed, Europe PubMed Central, EMBASE) between the dates of January 1, 2020 to August 26, 2020. Fifteen studies were identified for review. Thirteen reports focused on COVID-19 that was grown within a laboratory (in culture) from human biological sampling. Two studies followed contact tracing between humans. For 5 viral culture studies, the last day that COVID-19 was able to be identified in biological samples was 10 days before symptoms occurred. For another 5 culture studies, COVID-19 was identified in biological samples past day 10. The remaining 3 virus culture studies evaluated patients with severe or critical COVID-19 illness. COVID-19 was isolated up to 32 days in one of these studies. Two studies identified immunocompromised patients (patients with decreased immune function) from whom COIVD-19 was able to be isolated from for up to 20 days. For both contact tracing or spreading studies, when exposure occurred more than five days after symptoms were apparent, there was no evidence of COVID-19 spreading. The authors concluded that COVID-19 patients with mild to moderate symptoms are unlikely to spread the virus to others beyond 10 days of symptoms. However, studies have shown that patients with severe to critical symptoms, or those who are immunocompromised, may spread the virus for longer periods of time." +"Background: The efficacy of public health measures to control the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been well studied in young adults. Methods: We investigated SARS-CoV-2 infections among U.S. Marine Corps recruits who underwent a 2-week quarantine at home followed by a second supervised 2-week quarantine at a closed college campus that involved mask wearing, social distancing, and daily temperature and symptom monitoring. Study volunteers were tested for SARS-CoV-2 by means of quantitative polymerase-chain-reaction (qPCR) assay of nares swab specimens obtained between the time of arrival and the second day of supervised quarantine and on days 7 and 14. Recruits who did not volunteer for the study underwent qPCR testing only on day 14, at the end of the quarantine period. We performed phylogenetic analysis of viral genomes obtained from infected study volunteers to identify clusters and to assess the epidemiologic features of infections. Results: A total of 1848 recruits volunteered to participate in the study; within 2 days after arrival on campus, 16 (0.9%) tested positive for SARS-CoV-2, 15 of whom were asymptomatic. An additional 35 participants (1.9%) tested positive on day 7 or on day 14. Five of the 51 participants (9.8%) who tested positive at any time had symptoms in the week before a positive qPCR test. Of the recruits who declined to participate in the study, 26 (1.7%) of the 1554 recruits with available qPCR results tested positive on day 14. No SARS-CoV-2 infections were identified through clinical qPCR testing performed as a result of daily symptom monitoring. Analysis of 36 SARS-CoV-2 genomes obtained from 32 participants revealed six transmission clusters among 18 participants. Epidemiologic analysis supported multiple local transmission events, including transmission between roommates and among recruits within the same platoon. Conclusions: Among Marine Corps recruits, approximately 2% who had previously had negative results for SARS-CoV-2 at the beginning of supervised quarantine, and less than 2% of recruits with unknown previous status, tested positive by day 14. Most recruits who tested positive were asymptomatic, and no infections were detected through daily symptom monitoring. Transmission clusters occurred within platoons.","The strength of current public health measures to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or COVID-19 (a viral respiratory disease), has not been well studied in young adults. The authors investigated COVID-19 infections amongst U.S. Marine Corps recruits. These recruits underwent a two-week quarantine )or isolation) within their personal homes before participating in a second two-week quarantine. The second quarantine was supervised at a closed college campus where recruits wore masks, practiced social distancing, and received daily temperature and symptoms monitoring. Participants in the study were tested for COVID-19 by using nose swabs taken between the time of arrival and the second day of supervised quarantine. A second COVID-19 test run with nose swab samples was conducted on days 7 and 14. Marine recruits who did not want to participate in the study only received one COVID-19 test on day 14 (the final day of supervised quarantine). To identify clusters of unique COVID-19 cases and to better understand how the virus affects public health, the researchers studied the genetic makeup of COVID-19 within samples from the nose swabs. In total, 1848 recruits volunteered to participate in the study. Within the first two days of supervised quarantine, 16 recruits tested positive for (or had) COVID-19. Fifteen of the 16 positive cases did not show symptoms of illness. An additional 35 participants tested positive on day 7 or on day 14. Fifty-one participants tested positive at any time. Five of these patients had symptoms before their COVID-19 test returned positive. Of the recruits who declined to participate in the study, 26 of the 1554 recruits with available COVID-19 test results were positive on day 14. No COVID-19 infections were identified through clinical testing performed as a result of daily symptom monitoring. The evaluation of the genetic makeup of the virus identified six spreading clusters among 18 participants. Tracing of the virus transmission identified several spreading events, including between roommates and among recruits within the same platoon. The authors concluded that among the recruits, around 2% of those who had tested negative for (or did not have) COVID-19 on day 1 of supervised quarantine, along with 2% of those with unknown previous status, tested positive by day 14. Most recruits who tested positive showed no signs of illness. No infections were detected through daily symptom monitoring. Spreading clusters occurred within platoons." +"Background: The efficacy of public health measures to control the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has not been well studied in young adults. Methods: We investigated SARS-CoV-2 infections among U.S. Marine Corps recruits who underwent a 2-week quarantine at home followed by a second supervised 2-week quarantine at a closed college campus that involved mask wearing, social distancing, and daily temperature and symptom monitoring. Study volunteers were tested for SARS-CoV-2 by means of quantitative polymerase-chain-reaction (qPCR) assay of nares swab specimens obtained between the time of arrival and the second day of supervised quarantine and on days 7 and 14. Recruits who did not volunteer for the study underwent qPCR testing only on day 14, at the end of the quarantine period. We performed phylogenetic analysis of viral genomes obtained from infected study volunteers to identify clusters and to assess the epidemiologic features of infections. Results: A total of 1848 recruits volunteered to participate in the study; within 2 days after arrival on campus, 16 (0.9%) tested positive for SARS-CoV-2, 15 of whom were asymptomatic. An additional 35 participants (1.9%) tested positive on day 7 or on day 14. Five of the 51 participants (9.8%) who tested positive at any time had symptoms in the week before a positive qPCR test. Of the recruits who declined to participate in the study, 26 (1.7%) of the 1554 recruits with available qPCR results tested positive on day 14. No SARS-CoV-2 infections were identified through clinical qPCR testing performed as a result of daily symptom monitoring. Analysis of 36 SARS-CoV-2 genomes obtained from 32 participants revealed six transmission clusters among 18 participants. Epidemiologic analysis supported multiple local transmission events, including transmission between roommates and among recruits within the same platoon. Conclusions: Among Marine Corps recruits, approximately 2% who had previously had negative results for SARS-CoV-2 at the beginning of supervised quarantine, and less than 2% of recruits with unknown previous status, tested positive by day 14. Most recruits who tested positive were asymptomatic, and no infections were detected through daily symptom monitoring. Transmission clusters occurred within platoons.","The effectiveness of public health policies to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a viral breathing-related disease, has not been well studied in young adults. We checked SARS-CoV-2 infections in U.S. Marine Corps recruits who had a 2-week quarantine or isolation at home. They then had a second supervised 2-week quarantine at a closed college campus with mask wearing, social distancing from others, and daily temperature and symptom checks. Study volunteers were tested for SARS-CoV-2 by swabs obtained between the time of arrival and second day of supervised isolation and on days 7 and 14. Recruits who did not volunteer had testing only on day 14, at the end of the isolation period. 1848 recruits participated in the study. Within 2 days after arrival on campus, 16 (0.9%) tested positive for or had SARS-CoV-2, 15 of whom showed no symptoms. Another 35 participants (1.9%) tested positive or had SARS-CoV-2 on day 7 or day 14. Five of the 51 participants (9.8%) who tested positive at all had symptoms in the week before a positive test. Of those who decline to participate in the study, 26 (1.7%) of the 1554 recruits with test results tested positive on day 14. No SARS-CoV-2 infections were detected by clinical testing performed for daily symptom checks. Analyzing 36 sets of genetic data from 32 participants showed 6 disease-spreading clusters among 18 participants. Analysis notes multiple disease-spreading events, including spreading between roommates and among recruits in the same military group. Among Marine Corps recruits, around 2% with past test results detecting no SARS-CoV-2 at the beginning of supervised isolation, and less than 2% of recruits of unknown status previously, had results detecting SARS-CoV-2 by day 14. Most recruits with positive tests had no symptoms. No infections were detected from daily symptom checks. Disease-spreading clusters occurred within military groups." +"Background: Patients recovering from coronavirus disease 2019 (COVID-19) often continue to test positive for the causative virus by polymerase chain reaction (PCR) even after clinical recovery, thereby complicating return-to-work plans. The purpose of this study was to evaluate transmission potential of COVID-19 by examining viral load with respect to time. Methods: Health care personnel (HCP) at Cleveland Clinic diagnosed with COVID-19, who recovered without needing hospitalization, were identified. Threshold cycles (Ct) for positive PCR tests were obtained and viral loads calculated. The association of viral load with days since symptom onset was examined in a multivariable regression model, which was reduced by stepwise backward selection to only keep variables significant at a level of .05. Viral loads by day since symptom onset were predicted using the model and transmission potential evaluated by examination of a viral load-time curve. Results: Over 6 weeks, 230 HCP had 528 tests performed. Viral loads declined by orders of magnitude within a few days of symptom onset. The only variable significantly associated with viral load was time since onset of symptoms. Of the area under the curve (AUC) spanning symptom onset to 30 days, 96.9% lay within the first 7 days, and 99.7% within 10 days. Findings were very similar when validated using split-sample and 10-fold cross-validation. Conclusions: Among patients with nonsevere COVID-19, viral loads in upper respiratory specimens peak by 2 or 3 days from symptom onset and decrease rapidly thereafter. The vast majority of the viral load-time AUC lies within 10 days of symptom onset.","Patients recovering from COVID-19 (a viral respiratory disease) oftentimes continue to test positive for (or have) the virus. This can make ""return to work"" plans difficult. The goal of this study is to evaluate COVID-19's ability to spread by determining the amount of the virus within an organism, known as the viral load, over time. Health care personnel at Cleveland Clinic diagnosed with COVID-19, who recovered without needing hospitalization, were identified. The viral load within the personnel was calculated. The link between the viral load within the patient and the first day of symptoms was evaluated. The viral load per day since the beginning of symptom onset within the patient were predicted using statistical models. Over six weeks, 230 health care personnel had 528 tests performed. The viral load within patients decreased within a few days of the beginning of virus-related symptoms. The viral load within the patient was significantly linked to time since onset of symptoms. The majority of the participants had peak viral load within the first 7 to 10 days. Findings were similar when other statistical tests were run. The authors concluded that among patients with no mild to moderate COVID-19, viral loads peaked by 2 or 3 days from symptom onset and decreased rapidly thereafter. The largest amount of viral load was on average within 10 days of symptom onset." +"Background: Approximately 10% of adults in Germany have chronic kidney disease (CKD). The prevalence of CKD among patients being cared for by general practitioners is approximately 30%, and its prevalence in nursing homes is over 50%. An S3 guideline has been developed for the management of CKD in primary care. Methods: The guideline is based on publications retrieved by a systematic search of the literature for international guidelines published in the period 2013-2017, and additional searches on specific questions. It was created by the German College of General Practitioners and Family Physicians (Deutsche Gesellschaft f�r Allgemeinmedizin und Familienmedizin, DEGAM) and consented with the German Societies of Nephrology and Internal Medicine (DGfN, DGIM) and patient representation. Results: Upon the initial diagnosis of CKD (glomerular filtration rate [GFR] <60 mL/ min), the patient's blood pressure and urinary albumin-to-creatinine ratio (ACR) should be measured, and the urine should be examined for hematuria. Monitoring intervals are determined on an individual basis depending on the stage of disease and the patient's general state of health and personal preferences. Nephrological consultation should be obtained if the GFR is less than 30 mL/min, if CKD is initially diagnosed (GFR 30-59 mL/min) in the presence of persistent hematuria without any urological explanation or of albinuria in stage A2 or higher, if the patient has refractory hypertension requiring three or more antihypertensive drugs, or if the renal disease is rapidly progressive. The threshold for referring a patient should be kept low for persons under age 50; persons over age 70 should be referred only if warranted in consideration of their comorbidities and individual health goals. Conclusion: The main elements of the treatment of CKD are the treatment of hypertension and diabetes and the modification of lifestyle factors. An innovation from the primary care practioner's perspective is the assessment of albuminuria with the albumin-to-creatinine ratio.","About 10% of adults in Germany have chronic kidney disease, which is when the kidneys are damaged and can't filter waste and extra fluid from the blood. The percentage of chronic kidney disease among patients being cared for by primary care doctors (family doctors) is about 30% and is over 50% in nursing homes. A guideline has been developed for the care of chronic kidney disease in primary (family) care offices. This guideline is based on existing, available data in articles published during 2013 - 2017 and also on additional searches of data on specific questions. It is created by the German College of General Practitioners and Family Physicians and agreed with by the German Societies of Nephrology and Internal Medicine and patient representation. At the first diagnosis of chronic kidney disease, the patient's blood pressure, as well as a urine sample that may indicate a kidney complication from high proteins, should be measured. The urine should also be checked for the presence of blood. How often the patient should be monitored is based on the individual and depends on the stage of disease, the patient's overall health, and personal preferences. A doctor who specializes in kidney disease should be consulted based on tests that check how well the kidneys are working, if there is blood in the urine, if the patient's blood pressure requires 3 or more drugs, and if the kidney disease is quickly getting worse. The requirements and test levels to refer a patient under the age of 50 years for specialty care should be kept low. People over 70 should be referred only if necessary due to other illnesses and individual health goals. The main parts of treating chronic kidney disease are the treatment of high blood pressure and diabetes and changing lifestyle. A new assessment from the family doctor is a sign of kidney disease due to too much of a protein called albumin in the urine." +"Background: Methoxy polyethylene glycol-epoetin beta (PEG-EPO) is indicated for the treatment of anaemia due to chronic kidney disease. Its long half-life allows it to be administered once per month in maintenance therapy. Objective: To evaluate the use, effectiveness and cost of PEG-EPO in a group of pre-dialysis chronic renal failure patients. Method: Retrospective observational study in pre-dialysis patients who began treatment with PEG-EPO between May 2008 and February 2009. The following data were gathered: age, sex, haemoglobin levels (Hb) and erythropoiesis-stimulating agent (ESA) dose and frequency. The follow-up period was 12 months. Results: We included 198 patients. Mean Hb upon starting PEG-EPO in patients who had received no prior treatment was 10.8g/l, and 11.6g/l at 90 days (P<.0001). In patients previously treated with ESA, mean Hb before starting PEG-EPO treatment was 11.2g/l, and 11.4g/l at 12 months (P=.846). Hb values were higher than 12g/l (P<.0001) after 12 months of treatment in 25% of patients; of these, 45% had values above 13g/l. We observed doses 39% lower than those indicated on the drug leaflet, resulting in a reduction in the originally expected theoretical costs. Conclusions: The doses of PEG-EPO administered to patients with a prior history of ESA treatment were lower than those indicated by the drug leaflet, and Hb remained stable after 12 months of treatment. A large portion of the patients had levels above the 13g/l threshold.","Methoxy polyethylene glycol-epoetin beta (PEG-EPO) is an injection that is often used to treat anemia (low red blood cells) due to chronic kidney disease. It stays in the body long enough to be given once per month. The objective of this study is to evaluate the use, effectiveness and cost of PEG-EPO in a group of chronic kidney failure patients who have not started dialysis, a process of using a machine to clean the blood of a person whose kidneys are not working normally. This study uses data from pre-dialysis patients who started treatment with Methoxy polyethylene glycol-epoetin beta (PEG-EPO) between May 2008 and February 2009. The following data are gathered: age, sex, hemoglobin levels (count of proteins that carry oxygen in the blood) and the dose and frequency of medication called erythropoiesis-stimulating agent (ESA) to help make red blood cells. The follow-up period is 12 months. The study included 198 patients. The average hemoglobin levels when patients start PEG-EPO who had received no prior treatment is 10.8 grams/liter, and is 11.6 grams/liter at 90 days. In patients who are previously treated with ESA medications to help make red blood cells, the average hemoglobin levels before starting PEG-EPO treatment is 11.2 grams/liter, and is 11.4 grams/liter at 12 months. Hemoglobin levels are higher than 12 grams/liter after 12 months of treatment in 25% of patients. Among these patients, 45% have levels above 13 grams/liter. Researchers observed doses 39% lower than those listed on the drug leaflet or description, resulting in less cost than originally expected. In conclusion, the doses of PEG-EPO given to patients with a prior history of erythropoiesis-stimulating agent (ESA) treatment are lower than those noted in the drug leaflet. Also, hemoglobin levels remained stable after 12 months of treatment. A large portion of the patients had levels above the 13 grams/liter threshold." +"A panel of internists and nephrologists developed this practical approach for the Kidney Disease Outcomes Quality Initiative to guide assessment and care of chronic kidney disease (CKD) by primary care clinicians. Chronic kidney disease is defined as a glomerular filtration rate (GFR) <60 mL/min/1.73m and/or markers of kidney damage for at least 3 months. In clinical practice the most common tests for CKD include GFR estimated from the serum creatinine concentration (eGFR) and albuminuria from the urinary albumin-to-creatinine ratio. Assessment of eGFR and albuminuria should be performed for persons with diabetes and/or hypertension but is not recommended for the general population. Management of CKD includes reducing the patient's risk of CKD progression and risk of associated complications, such as acute kidney injury and cardiovascular disease, anemia, and metabolic acidosis, as well as mineral and bone disorder. Prevention of CKD progression requires blood pressure <140/90 mm Hg, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for patients with albuminuria and hypertension, hemoglobin A1c ?7% for patients with diabetes, and correction of CKD-associated metabolic acidosis. To reduce patient safety hazards from medications, the level of eGFR should be considered when prescribing, and nephrotoxins should be avoided, such as nonsteroidal anti-inflammatory drugs. The main reasons to refer to nephrology specialists are eGFR <30 mL/min/1.73 m(2), severe albuminuria, and acute kidney injury. The ultimate goal of CKD management is to prevent disease progression, minimize complications, and promote quality of life.","A group of internal medicine and kidney doctors developed a practical approach to guide the assessment (diagnosis) and care of chronic kidney disease by primary care doctors. Chronic kidney disease is defined by using a glomerular filtration rate, a blood test that checks how well your kidneys are working, and/or other measurements or conditions that are a sign of kidney damage for at least 3 months. The most common tests for chronic kidney disease include the glomerular filtration rate that is estimated from the amount of creatinine (a waste product from the normal wear and tear on muscles) in the blood and too much albumin (a blood protein) in the urine which is called albuminuria. These tests for creatinine levels and albumin proteins should be done for people with diabetes and/or high blood pressure but are not recommended for the general population. Managing chronic kidney disease includes reducing the patient's risk of the disease getting worse and risk of related complications, such as acute or immediate kidney injury or heart disease. To prevent chronic kidney disease from worsening, managing blood pressure, using medications to treat high albumin levels and high blood pressure, measuring hemoglobin levels (red blood cells) for patients with diabetes, and correcting when there is too much acid in the body's fluids is needed. To reduce the negative effect of medications on patients, the level of creatinine should be noted when prescribing drugs, and nephrotoxins which can damage the kidneys should be avoided. The main reasons to send a patient to a kidney specialist are based on creatinine levels, severe albuminuria (too much protein in urine), and acute kidney injury (a sudden episode of kidney failure). The main goal of managing chronic kidney disease is to prevent the disease from getting worse, to minimize complications, and to promote quality of life." +"A panel of internists and nephrologists developed this practical approach for the Kidney Disease Outcomes Quality Initiative to guide assessment and care of chronic kidney disease (CKD) by primary care clinicians. Chronic kidney disease is defined as a glomerular filtration rate (GFR) <60 mL/min/1.73m and/or markers of kidney damage for at least 3 months. In clinical practice the most common tests for CKD include GFR estimated from the serum creatinine concentration (eGFR) and albuminuria from the urinary albumin-to-creatinine ratio. Assessment of eGFR and albuminuria should be performed for persons with diabetes and/or hypertension but is not recommended for the general population. Management of CKD includes reducing the patient's risk of CKD progression and risk of associated complications, such as acute kidney injury and cardiovascular disease, anemia, and metabolic acidosis, as well as mineral and bone disorder. Prevention of CKD progression requires blood pressure <140/90 mm Hg, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for patients with albuminuria and hypertension, hemoglobin A1c ?7% for patients with diabetes, and correction of CKD-associated metabolic acidosis. To reduce patient safety hazards from medications, the level of eGFR should be considered when prescribing, and nephrotoxins should be avoided, such as nonsteroidal anti-inflammatory drugs. The main reasons to refer to nephrology specialists are eGFR <30 mL/min/1.73 m(2), severe albuminuria, and acute kidney injury. The ultimate goal of CKD management is to prevent disease progression, minimize complications, and promote quality of life.","A group of specialists created this practical approach for Kidney Disease Outcomes Quality Initiative to guide analysis and care of long-lasting or chronic kidney disease (CKD) by primary care workers. Long-lasting kidney disease is a low kidney filtration rate and/or markers of kidney damage for at least 3 months. In clinical practice, the most common tests for CKD include kidney filtration rate of blood creatinine, a chemical waste, (eGFR) and high blood albumin, a blood protein, from the albumin-to-creatinine ratio in urine. Measuring eGFR and albumin levels should be done in persons with diabetes and/or high blood pressure but not for the general population. Managing CKD includes lowering the patient's risk of CKD worsening and risk of associated issues, like immediate kidney injury, heart disease, low blood level, high acid level, and mineral and bone disorder. Preventing CKD progression requires blood pressure <140/90 mm Hg, certain blood pressure medications for patients with high blood pressure and albumin, lower blood sugar for diabetics, and correcting high body acid levels linked with CKD. To reduce patient safety hazards from medications, eGFR should be considering when prescribing. Kidney toxins should be avoided, like a class of anti-inflammatory drugs. The main reasons to contact kidney specialists are eGFR <30 mL/min/1.73 m(2), high blood albumin, and immediate kidney injury. The goal of CKD treatment is prevent disease worsening, reduce issues, and better quality of life." +"Importance: Chronic kidney disease (CKD) is the 16th leading cause of years of life lost worldwide. Appropriate screening, diagnosis, and management by primary care clinicians are necessary to prevent adverse CKD-associated outcomes, including cardiovascular disease, end-stage kidney disease, and death. Observations: Defined as a persistent abnormality in kidney structure or function (eg, glomerular filtration rate [GFR] <60 mL/min/1.73 m2 or albuminuria ?30 mg per 24 hours) for more than 3 months, CKD affects 8% to 16% of the population worldwide. In developed countries, CKD is most commonly attributed to diabetes and hypertension. However, less than 5% of patients with early CKD report awareness of their disease. Among individuals diagnosed as having CKD, staging and new risk assessment tools that incorporate GFR and albuminuria can help guide treatment, monitoring, and referral strategies. Optimal management of CKD includes cardiovascular risk reduction (eg, statins and blood pressure management), treatment of albuminuria (eg, angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers), avoidance of potential nephrotoxins (eg, nonsteroidal anti-inflammatory drugs), and adjustments to drug dosing (eg, many antibiotics and oral hypoglycemic agents). Patients also require monitoring for complications of CKD, such as hyperkalemia, metabolic acidosis, hyperphosphatemia, vitamin D deficiency, secondary hyperparathyroidism, and anemia. Those at high risk of CKD progression (eg, estimated GFR <30 mL/min/1.73 m2, albuminuria ?300 mg per 24 hours, or rapid decline in estimated GFR) should be promptly referred to a nephrologist. Conclusions and relevance: Diagnosis, staging, and appropriate referral of CKD by primary care clinicians are important in reducing the burden of CKD worldwide.","Chronic kidney disease (CKD) is the 16th leading cause of years of life lost worldwide. Appropriate screening, diagnosis, and care by primary care (family) doctors are necessary to prevent negative outcomes associated with CKD, including heart disease, end-stage kidney disease, and death. Defined as an ongoing impairment in kidney structure or function for more than 3 months, chronic kidney disease affects 8% to 16% of people worldwide. In developed countries, CKD is most commonly associated with diabetes and high blood pressure. However, less than 5% of patients with early CKD report knowing about of their disease. Among people diagnosed as having CKD, new risk assessment tools can help guide treatment, monitoring, and inform when to send patients to a specialist. These new tools include using the glomerular filtration rate, a blood test that checks how well your kidneys are working, and albuminuria, which is too much albumin (a blood protein) in the urine. The best management of CKD includes reducing risk of heart disease, treating albuminuria, avoiding medications that are toxic to the kidneys, and changes to drug dosing, such as antibiotics. Patients also need monitoring for complications with CKD, such as higher than normal potassium levels, too much acid in the fluids of the body, too much phosphorus in the blood, low vitamin D, overactive glands in the neck that produce parathyroid (calcium-regulating) hormone, and anemia (low red blood cells). Those at high risk of chronic kidney disease progression based on tests that check how well the kidneys are working or too much albumin (a protein) in the urine, which is called albuminuria, should be quickly sent to a kidney specialist. Diagnosis, determining the stage, and appropriate referral of chronic kidney disease by primary care doctors are important in reducing the negative impact of chronic kidney disease worldwide." +"Due to the unique role of the kidney in the metabolism of nutrients, patients with chronic kidney disease (CKD) lose the ability to excrete solutes and maintain homeostasis. Nutrient intake modifications and monitoring of nutritional status in this population becomes critical, since it can affect important health outcomes, including progression to kidney failure, quality of life, morbidity, and mortality. Although there are multiple hemodynamic and metabolic factors involved in the progression and prognosis of CKD, nutritional interventions are a central component of the care of patients with non-dialysis CKD (ND-CKD) and of the prevention of overweight and possible protein energy-wasting. Here, we review the reno-protective effects of diet in adults with ND-CKD stages 3-5, including transplant patients.","Due to the unique role of the kidney in turning nutrients into fuel, patients with chronic kidney disease (CKD) lose the ability to release dissolved substances and to maintain a healthy internal balance of water, sodium, and other elements in the body. Changing the nutrients that are consumed and checking for how nutrients impact health in this population is important, since it can impact health results, including advancing to kidney failure, quality of life, illness, and death. Although there are other factors involved in the progression and the likely course of chronic kidney disease, nutritional steps are a main part of the care of patients with chronic kidney disease who are not on dialysis, a process of filtering the blood of a person whose kidneys are not working normally by using a machine. This review discusses how diet in adults with chronic kidney disease stages 3-5 who are not on dialysis can have a protective effect on kidneys, including transplant patients." +"Background: Dietary changes are routinely recommended in people with chronic kidney disease (CKD) on the basis of randomised evidence in the general population and non-randomised studies in CKD that suggest certain healthy eating patterns may prevent cardiovascular events and lower mortality. People who have kidney disease have prioritised dietary modifications as an important treatment uncertainty. Objectives: This review evaluated the benefits and harms of dietary interventions among adults with CKD including people with end-stage kidney disease (ESKD) treated with dialysis or kidney transplantation. Main results: We included 17 studies involving 1639 people with CKD. Three studies enrolled 341 people treated with dialysis, four studies enrolled 168 kidney transplant recipients, and 10 studies enrolled 1130 people with CKD stages 1 to 5. Eleven studies (900 people) evaluated dietary counselling with or without lifestyle advice and six evaluated dietary patterns (739 people), including one study (191 people) of a carbohydrate-restricted low-iron, polyphenol enriched diet, two studies (181 people) of increased fruit and vegetable intake, two studies (355 people) of a Mediterranean diet and one study (12 people) of a high protein/low carbohydrate diet. Risks of bias in the included studies were generally high or unclear, lowering confidence in the results. Participants were followed up for a median of 12 months (range 1 to 46.8 months). Studies were not designed to examine all-cause mortality or cardiovascular events. In very-low quality evidence, dietary interventions had uncertain effects on all-cause mortality or ESKD. In absolute terms, dietary interventions may prevent one person in every 3000 treated for one year avoiding ESKD, although the certainty in this effect was very low. Across all 17 studies, outcome data for cardiovascular events were sparse. Dietary interventions in low quality evidence were associated with a higher health-related quality of life (2 studies, 119 people: MD in SF-36 score 11.46, 95% CI 7.73 to 15.18; I2 = 0%). Adverse events were generally not reported. Dietary interventions lowered systolic blood pressure (3 studies, 167 people: MD -9.26 mm Hg, 95% CI -13.48 to -5.04; I2 = 80%) and diastolic blood pressure (2 studies, 95 people: MD -8.95, 95% CI -10.69 to -7.21; I2 = 0%) compared to a control diet. Dietary interventions were associated with a higher estimated glomerular filtration rate (eGFR) (5 studies, 219 people: SMD 1.08; 95% CI 0.26 to 1.97; I2 = 88%) and serum albumin levels (6 studies, 541 people: MD 0.16 g/dL, 95% CI 0.07 to 0.24; I2 = 26%). A Mediterranean diet lowered serum LDL cholesterol levels (1 study, 40 people: MD -1.00 mmol/L, 95% CI -1.56 to -0.44). Authors' conclusions: Dietary interventions have uncertain effects on mortality, cardiovascular events and ESKD among people with CKD as these outcomes were rarely measured or reported. Dietary interventions may increase health-related quality of life, eGFR, and serum albumin, and lower blood pressure and serum cholesterol levels. Based on stakeholder prioritisation of dietary research in the setting of CKD and preliminary evidence of beneficial effects on risks factors for clinical outcomes, large-scale pragmatic RCTs to test the effects of dietary interventions on patient outcomes are required.","Changes in diet are often recommended for people with chronic kidney disease on the basis of evidence in the general population and in other studies of chronic kidney disease. People who have kidney disease have prioritized changes in their diet as uncertain treatment. This review evaluates the benefits and harms of dietary interventions (changing diet and diet behavior to reach a health goal) among adults with chronic kidney disease, including people with end-stage kidney disease treated with dialysis (a process that uses a machine to clean the blood because the kidneys are not working) or kidney transplantation or donation. Researchers include 17 studies involving 1639 people with chronic kidney disease. Three studies include 341 people treated with dialysis, four studies have 168 kidney transplant recipients, and 10 studies have 1130 people with chronic kidney disease at stages ranging from 1 to 5. Among these studies, 11 evaluated dietary counselling with or without lifestyle advice, and 6 evaluated dietary patterns, including 1 study of a low-carb/low-iron with many plant-based foods diet, 2 studies of increased fruit and vegetable intake, 2 studies of a Mediterranean diet and 1 study of a high protein/low carb diet. Risks of bias in these studies are generally high or unclear, lowering confidence in how true the results are in these papers. Participants are followed up for about 12 months, but the time ranges between 1 to 46.8 months. Studies are not designed to examine all causes of illness or heart disease events. In very low quality evidence, dietary interventions or treatment have uncertain effects on deaths from any cause or end-stage kidney disease. Dietary interventions to treat kidney disease may prevent one person in every 3000 treated for one year to avoid end-stage kidney disease, although the certainty that this result will happen is very low. Across all 17 studies, outcome data for heart events are limited. Dietary interventions in low quality evidence studies are associated with a higher health-related quality of life. Adverse (unexpected and negative) events are generally not reported. In some studies, dietary interventions lowered systolic blood pressure (top blood pressure number) and diastolic blood pressure (bottom blood pressure number) compared to a control diet. Dietary interventions are associated with a higher estimated glomerular filtration rate (eGFR), a blood test that measures removal of creatinine levels which are waste products from digestion and muscle breakdown. They are also linked to higher albumin (liver proteins that keep fluid in the bloodstream) levels in the blood. A Mediterranean diet lowered LDL (bad) cholesterol levels. In conclusion, dietary interventions have uncertain effects on death, heart events, and end-stage kidney disease among people with chronic kidney disease because these effects are rarely measured or described. Dietary interventions may increase health-related quality of life, eGFR, and albumin levels in the blood, and lower blood pressure and cholesterol levels. Large-scale clinical studies to test the effects of dietary interventions on patient outcomes are needed." +"Background: Dietary changes are routinely recommended in people with chronic kidney disease (CKD) on the basis of randomised evidence in the general population and non-randomised studies in CKD that suggest certain healthy eating patterns may prevent cardiovascular events and lower mortality. People who have kidney disease have prioritised dietary modifications as an important treatment uncertainty. Objectives: This review evaluated the benefits and harms of dietary interventions among adults with CKD including people with end-stage kidney disease (ESKD) treated with dialysis or kidney transplantation. Main results: We included 17 studies involving 1639 people with CKD. Three studies enrolled 341 people treated with dialysis, four studies enrolled 168 kidney transplant recipients, and 10 studies enrolled 1130 people with CKD stages 1 to 5. Eleven studies (900 people) evaluated dietary counselling with or without lifestyle advice and six evaluated dietary patterns (739 people), including one study (191 people) of a carbohydrate-restricted low-iron, polyphenol enriched diet, two studies (181 people) of increased fruit and vegetable intake, two studies (355 people) of a Mediterranean diet and one study (12 people) of a high protein/low carbohydrate diet. Risks of bias in the included studies were generally high or unclear, lowering confidence in the results. Participants were followed up for a median of 12 months (range 1 to 46.8 months). Studies were not designed to examine all-cause mortality or cardiovascular events. In very-low quality evidence, dietary interventions had uncertain effects on all-cause mortality or ESKD. In absolute terms, dietary interventions may prevent one person in every 3000 treated for one year avoiding ESKD, although the certainty in this effect was very low. Across all 17 studies, outcome data for cardiovascular events were sparse. Dietary interventions in low quality evidence were associated with a higher health-related quality of life (2 studies, 119 people: MD in SF-36 score 11.46, 95% CI 7.73 to 15.18; I2 = 0%). Adverse events were generally not reported. Dietary interventions lowered systolic blood pressure (3 studies, 167 people: MD -9.26 mm Hg, 95% CI -13.48 to -5.04; I2 = 80%) and diastolic blood pressure (2 studies, 95 people: MD -8.95, 95% CI -10.69 to -7.21; I2 = 0%) compared to a control diet. Dietary interventions were associated with a higher estimated glomerular filtration rate (eGFR) (5 studies, 219 people: SMD 1.08; 95% CI 0.26 to 1.97; I2 = 88%) and serum albumin levels (6 studies, 541 people: MD 0.16 g/dL, 95% CI 0.07 to 0.24; I2 = 26%). A Mediterranean diet lowered serum LDL cholesterol levels (1 study, 40 people: MD -1.00 mmol/L, 95% CI -1.56 to -0.44). Authors' conclusions: Dietary interventions have uncertain effects on mortality, cardiovascular events and ESKD among people with CKD as these outcomes were rarely measured or reported. Dietary interventions may increase health-related quality of life, eGFR, and serum albumin, and lower blood pressure and serum cholesterol levels. Based on stakeholder prioritisation of dietary research in the setting of CKD and preliminary evidence of beneficial effects on risks factors for clinical outcomes, large-scale pragmatic RCTs to test the effects of dietary interventions on patient outcomes are required.","Diet changes are usually recommended in people with long-lasting or chronic kidney disease (CKD) since studies suggest certain healthy eating patterns may prevent heart-related events and lower deaths. People with kidney disease have important diet changes as a treatment uncertainty. This review explored the pros and cons of dietary treatment in adults with CKD including those with kidney failure treated with an artificial kidney machine or kidney transplant. We included 17 studies with 1639 people with CKD. Three studies used 341 people treated with an artifical kidney disease. Four studies had 168 kidney transplant receivers. 10 studies had 1130 people with low to severe CKD. Eleven studies (900 people) evaluated diet counselling with or without lifestyle advice. Six evaluated diet patterns (739 people), including one study (191 people) of a carb-restricted low-iron, high plant-nutrient diet, two studies (181 people) of increased fruit and vegetable intake, two studies (355 people) of a Mediterranean diet and one study (12 people) of a high protein/low carb diet. Risk of bias in the studies were generally high or unclear, casting doubts in the results. Participants were checked for an average of 12 months. Studies were not made to examine all-cause death or heart-related events. In very-low quality results, diet interventions had uncertain effects on all-cause deaths or kidney failure. In established results, diet treatments may prevent kidney failure in one in every 3000 people, although the certainty of this effect was very low. Across all 17 studies, outcome data for heart-related evens was rare. Diet treatments in low quality evidence was linked with a higher heart-related quality of life. Side effects were generally not reported. Diet treatments lowered systolic and diastolic blood pressure compared to a control or regular diet. Diet treatments were linked with a higher kidney filtration rate and blood levels of albumin, a blood protein. A Mediterranean diet lowered ""unwanted"" blood cholesterol levels. Diet treatments have uncertain effects on death, heart-related events, and kidney failure among people with CKD since these outcomes were rarely measured or reported. Diet treatment may increased health-related quality of life, kidney filtration rate, and blood albumin. Diet treatment may lower blood pressure and blood cholesterol levels. Based on the importance of diet research for CKD and initial evidence of beneficial effects on health, large-scale studies to test the effects of diet treatments on patient outcomes are needed." +"Protein-energy wasting (PEW), characterized by a decline in body protein mass and energy reserves, including muscle and fat wasting and visceral protein pool contraction, is an underappreciated condition in early to moderate stages of chronic kidney disease (CKD) and a strong predictor of adverse outcomes. The prevalence of PEW in early to moderate CKD is ?20-25% and increases as CKD progresses, in part because of activation of proinflammatory cytokines combined with superimposed hypercatabolic states and declines in appetite. This anorexia leads to inadequate protein and energy intake, which may be reinforced by prescribed dietary restrictions and inadequate monitoring of the patient's nutritional status. Worsening uremia also renders CKD patients vulnerable to potentially deleterious effects of uncontrolled diets, including higher phosphorus and potassium burden. Uremic metabolites, some of which are anorexigenic and many of which are products of protein metabolism, can exert harmful effects, ranging from oxidative stress to endothelial dysfunction, nitric oxide disarrays, renal interstitial fibrosis, sarcopenia, and worsening proteinuria and kidney function. Given such complex pathways, nutritional interventions in CKD, when applied in concert with nonnutritional therapeutic approaches, encompass an array of strategies (such as dietary restrictions and supplementations) aimed at optimizing both patients' biochemical variables and their clinical outcomes. The applicability of many nutritional interventions and their effects on outcomes in patients with CKD with PEW has not been well studied. This article reviews the definitions and pathophysiology of PEW in patients with non-dialysis-dependent CKD, examines the current indications for various dietary modification strategies in patients with CKD (eg, manufactured protein-based supplements, amino acids and their keto acid or hydroxyacid analogues), discusses the rationale behind their potential use in patients with PEW, and highlights areas in need of further research.","Protein-energy wasting is a decline in the amount of protein in the body and leads to less stored energy. It is a condition present in early to moderate stages of chronic kidney disease and a signal that negative health outcomes may occur. Protein-energy wasting often increases as chronic kidney disease gets worse, in part because of more inflammation (redness and swelling from fighting an infection) combined with too much breakdown of proteins and loss of appetite. This leads to not enough proteins and energy, which may be held up by dietary restrictions from doctors and not enough monitoring of how the patient's nutrition impacts their health. Worsening uremia, which is when there is too much waste in the blood, may make uncontrolled diets have a negative impact on chronic disease patients. Too many waste products in the blood that would normally be removed by urine can have harmful effects, including an imbalance of free radicals and antioxidants in the body (which can lead to cell and tissue damage), endothelial dysfunction which is damaged functioning of the lining of blood vessels impacting the heart, and other conditions. Nutritional interventions (changing diet and diet behavior to reach a health goal) in chronic kidney disease, when combined with other therapies unrelated to nutrition, create a number of strategies aimed at improving the internal systems of the body in the patient and the patient's health outcomes. How nutritional interventions can work and their effects on patients with chronic kidney disease with protein-energy wasting is not well studied. This article reviews the definitions and the process of protein-energy wasting in patients with chronic kidney disease who are not on dialysis, and examines when changes in the diet is appropriate and areas that need further research." +"Adherence to a Mediterranean lifestyle may be a useful primary and secondary prevention strategy for chronic kidney disease (CKD). This cross-sectional study aimed to explore adherence to a Mediterranean lifestyle and its association with cardiometabolic markers and kidney function in 99 people aged 73?2 � 10?5 years with non-dialysis dependant CKD (stages 3-5) at a single Australian centre. Adherence was assessed using an a priori index, the Mediterranean Lifestyle (MEDLIFE) index. Cardiometabolic markers (total cholesterol, LDL-cholesterol, HbA1c and random blood glucose) and kidney function (estimated GFR) were sourced from medical records and blood pressure measured upon recruitment. Overall, adherence to a Mediterranean lifestyle was moderate to low with an average MEDLIFE index score of 11?33 � 3?31. Adherence to a Mediterranean lifestyle was associated with employment (r 0?30, P = 0?004). Mediterranean dietary habits were associated with cardiometabolic markers, such as limiting sugar in beverages was associated with lower diastolic blood pressure (r 0?32, P = 0?002), eating in moderation with favourable random blood glucose (r 0?21, P = 0?043), having more than two snack foods per week with HbA1c (r 0?29, P = 0?037) and LDL-cholesterol (r 0?41, P = 0?002). Interestingly, eating in company was associated with a lower frequency of depression (? 2 5?975, P = 0?015). To conclude, Mediterranean dietary habits were favourably associated with cardiometabolic markers and management of some comorbidities in this group of people with non-dialysis dependent CKD.","Keeping a Mediterranean lifestyle may be a useful primary and secondary prevention plan for chronic kidney disease (CKD). This study aims to explore adherence (commitment) to a Mediterranean lifestyle and its association with blood pressure, cholesterol, and other heart related measures, as well as its impact on kidney function. This study includes 99 people aged 73.2 years (plus or minus 10.5 years) with chronic kidney disease who are not on dialysis, a process that uses a machine to filter blood. Adherence is assessed (measured) using the Mediterranean Lifestyle (MEDLIFE) index, that includes questions on food consumption, dietary habits, physical activity, rest, and social interactions. Tests on total cholesterol, LDL (""bad"") cholesterol, blood sugar levels in the last 2-3 months and at any random time, and kidney function are collected from medical records and blood pressure measured at the start of the study. Overall, adherence to a Mediterranean lifestyle is moderate to low with an average MEDLIFE index score of 11?33 � 3?31. Adherence to a Mediterranean lifestyle is associated with employment. Mediterranean dietary habits are associated with certain heart-related measures, such as how limiting sugar in beverages is associated with lower diastolic blood pressure (bottom number of blood pressure readings), eating in moderation with favorable blood sugar levels tested at random, having more than two snack foods per week with blood sugar tests, and LDL-cholesterol. Interestingly, eating with others is associated with a lower frequency of depression. In conclusion, Mediterranean dietary habits are positively linked with heart-related measures and care of other health problems in this group of people with non-dialysis chronic kidney disease." +"Introduction: Secondary hyperparathyroidism (SHPT) represents a complication of chronic kidney disease (CKD). Vitamin D system is altered since early CKD, and vitamin D deficiency is an established trigger of SHPT. Although untreated SHPT may degenerate into tertiary hyperparathyroidism with detrimental consequences in advanced CKD, best treatments for counteracting SHPT from stage 3 CKD are still debated. Enthusiasm on prescription of vitamin D receptor activators (VDRA) in non-dialysis renal patients, has been mitigated by the risk of low bone turnover and positive calcium-phosphate balance. Nutritional vitamin D is now suggested as first-line therapy to treat SHPT with low 25(OH)D insufficiency. However, no high-grade evidence supports the best choice between ergocalciferol, cholecalciferol, and calcifediol (in its immediate or extended-release formulation). Areas covered: The review discusses available data on safety and efficacy of nutritional vitamin D, VDRA and nutritional therapy in replenishing 25(OH)D deficiency and counteracting SHPT in non-dialysis CKD patients. Expert opinion: Best treatment for low 25(OH)D and SHPT remains unknown, due to incomplete understanding of the best homeostatic, as mutable, adaptation of mineral metabolism to CKD progression. Nutritional vitamin D and nutritional therapy appear safest interventions, whenever contextualized with single-patient characteristics. VDRA should be restricted to uncontrolled SHPT by first-line therapy.","A disease of the parathyroid (calcium-regulating) glands in the neck that is caused by another disease is called secondary hyperparathyroidism (SHPT), with symptoms that include weak bones, kidney stones, and tiredness. SHPT represents a complication or bad effect of chronic kidney disease (CKD). The vitamin D system is altered early in CKD, and not enough vitamin D is an established trigger of SHPT. Untreated SHPT may become tertiary hyperparathyroidism (when too much of the parathyroid hormone is produced even when the original problem is corrected) with harmful consequences in advanced chronic kidney disease. However, the best treatments for acting against SHPT from stage 3 chronic kidney disease are still debated. Enthusiasm on prescription of vitamin D treatments in non-dialysis kidney patients is lessened by the risk of low bone turnover (when the bone tissue is reabsorbed and replaced by a new bone), and positive calcium-phosphate balance that makes sure systems in the body work well. Nutritional vitamin D is now suggested as first-line therapy to treat secondary hyperparathyroidism with low vitamin D blood test scores. However, no high-grade evidence supports the best choice between which vitamin D product to prescribe. Other areas covered in this review are the data available on safety and effectiveness (success) of vitamin D, vitamin D prescriptions, and nutritional therapy in restoring vitamin D to normal levels (via diet) and acting against secondary hyperparathyroidism. The expert opinion is that the best treatment for low vitamin D levels and secondary hyperparathyroidism remains unknown due to some missing key information. Nutritional vitamin D and nutritional therapy appear to be the safest interventions (treatments), when considering the individual characteristics of each patient. Prescriptions for vitamin D should be limited to only uncontrolled secondary hyperparathyroidism by first treatment recommended." +"Introduction: Secondary hyperparathyroidism (SHPT) represents a complication of chronic kidney disease (CKD). Vitamin D system is altered since early CKD, and vitamin D deficiency is an established trigger of SHPT. Although untreated SHPT may degenerate into tertiary hyperparathyroidism with detrimental consequences in advanced CKD, best treatments for counteracting SHPT from stage 3 CKD are still debated. Enthusiasm on prescription of vitamin D receptor activators (VDRA) in non-dialysis renal patients, has been mitigated by the risk of low bone turnover and positive calcium-phosphate balance. Nutritional vitamin D is now suggested as first-line therapy to treat SHPT with low 25(OH)D insufficiency. However, no high-grade evidence supports the best choice between ergocalciferol, cholecalciferol, and calcifediol (in its immediate or extended-release formulation). Areas covered: The review discusses available data on safety and efficacy of nutritional vitamin D, VDRA and nutritional therapy in replenishing 25(OH)D deficiency and counteracting SHPT in non-dialysis CKD patients. Expert opinion: Best treatment for low 25(OH)D and SHPT remains unknown, due to incomplete understanding of the best homeostatic, as mutable, adaptation of mineral metabolism to CKD progression. Nutritional vitamin D and nutritional therapy appear safest interventions, whenever contextualized with single-patient characteristics. VDRA should be restricted to uncontrolled SHPT by first-line therapy.","Secondary hyperparathyroidism (SHPT), which is when the parathyroid glands become hyperactive due to a disease outside the glands, can be an effect of long-lasting or chronic kidney disease (CKD). Vitamin D metabolism is altered since early CKD. Vitamin D loss is a known trigger of SHPT. While untreated SHPT may worsen to uncontrolled, excess parathyroid hormone production with harmful effects in advanced CKD, best treatments for preventing this worsening are unknown. The idea of using vitamin D target site or receptor activators (VDRA) in working kidney patients, has been weakened by the risk of bone breakdown and calcium-phosphate imbalance. Nutritional vitamin D is now suggested as first-choice therapy for SHPT and low active vitamin D levels. Still, no high-quality evidence supports the best choice among different vitamin D medications. The review explores available data on the safety and success of nutritional vitamin D, VDRA, and nutritional therapy in replenishing active vitamin D shortage and treating SHPT in working kidney CKD patients. Best treatment for low active vitamin D and SHPT is unknown, due to a partial grasp of the best self-regulating mechanism of mineral metabolism to CKD progression. Nutritional vitamin D and therapy appear safest treatments, when considering single-patient characteristics. VDRA should be limited to uncontrolled SHPT by first-choice therapy." +"Chronic kidney disease (CKD) is a prevalent worldwide public burden that increasingly compromises overall health as the disease progresses. Two of the most negatively affected tissues are bone and skeletal muscle, with CKD negatively impacting their structure, function and activity, impairing the quality of life of these patients and contributing to morbidity and mortality. Whereas skeletal health in this population has conventionally been associated with bone and mineral disorders, sarcopenia has been observed to impact skeletal muscle health in CKD. Indeed, bone and muscle tissues are linked anatomically and physiologically, and together regulate functional and metabolic mechanisms. With the initial crosstalk between the skeleton and muscle proposed to explain bone formation through muscle contraction, it is now understood that this communication occurs through the interaction of myokines and osteokines, with the skeletal muscle secretome playing a pivotal role in the regulation of bone activity. Regular exercise has been reported to be beneficial to overall health. Also, the positive regulatory effect that exercise has been proposed to have on bone and muscle anatomical, functional, and metabolic activity has led to the proposal of regular physical exercise as a therapeutic strategy for muscle and bone-related disorders. The detection of bone- and muscle-derived cytokine secretion following physical exercise has strengthened the idea of a cross communication between these organs. Hence, this review presents an overview of the impact of CKD in bone and skeletal muscle, and narrates how these tissues intrinsically communicate with each other, with focus on the potential effect of exercise in the modulation of this intercommunication.","Chronic kidney disease is a common health condition around the world and impacts the overall health of a person as the disease gets worse. Bones and muscles attached to bones are tissues highly affected by chronic kidney disease, which damages their functions and activities and contributes to poor quality of life. Sarcopenia is a disorder that results in loss of muscle mass and function and is found to impact overall skeletal muscle health in chronic kidney disease. Bone and muscle tissues are linked in the body, and together, they regulate systems in the body that help the body function and process and distribute nutrients. The skeletal muscle cells release small proteins that regulate different parts of the body, including bone activity. Regular exercise is found to be beneficial to overall health. Also, the positive effect exercise is thought to have on bones and muscles, as well as on function and activity, leads to the suggestion of regular physical exercise as a way to help muscle and bone-related disorders. The detection of bone and muscle proteins after exercise strengthens the idea of a cross communication between these organs. This review presents an overview of the impact of chronic kidney disease in bones and muscles attached to bones and describes how these tissues communicate with each other, with a focus on the possible effect of exercise." +"The presence of chronic heart failure (CHF) results in a significant risk of leg oedema. Medical compression (MC) treatment is one of the basic methods of leg oedema elimination in patients with chronic venous disease and lymphedema, but it is not routinely considered in subjects with CHF-related swelling. In the study, an overview of the current knowledge related to the benefits and risk of using MC in the supportive treatment of leg oedema in CHF patients is presented. The available studies dedicated the comprehensive management of leg swelling using MC in CHF patients published in the English language literature till December 2019 were evaluated in term of the treatment efficacy and safety. In studies performed on CHF populations, manual lymphatic drainage, MC stocking, multilayer bandaged, as well as intermittent pneumatic compression or electric calf stimulations were used. The current evidence is based on non-randomized studies, small study cohorts, as well as very heterogenous populations. The use of the intermittent pneumatic compression in CHF patients significantly increases the right auricular pressure and mean pulmonary artery pressures as well as decreases systemic vascular resistance in most patients without the clinical worsening. The transient and rapid increase in the human atrial natriuretic peptide, after an application of the MC stocking in New York Heart Association (NYHA) class II patients was observed without clinical exacerbation. An application of the multilayer bandages in NYHA classes III and IV patients lead a significant increase in the right arterial pressure and lead to transient deterioration of the right and the left ventricular functions. In the manual lymphatic drainage study, aside from expected leg circumference reduction, no clinical worsening was observed. In a pilot study performed in a small cohort of CHF patients, electrical calf stimulation use resulted in a reduction in the lean mass of the legs without cardiac function worsening. The use of local leg compression can be considered stable CHF patients without decompensated heart function for both CHF-related oedema treatment and for treatment of the concomitant diseases leading to leg swelling occurrence. The use of MC in more severe classes of CHF (NYHA III and IV) should be the subject of future clinical studies to select the safest and most efficient compression method as well as to select the patients who benefit most from this kind of treatment.","Long-lasting or chronic heart failure (CHF) results in a significant risk of leg oedema. Leg oedema is swelling due to excess fluid accumulation in the body. Medical compression (MC) treatment is a basic method to eliminate leg oedema in patients with chronic venous disease (abnormal veins) and lymphedema (swelling). However, it is not routinely considered in subjects with CHF-related swelling. This study is an overview of evidence related to the benefits and risk of using MC in the treatment of leg oedema in CHF patients. This paper reviews research published in English up until December 2019. The reviewed paper focused on the management of leg swelling through the use of MC within CHF patients. All reviewed papers were evaluated for treatment efficacy and safety. In studies of CHF populations, several treatment options were used. These options include manual lymphatic drainage, MC stocking, multilayer bandaged, and electric calf stimulations. The current evidence is based on non-randomized studies, small study cohorts, as well as very diverse populations. Intermittent pneumatic compression is a treatment that uses a device that squeezes fluids from an infected area. The treatment in CHF patients significantly increased pressure in the lungs and heart. The treatment decreased systemic vascular resistance, or the resistance that must be overcome to push blood through veins, in most patients without the disease worsening. Human atrial natriuretic peptide, a substance in the body that reduces fluid volume, increased in patients without clinical exacerbation or pain. Use of multilayer bandages in patients significantly increased the right arterial (section of the heart) pressure. Use of multilayer bandages also lead to deterioration of heart chamber function. In the manual lymphatic drainage study, aside from reducing leg size, no clinical worsening was observed. In a trial study performed in a small cohort of CHF patients, electrical calf stimulation resulted in reduced lean mass of the legs without cardiac function worsening. The use of local leg compression within CHF patients could be considered. Use of local leg compression did not decompensate heart function in patients with either CHF-related oedema or concomitant (accompanying) diseases leading to leg swelling. The use of MC in more severe classes of CHF should be further studied to select the safest and most efficient compression method. The patients who would benefit most from MC treatment should also be identified." +"Objectives: This study was conducted to determine hemodynamic and clinical tolerance under short-stretch compression therapy in elderly patients suffering from mixed-etiology leg ulcers. Design: Transversal observational study conducted in 25 hospitalized patients with a moderate peripheral arterial occlusive disease defined as an ankle-brachial pressure index>0.5, an ankle pressure of> 70mm Hg and a toe cuff pressure (TP)> 50mm Hg. Material and methods: Short-stretch bandages were applied daily with pressures from 20 to 30mm Hg. Ankle-brachial pressure, great toe laser Doppler flowmetry (LDF) and transcutaneous oxygen pressure (TcPO2) on dorsum of the foot were measured at baseline and after its removal at 24hours. Great toe LDF was also measured at 10minutes after bandage application. Compression pressure (CP) was measured with a sub-bandage device at baseline, at 10minutes and before bandage removal at 24hours. Clinical tolerance was evaluated taking into account the patient's pain and skin tolerance. Results: Mean age of patients was 80�15 years. Median duration of ulcers was 18 months. Hypertension was highly prevalent. One third of patients had diabetes. Toe pressure index and TcPO2 values did not significantly change under compression therapy (P=0.51 and P=0.09, respectively) whereas CP decreased significantly during 24hours. The loss of CP was significant 10minutes after bandage application (P<0.001). Nearly all ulcers were painful prior to placement of compression therapy and required level 1 analgesics. One patient required level 2 analgesic for pain relief. No increase in pain and no ischemic skin damage occurred under compression therapy. Conclusions: In elderly patients with mixed leg ulcers and with an absolute TP>50mm Hg, short-stretch compression of up to 30mm Hg does not adversely affect arterial flow and appears clinically well tolerated. Such bandages with appropriate levels of compression may aid ulcer healing by treating the venous part of the disease.","The aim of this study was to determine how short-stretch compression therapy affected blood flow and clinical tolerance (how much a patient could take). The study was conducted in elderly patients suffering from leg ulcers (sores) caused by various reasons. This observational study was conducted in 25 hospitalized patients with moderate peripheral aterial occlusive disease, or limited blood flow to lower limbs. Short-stretch bandages were applied daily with pressures ranging from 20 to 30mm Hg. Several health measures were taken before the bandages were applied and after 24 hours. These measures include: ankle-brachial pressure, great toe laser Doppler flowmetry (LDF), and transcutaneous oxygen pressure (TcPO2) on top of the foot. LDF measures blood flow. TcPO2 measures oxygen in the skin. Great toe LDF was also measured at 10 minutes after bandage application. Compression pressure (CP) was measured before bandages were placed on, at 10 minutes, and before bandage removal at 24 hours. Clinical tolerance was evaluated taking into account the patient's pain and skin tolerance. The average age of patients was 80 � 15 years. Median (average) duration of ulcers was 18 months. Hypertension (high blood pressure) was highly common. One third of patients had diabetes. Toe pressure index and TcPO2 values did not significantly change under compression therapy. CP decreased significantly during 24 hours. The loss of CP was significant 10 minutes after bandages were put on. Nearly all ulcers were painful prior to placement of compression therapy and required level 1 (minor) pain medication. One patient required level 2 (more intense) pain medication for pain relief. No increase in pain and no skin damage due to low blood flow occurred under compression therapy. The authors conclude that elderly patients with mixed leg ulcers using short-stretch compression did not have adversely (negatively) affected blood flow to the heart. The treatment was clinically well tolerated. Bandages with appropriate levels of compression may aid ulcer healing by treating the diseased veins." +"Objectives: This study was conducted to determine hemodynamic and clinical tolerance under short-stretch compression therapy in elderly patients suffering from mixed-etiology leg ulcers. Design: Transversal observational study conducted in 25 hospitalized patients with a moderate peripheral arterial occlusive disease defined as an ankle-brachial pressure index>0.5, an ankle pressure of> 70mm Hg and a toe cuff pressure (TP)> 50mm Hg. Material and methods: Short-stretch bandages were applied daily with pressures from 20 to 30mm Hg. Ankle-brachial pressure, great toe laser Doppler flowmetry (LDF) and transcutaneous oxygen pressure (TcPO2) on dorsum of the foot were measured at baseline and after its removal at 24hours. Great toe LDF was also measured at 10minutes after bandage application. Compression pressure (CP) was measured with a sub-bandage device at baseline, at 10minutes and before bandage removal at 24hours. Clinical tolerance was evaluated taking into account the patient's pain and skin tolerance. Results: Mean age of patients was 80�15 years. Median duration of ulcers was 18 months. Hypertension was highly prevalent. One third of patients had diabetes. Toe pressure index and TcPO2 values did not significantly change under compression therapy (P=0.51 and P=0.09, respectively) whereas CP decreased significantly during 24hours. The loss of CP was significant 10minutes after bandage application (P<0.001). Nearly all ulcers were painful prior to placement of compression therapy and required level 1 analgesics. One patient required level 2 analgesic for pain relief. No increase in pain and no ischemic skin damage occurred under compression therapy. Conclusions: In elderly patients with mixed leg ulcers and with an absolute TP>50mm Hg, short-stretch compression of up to 30mm Hg does not adversely affect arterial flow and appears clinically well tolerated. Such bandages with appropriate levels of compression may aid ulcer healing by treating the venous part of the disease.","This study aimed to find blood flow and tolerance under less-stretchable compression treatment in elderly patients with mixed-cause leg sores or open wounds (leg ulcers). We studied 25 hospitalized patients with blocked blood vessels in the limbs. Less-stretchable compression bandages were applied daily. Ankle pressure, toe blood flow, and oxygen pressure at the skin on the top of the foot was measured at the start and after bandage removal at 24 hours. Big toe blood flow was measured 10 minutes after applying the bandage. Compression pressure was measured with a special device at the start, at 10 minutes, and before bandage removal at 24 hours. Patient tolerance was measured while considering the patient's pain and skin tolerance. Average age of patients was 80 years. Average duration of sores or open wounds was 18 months. High blood pressure was common. One third of patients had diabetes. Neither pressure nor oxygen to the toes changed with compression therapy, but compression pressure decreased over 24 hours. The compression pressure loss was noticeable 10 minutes after applying the bandage. Nearly all ulcers were painful before compression therapy and needed painkillers. One patient needed a more powerful pain killer. No increase in pain or blood-flow-related skin damage occured with compression. In elderly patients with mixed leg ulcers and sufficient toe pressure, less-stretchable compression does not negatively affect blood flow and appears tolerated. Bandages with appropriate compression may aid ulcer healing by treating the blood flow part of the disease." +"Compression therapy is the basic therapy in phlebology and lymphology. The pressure under the bandages has to exceed the intravenous pressure especially in standing position. Different compression materials such as short stretch systems, long stretch bandages and compression garments work differently on ambulatory venous hypertension, speed of reducing edema and arterial flow. Compression with high stiffness, inelastic materials is more effective than compression with low stiffness, elastic materials. These materials have to be placed correctly. Inelastic systems should be applied with high initial pressure because the pressure will loose at some time after walking. Even after one week of wearing, inelastic bandages keep higher resting and working pressure during walking than elastic bandages. However, more important is that they have lower resting pressure than elastic materials. Long stretch bandages and compression garments with great extensibility ensure low working pressure and higher resting pressure than short stretch systems.","Compression therapy is the basic therapy when treating the circulatory (blood) or lymphatic (body drainage) system. The pressure under the bandages has to exceed the intravenous pressure, especially when standing. Intravenous pressure is the pressure of blood in veins. Different compression materials work differently on ambulatory venous hypertension (excess pressure in veins). The material used can affect both the rate in which swelling is reduced and blood flow. Some compression materials include short stretch systems, long stretch bandages, and compression garments. Compression with very stiff materials is more effective than compression with low stiffness, elastic materials. These materials have to be placed correctly. Inelastic systems should be applied with high initial pressure. This is because the pressure will decrease after walking. Even after one week of wearing, inelastic bandages keep higher optimal pressure during walking than elastic bandages. More importantly, inelastic bandages have lower resting pressure than elastic materials. Long stretch bandages and compression garments that are able to stretch ensure low working pressure and higher resting pressure than short stretch systems." +"Aim: A review is given on the different tools of compression therapy and their mode of action. Methods: Interface pressure and stiffness of compression devices, alone or in combination can be measured in vivo. Hemodynamic effects have been demonstrated by measuring venous volume and flow velocity using MRI, Duplex and radioisotopes, venous reflux and venous pumping function using plethysmography and phlebodynamometry. Oedema reduction can be measured by limb volumetry. Results: Compression stockings exerting a pressure of ~20 mm Hg on the distal leg are able to increase venous blood flow velocity in the supine position and to prevent leg swelling after prolonged sitting and standing. In the upright position, an interface pressure of more than 50 mmHg is needed for intermittent occlusion of incompetent veins and for a reduction of ambulatory venous hypertension during walking. Such high intermittent interface pressure peaks exerting a ""massaging effect"" may rather be achieved by short stretch multilayer bandages than by elastic stockings. Conclusion: Compression is a cornerstone in the management of venous and lymphatic insufficiency. However, this treatment modality is still underestimated and deserves better understanding and improved educational programs, both for patients and medical staff.","This study aimed to evaluate different tools used in compression therapy and assess (measure) how they work. The levels of pressure and stiffness of the compression devices, alone or in combination with other materials, can be measured on living organisms. Hemodynamic (blood flow) effects have been demonstrated by measuring venous (vein) volume and flow velocity using several testing methods. Venous reflux (reverse flow) and venous pumping function have been demonstrated using bodily fluid volume and pressure measurements. Oedema (swelling) reduction can be measured by limb volumetry, a method of suspending a limb in water to determine the amount of water displaced. Compression stockings putting pressure on the lower leg are able to increase venous blood flow velocity while patients are lying down. Compression stockings are also able to prevent leg swelling after prolonged sitting and standing. In the upright position, specific pressure (>50 mmHg) is needed for intermittent (irregular) closing of abnormal veins and for pressure reduction during walking. High, intermittent pressure peaks exerting a ""massaging effect"" may be achieved by short stretch multilayer bandages instead of elastic stockings. Compression is important in the management of not fully functioning venous and lymphatic systems. However, using compression as a treatment is still underestimated. Compression deserves better understanding and improved educational programs for both patients and medical staff." +"Background: A too high resting pressure of compression devices is poorly tolerated and may cause skin defects, especially in patients with concomitant arterial occlusive disease. Aim: To investigate whether low compression pressure will improve venous pumping function in patients with venous incompetence. Material and methods: Venous pumping function was assessed in 20 patients with severe reflux in the great saphenous vein by measuring ejection fraction (EF) using strain-gauge plethysmography. Measurements were repeated after application of knee-high medical compression stockings and of inelastic bandages applied with a pressure of 20, 40 and 60 mmHg in the supine position. Results: EF was significantly reduced compared with healthy controls. Compression stockings exerting a median pressure of 27 mmHg (interquartile range [IQR] 25-29) in the supine and 30.5 mmHg (IQR 28.25-34.25) in the standing position produced a moderate, non-significant improvement of EF of 17%. Inelastic bandages with a resting pressure of 20.5 mmHg (IQR 20-22) in the supine position resulting in a standing pressure of 36 mmHg (IQR 33-40.75) led to a significant increase of EF of 61.5% (P < 0.01). A further increase of the resting pressure to 40 and 60 mmHg achieved an increase of the EF of 91% and 98%, respectively (P < 0.001). Conclusions: In patients with venous pumping failure, inelastic bandages produce a significant pressure-dependent increase of EF. A significant improvement in venous pumping function was achieved with inelastic bandages even at a resting pressure of 20 mmHg.","A too high resting pressure of compression devices, or when the device is just lying on the skin, is poorly tolerated and may cause skin defects. This is especially common in patients with concomitant arterial occlusive disease, blockage of an artery. The goal of this study was to investigate if low compression pressure improves vein pumping function in patients with defective veins. Vein pumping function was assessed (measured) in 20 patients with severe reflux, or the backup of blood, in the great saphenous vein in the leg. This was done by measuring ejection fraction (EF; percentage of blood leaving the heart when it contracts). Measurements were taken after application of knee-high medical compression stockings and of inelastic bandages applied while lying down. Results showed EF was significantly reduced compared with healthy controls. Compression stockings produced a moderate, non-significant improvement of EF. Inelastic bandages led to a significant increase of EF. Increased pressure of the inelastic bandages achieved an increase of the EF. The study concluded that, in patients with venous (vein) pumping failure, inelastic bandages produce a significant pressure-dependent increase of EF. This means that as pressure increases, EF increases. Significant improvement in venous pumping function was achieved with inelastic bandages, even at resting pressures." +"Background: A too high resting pressure of compression devices is poorly tolerated and may cause skin defects, especially in patients with concomitant arterial occlusive disease. Aim: To investigate whether low compression pressure will improve venous pumping function in patients with venous incompetence. Material and methods: Venous pumping function was assessed in 20 patients with severe reflux in the great saphenous vein by measuring ejection fraction (EF) using strain-gauge plethysmography. Measurements were repeated after application of knee-high medical compression stockings and of inelastic bandages applied with a pressure of 20, 40 and 60 mmHg in the supine position. Results: EF was significantly reduced compared with healthy controls. Compression stockings exerting a median pressure of 27 mmHg (interquartile range [IQR] 25-29) in the supine and 30.5 mmHg (IQR 28.25-34.25) in the standing position produced a moderate, non-significant improvement of EF of 17%. Inelastic bandages with a resting pressure of 20.5 mmHg (IQR 20-22) in the supine position resulting in a standing pressure of 36 mmHg (IQR 33-40.75) led to a significant increase of EF of 61.5% (P < 0.01). A further increase of the resting pressure to 40 and 60 mmHg achieved an increase of the EF of 91% and 98%, respectively (P < 0.001). Conclusions: In patients with venous pumping failure, inelastic bandages produce a significant pressure-dependent increase of EF. A significant improvement in venous pumping function was achieved with inelastic bandages even at a resting pressure of 20 mmHg.","A too high pressure from compression devices is poorly tolerated and may causes skin damage, espeically in those with blocked blood vessels in limbs. We aim to check if low compression pressure may improve blood vessel pumping in patients with impaired blood vessels. Blood vessel pumping function was measured in 20 patients with severely impaired blood flow in the body's largest vein. Measurements were repeated after using knee-high compression socks and inelastic bandages applied with low, medium, and high pressure while lying down. The amount of blood pumped was compared to healthy patients. Compression socks exerted an average pressure of 27 mmHg while lying down and slightly higher pressure of 30.5 mmHg while standing. This led to a minor improvement in the amount of blood pumped, or ejection fraction (EF), by 17%. Inelastic bandages with a pressure of 20.5 mmHg while lying down led to a standing pressure of 36 mmHg, which led to a major increase in EF by 61.5%. A larger increase of pressure to 40 and 60 mmHg led to an increase in the amount of blood pumped of 91% and 98%, respectively. In those with impaired blood vessel pumping, inelastic bandages lead to a pressure-dependent increase of EF. Inelastic bandages even with a pressure of 20 mmHg improved blood vessel pumping." +"Although compression therapy was initially described over 2,000 years ago (Felty and Rooke Semin Vasc Surg Mar 18:36-40, 1), several patients with edema do not receive appropriate compression therapy. Instead, most patients with edema are treated primarily with diuretics. Compression therapy is the cornerstone of treatment of venous edema and lymphatic disorders. Compression therapy decreases the foot and leg volume and reduces venous reflux and venous hypertension. Compression can be achieved by multiple different modalities, such as inelastic bandages; multilayered wraps; short, medium, and long stretch bandages; graduated compression stockings; and pneumatic compression devices. The major criticism of compression therapy is poor patient compliance. Compliance can be improved by selecting appropriate compression therapy tailored to the needs of the individual patient and by providing adequate patient education.","Although compression therapy was first described over 2,000 years ago, many patients with edema do not receive appropriate compression therapy. Edema is swelling within the body due to excess fluid build up. Instead, most patients with swelling are treated primarily with diuretics (drugs that promote urination). Compression therapy is a vital treatment for venous edema (vein swelling) and lymphatic disorders (disorders of the body's drainage system). Compression therapy decreases the foot and leg volume. Compression therapy also reduces venous reflux and venous hypertension. Venous reflux is abnormal back up of blood in the veins. Venous hypertension is abnormal blood pressure. Compression can be achieved by multiple different methods. These methods include inelastic bandages; multilayered wraps; short, medium, and long stretch bandages; graduated (pressure-varying) compression stockings; and pneumatic (inflatable) compression devices. The major criticism of compression therapy is that patients do not always comply with orders. Compliance with doctor orders can be increased by selecting the right compression therapy for the individual patient. Patients should also be provided with adequate education on the treatment." +"Chronic venous insufficiency (CVI) has a significant socioeconomic impact. The existent venous hypertension and the subsequent capillary hypertension result in trophic skin damage culminating in an ulcer. Venous ulcers affect 1-3% of the adult population. Compression therapy provides the basis for noninvasive treatment of CVI. It can be applied alone or in combination with invasive strategies. A variety of materials are available for phlebological compression therapy in the form of compression bandages and compression hosiery. Knowledge of the different qualities of the compression materials and their mode of action is important in choosing the correct means of compression with regard to clinical findings and the patient's needs. As far as possible, the compression method applied should be monitored for any loss of effectivity during regular follow-up examinations of the patients. The following article deals with this topic. A new option for compression therapy of crural ulcers is presented and the possibility for checking the effectiveness of the compression stockings during outpatient","Chronic venous insufficiency (CVI), or malfunctioning veins, has a significant impact on a person's social and economic status. Continual pressure in the circulatory system can result in skin damage before forming an ulcer (sore). Venous ulcers (sores from irregular blood flow) affect 1-3% of the adult population. Compression therapy provides the basis for noninvasive (nonsurgical) treatment of CVI. It can be applied alone or in combination with invasive (e.g. surgery) strategies. A variety of materials are available for compression therapy in the form of bandages or hosiery (legwear). Knowledge of the different compression materials and how they work is important in choosing the correct compression treatment to meet health goals and patient needs. The compression method applied should be monitored for any decrease in effectiveness. The following article deals with this topic. This paper presents a new option for compression therapy of crural (leg) ulcers. This paper also checks the effectiveness of the compression stockings during outpatient treatment." +"Venous (gravitational) leg ulcers are unsightly, sometimes painful and often difficult to heal. They are associated with incompetence of valves in the deep leg veins and venous hypertension. The main approaches in the management of venous leg ulcers have been to reduce the 'back pressure' in the veins by surgical removal of any varicose veins, postural drainage (elevation of the legs when the patient is lying or seated), and use of compression therapy with bandages, hosiery or intermittent pneumatic compression. In this article, we review the efficacy and discuss correct use of compression therapy.","Venous (gravitational) leg ulcers (leg sores) are unappealing to the eye, sometimes painful, and often difficult to heal. They are associated with incompetence of valves in the deep leg veins and venous hypertension (high blood pressure in veins). There are several approaches used in the management of venous leg ulcers. These approaches focus on reducing the 'back pressure' or 'reverse pressure' in the veins. These approaches include surgical removal of any varicose veins (twisted, enlarged veins), postural drainage (elevation of the legs when the patient is lying or seated), and use of compression therapy with bandages, hosiery (legwear) or intermittent (periodic) pneumatic (inflatable) compression. This article reviews the success and correct use of compression therapy." +"Venous (gravitational) leg ulcers are unsightly, sometimes painful and often difficult to heal. They are associated with incompetence of valves in the deep leg veins and venous hypertension. The main approaches in the management of venous leg ulcers have been to reduce the 'back pressure' in the veins by surgical removal of any varicose veins, postural drainage (elevation of the legs when the patient is lying or seated), and use of compression therapy with bandages, hosiery or intermittent pneumatic compression. In this article, we review the efficacy and discuss correct use of compression therapy.","Venous leg ulcers (leg sores from veins) are ugly, sometimes painful, and often difficult to heal. Venous leg ulcers are linked to high blood pressure in impaired leg veins. Main treatments of venous leg ulcers have been to reduce pressure in veins by surgical removal of enlarged veins, drainage using gravity, and compression from bandages, legwear, or inflatable leg sleeves. In this article, we review the effectiveness and correct use of compression therapy." +"Background: Up to 1% of adults will suffer from leg ulceration at some time. The majority of leg ulcers are venous in origin and are caused by high pressure in the veins due to blockage or weakness of the valves in the veins of the leg. Prevention and treatment of venous ulcers is aimed at reducing the pressure either by removing / repairing the veins, or by applying compression bandages / stockings to reduce the pressure in the veins. The vast majority of venous ulcers are healed using compression bandages. Once healed they often recur and so it is customary to continue applying compression in the form of bandages, tights, stockings or socks in order to prevent recurrence. Compression bandages or hosiery (tights, stockings, socks) are often applied for ulcer prevention. Objectives: To assess the effects of compression hosiery (socks, stockings, tights) or bandages in preventing the recurrence of venous ulcers. To determine whether there is an optimum pressure/type of compression to prevent recurrence of venous ulcers. Main results: No trials compared recurrence rates with and without compression. One trial (300 patients) compared high (UK Class 3) compression hosiery with moderate (UK Class 2) compression hosiery. A intention to treat analysis found no significant reduction in recurrence at five years follow up associated with high compression hosiery compared with moderate compression hosiery (relative risk of recurrence 0.82, 95% confidence interval 0.61 to 1.12). This analysis would tend to underestimate the effectiveness of the high compression hosiery because a significant proportion of people changed from high compression to medium compression hosiery. Compliance rates were significantly higher with medium compression than with high compression hosiery. One trial (166 patients) found no difference in recurrence between two types of medium (UK Class 2) compression hosiery (relative risk of recurrence with Medi was 0.74, 95% confidence interval 0.45 to 1.2). Both trials reported that not wearing compression hosiery was strongly associated with ulcer recurrence and this is circumstantial evidence that compression reduces ulcer recurrence. No trials were found which evaluated compression bandages for preventing ulcer recurrence. Reviewer's conclusions: No trials compared compression with vs no compression for prevention of ulcer recurrence. Not wearing compression was associated with recurrence in both studies identified in this review. This is circumstantial evidence of the benefit of compression in reducing recurrence. Recurrence rates may be lower in high compression hosiery than in medium compression hosiery and therefore patients should be offered the strongest compression with which they can comply. Further trials are needed to determine the effectiveness of hosiery prescribed in other settings, i.e. in the UK community, in countries other than the UK.","Up to 1% of adults will suffer from leg ulceration (leg sores) at some time. The majority of leg ulcers come from issues within veins. They are caused by high pressure in the veins due to blockage or weakness of the valves in the veins of the leg that prevent backflow or reverse blood flow. Prevention and treatment of venous ulcers is aimed at reducing the pressure. This is achieved by removing or repairing the veins. It can also be achieved by applying compression material to reduce vein pressure. Most venous ulcers are healed using compression bandages. Once healed, they often recur or reappear. Therefore, it is common to continue applying compression in the form of bandages, tights, stockings, or socks to prevent recurrence. Compression bandages or hosiery (tights, stockings, socks) are often applied for ulcer prevention. The aim of this study was to assess (measure) the effects of compression hosiery (socks, stockings, tights) or bandages in preventing the recurrence of venous ulcers. The study also aimed to determine whether there is an optimum pressure/type of compression to prevent recurrence of venous ulcers. None of the reviewed reports compared recurrence rates with and without compression. One trial (300 patients) compared high compression hosiery with moderate compression hosiery. No significant reduction in recurrence at five years follow up was associated with high compression hosiery when compared with moderate compression hosiery. This may underestimate the effectiveness of the high compression hosiery as a large proportion of people changed from high compression to medium compression hosiery. Compliance rates, or the amount of people who used compression consistently, were higher with medium compression than with high compression hosiery. One trial found no difference in recurrence between two types of medium compression hosiery. Both trials reported that not wearing compression hosiery was strongly associated with ulcer recurrence. This is circumstantial evidence that compression reduces ulcer recurrence. No studies that evaluated compression bandages for preventing ulcer recurrence were found. The authors concluded on several points following this evidence review. First, no trials compared compression with no compression for prevention of reoccurring ulcers. Second, not wearing compression was associated with ulcer reoccurrence. This is circumstantial evidence of the benefit of compression in reducing recurrence. Third, recurrence rates may be lower if patients wear high compression hosiery over medium compression hosiery. Because of this, patients should be offered the strongest compression they can tolerate. Lastly, further studies are needed to understand the effectiveness of hosiery utilized in alternative locations." +"Objectives: This study was conducted to define bandage pressures that are safe and effective in treating leg ulcers of mixed arterial-venous etiology. Methods: In 25 patients with mixed-etiology leg ulcers who received inelastic bandages applied with pressures from 20 to 30, 31 to 40, and 41 to 50 mm Hg, the following measurements were performed before and after bandage application to ensure patient safety throughout the investigation: laser Doppler fluxmetry (LDF) close to the ulcer under the bandage and at the great toe, transcutaneous oxygen pressure (TcPo(2)) on the dorsum of the foot, and toe pressure. Ejection fraction (EF) of the venous pump was performed to assess efficacy on venous hemodynamics. Results: LDF values under the bandages increased by 33% (95% confidence interval [CI], 17-48; P < .01), 28% (95% CI, 12-45; P < .05), and 10% (95% CI, -7 to 28), respectively, under the three pressure ranges applied. At toe level, a significant decrease in flux of -20% (95% CI, -48 to 9; P < .05) was seen when bandage pressure >41 mm Hg. Toe pressure values and TcPo(2) showed a moderate increase, excluding a restriction to arterial perfusion induced by the bandages. Inelastic bandages were highly efficient in improving venous pumping function, increasing the reduced ejection fraction by 72% (95% CI, 50%-95%; P < .001) under pressure of 21 to 30 mm Hg and by 103% (95% CI, 70%-128%; P < .001) at 31 to 40 mm Hg. Conclusions: In patients with mixed ulceration, an ankle-brachial pressure index >0.5 and an absolute ankle pressure of >60 mm Hg, inelastic compression of up to 40 mm Hg does not impede arterial perfusion but may lead to a normalization of the highly reduced venous pumping function. Such bandages are therefore recommended in combination with walking exercises as the basic conservative management for patients with mixed leg ulcers.","This study was conducted to find what bandage pressures are safe and effective in treating leg ulcers (leg sores) caused by various vein disorders. The study evaluated 25 patients with leg ulcers who received inelastic bandages applied with various pressures (20 to 30, 31 to 40, and 41 to 50 mm Hg). Several measurements were performed before and after bandage application to ensure patient safety throughout the investigation. These measurements included laser Doppler fluxmetry (LDF), transcutaneous oxygen pressure (TcPo(2)), and toe pressure. LDF measures blood flow. TcPO2 measures oxygen in the skin. Ejection fraction (EF) of the venous pump, or the blood flowing from the heart, was performed to assess blood flow from the heart every time it contracts. LDF values under the bandages increased at all three pressure ranges. At toe level, a significant decrease in flux (blood buildup) was seen when bandage pressure was >41 mm Hg. Toe pressure values and TcPo(2) moderately increased. Inelastic bandages were highly efficient in improving venous pumping function. This is when a machine compresses veins to force blood flow to the heart. The study concluded that patients with mixed ulceration using inelastic compression of up to 40 mm Hg do not experience impeded (blocked) arterial perfusion. Arterial perfusion is when a patient has their blood drawn, has the blood mixed with medication, and has the blood pumped back into the host. However, this inelastic compression may lead to a regularly decreased venous pumping function. These bandages are recommended in combination with walking exercises as the basic treatment for patients with mixed leg ulcers." +"Cystic fibrosis is a monogenic, autosomal, recessive disease characterized by an alteration of chloride transport caused by mutations in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene. The loss of Phe residue in position 508 (?F508-CFTR) causes an incorrect folding of the protein causing its degradation and electrolyte imbalance. CF patients are extremely predisposed to the development of a chronic inflammatory process of the bronchopulmonary system. When the cells of a tissue are damaged, the immune cells are activated and trigger the production of free radicals, provoking an inflammatory process. In addition to routine therapies, today drugs called correctors are available for mutations such as ?F508-CFTR as well as for others less frequent ones. These active molecules are supposed to facilitate the maturation of the mutant CFTR protein, allowing it to reach the apical membrane of the epithelial cell. Matrine induces ?F508-CFTR release from the endoplasmic reticulum to cell cytosol and its localization on the cell membrane. We now have evidence that Matrine and Lumacaftor not only restore the transport of mutant CFTR protein, but probably also counteract the inflammatory process by improving the course of the disease.","Cystic fibrosis is a deadly disease inherited from both parents characterized by changes in a compound (chloride) movement caused by genetic changes in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. One gene change, ?F508-CFTR, causes the resulting protein the gene creates to fold incorrectly, which leads to its destruction and mineral imbalance. CF patients are at very high risk of developing long-term inflammation (redness and swelling from fighting an infection) of part of the lungs. When tissue cells are damaged, immune cells are stimulated and produce unstable molecules, prompting the immune system to defend the body. In addition to normal treatments, drugs called correctors are available for changes like ?F508-CFTR and other less common changes. Correctors help the CFTR protein form the right shape to move to the surface of the epithelial cell (cell that covers outer surface of the internal organs). Matrine, a drug, starts ?F508-CFTR release from the cell's transportation system through the cell liquid to the surface. We now have proof that Matrine and Lumacaftor, another drug, not only allow the changed CFTR to move, but probably neutralize inflammation by improving the course of the disease." +"Background: Cystic fibrosis (CF) is a common life-shortening genetic condition caused by a variant in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. A class II CFTR variant F508del (found in up to 90% of people with CF (pwCF)) is the commonest CF-causing variant. The faulty protein is degraded before reaching the cell membrane, where it needs to be to effect transepithelial salt transport. The F508del variant lacks meaningful CFTR function and corrective therapy could benefit many pwCF. Therapies in this review include single correctors and any combination of correctors and potentiators.","Cystic fibrosis (CF) is a common life-shortening inherited condition caused by a change in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common change, F508del, is a protein processing change, and up to 90% of people with CF have this change. The faulty protein is destroyed before reaching the cell membrane, where it needs to be to move salt across epithelial cells (cells that cover outer surface of the internal organs). The F508del change doesn't work properly and treatment to fix this could help many people with CF. We review single correctors, which help the CFTR protein form the right shape to move to the cell surface, and any combination of correctors and potentiators, which are CFTR modulators (influencers) that hold the gate to the CFTR channel open so chloride can flow through the cell membrane." +"Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane regulator (CFTR) gene, which encodes a chloride channel located at the apical surface of epithelial cells. Unsaturated Fatty Acid (UFA) deficiency has been a persistent observation in tissues from patients with CF. However, the impacts of such deficiencies on the etiology of the disease have been the object of intense debates. The aim of the present review is first to highlight the general consensus on fatty acid dysregulations that emerges from, sometimes apparently contradictory, studies. In a second step, a unifying mechanism for the potential impacts of these fatty acid dysregulations in CF cells, based on alterations of membrane biophysical properties (known as lipointoxication), is proposed. Finally, the contribution of lipointoxication to the progression of the CF disease and how it could affect the efficacy of current treatments is also discussed.","Cystic fibrosis (CF) is a disease inherited from both parents caused by genetic changes in the CF transmembrane conductance Regulator (CFTR) gene, which produces a compound (chloride) channel at the surface of epithelial cells (cells that cover outer surface of the internal organs). Not enough Unsaturated Fatty Acid (UFA) has continually been seen in CF patients. Scientists do not agree on the role of not enough UFA in causing CF. We aim to discuss current beliefs on improper functioning of UFAs that comes from studies that sometime disagree. Next, we suggest a way in which possible improper functioning of UFAs impacts CF cells, based on changes in the biological and physical characteristics of the cell membrane (known as lipointoxication). Finally, we discuss how lipointoxication might play a role in the progression of CF disease and how it could affect how well current treatments work." +"Cystic Fibrosis (CF) is an autosomal recessive disease caused by mutations in the CF transmembrane regulator (CFTR) gene, which encodes a chloride channel located at the apical surface of epithelial cells. Unsaturated Fatty Acid (UFA) deficiency has been a persistent observation in tissues from patients with CF. However, the impacts of such deficiencies on the etiology of the disease have been the object of intense debates. The aim of the present review is first to highlight the general consensus on fatty acid dysregulations that emerges from, sometimes apparently contradictory, studies. In a second step, a unifying mechanism for the potential impacts of these fatty acid dysregulations in CF cells, based on alterations of membrane biophysical properties (known as lipointoxication), is proposed. Finally, the contribution of lipointoxication to the progression of the CF disease and how it could affect the efficacy of current treatments is also discussed.","Cystic Fibrosis (CF) is an inherited disease, which leads to mucus buildup in many organs, caused by mutations in a specific gene, which encodes a channel located at the surface of boundary cells. Lack of Unsaturated Fatty Acid (UFA), a certain form of fat, has been a common observation for patients with CF. However, the effects of such deficiencies on the causes of the disease are debated. This review aims to highlight the general consensus on fatty acid impairment that comes from, sometimes contradictory, studies. In a second step, how the possible effects of this fatty acid impairment occur in CF cells, based on changes in cell boundary properties, is explored. Finally, how fat toxicity contribtues to progression of the CF disease and affects the success of current treatments is discussed." +"Human primary bronchial epithelial cells differentiated in vitro represent a valuable tool to study lung diseases such as cystic fibrosis (CF), an inherited disorder caused by mutations in the gene coding for the Cystic Fibrosis Transmembrane Conductance Regulator. In CF, sphingolipids, a ubiquitous class of bioactive lipids mainly associated with the outer layer of the plasma membrane, seem to play a crucial role in the establishment of the severe lung complications. Nevertheless, no information on the involvement of sphingolipids and their metabolism in the differentiation of primary bronchial epithelial cells are available so far. Here we show that ceramide and globotriaosylceramide increased during cell differentiation, whereas glucosylceramide and gangliosides content decreased. In addition, we found that apical plasma membrane of differentiated bronchial cells is characterized by a higher content of sphingolipids in comparison to the other cell membranes and that activity of sphingolipids catabolic enzymes associated with this membrane results altered with respect to the total cell activities. In particular, the apical membrane of CF cells was characterized by high levels of ceramide and glucosylceramide, known to have proinflammatory activity. On this basis, our data further support the role of sphingolipids in the onset of CF lung pathology.","Cells on the surface of the bronchi (two tubes that carry air to your lungs) extracted from humans and grown in the lab are a valuable tool to study lung disease such as cystic fibrosis (CF), an inherited disease caused by a change in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein which helps transport chloride. In CF, sphingolipids, a common type of lipids found in cell surroundings, seem to play an important role in the onset of serious lung problems. Yet information is lacking on the involvement of sphingolipids and their metabolism (digestion) in the process by which cells on the surface of the bronchi change their type. Two types of sphingolipids increased and two decreased as dividing cells changed type. Cells on the surface of the bronchi have more sphingolipids compared to surfaces of other cells. The surface of CF cells had high levels of two sphingolipids, known to promote inflammation (redness and swelling from fighting an infection). Our results support the role of sphingolipids in the onset of CF lung problems." +"Cystic fibrosis patients display multi-organ system dysfunction (e.g. pancreas, gastrointestinal tract, and lung) with pathogenesis linked to a failure of Cl- secretion from the epithelial surfaces of these organs. If unmanaged, organ dysfunction starts early and patients experience chronic respiratory infection with reduced lung function and a failure to thrive due to gastrointestinal malabsorption. Early mortality is typically caused by respiratory failure. In the past 40 years of newborn screening and improved disease management have driven the median survival up from the mid-teens to 43-53, with most of that improvement coming from earlier and more aggressive management of the symptoms. In the last decade, promising pharmacotherapies have been developed for the correction of the underlying epithelial dysfunction, namely, Cl- secretion. A new generation of systemic drugs target the mutated Cl- channels in cystic fibrosis patients and allow trafficking of the immature mutated protein to the cell membrane (correctors), restore function to the channel once in situ (potentiators), or increase protein levels in the cells (amplifiers). Restoration of channel function prior to symptom development has the potential to significantly change the trajectory of disease progression and their evidence suggests that a modest restoration of Cl- secretion may delay disease progression by decades. In this article, we review epithelial vectorial ion and fluid transport, its quantification and measurement as a marker for cystic fibrosis ion transport dysfunction, and highlight some of the recent therapies targeted at the dysfunctional ion transport of cystic fibrosis.","People with cystic fibrosis have organs that do not function correctly (e.g., pancreas, digestive system, and lung) linked to not enough CI- (chloride) production and release from epithelial cells (cells that cover outer surface of the internal organs). If not treated, organs quickly stop working and patients have long-term respiratory infection with decreased lung function and a decline in health from poor absorption of food. Early death usually happens when lungs can't get enough oxygen into the blood. The past 40 years of newborn checks and better ways to treat disease have increased the age that half of patients are still alive from the mid-teens to 43-53, with most of the increase due to earlier and more aggressive management of the symptoms. In the last 10 years, drugs have been made to correct underlying problems in epithelial cells, mainly, CI- production and release. New drugs for cystic fibrosis patients that work throughout the body target the changed atom (Cl-; chloride) channels and help the changed protein to move to the cell surface (correctors), hold the gate to the channel open so chloride can flow through the cell membrane (potentiators), or increase protein levels in the cells (amplifiers). Restoring channel function before symptoms develop could change the course of the disease and a small repair of Cl- production and release may delay disease worsening by decades. We look at movement of ions (charged atoms) and fluids in epithelial cells, how to count and measure this movement as a sign of cystic fibrosis transport problems, and discuss recent treatments for cystic fibrosis transport problems." +"Cystic fibrosis (CF) is an autosomal recessive disease caused by the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein which primarily acts as a chloride channel. CFTR has mainly been studied in epithelial cells although it is also functional and expressed in other cell types including endothelial cells. The present review summarizes current knowledge on the role of the endothelium in CF. More specifically, this review highlights the role of endothelial cells in CF in acting as a semipermeable barrier, as a key regulator of angiogenesis, coagulation, the vascular tone and the inflammatory responses. It could contribute to different aspects of the disease including cardiovascular symptoms, excessive blood vessel formation, pulmonary and portal hypertension and CF-related diabetes. Despite the important role of vascular endothelium in many biological processes, it has largely been under investigated in CF.","Cystic fibrosis (CF) is a disease inherited from both parents caused when the CF transmembrane conductance Regulator (CFTR) protein no longer functions, which acts as a compound (chloride) channel. Scientists have mostly studied CFTR in epithelial cells (cells that cover outer surface of the internal organs) although it also works and is seen in other cell types including endothelial cells (cells that cover the blood vessel inner surface). This review summarizes what is known on the role of endothelium in CF. We summarize the role of endothelial cells in CF in acting as a barrier that allows only some things to pass through, partly controlling formation of new blood vessels, clotting, blood vessel constriction, and inflammation. Endothelial cells could play a role in different parts of the disease including heart symptoms, formation of too many blood vessels, two kinds of high blood pressure and CF-related diabetes. Vascular endothelium (the inner cellular lining of arteries, veins, and capillaries) is important to many processes in the body, but it has not been studied enough in CF." +"Cystic fibrosis (CF) is an autosomal recessive disease caused by the loss of function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein which primarily acts as a chloride channel. CFTR has mainly been studied in epithelial cells although it is also functional and expressed in other cell types including endothelial cells. The present review summarizes current knowledge on the role of the endothelium in CF. More specifically, this review highlights the role of endothelial cells in CF in acting as a semipermeable barrier, as a key regulator of angiogenesis, coagulation, the vascular tone and the inflammatory responses. It could contribute to different aspects of the disease including cardiovascular symptoms, excessive blood vessel formation, pulmonary and portal hypertension and CF-related diabetes. Despite the important role of vascular endothelium in many biological processes, it has largely been under investigated in CF.","Cystic fibrosis (CF) is an inherited disease caused by loss of function of a special cell boundary channel and leads to mucus buildup in many organs. This special cell boundary channel has been studied in boundary cells. However, it is also present in other cell types like endothelial cells (cells that line blood vessels and empty areas of the body). This review article summarizes current knowledge on the role of the endothelium in CF. More specifically, this review highlights how endothelial cells in CF act as a barrier which regulates blood vessel creation, blood clotting, vessel activity, and inflammation. It could contribute to different aspects of the disease like heart-related symptoms, excessive blood vessel formation, lung and vein-related high blood pressure and CF-related diabetes. Despite the important role of blood vessel boundary cells in many biological processes, it has largely been under-investigated in CF." +"Background and purpose: Cystic fibrosis (CF) is a lethal autosomal recessive genetic disease that originates from the defective function of the CF transmembrane conductance regulator (CFTR) protein, a cAMP-dependent anion channel involved in fluid transport across epithelium. Because small synthetic transmembrane anion transporters (anionophores) can replace the biological anion transport mechanisms, independent of genetic mutations in the CFTR, such anionophores are candidates as new potential treatments for CF. Experimental approach: In order to assess their effects on cell physiology, we have analysed the transport properties of five anionophore compounds, three prodigiosines and two tambjamines. Chloride efflux was measured in large uni-lamellar vesicles and in HEK293 cells with chloride-sensitive electrodes. Iodide influx was evaluated in FRT cells transfected with iodide-sensitive YFP. Transport of bicarbonate was assessed by changes of pH after a NH4 + pre-pulse using the BCECF fluorescent probe. Assays were also carried out in FRT cells permanently transfected with wild type and mutant human CFTR. Key results: All studied compounds are capable of transporting halides and bicarbonate across the cell membrane, with a higher transport capacity at acidic pH. Interestingly, the presence of these anionophores did not interfere with the activation of CFTR and did not modify the action of lumacaftor (a CFTR corrector) or ivacaftor (a CFTR potentiator). Conclusion and implications: These anionophores, at low concentrations, transported chloride and bicarbonate across cell membranes, without affecting CFTR function. They therefore provide promising starting points for the development of novel treatments for CF.","Cystic fibrosis (CF) is a deadly disease inherited from both parents that is caused when the CF transmembrane conductance regulator (CFTR) protein does not work correctly, a channel involved with movement of ions (charged atoms) and fluids in epithelial cells (cells that cover the outer surface of the internal organs). Anionophores, which are small human-made substances that move negative ions (anions) across membranes, can replace biological anion movement regardless of gene changes in the CFTR and are possible treatments for CF. We looked at the movement properties of five anionophore substances. We measured the flow of chloride out of the cell. We measured the flow of iodide into the cell. We measured the movement of bicarbonate (compound). We saw that all five compounds are able to move halides and bicarbonate (compounds) across the cell membrane, with more moved in acidic conditions. Anionophores did not change CFTR activation and did not change the effects of a lumacaftor (corrector that helps the changed protein to move to the cell surface) or ivacaftor (potentiator that holds the gate to the channel open so chloride can flow through the cell membrane). We conclude that anionophores, at low concentrations, moved chloride and bicarbonate (compounds) across cell membranes, without changing CFTR function. New CF treatments could be developed starting from anionophores." +"Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains the most common life-shortening diseases affecting the exocrine organs. The absence of this channel results in an imbalance of ion concentrations across the cell membrane and results in more abnormal secretion and mucus plugging in the gastrointestinal tract and in the lungs of CF patients. The direct introduction of fully functional CFTR by gene therapy has long been pursued as a therapeutical option to restore CFTR function independent of the specific CFTR mutation, but the different clinical trials failed to propose persuasive evidence of this strategy. The last ten years has led to the development of new pharmacotherapies which can activate CFTR function in a mutation-specific manner. Although approximately 2,000 different disease-associated mutations have been identified, a single codon deletion, F508del, is by far the most common and is present on at least one allele in approximately 70% of the patients in CF populations. This strategy is limited by chemistry, the knowledge on CFTR and the heterogenicity of the patients. New research efforts in CF aim to develop other therapeutical approaches to combine different strategies. Targeting RNA appears as a new and an important opportunity to modulate dysregulated biological processes. Abnormal miRNA activity has been linked to numerous diseases, and over the last decade, the critical role of miRNA in regulating biological processes has fostered interest in how miRNA binds to and interacts explicitly with the target protein. Herein, this review describes the different strategies to identify dysregulated miRNA opens up a new concept and new opportunities to correct CFTR deficiency. This review describes therapeutic applications of antisense techniques currently under investigation in CF.","Changes in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), one of the most common life-shortening diseases affecting organs that make and release substances into transporting ducts. The absence of this protein from the CFTR gene causes an imbalance of ion (charged atom) concentrations across the cell membrane and causes release and buildup of abnormally high levels of mucus in the digestive tract and lungs of CF patients. Scientists have tried transferring working CFTR into a patient's cells regardless of the specific CFTR gene change, but patient trials were not successful. New drugs that can stimulate CFTR function based on the specific gene change have been made in the last ten years. Of the roughly 2,000 different gene changes linked to CF, the most common change is F508del, a deletion of a sequence of three consecutive gene compounds, and about 70% of people with CF have at least one form of it. Chemistry, CFTR knowledge, and genetic differences of patients limit the ability to stimulate CFTR function based on the specific gene change. New CF research aims to develop other treatments that combine different approaches. Looking at RNA (which changes the genetic information of DNA into proteins) is a new and important chance to fix incorrectly functioning biological processes. Scientists have linked abnormal microRNA (miRNA; short type of non-coding RNA that does not encode a protein) to many diseases, and over the last decade, scientists have developed interest in how miRNA interacts with specific proteins. We describe different ways to find incorrectly functioning miRNA that might help correct lack of CFTR. This review describes RNA treatments currently being studied in CF." +"The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl- channel that apparently has evolved from an ancestral active transporter. Key to the CFTR's switch from pump to channel function may have been the appearance of one or more ""lateral portals."" Such portals connect the cytoplasm to the transmembrane channel pore, allowing a continuous pathway for the electrodiffusional movement of Cl- ions. However, these portals remain the least well-characterized part of the Cl- transport pathway; even the number of functional portals is uncertain, and if multiple portals do exist, their relative functional contributions are unknown. Here, we used patch-clamp recording to identify the contributions of positively charged amino acid side chains located in CFTR's cytoplasmic transmembrane extensions to portal function. Mutagenesis-mediated neutralization of several charged side chains reduced single-channel Cl- conductance. However, these same mutations differentially affected channel blockade by cytoplasmic suramin and Pt(NO2)42- anions. We considered and tested several models by which the contribution of these positively charged side chains to one or more independent or non-independent portals to the pore could affect Cl- conductance and interactions with blockers. Overall, our results suggest the existence of a single portal that is lined by several positively charged side chains that interact electrostatically with both Cl- and blocking anions. We further propose that mutations at other sites indirectly alter the function of this single portal. Comparison of our functional results with recent structural information on CFTR completes our picture of the overall molecular architecture of the Cl- permeation pathway.","The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride (Cl-) channel descended from an active transporter (requiring energy for movement). One or more ""lateral portals"" may have appeared, switching the active pump to a channel. ""Lateral portals"" allow Cl- ions (charged atoms) to move under the influence of an electric field. These portals are the least understood part of Cl- movement. Scientists do not know the number of working portals, and if more than one, which portal does what. We used a cell test to find out how positively charged side chemical groups in CFTR contribute to how the portal works. Neutralization of many charged side chemical groups caused by gene sequence changes reduced movement of Cl- through a single channel. However, these gene sequence changes affected channel blockade by negatively charged atoms differently. We used many models to look at ways these positively charged chemical groups changed one or more portals and its effect on Cl- movement and interaction with blockers. Our results suggest one portal is lined by many positively charged side chemical groups that interact with both CL- and other blocking negatively charged ions. We further suggest that gene sequence changes at other sides change how well the single portal works. We compared our results with recent information on CFTR structure to understand the pathway of Cl- transport at a molecule level." +"The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl- channel that apparently has evolved from an ancestral active transporter. Key to the CFTR's switch from pump to channel function may have been the appearance of one or more ""lateral portals."" Such portals connect the cytoplasm to the transmembrane channel pore, allowing a continuous pathway for the electrodiffusional movement of Cl- ions. However, these portals remain the least well-characterized part of the Cl- transport pathway; even the number of functional portals is uncertain, and if multiple portals do exist, their relative functional contributions are unknown. Here, we used patch-clamp recording to identify the contributions of positively charged amino acid side chains located in CFTR's cytoplasmic transmembrane extensions to portal function. Mutagenesis-mediated neutralization of several charged side chains reduced single-channel Cl- conductance. However, these same mutations differentially affected channel blockade by cytoplasmic suramin and Pt(NO2)42- anions. We considered and tested several models by which the contribution of these positively charged side chains to one or more independent or non-independent portals to the pore could affect Cl- conductance and interactions with blockers. Overall, our results suggest the existence of a single portal that is lined by several positively charged side chains that interact electrostatically with both Cl- and blocking anions. We further propose that mutations at other sites indirectly alter the function of this single portal. Comparison of our functional results with recent structural information on CFTR completes our picture of the overall molecular architecture of the Cl- permeation pathway.","The cystic fibrosis transmembrane conductance regulator (CTFR) is a chloride transporter that apparently has evolved from an ancestral active transporter. Key to the CFTR's switch from pump to channel function may have been the appearance of one or more ""lateral portals."" Lateral portals connect the cell's inner fluid to the channel on the cell boundary, allowing a continuous pathway for chloride ion movement. However, these portals are the least studied part of the chloride transport pathway. Even the number of active portals in unknown, and if multiple portals do exists, their relative contributions are unknown. Here, we use electrical recordings to identify the contributions of positively charged protein segments located in CFTR's extensions to portal function. Mutation-controlled silencing of several charged protein segments reduced single-channel chloride transport. However, these same mutations uniquely affected channel blocking by specific inner-cell, negatively-charged particles. We considered and tested many models by which the contribution of these positive protein segments to one or more independent or non-independent portals to the channel could affect chloride transport and interactions with blockers. Overall, our results suggest the existence of a single portal lined with several positively-charged protein segments that interact electrically with both chloride and negative-charged, blocking particles. We propose that mutations at other sites indirectly affect the function of this one portal. Comparing our results with recent structural information on CTFR completes our picture of the overall molecular architecture of the chloride transport pathway." +"Background/aims: The CFTR-Associated Ligand (CAL), a PDZ domain containing protein with two coiled-coil domains, reduces cell surface WT CFTR through degradation in the lysosome by a well-characterized mechanism. However, CAL's regulatory effect on ?F508 CFTR has remained almost entirely uninvestigated. Methods: In this study, we describe a previously unknown pathway for CAL by which it regulates the membrane expression of ?F508 CFTR through arrest of ?F508 CFTR trafficking in the endoplasmic reticulum (ER) using a combination of cell biology, biochemistry and electrophysiology. Results: We demonstrate that CAL is an ER localized protein that binds to ?F508 CFTR and is degraded in the 26S proteasome. When CAL is inhibited, ?F508 CFTR retention in the ER decreases and cell surface expression of mature functional ?F508 CFTR is observed alongside of enhanced expression of plasma membrane scaffolding protein NHERF1. Chaperone proteins regulate this novel process, and ?F508 CFTR binding to HSP40, HSP90, HSP70, VCP, and Aha1 changes to improve ?F508 CFTR cell surface trafficking. Conclusion: Our results reveal a pathway in which CAL regulates the cell surface availability and intracellular retention of ?F508 CFTR.","The CFTR-Associated Ligand (CAL) reduces the cell surface of normal CFTR through destroying it in a well-understood way. The CFTR protein is a channel involved with movement of ions (charged atoms) and fluids in epithelial cells (cells that cover the outer surface of the internal organs). However, few scientists have studied how CAL controls ?F508 CFTR, a specific gene sequence change seen in the CFTR gene which slightly alters the CFTR protein. In this study, we describe a previously unknown way CAL controls ?F508 CFTR through stopping ?F508 CFTR movement in the cell's transportation system. We show that CAL binds to ?F508 CFTR in one location of the cell and is destroyed in another location of the cell. When CAL is stopped, the amount of ?F508 CFTR held within the cell decreases and working ?F508 CFTR is seen on the cell surface. The binding of ?F508 CFTR to proteins improves the cell surface movement conducted by ?F508 CFTR. We conclude that CAL controls the cell surface availability and amount held within the cell of ?F508 CFTR." +"47,XXX (triple X) and Turner syndrome (45,X) are sex chromosomal abnormalities with detrimental effects on health with increased mortality and morbidity. In karyotypical normal females, X-chromosome inactivation balances gene expression between sexes and upregulation of the X chromosome in both sexes maintain stoichiometry with the autosomes. In 47,XXX and Turner syndrome a gene dosage imbalance may ensue from increased or decreased expression from the genes that escape X inactivation, as well as from incomplete X chromosome inactivation in 47,XXX. We aim to study genome-wide DNA-methylation and RNA-expression changes can explain phenotypic traits in 47,XXX syndrome. We compare DNA-methylation and RNA-expression data derived from white blood cells of seven women with 47,XXX syndrome, with data from seven female controls, as well as with seven women with Turner syndrome (45,X). To address these questions, we explored genome-wide DNA-methylation and transcriptome data in blood from seven females with 47,XXX syndrome, seven females with Turner syndrome, and seven karyotypically normal females (46,XX). Based on promoter methylation, we describe a demethylation of six X-chromosomal genes (AMOT, HTR2C, IL1RAPL2, STAG2, TCEANC, ZNF673), increased methylation for GEMIN8, and four differentially methylated autosomal regions related to four genes (SPEG, MUC4, SP6, and ZNF492). We illustrate how these changes seem compensated at the transcriptome level although several genes show differential exon usage. In conclusion, our results suggest an impact of the supernumerary X chromosome in 47,XXX syndrome on the methylation status of selected genes despite an overall comparable expression profile.","47,XXX (triple X) and Turner syndrome (45,X) are sex chromosomal (gene material) abnormalities with detrimental effects on health. Both syndromes are associated with increased death and disease suffering. In females with normal chromosomes, X-chromosome (sex chromosome) inactivation balances gene expression between sexes. Upregulation (increase in activity) of the X chromosome in both sexes maintains balance with the autosomes (chromosomes not involved in sex determination). In both syndromes, a gene dosage imbalance may be caused by increased or decreased expression from the genes that escape X inactivation. A gene dosage imbalance may also be caused by incomplete X chromosome inactivation in 47,XXX. This study aimed to evaluate genome-wide DNA-methylation (addition of methyl groups to DNA) and RNA (genetic material)-expression changes. This was done in the hope that these alterations may explain phenotypic traits, or observable character traits, associated with 47,XXX syndrome. This study compared DNA-methylation and RNA-expression data taken from white blood cells of seven women with 47,XXX syndrome. This data was compared with data from seven female controls and seven women with Turner syndrome (45,X). This study evaluated genome-wide DNA-methylation and RNA data in blood from seven females with 47,XXX syndrome, seven females with Turner syndrome, and seven normal females (46,XX). The study identified the loss of methylation of six X-chromosomal genes, increased methylation for one specific gene, and four differentially methylated autosomal regions related to four genes. This data illustrates how these changes seem centered at the RNA level. In conclusion, this study suggests an impact of excess X chromosome in 47,XXX syndrome on the methylation status of selected genes." +"The pathogenesis of Turner syndrome (TS) and the genotype-phenotype relationship has been thoroughly investigated during the last decade. It has become evident that the phenotype seen in TS does not only depend on simple gene dosage as a result of X chromosome monosomy. The origin of TS specific comorbidities such as infertility, cardiac malformations, bone dysgenesis, and autoimmune diseases may depend on a complex relationship between genes as well as transcriptional and epigenetic factors affecting gene expression across the genome. Furthermore, two individuals with TS with the exact same karyotype may exhibit completely different traits, suggesting that no conventional genotype-phenotype relationship exists. Here, we review the different genetic mechanisms behind differential gene expression, and highlight potential key-genes essential to the comorbidities seen in TS and other X chromosome aneuploidy syndromes. KDM6A, important for germ cell development, has shown to be differentially expressed and methylated in Turner and Klinefelter syndrome across studies. Furthermore, TIMP1/TIMP3 genes seem to affect the prevalence of bicuspid aortic valve. KDM5 C could play a role in the neurocognitive development of Turner and Klinefelter syndrome. However, further research is needed to elucidate the genetic mechanism behind the phenotypic variability and the different phenotypic traits seen in TS.","The disease development of Turner syndrome (TS), and how gene expression effects physical appearance, has been heavily investigated over the last decade. Turner syndrome is a condition where there is an abnormal amount of chromosomes (genetic material). Phenotype (observable characteristics) seen in TS does not only depend on the number of copies of a gene as a result of X chromosome monosomy. Monosomy indicates there is an absence of one member of a chromosome pair; instead of 46 chromosomes in each cell of the body, there is 45. The origin of TS specific comorbidities (presence of two or more diseases) may depend on crosstalk between genes as well as factors affecting gene expression. These comorbidities include infertility, heart-related malformations, defective bone development, and autoimmune diseases (in which immune cells attack healthy cells). Furthermore, two people with TS with the exact same karyotype, number and visual appear of chromosomes, may exhibit completely different traits. This suggests that no conventional genotype-phenotype relationship exists. This study reviews the different genetic mechanisms behind differential (function-unique) gene expression. This study also highlights potential key-genes essential to the comorbidities seen in TS and other X chromosome aneuploidy (abnormal chromosome number) syndromes. KDM6A, a gene important for germ cell development, has shown to be differentially expressed and methylated in Turner and Klinefelter syndrome (male born with extra X chromosome copy) patients. Furthermore, TIMP1/TIMP3 genes seem to affect the prevalence (amount) of bicuspid aortic valve, an abnormality in the aortic valve of the heart. KDM5 C could play a role in the brain- and memory-related development of Turner and Klinefelter syndrome. However, further research is needed to determine the genetic mechanism behind the phenotypic variability and the different phenotypic traits seen in TS." +"X-chromosome inactivation generally results in dosage equivalence for expression of X-linked genes between 46,XY males and 46,XX females. The 20-30% of genes that escape silencing are thus candidates for having a role in the phenotype of Turner syndrome. Understanding which genes escape from silencing, and how they avoid this chromosome-wide inactivation is therefore an important step toward understanding Turner Syndrome. We have examined the mechanism of escape using a previously reported knock-in of a BAC containing the human escape gene RPS4X in mouse. We now demonstrate that escape from inactivation for RPS4X is already established by embryonic Day 9.5, and that both silencing and escape are faithfully maintained across the lifespan. No overt abnormalities were observed for transgenic mice up to 1 year of age despite robust transcription of the human RPS4X gene with no detectable downregulation of the mouse homolog. However, there was no significant increase in protein levels, suggesting translational compensation in the mouse. Finally, while many of the protein-coding genes have been assessed for their inactivation status, less is known about the X-linked RNA genes, and we propose that for many microRNA genes their inactivation status can be predicted as they are intronic to genes for which the inactivation status is known.","X-chromosome inactivation generally results in gene expression equivalence of X-linked genes between 46,XY males and 46,XX females. The 20-30% of genes that escape silencing may influence the phenotype (physical traits) of Turner syndrome. Turner syndrome is a condition where there is an abnormal amount of chromosomes (genetic material). Understanding which genes escape from silencing, and how they avoid this chromosome-wide inactivation, is an important step toward understanding Turner Syndrome. This study examined the mechanism of escape using a mouse model where a specific human escape gene, RPS4X, was inserted into the genome. The study showed that escape from inactivation for RPS4X is already established by embryonic Day 9.5. Additionally, the study demonstrated that both silencing and escape are maintained across the entire lifespan. No overt (obvious) abnormalities were observed for the mice up to 1 year of age. However, there was no significant increase in protein levels. This suggest translational compensation (altered conversion of RNA to proteins) in the mouse. Finally, while many of the protein-coding genes have been assessed (measured) for their inactivation status, less is known about the X-linked RNA genes. The authors propose that for many microRNA (RNA involved in silencing) genes, inactivation status can be predicted." +"Turner Syndrome (TS) is an unfavorable genetic condition with a prevalence of 1:2500 in newborn girls. Prompt and effective diagnosis is very important to appropriately monitor the comorbidities. The aim of the present study was to propose a feasible and practical molecular diagnostic tool for newborn screening by quantifying the gene dosage of the SHOX, VAMP7, XIST, UBA1, and SRY genes by quantitative polymerase chain reaction (qPCR) in individuals with a diagnosis of complete X monosomy, as well as those with TS variants, and then compare the results to controls without chromosomal abnormalities. According to our results, the most useful markers for these chromosomal variants were the genes found in the pseudoautosomic regions 1 and 2 (PAR1 and PAR2), because differences in gene dosage (relative quantification) between groups were more evident in SHOX and VAMP7 gene expression. Therefore, we conclude that these markers are useful for early detection in aneuploidies involving sex chromosomes.","Turner Syndrome (TS) is a genetic condition found in 1 out of every 2500 newborn girls. Turner syndrome is a condition where there is an abnormal amount of chromosomes (genetic material). Prompt and effective diagnosis is very important to appropriately monitor the comorbidities (two or more diseases in one patient). The aim of the study was to propose a feasible and practical diagnostic tool for newborn screening. The screening would be completed by quantifying (measuring) the dosage of specific genes in individuals with a diagnosis of complete X monosomy and TS variants. The gene doses would be compared to controls without chromosomal abnormalities. Monosomy indicates there is an absence of one member of a chromosome pair; instead of 46 chromosomes in each cell of the body, there is 45. Study results showed the most useful indicators for these chromosomal variants were the genes found in the pseudoautosomic regions 1 and 2 (PAR1 and PAR2). The authors concluded that these markers are useful for early detection in chromosomal imbalances, specifically those involving sex chromosomes." +"Turner syndrome is a chromosomal abnormality characterized by the absence of whole or part of the X chromosome in females. This X aneuploidy condition is associated with a diverse set of clinical phenotypes such as gonadal dysfunction, short stature, osteoporosis and Type II diabetes mellitus, among others. These phenotypes differ in their severity and penetrance among the affected individuals. Haploinsufficiency for a few X linked genes has been associated with some of these disease phenotypes. RNA sequencing can provide valuable insights to understand molecular mechanism of disease process. In the current study, we have analysed the transcriptome profiles of human untransformed 45,X and 46,XX fibroblast cells and identified differential expression of genes in these two karyotypes. Functional analysis revealed that these differentially expressing genes are associated with bone differentiation, glucose metabolism and gonadal development pathways. We also report differential expression of lincRNAs in X monosomic cells. Our observations provide a basis for evaluation of cellular and molecular mechanism(s) in the establishment of Turner syndrome phenotypes.","Turner syndrome is a chromosomal abnormality. The disease is characterized by the absence of the whole or part of the X chromosome in females. This X aneuploidy condition, or condition of having abnormal number of chromosomes, is associated with a diverse set of clinical phenotypes. These phenotypes, or outward characteristics, include ovary dysfunction, short stature, brittle bones, and Type II diabetes mellitus. These phenotypes differ in their severity and penetrance (extent) among those with the syndrome. Haploinsufficiency, or when one copy of a gene is deleted, for a few X linked genes has been associated with some of these disease phenotypes. RNA (special genetic material to create proteins) quantification can provide valuable insights to understand how these diseases form. This study analyzed RNA profiles of human 45,X (abnormal) and 46,XX (normal) cells. This study identified differential (unique function) expression of genes in these two chromosomal types. Analysis revealed that these differentially expressing genes are associated with bone differentiation, glucose metabolism, and gonadal development pathways. This study also reported differential expression of non-coding RNAs (RNAs that cannot be transformed into proteins) in X cells with abnormal chromosome count. This study provides a basis for evaluation of cellular and molecular mechanism(s) in the establishment of Turner syndrome phenotypes." +"Turner syndrome is a sex chromosome aneuploidy with characteristic malformations. Amniotic fluid, a complex biological material, could contribute to the understanding of Turner syndrome pathogenesis. In this pilot study, global gene expression analysis of cell-free RNA in amniotic fluid supernatant was utilized to identify specific genes/organ systems that may play a role in Turner syndrome pathophysiology. Cell-free RNA from amniotic fluid of five mid-trimester Turner syndrome fetuses and five euploid female fetuses matched for gestational age was extracted, amplified, and hybridized onto Affymetrix(�) U133 Plus 2.0 arrays. Significantly differentially regulated genes were identified using paired t tests. Biological interpretation was performed using Ingenuity Pathway Analysis and BioGPS gene expression atlas. There were 470 statistically significantly differentially expressed genes identified. They were widely distributed across the genome. XIST was significantly down-regulated (p < 0.0001); SHOX was not differentially expressed. One of the most highly represented organ systems was the hematologic/immune system, distinguishing the Turner syndrome transcriptome from other aneuploidies we previously studied. Manual curation of the differentially expressed gene list identified genes of possible pathologic significance, including NFATC3, IGFBP5, and LDLR. Transcriptomic differences in the amniotic fluid of Turner syndrome fetuses are due to genome-wide dysregulation. The hematologic/immune system differences may play a role in early-onset autoimmune dysfunction. Other genes identified with possible pathologic significance are associated with cardiac and skeletal systems, which are known to be affected in females with Turner syndrome. The discovery-driven approach described here may be useful in elucidating novel mechanisms of disease in Turner syndrome.","Turner syndrome is a condition where there is an abnormal number of chromosomes (genetic material). Amniotic fluid, the fluid surrounding a fetus, could contribute to the understanding of Turner syndrome development. In this pilot study, gene expression analysis of cell-free RNA (genetic material to create proteins) in amniotic fluid was analyzed. The fluid was evaluated to identify genes/organ systems that may play a role in Turner syndrome development. Cell-free RNA from amniotic fluid of five mid-trimester Turner syndrome fetuses and five control female fetuses was extracted. Significantly differentially (functionally unique) regulated genes were identified. Biological interpretation was performed to determine gene expression. There were 470 statistically significantly differentially expressed genes identified. They were widely distributed across the genome. XIST was significantly down-regulated (decreased in activity). SHOX was not differentially expressed. One of the most highly represented organ systems was the hematologic (blood) and immune system. Organization of the differentially expressed gene list identified genes of possible disease development significance. Transcriptomic (RNA) differences in the amniotic fluid of Turner syndrome fetuses are due to genome-wide dysregulation. The hematologic/immune system differences may play a role in early-onset autoimmune dysfunction (in which infection-fighting cells attack healthy cells). Other genes identified with possible pathologic (harmful) significance were associated with cardiac (heart) and skeletal systems. These systems are known to be affected in females with Turner syndrome. This data may be useful in identifying how Turner syndrome develops." +"Background: Turner syndrome (TS) is a sex chromosome aneuploidy with a variable spectrum of symptoms including short stature, ovarian failure and skeletal abnormalities. The etiology of TS is complex, and the mechanisms driving its pathogenesis remain unclear. Methods: In our study, we used the online Gene Expression Omnibus (GEO) microarray expression profiling dataset GSE46687 to identify differentially expressed genes (DEGs) between monosomy X TS patients and normal female individuals. The relevant data on 26 subjects with TS (45,XO) and 10 subjects with the normal karyotype (46,XX) was investigated. Then, tissue-specific gene expression, functional enrichment, and protein-protein interaction (PPI) network analyses were performed, and the key modules were identified. Results: In total, 25 upregulated and 60 downregulated genes were identified in the differential expression analysis. The tissue-specific gene expression analysis of the DEGs revealed that the system with the most highly enriched tissue-specific gene expression was the hematologic/immune system, followed by the skin/skeletal muscle and neurologic systems. The PPI network analysis, construction of key modules and manual screening of tissue-specific gene expression resulted in the identification of the following five genes of interest: CD99, CSF2RA, MYL9, MYLPF, and IGFBP2. CD99 and CSF2RA are involved in the hematologic/immune system, MYL9 and MYLPF are related to the circulatory system, and IGFBP2 is related to skeletal abnormalities. In addition, several genes of interest with possible roles in the pathogenesis of TS were identified as being associated with the hematologic/immune system or metabolism. Conclusion: This discovery-driven analysis may be a useful method for elucidating novel mechanisms underlying TS. However, more experiments are needed to further explore the relationships between these genes and TS in the future.","Turner syndrome (TS) is a sex chromosome aneuploidy or condition of having abnormal number of chromosomes. The disease has a broad spectrum of symptoms including short stature, ovarian failure, and skeletal abnormalities. The cause of TS is complex. The mechanisms driving its development are unclear. In this study, an online database was used to identify differentially expressed (functionally unique) genes (DEGs) between monosomy X TS patients (one chromosome lacks its partner) and normal female individuals. Data on 26 subjects with TS (45,XO) and 10 subjects with the normal chromosomal count (46,XX) was investigated. Several genetic analyses were performed. In total, 25 upregulated (increased in activity) and 60 downregulated (decreased in activity) genes were identified. The system with the most highly enriched tissue-specific gene expression was the hematologic (blood) and immune system. This was followed by the skin/skeletal muscle and brain-related systems. Additionally, analysis resulted in the identification of five genes of interest. Two of these genes, CD99 and CSF2RA, are involved in the hematologic (blood)/immune system. Others, MYL9 and MYLPF, are related to the circulatory (heart and blood vessels) system. A fifth gene, IGFBP2, is related to skeletal abnormalities. Additionally, several genes of interest with possible roles in the pathogenesis (disease creation) of TS were identified as being associated with the hematologic/immune system or metabolism. This analysis may be a useful method for identifying novel mechanisms underlying TS. However, more experiments are needed to explore the relationships between these genes and TS." +"Turner Syndrome (TS) is a condition where several genes are affected but the molecular mechanism remains unknown. Identifying the genes that regulate the TS network is one of the main challenges in understanding its aetiology. Here, we studied the regulatory network from manually curated genes reported in the literature and identified essential proteins involved in TS. The power-law distribution analysis showed that TS network carries scale-free hierarchical fractal attributes. This organization of the network maintained the self-ruled constitution of nodes at various levels without having centrality-lethality control systems. Out of twenty-seven genes culminating into leading hubs in the network, we identified two key regulators (KRs) i.e. KDM6A and BDNF. These KRs serve as the backbone for all the network activities. Removal of KRs does not cause its breakdown, rather a change in the topological properties was observed. Since essential proteins are evolutionarily conserved, the orthologs of selected interacting proteins in C. elegans, cat and macaque monkey (lower to higher level organisms) were identified. We deciphered three important interologs i.e. KDM6A-WDR5, KDM6A-ASH2L and WDR5-ASH2L that form a triangular motif. In conclusion, these KRs and identified interologs are expected to regulate the TS network signifying their biological importance.","Turner Syndrome (TS) is a condition where several genes are affected. However, how this occurs remains unknown. Turner syndrome is a condition where there is an abnormal amount of chromosomes (genetic material). Identifying the genes that regulate the TS network is one of the main challenges in understanding its cause. This study evaluated the regulatory network of genes reported in scientific literature and identified essential proteins involved in TS. A statistical evaluation was completed to model a TS network. Out of twenty-seven genes, the authors identified two key regulators (KRs) i.e. KDM6A and BDNF. These KRs serve as the backbone for all the network activities. Removal of KRs does not cause its breakdown, rather a change in the network properties was observed. Essential (necessary) proteins are evolutionarily conserved (kept). Because of this, genes of selected interacting proteins in C. elegans, cat, and macaque monkey were identified. The authors deciphered three important interologs, interactions between pairs of proteins. In conclusion, these KRs and identified interologs are expected to regulate the TS network. This data demonstrates their biological importance." +"Turner syndrome (TS) is one of the most common sexual chromosome abnormalities and is clearly associated with an increased risk of autoimmune diseases, particularly thyroid disease and coeliac disease (CD). Single-nucleotide polymorphism analyses have been shown to provide correlative evidence that specific genes are associated with autoimmune disease. Our aim was to study the functional polymorphic variants of PTPN22 and ZFAT in relation to thyroid disease and those of MYO9B in relation to CD. A cross-sectional comparative analysis was performed on Mexican mestizo patients with TS and age-matched healthy females. Our data showed that PTPN22 C1858T (considered a risk variant) is not associated with TS (X2 = 3.50, p = .61, and OR = 0.33 [95% CI = 0.10-1.10]). Also, ZFAT was not associated with TS (X2 = 1.2, p = .28, and OR = 1.22 [95% CI = 0.84-1.79]). However, for the first time, rs2305767 MYO9B was revealed to have a strong association with TS (X2 = 58.6, p = .0001, and OR = 10.44 [95% C = 5.51-19.80]), supporting a high level of predisposition to CD among TS patients. This report addresses additional data regarding the polymorphic variants associated with autoimmune disease, one of the most common complications in TS.","Turner syndrome (TS) is one of the most common sexual chromosome abnormalities. TS is associated with an increased risk of autoimmune diseases (in which immune cells attack healthy cells), particularly metabolism-affecting thyroid disease and coeliac disease (CD)--gluten sensitivity. Genetic analyses have provided evidence that correlates specific genes with autoimmune diseases. This report aimed to study the genetic variants of PTPN22 and ZFAT (protein-coding genes) in relation to thyroid disease. Additionally, this study evaluated the variants (gene types) of MYO9B (another protein-coding gene) to CD. An analysis was performed on Mexican, mixed heritage patients with TS. These patients were age-matched to healthy females. Data showed that PTPN22 C1858T, a PTPN22 variant, is not associated with TS. Also, ZFAT was not associated with TS. However, rs2305767 MYO9B, a MYO9B variant, was revealed to have a strong association with TS. This suggests patients with this variant have increased susceptibility to CD among TS patients. This report addresses additional data regarding the genetic variants associated with autoimmune disease. Autoimmune disease is one of the most common complications found in TS patients." +"Estimates of COVID-19 mRNA vaccine effectiveness (VE) have declined in recent months because of waning vaccine induced immunity over time, possible increased immune evasion by SARS-CoV-2 variants, or a combination of these and other factors. CDC recommends that all persons aged ≥12 years receive a third dose (booster) of an mRNA vaccine ≥5 months after receipt of the second mRNA vaccine dose and that immunocompromised individuals receive a third primary dose. A third dose of BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine increases neutralizing antibody levels, and three recent studies from Israel have shown improved effectiveness of a third dose in preventing COVID-19 associated with infections with the SARS-CoV-2 B.1.617.2 (Delta) variant. Yet, data are limited on the real-world effectiveness of third doses of COVID-19 mRNA vaccine in the United States, especially since the SARS-CoV-2 B.1.1.529 (Omicron) variant became predominant in mid-December 2021. The VISION Network examined VE by analyzing 222,772 encounters from 383 emergency departments (EDs) and urgent care (UC) clinics and 87,904 hospitalizations from 259 hospitals among adults aged ≥18 years across 10 states from August 26, 2021 to January 5, 2022. Analyses were stratified by the period before and after the Omicron variant became the predominant strain (>50% of sequenced viruses) at each study site. During the period of Delta predominance across study sites in the United States (August-mid-December 2021), VE against laboratory-confirmed COVID-19-associated ED and UC encounters was 86% 14-179 days after dose 2, 76% ≥180 days after dose 2, and 94% ≥14 days after dose 3. Estimates of VE for the same intervals after vaccination during Omicron variant predominance were 52%, 38%, and 82%, respectively. During the period of Delta variant predominance, VE against laboratory-confirmed COVID-19-associated hospitalizations was 90% 14-179 days after dose 2, 81% ≥180 days after dose 2, and 94% ≥14 days after dose 3. During Omicron variant predominance, VE estimates for the same intervals after vaccination were 81%, 57%, and 90%, respectively. The highest estimates of VE against COVID-19-associated ED and UC encounters or hospitalizations during both Delta- and Omicron-predominant periods were among adults who received a third dose of mRNA vaccine. All unvaccinated persons should get vaccinated as soon as possible. All adults who have received mRNA vaccines during their primary COVID-19 vaccination series should receive a third dose when eligible, and eligible persons should stay up to date with COVID-19 vaccinations.","It is estimated that the effectiveness of COVID-19 mRNA vaccines has declined in recent months. There are several possible reasons for this. Vaccine-induced immunity decreases over time. New strains of the SARS-CoV-2 virus can become resistant to the vaccine, a process called immune evasion. A combination of these two phenomena or other factors could also cause decreased vaccine effectiveness. The US Centers for Disease Control and Prevention recommends that all people 12 years and older receive a third booster shot of an mRNA vaccine 5 months or later after receiving the second primary shot. Patients with a weakened immune system should receive a third primary shot. A third dose of the Pfizer vaccine (BNT162b2 COVID-19 vaccine) increases the blood level of antibodies that neutralize the virus and prevent infection. Three recent studies from Israel have shown that a third booster dose helps prevent COVID-19 caused by the Delta variant (SARS-CoV-2 B.1.617.2). However, in the United States there is little data to prove the effectiveness of third booster shots to prevent COVID-19, especially since the Omicron variant (SARS-CoV-2 B.1.1.529) became the most common strain in mid-December 2021. From August 26, 2021 to January 5, 2022, the VISION Network examined vaccine effectiveness among adults 18 and older across 10 states in the US by studying over 222,000 patients in 383 emergency departments and urgent care clinics, and over 87,000 hospitalized inpatients from 259 hospitals. The analysis was split apart at each study site by looking at the periods before and after the Omicron strain became the most common strain. During the time when the Delta strain was most common in the US (August to mid-December 2021), in emergency departments and urgent care clinics vaccine effectiveness in preventing infection was 86% effective 14-179 days after dose 2, dropped to 76% more than 180 days after dose 2, but increased up to 94% 14 days or more after dose 3. When the Omicron strain was most common, vaccine effectiveness for the same time intervals was only 52%, 38%, and 82%, respectively. In hospitalized patients, during the Delta strain period vaccine effectiveness was 90% 14-179 days after dose 2, 81% 180 days or longer after dose 2, and 94% 14 days or more after dose 3. During the Omicron period, estimates for the same time intervals after vaccination were 81%, 57%, and 90%, respectively. The highest estimates of vaccine effectiveness in both patient populations during both the Delta and Omicron periods were in adults who had received a third dose of mRNA vaccine. Based on this data, we recommed that all unvaccinated persons should get vaccinated as soon as possible. All adults who have received their first two doses of COVID-19 mRNA vaccines should receive a third dose as soon as they are eligible, and eligible persons should stay up to date with COVID-19 vaccinations and boosters." +"There is considerable interest in the waning of effectiveness of coronavirus disease 2019 (COVID-19) vaccines and vaccine effectiveness (VE) of booster doses. Using linked national Brazilian databases, we undertook a test-negative design study involving almost 14 million people (~16 million tests) to estimate VE of Corona Vac over time and VE of BNT162b2 booster vaccination against RT-PCR-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 outcomes (hospitalization or death). Compared with unvaccinated individuals, CoronaVac VE at 14-30 d after the second dose was 55.0% (95% confidence interval (CI): 54.3-55.7) against confirmed infection and 82.1% (95% CI: 81.4-82.8) against severe outcomes. VE decreased to 34.7% (95% CI: 33.1-36.2) against infection and 72.5% (95% CI: 70.9-74.0) against severe outcomes over 180 d after the second dose. A BNT162b2 booster, 6 months after the second dose of CoronaVac, improved VE against infection to 92.7% (95% CI: 91.0-94.0) and VE against severe outcomes to 97.3% (95% CI: 96.1-98.1) 14-30 d after the booster. Compared with younger age groups, individuals 80 years of age or older had lower protection after the second dose but similar protection after the booster. Our findings support a BNT162b2 booster vaccine dose after two doses of CoronaVac, particularly for the elderly.","We are interested in studying the waning effectiveness of COVID-19 vaccines and the effectiveness of booster doses. Using national Brazilian databases, we studied the trends of negative test results of almost 14 million people (representing about 16 million tests) to estimate the reduced effectiveness of CoronaVac COVID-19 vaccines over time. We also studied the effects of the Pfizer BNT162b2 booster dose on the rates of confirmed COVID-19 infection and severe outcomes (hospitalization or death). Compared with unvaccinated individuals, the effectiveness of the CoronaVac vaccine at 14-30 days after the second dose was 55% against confirmed infection and 82.1% against severe outcomes. Vaccine effectiveness decreased to 34.7% against infection and 72.5% against severe outcomes over 180 days after the second dose. A Pfizer BNT162b2 booster shot given 6 months after the second dose of CoronaVac, improved vaccine effectiveness by 92.7% against infection and 97.3% against severe outcomes 14-30 days after the booster. Compared with younger age groups, individuals 80 years of age or older had lower protection after the second dose but similar protection after the booster. Based on these results, we recommend a BNT162b2 booster vaccine dose after two doses of CoronaVac, particularly for the elderly." +"Background: Immunization against SARS-CoV-2, the causative agent of coronavirus disease-19 (COVID-19) occurs via natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced immunological memory will last. Methods: We performed a longitudinal evaluation of immunological memory to SARS-CoV-2 up to one year post infection and following mRNA vaccination in naïve and COVID-19 recovered individuals. Results: We found that memory cells are still detectable 8 months after vaccination, while antibody levels decline significantly especially in naïve subjects. We also found that a booster injection is efficacious in reactivating immunological memory to spike protein in naïve subjects, while it results ineffective in previously SARS-CoV-2 infected individuals. Finally, we observed a similar kinetics of decay of humoral and cellular immunity to SARS-CoV-2 up to one year following natural infection in a cohort of unvaccinated individuals. Conclusion: Short-term persistence of humoral immunity, together with the reduced neutralization capacity versus the currently prevailing SARS-CoV-2 variants, may account for reinfections and breakthrough infections. Long-lived memory B and CD4+ T cells may protect from severe disease development. A booster dose restores optimal anti-spike immunity in naïve subjects, while the need for vaccinated COVID-19 recovered subjects has yet to be defined.","Immunity to SARS-CoV-2, the virus that causes coronavirus disease-19 (COVID-19) occurs from natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced immunity will last. We performed a long-term study of immunity to SARS-CoV-2 up to one year post infection and following mRNA vaccination in unexposed people and in people who have recovered from COVID-19 infection. We found that memory cells (immune cells that ""remember"" having encountered an infection before) are still detectable 8 months after vaccination, while viral antibody blood levels decline significantly, especially in previously unexposed people. We also found that a booster shot is effective in reactivating immunity to the virus spike protein in previously unexposed people, while it is ineffective in people who were previously infected with SARS-CoV-2. Finally, we found a similar reduction of immunity to SARS-CoV-2 up to one year following natural infection in a group of unvaccinated individuals. We conclude that short-term immunity, together with the reduced ability of the immune system to block the newer strains of SARS-CoV-2, might account for breakthrough infections in vaccinated people and reinfections in people who were previously infected. A booster dose restores the strongest immunity against the viral spike protein in unexposed people, but it is not clear if people who have recovered from COVID-19 need to have a booster." +"Recognizing that anti-SARS-CoV-2 antibody levels wane over time following the 2-dose SARS-CoV-2 mRNA series, the FDA approved a booster dose for people greater than 12 years old. Limited data exist on whether a booster dose of the mRNA vaccine results in greater antibody protection than the primary series. We examined total and neutralizing antibodies to the spike protein of SARS-CoV-2, and neutralizing antibodies against Washington-1 (WA-1) and variants of concern (VOC) including Beta, Delta and Omicron in a longitudinal cohort. Healthcare workers (HWs) were included in the analysis if serum was collected 1) within 14-44 days post-dose2 of an mRNA SARS-CoV-2 vaccine (Timepoint 1, TP1), or 2) at least 8 months post-dose2 (Timepoint 2, TP2), or 3) within 14-44 days following mRNA booster (Timepoint 3, TP3). HWs with prior covid-positive PCR were excluded. We found that there is little to no neutralizing capability following a 2-dose mRNA vaccine series against the omicron variant, and neutralizing capacity to any variant strain tested has been lost by 8-months post two-dose vaccination series. However, the mRNA booster series eliminates the immune escape observed by the omicron variant with the two-dose series. Neutralizing titers were significantly higher for all variants post-boost compared to the titers post two-dose series. The longitudinal nature of our cohort facilitated the analysis of paired samples pre and post boost, showing a greater than 15-fold increase in neutralization against omicron post-boost in these paired samples. An mRNA booster dose provides greater quantity and quality of antibodies compared to a two-dose regimen and is critical to provide any protection against the omicron variant.","After vaccination with the 2-dose COVID-19 mRNA vaccine, blood levels of antibodies against the spike protein of SARS-CoV-2 drop over time. To increase blood levels of antibodies again, the FDA approved a booster dose for people greater than 12 years old. However, limited data exist on whether a booster dose of the mRNA vaccine results in greater antibody protection than the primary series. We measured the blood levels of all types of antibodies against the spike protein of SARS-CoV-2, and a specific type of antibodies - called neutralizing antibodies - against Washington-1 and other variants of concern including Beta, Delta and Omicron. We followed the trends in antibody levels at several points in time after vaccination. Healthcare workers were included in the analysis if serum was collected within 14-44 days post-dose 2 of an mRNA SARS-CoV-2 vaccine, or at least 8 months post-dose 2, or within 14-44 days following an mRNA booster shot. Healthcare workers who had previously tested positive to COVID-19 were excluded from this study. We found that there are few to no neutralizing antibodies produced against the omicron variant following a 2-dose mRNA vaccine series. By 8-months post two-dose vaccination series, no neutralizing antibodies remain in blood circulation. However, the mRNA booster reactivates immunity to the omicron variant after the two-dose vaccination. Neutralizing antibody blood levels were significantly higher for all variants post-booster compared to the levels after the first two shots. The long-term nature of our study helped us to analyze the trends of antibody blood levels over time. We saw a 15-fold increase in neutralizing antibodies against the omicron variant following the booster shot. An mRNA booster dose provides greater quantity and quality of antibodies compared to a two-dose vaccine and is critical to provide any protection against the omicron variant." +"Background: Vaccine effectiveness against COVID-19 beyond 6 months remains incompletely understood. We aimed to investigate the effectiveness of COVID-19 vaccination against the risk of infection, hospitalisation, and death during the first 9 months after vaccination for the total population of Sweden. Methods: This retrospective, total population cohort study was done using data from Swedish nationwide registers. The cohort comprised all individuals vaccinated with two doses of ChAdOx1 nCoV-19, mRNA-1273, or BNT162b2, and matched unvaccinated individuals, with data on vaccinations and infections updated until Oct 4, 2021. Two outcomes were evaluated. The first was SARS-CoV-2 infection of any severity from Jan 12 to Oct 4, 2021. The second was severe COVID-19, defined as hospitalisation for COVID-19 or all-cause 30-day mortality after confirmed infection, from March 15 to Sept 28, 2021. Findings: Between Dec 28, 2020, and Oct 4, 2021, 842 974 individuals were fully vaccinated (two doses), and were matched (1:1) to an equal number of unvaccinated individuals (total study cohort n=1 685 948). For the outcome SARS-CoV-2 infection of any severity, the vaccine effectiveness of BNT162b2 waned progressively over time, from 92% (95% CI 92 to 93; p<0·001) at 15-30 days, to 47% (39 to 55; p<0·001) at 121-180 days, and to 23% (-2 to 41; p=0·07) from day 211 onwards. Waning was slightly slower for mRNA-1273, with a vaccine effectiveness of 96% (94 to 97; p<0·001) at 15-30 days and 59% (18 to 79; p=0·012) from day 181 onwards. Waning was also slightly slower for heterologous ChAdOx1 nCoV-19 plus an mRNA vaccine, for which vaccine effectiveness was 89% (79 to 94; p<0·001) at 15-30 days and 66% (41 to 80; p<0·001) from day 121 onwards. By contrast, vaccine effectiveness for homologous ChAdOx1 nCoV-19 vaccine was 68% (52 to 79; p<0·001) at 15-30 days, with no detectable effectiveness from day 121 onwards (-19% [-98 to 28]; p=0·49). For the outcome of severe COVID-19, vaccine effectiveness waned from 89% (82 to 93; p<0·001) at 15-30 days to 64% (44 to 77; p<0·001) from day 121 onwards. Overall, there was some evidence for lower vaccine effectiveness in men than in women and in older individuals than in younger individuals. Interpretation: We found progressively waning vaccine effectiveness against SARS-CoV-2 infection of any severity across all subgroups, but the rate of waning differed according to vaccine type. With respect to severe COVID-19, vaccine effectiveness seemed to be better maintained, although some waning became evident after 4 months. The results strengthen the evidence-based rationale for administration of a third vaccine dose as a booster.","The effectiveness of a vaccine against COVID-19 6 months after vaccination is not fully understood. We studied the effectiveness of COVID-19 vaccination against the risk of infection, hospitalisation, and death during the first 9 months after vaccination for the total population of Sweden. We took our data from Swedish nationwide registers. The data were from all individuals vaccinated with two doses of ChAdOx1 nCoV-19 (AstraZeneca), mRNA-1273 (Moderna), or BNT162b2 (Pfizer) vaccines, and matched unvaccinated individuals, with data on vaccinations and infections updated until Oct 4, 2021. Two outcomes were evaluated. The first was SARS-CoV-2 infection of any severity from Jan 12 to Oct 4, 2021. The second was severe COVID-19, defined as hospitalisation for COVID-19 or death from any cause 30 days after confirmed infection, from March 15 to Sept 28, 2021. Between Dec 28, 2020, and Oct 4, 2021, 842 974 individuals were fully vaccinated (two doses). We compared these individuals to an equal number of unvaccinated individuals. The total number of people studied was 1,685,948. In patients who had SARS-CoV-2 infection of any severity, the vaccine effectiveness of BNT162b2 dropped progressively over time, from 92% at 15-30 days after vaccination, to 47% at 121-180 days, and to 23% from day 211 onwards. Reduced vaccine effectiveness was slightly slower for the mRNA-1273 vaccine, with a vaccine effectiveness of 96% at 15-30 days and 59% from day 181 onwards. Reduction of vaccine effectiveness was also slightly slower for the combination of the ChAdOx1 nCoV-19 vaccine plus an mRNA vaccine, for which vaccine effectiveness was 89% at 15-30 days and 66% from day 121 onwards. By contrast, vaccine effectiveness for the ChAdOx1 nCoV-19 vaccine only (not combined with another vaccine) was 68% at 15-30 days, with no detectable effectiveness from day 121 onwards. In patients who had severe COVID-19, vaccine effectiveness dropped from 89% at 15-30 days to 64% from day 121 onwards. Overall, there was some evidence for lower vaccine effectiveness in men than in women and in older individuals than in younger individuals. We found progressively reduced vaccine effectiveness against SARS-CoV-2 infection of any severity across all subgroups of patients, but the rate of reduction differed according to vaccine type. In patients who had severe COVID-19, vaccine effectiveness seemed to be better maintained, although some reduction became evident after 4 months. Our study provides evidence that a third vaccine dose as a booster will improve immunity against COVID-19." +"Objectives: To determine the status of immune responses after primary and booster immunization for coronavirus disease 2019 (COVID-19) variants and evaluate the differences in disease-resistance based upon titers of neutralizing antibodies (NAbs) against the variants. Methods: Participants aged 18 - 59 y received two doses of inactivated COVID-19 vaccine, 14 days apart, and a booster dose after 12 m. Blood samples were collected before vaccination (baseline), 1 and 6 m after primary immunization, and at multiple instances within 21 d of booster dose. NAbs against the spike protein of Wuhan-Hu-1 and three variants were measured using pseudovirus neutralization assays. Results: Out of 400 enrolled participants, 387 completed visits scheduled within 6 m of the second dose, and 346 participated received the booster dose in the follow-up research. After 1 m of primary immunization, geometric mean titers (GMTs) of NAbs peaked for Wuhan-Hu-1, while GMTs of other variants were < 30. After 6 m of primary immunization, GMTs of NAbs against all strains were < 30. After 3 d of booster immunization, GMTs were unaltered, seroconversion rates reached approximately 50% after 7 d, and GMTs of NAbs against all strains peaked at 14 d. Conclusion: Two-dose of inactivated COVID-19 vaccine induced the formation of NAbs and memory-associated immune responses, and high titers of NAbs against the variants obtained after booster immunization may further improve the effectiveness of the vaccine.","We studied the immune response after primary and booster immunization for coronavirus disease 2019 (COVID-19) variants. We evaluated the differences in disease resistance based upon blood levels of neutralizing antibodies (antibodies that inactivate the virus) against the variants. Participants aged 18 - 59 years old received two doses of inactivated COVID-19 vaccine, 14 days apart, and a booster dose after 12 months. Blood samples were collected before vaccination, 1 and 6 months after primary immunization, and several times within 21 days of booster dose. Neutralizing antibodies against the spike protein of the Wuhan-Hu-1 variant and three other variants were measured. Out of 400 enrolled participants, 387 completed visits scheduled within 6 months of the second dose, and 346 participants received the booster dose in the follow-up research. After 1 month of primary immunization, blood levels of neutralizing antibodies peaked for Wuhan-Hu-1, while blood levels against other variants were lower. After 6 months of primary immunization, blood levels against all strains were reduced. After 3 days of booster immunization, blood levels were unchanged. However, blood levels increased approximately 50% after 7 days, and peaked at 14 days for all strains. Two doses of inactivated COVID-19 vaccine produced neutralizing antibodies and immunity, and high levels of neutralizing antibodies against the variants after booster immunization could further improve the effectiveness of the vaccine." +"Objectives: To estimate the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe covid-19 at different time after vaccination. Design: Retrospective cohort study. Setting: Italy, 27 December 2020 to 7 November 2021. Participants: 33 250 344 people aged ≥16 years who received a first dose of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine and did not have a previous diagnosis of SARS-CoV-2 infection. Main outcome measures: SARS-CoV-2 infection and severe covid-19 (admission to hospital or death). Data were divided by weekly time intervals after vaccination. Incidence rate ratios at different time intervals were estimated by multilevel negative binomial models with robust variance estimator. Sex, age group, brand of vaccine, priority risk category, and regional weekly incidence in the general population were included as covariates. Geographic region was included as a random effect. Adjusted vaccine effectiveness was calculated as (1-IRR)×100, where IRR=incidence rate ratio, with the time interval 0-14 days after the first dose of vaccine as the reference. Results: During the epidemic phase when the delta variant was the predominant strain of the SARS-CoV-2 virus, vaccine effectiveness against SARS-CoV-2 infection significantly decreased (P<0.001) from 82% (95% confidence interval 80% to 84%) at 3-4 weeks after the second dose of vaccine to 33% (27% to 39%) at 27-30 weeks after the second dose. In the same time intervals, vaccine effectiveness against severe covid-19 also decreased (P<0.001), although to a lesser extent, from 96% (95% to 97%) to 80% (76% to 83%). High risk people (vaccine effectiveness -6%, -28% to 12%), those aged ≥80 years (11%, -15% to 31%), and those aged 60-79 years (2%, -11% to 14%) did not seem to be protected against infection at 27-30 weeks after the second dose of vaccine. Conclusions: The results support the vaccination campaigns targeting high risk people, those aged ≥60 years, and healthcare workers to receive a booster dose of vaccine six months after the primary vaccination cycle. The results also suggest that timing the booster dose earlier than six months after the primary vaccination cycle and extending the offer of the booster dose to the wider eligible population might be warranted.","We studied the effectiveness of mRNA vaccines against SARS-CoV-2 infection and severe COVID-19 at different times after vaccination. This study was performed in Italy from December 27, 2020 to November 7, 2021. The participants included people aged 16 years and older who received a first dose of BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine and did not have a previous diagnosis of SARS-CoV-2 infection. We tracked the number of people with SARS-CoV-2 infection and severe COVID-19 (admission to hospital or death). The data was calculated for each week following vaccination. The incidence rate of infection at different time intervals was estimated using statistical models. We recorded the sex, age group, brand of vaccine, and priority risk category of patients, and recorded the regional weekly incidence in the general population. We tracked the number of cases according to geographic region. Using infection rates at 0-14 days after the first dose of vaccine as our starting point, we followed the trend of vaccine effectiveness During the epidemic phase when the delta variant was the most common strain of the SARS-CoV-2 virus, vaccine effectiveness against SARS-CoV-2 infection significantly decreased from 82% at 3-4 weeks after the second dose of vaccine to 33% at 27-30 weeks after the second dose. In the same time range, vaccine effectiveness against severe COVID-19 also decreased, although to a lesser extent, from an average of 96% to an average of 80%. High risk people, those aged more than 80 years old, and those aged 60-79 years did not seem to be protected against infection at 27-30 weeks after the second dose of vaccine. Our results support vaccinating high risk people, those older than 60 years, and healthcare workers with a booster dose of vaccine six months after the primary vaccination cycle. Our results also suggest that giving the booster dose earlier than six months after the primary vaccination cycle and extending the offer of the booster dose to other groups of people might be a good idea." +"The BNT162b2 vaccine is highly effective against COVID-19 infection and was delivered with a 3-week time interval in registration studies 1. However, many countries extended this interval to accelerate population coverage with a single vaccine. It is not known how immune responses are influenced by delaying the second dose. We provide the assessment of immune responses in the first 14 weeks after standard or extended-interval BNT162b2 vaccination and show that delaying the second dose strongly boosts the peak antibody response by 3.5-fold in older people. This enhanced antibody response may offer a longer period of clinical protection and delay the need for booster vaccination. In contrast, peak cellular-specific responses were the strongest in those vaccinated on a standard 3-week vaccine interval. As such, the timing of the second dose has a marked influence on the kinetics and magnitude of the adaptive immune response after mRNA vaccination in older people.","The BNT162b2 vaccine (Pfizer) is highly effective against COVID-19 infection. In registration studies, the two doses were delivered 3 weeks apart.. However, many countries extended the time between the first and second doses to maximize the number of people vaccinated with one dose. It is not known how antibody responses or cellular immune responses are influenced by delaying the second dose. We studied the immune response in the first 14 weeks after the standard 3-week interval or the extended interval BNT162b2 vaccination. We showed that delaying the second dose strongly boosts the peak antibody response by 3.5-fold in older people. This enhanced antibody response may offer a longer period of protection against infection and delay the need for booster vaccination. In contrast, peak cellular-specific responses were the strongest in those vaccinated on a standard 3-week vaccine interval. The timing of the second dose has a strong influence on the antibody response after BNT162b2 vaccination in older people." +"Introduction: Coronavirus disease 2019 (COVID-19) vaccines are nothing short of a miracle story halting the pandemic across the globe. Nearly half of the global population has received at least one dose. Nevertheless, antibody levels in vaccinated people have shown waning, and breakthrough infections have occurred. Our study aims to measure antibody kinetics following AZD1222 (ChAdOx1) vaccination six months after the second dose and the factors affecting the kinetics. Materials and methods: We conducted a prospective longitudinal study monitoring for six months after the second of two AZD1222 (ChAdOx1) vaccine doses in healthcare professionals and healthcare facility employees at Veer Surendra Sai Institute of Medical Sciences and Research (included doctors, nurses, paramedical staff, security and sanitary workers, and students). Two 0.5-mL doses of the vaccine were administered intramuscularly, containing 5 x 1010 viral particles 28 to 30 days between doses. We collected blood samples one month after the first dose (Round 1), one month after the second dose (Round 2), and six months after the second dose (Round 3). We tested for immunoglobulin G (IgG) levels against the receptor-binding domain of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by chemiluminescence microparticle immunoassay. We conducted a linear mixed model analysis to study the antibody kinetics and influencing factors. Results: Our study included 122 participants (mean age, 41.5 years; 66 men, 56 women). The geometric mean IgG titers were 138.01 binding antibody units (BAU)/mL in Round 1, 176.48 BAU/mL in Round 2, and 112.95 BAU/mL in Round 3. Seven participants showed seroreversion, and 11 had breakthrough infections. Eighty-six participants showed a substantial decline in antibody titer from Rounds 2 to 3. Persons aged 45 or older had higher mean titer than people aged younger than 45 years. Overweight and obese (BMI ≥ 25 kg/m2) had a higher mean titer than average or underweight persons. The only significant predictor of IgG titers at six months was SARS-CoV-2 infection on mixed model analysis. Conclusion: We found a substantial decline in antibody levels leading to seven cases of seroreversion in healthcare professionals who received the ChAdOx1 vaccine. History of prior COVID-19 was the only significant factor in antibody levels at six months. Seroreversion and breakthrough infection warrant further research into the optimal timing and potential benefits of booster doses of the AZD1222 (ChAdOx1) COVID-19 vaccine.","Coronavirus disease 2019 (COVID-19) vaccines are nothing short of a miracle story halting the pandemic across the globe. Nearly half of the global population has received at least one dose. Nevertheless, antibody blood levels in vaccinated people drop over time, and breakthrough infections have occurred. We studied the trends in antibody blood levels six months after the second dose of the AZD1222 (ChAdOx1) AstraZeneca vaccine. We conducted a 6 month study after the second of two AZD1222 (ChAdOx1) vaccine doses in healthcare professionals and healthcare facility employees at Veer Surendra Sai Institute of Medical Sciences and Research. The study population included doctors, nurses, paramedical staff, security and sanitary workers, and students. Two doses of the vaccine were injected into the upper arm, with 28 to 30 days between doses. We collected blood samples one month after the first dose (Round 1), one month after the second dose (Round 2), and six months after the second dose (Round 3). We measured blood levels of antibodies against the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We used statistical methods to measure the change in antibody blood levels over time. Our study included 122 participants (mean age, 41.5 years; 66 men, 56 women). Antibody blood levels were 138.01 in Round 1, increased to 1,176.48 in Round 2, and dropped to 112.95 in Round 3. Seven participants showed a complete loss of measurable blood antibodies, and 11 had breakthrough infections. Eighty-six participants showed a substantial decline in antibody levels from Rounds 2 to 3. Persons aged 45 or older had higher antibody levels than people aged younger than 45 years. Overweight and obese people (body mass index larger than 25) had higher antibody levels than average or underweight persons. The only people who maintained high levels of antibodies at 6 months were in people who had been infected with SARS-CoV2. We found a substantial decline in antibody levels leading to seven cases of loss of antibodies in healthcare professionals who received the ChAdOx1 vaccine. A history of prior COVID-19 infection was the only significant reason for high antibody levels at six months. More research needs to be conducted on the optimal timing and potential benefits of booster doses of the AZD1222 (ChAdOx1) COVID-19 vaccine to avoid breakthrough infections or loss of immunity." +"The timing of the development of specific adaptive immunity after natural SARS-CoV-2 infection, and its relevance in clinical outcome, has not been characterized in depth. Description of the long-term maintenance of both cellular and humoral responses elicited by real-world anti-SARS-CoV-2 vaccination is still scarce. Here we aimed to understand the development of optimal protective responses after SARS-CoV-2 infection and vaccination. We performed an early, longitudinal study of S1-, M- and N-specific IFN-γ and IL-2 T cell immunity and anti-S total and neutralizing antibodies in 88 mild, moderate or severe acute COVID-19 patients. Moreover, SARS-CoV-2-specific adaptive immunity was also analysed in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2-vaccinees and 30 uninfected healthy controls. Upon natural infection, cellular and humoral responses were early and coordinated in mild patients, while weak and inconsistent in severe patients. The S1-specific cellular response measured at hospital arrival was an independent predictive factor against severity. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibodies and neutralization capacity declined. Finally, a robust Th1-driven immune response was developed in uninfected BNT162b2-vaccinees. Three months post-vaccination, the cellular response was comparable, while the humoral response was consistently stronger, to that measured in COVID-19 recovered patients. Thus, measurement of both humoral and cellular responses provides information on prognosis and protection from infection, which may add value for individual and public health recommendations.","The timing of the development of immunity after natural SARS-CoV-2 infection has not been studied in depth. Data about long-term immunity following anti-SARS-CoV-2 vaccination is still scarce. We studied the the development of the strongest protective immune responses after SARS-CoV-2 infection and vaccination. We performed a long-term study of the immune responses and antibody blood levels in patients with mild, moderate or severe acute COVID-19 infection. Immune response was also studied in 234 COVID-19 recovered subjects, 28 uninfected BNT162b2 (Pfizer)-vaccinees and 30 uninfected healthy unvaccinated people. During natural infection, immune responses were early and coordinated in patients with mild COVID-19, while the immune responses were weak and inconsistent in patients with severe illness. Immunity in patients was measured at hospital arrival. Patients with a strong cellular immune response against the virus spike protein had a less severe illness. In COVID-19 recovered patients, four to seven months post-infection, cellular immunity was maintained but antibody blood levels and the capacity of the antibodies to block the virus declined. In uninfected BNT162b2-vaccinees, a strong cellular immune response developed. Three months post-vaccination, the cellular immune response was comparable to that measured in patients who recovered from COVID-19. In vaccinated people, the antibody response was consistently stronger to that measured in COVID-19 recovered patients. Our study of the cellular immune response and the antibody response provides information about protection from infection and the likelihood of developing severe infection. This information could be used to influence public health recommendations." +"Nephrotic syndrome (NS) is one of the most common glomerular diseases that affect children. Renal histology reveals the presence of minimal change nephrotic syndrome (MCNS) in more than 80% of these patients. Most patients with MCNS have favorable outcomes without complications. However, a few of these children have lesions of focal segmental glomerulosclerosis, suffer from severe and prolonged proteinuria, and are at high risk for complications. Complications of NS are divided into two categories: disease-associated and drug-related complications. Disease-associated complications include infections (e.g., peritonitis, sepsis, cellulitis, and chicken pox), thromboembolism (e.g., venous thromboembolism and pulmonary embolism), hypovolemic crisis (e.g., abdominal pain, tachycardia, and hypotension), cardiovascular problems (e.g., hyperlipidemia), acute renal failure, anemia, and others (e.g., hypothyroidism, hypocalcemia, bone disease, and intussusception). The main pathomechanism of disease-associated complications originates from the large loss of plasma proteins in the urine of nephrotic children. The majority of children with MCNS who respond to treatment with corticosteroids or cytotoxic agents have smaller and milder complications than those with steroid-resistant NS. Corticosteroids, alkylating agents, cyclosporin A, and mycophenolate mofetil have often been used to treat NS, and these drugs have treatment-related complications. Early detection and appropriate treatment of these complications will improve outcomes for patients with NS.","Nephrotic Syndrome (NS) is one of the most common kidney diseases in children. Most of the time, looking at kidney tissue under a microscope shows that there is Minimal Change Nephrotic Syndrome (MCNS). Most people with MCNS can be cured without other issues. However, some children with NS have a different form called focal segmental glomerulosclerosis. Children with this form have excess protein in their urine for long periods of time and are at high risk for additional problems. Additional problems caused by NS come in two categories: problems caused by the disease, and problems caused by drugs used to treat the disease. Problems caused by the disease include infections, blood clots, shock, heart disease, kidney failure, anemia, and others. The main way NS causes problems is from the large loss of proteins from the blood through urine. Most children with MCNS that is treatable with drugs have fewer additional problems that children with NS that drugs cannot help. Several drugs have been used to treat NS. These drugs can cause additional problems when used to treat NS. Finding additional problems early will improve results for patients with NS." +"Background and objectives: There are very little data available regarding nephrotic syndrome (NS) in elderly (aged ?65 years) Japanese. The aim of this study was to examine the causes and outcomes of NS in elderly patients who underwent renal biopsies between 2007 and 2010. Design, setting, participants, and measurements: From July 2007 to June 2010, all of the elderly (aged ?65 years) Japanese primary NS patients who underwent native renal biopsies and were registered in the Japan renal biopsy registry (J-RBR; 438 patients including 226 males and 212 females) were identified. From this cohort, 61 patients [28 males and 33 females including 29, 19, 6, 4, and 3 patients with membranous nephropathy (MN), minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), and other conditions, respectively] were registered from the representative multi-centers over all districts of Japan, and analyzed retrospectively. The treatment outcome was assessed using proteinuria-based criteria; i.e., complete remission (CR) was defined as urinary protein level of <0.3 g/day or g/g Cr, and incomplete remission type I (ICR-I) was defined as urinary protein level of <1.0-0.3 g/day or g/g Cr, and renal dysfunction was defined as a serum creatinine (Cr) level of 1.5 times the baseline level. Results: In this elderly primary NS cohort, MN was the most common histological type of NS (54.8 %), followed by MCNS (19.4 %), FSGS (17.4 %), and MPGN (8.4 %). Of the patients with MN, MCNS, or FSGS, immunosuppressive therapy involving oral prednisolone was performed in 25 MN patients (86.2 %), 18 MCNS patients (94.7 %), and all 6 FSGS patients (100 %). CR was achieved in all 19 (100 %) MCNS patients. In addition, CR and ICR-I were achieved in 16 (55.2 %) and 18 (62.1 %) MN patients and 4 (66.7 %) and 5 (83.3 %) FSGS patients, respectively. There were significant differences in the median time to CR among the MCNS, FSGS, and MN patients (median: 26 vs. 271 vs. 461 days, respectively, p < 0.001), and between the elderly (65-74 years, n = 7) and very elderly (aged ?75 years, n = 12) MCNS patients (7 vs. 22 days, p = 0.037). Relapse occurred in two (6.9 %) of the MN and nine (47.4 %) of the MCNS patients. Renal dysfunction was observed in five (7.2 %) of the MN patients. Serious complications developed in eight (14.8 %) patients, i.e., two (3.7 %) patients died, four (7.4 %, including three MCNS patients) were hospitalized due to infectious disease, and two (3.7 %) developed malignancies. The initiation of diabetic therapy was necessary in 14 of the 61 patients (23.0 %) with much higher initial steroid dosage. Conclusion: Renal biopsy is a valuable diagnostic tool for elderly Japanese NS patients. In this study, most of elderly primary NS patients respond to immunosuppressive therapy with favorable clinical outcomes. On the other hand, infectious disease is a harmful complication among elderly NS patients, especially those with MCNS. In future, modified clinical guidelines for elderly NS patients should be developed.","There�s not a lot of information about Nephrotic Syndrome (NS) in older Japanese people. The goal of this study was to look at the causes and outcomes of NS in older patients that had kidney biopsies (tissue samples) between 2007 and 2010. From a registry in Japan, we found all Japanese NS patients 65 or older who had kidney biopsies (tissue samples) from July 2007 to June 2010. This included 438 patients, 226 men and 212 women. Out of these patients, we looked closer at 61 that had certain types of NS. To know how well treatments worked, we looked at the levels of protein in the patients� urine. In this group of older people with NS, more than half (58%) had a type called Membranous Nephropathy (MN). Another 19% had Minimal Change Nephrotic Syndrome (MCNS), 17% had Focal Segmental Glomerosclerosis (FSGS), and 8% had membranoproliferative glomerulonephritis (MPGN). A drug called prednisolone, which suppresses the immune system, was given to 86% of the patients with MN, 94% of the patients with MCNS, and all 6 patients with FSGS. The disease was completely cured in all 19 MCNS patients. Fifty-five percent of MN patients were completely cured and 62% were at least partially cured. Sixty-six percent of FSGS patients were completely cured and 83% were partially cured. There were meaningful differences in how long it took for different types of NS to be cured. The differences depended both on the type of NS (MCNS, FSGS, or MN) and whether MCNS patients were 75 or older. The disease came back in 7% of patients with MN and 47% of patients with MCNS. Seven percent of patients with MN had problems with kidney function. Eight patients had serious problems. For example, two of them died, four were hospitalized for infections, and two developed malignant tumors. Treatment for diabetes was needed for 14 of the 61 patients with higher initial steroid dosage. Conclusions we can make include the fact that kidney biopsies are valuable for diagnosing NS in older Japanese patients. Also, in this study, most older NS patients responded well to drugs that suppress the immune system. On the other hand, infections are a harmful related problem among older people with NS, especially if they have MCNS. In the future, doctors should update guidelines for older NS patients." +"Background: Few studies have examined the treatment and outcome of adult-onset minimal change nephrotic syndrome (MCNS). We retrospectively studied 125 patients who had MCNS with onset in either adulthood or late adolescence. Presenting characteristics, duration of initial treatment and response to treatment, relapse patterns, complications, and long-term outcome were studied. Study design: Case series. Setting & participants: Patients with new-onset nephrotic syndrome 16 years or older and a histologic diagnosis of MCNS in 1985 to 2011 were identified from pathology records of 10 participating centers. Outcomes: Partial and complete remission, treatment resistance, relapse, complications, renal survival. Results: Corticosteroids were given as initial treatment in 105 (84%) patients. After 16 weeks of corticosteroid treatment, 92 (88%) of these patients had reached remission. Median time to remission was 4 (IQR, 2-7) weeks. 7 (6%) patients initially received cyclophosphamide with or without corticosteroids, and all attained remission after a median of 4 (IQR, 3-11) weeks. 13 (10%) patients reached remission without immunosuppressive treatment. One or more relapses were observed in 57 (54%) patients who received initial corticosteroid treatment. Second-line cyclophosphamide resulted in stable remission in 57% of patients with relapsing MCNS. Acute kidney injury was observed in 50 (40%) patients. Recovery of kidney function occurred almost without exception. Arterial or venous thrombosis occurred in 11 (9%) patients. At the last follow-up, 113 (90%) patients were in remission and had preserved kidney function. 3 patients with steroid-resistant MCNS progressed to end-stage renal disease, which was associated with focal segmental glomerulosclerosis lesions on repeat biopsy. Limitations: Retrospective design, variable treatment protocols. Conclusions: The large majority of patients who had MCNS with onset in adulthood or late adolescence were treated with corticosteroids and reached remission, but many had relapses. Cyclophosphamide resulted in stable remission in many patients with relapses. Significant morbidity was observed due to acute kidney injury and other complications. Progression to end-stage renal disease occurred in a few patients and was explained by focal segmental glomerulosclerosis.","Minimal Change Nephrotic Syndrome (MCNS) is a kidney disease that can lead to a group of symptoms called Nephrotic Syndrome (NS). Not many studies have looked at the treatment and results of MCNS that starts in adulthood. We looked at 125 patients from other studies that had MCNS appear as a late adolescent or adult. We studied how the disease appeared, how long it was treated, and how patients responded to the treatment. We also studied further problems caused by the disease and treatment, as well as long-term outcomes. The type of this study is to look at various cases. We looked at pathology reports from 1985 to 2011 from 10 participating health care centers. From these, we found patients 16 years or older with new NS and a diagnosis of MCNS confirmed by looking at tissue under a microscope. The cases had a variety of outcomes: partial and complete reversal of the disease, resistance of the disease to treatment, the disease coming back, further problems caused by the disease, and how long the kidneys functioned. Eighty-four percent of patients were given corticosteroids as an initial treatment. After 16 weeks of corticosteroids, 88% of these patients were cured. On average, time to reversing the disease was around 4 weeks. Six percent of patients at first were given a cancer drug called cyclophosphamide, either with or without corticosteroids. All these patients were cured, in about 4 weeks on average. Ten percent of patients were cured without drugs that suppress the immune system. The disease returned at least once in 54% of patients that initially were given corticosteroids. Cyclophosphamide used as a second-choice alternative drug cured 57% of the patients who had returning MCNS. Forty percent of the patients had serious kidney damage. Kidney function returned in almost every case. Nine percent of patients had blood clots. At the last follow-up, 90% of the patients still had the disease reversed and had functioning kidneys. Three patients with steroid-resistant MCNS continued to kidney failure. The kidney failure came along with damage to the small structures of the kidney that were seen under a microscope. This study is limited because we only looked at past patients and they were not all given the same treatments and dosages. The first conclusion we can make is that most patients with MCNS that appeared as an adult or late adolescent were cured with corticosteroids. However, many had the disease come back. In many of the patients for whom the disease came back, treatment with cyclophosphamide kept it from coming back again. Significant health problems were seen from serious damage to the kidneys and other problems caused by the disease. In a few patients, the disease continued to kidney failure, and this could be explained by damage to the small structures of the kidney." +"Background: Despite recent advances in immunosuppressive therapy for patients with primary nephrotic syndrome, its effectiveness and safety have not been fully studied in recent nationwide real-world clinical data in Japan. Methods: A 5-year cohort study, the Japan Nephrotic Syndrome Cohort Study, enrolled 374 patients with primary nephrotic syndrome in 55 hospitals in Japan, including 155, 148, 38, and 33 patients with minimal change disease (MCD), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other glomerulonephritides, respectively. The incidence rates of remission and relapse of proteinuria, 50% and 100% increases in serum creatinine, end-stage kidney disease (ESKD), all-cause mortality, and other major adverse outcomes were compared among glomerulonephritides using the Log-rank test. Incidence of hospitalization for infection, the most common cause of mortality, was compared using a multivariable-adjusted Cox proportional hazard model. Results: Immunosuppressive therapy was administered in 339 (90.6%) patients. The cumulative probabilities of complete remission within 3 years of the baseline visit was ? 0.75 in patients with MCD, MN, and FSGS (0.95, 0.77, and 0.79, respectively). Diabetes was the most common adverse events associated with immunosuppressive therapy (incidence rate, 71.0 per 1000 person-years). All-cause mortality (15.6 per 1000 person-years), mainly infection-related mortality (47.8%), was more common than ESKD (8.9 per 1000 person-years), especially in patients with MCD and MN. MCD was significantly associated with hospitalization for infection than MN. Conclusions: Patients with MCD and MN had a higher mortality, especially infection-related mortality, than ESKD. Nephrologists should pay more attention to infections in patients with primary nephrotic syndrome.","New discoveries in treatments that suppress the immune system have helped patients with Nephrotic Syndrome (NS), a group of symptoms relating to the kidneys. However, the safety and effectiveness of these treatments has not been fully studied for recent cases in Japan. A study 5 years ago followed 374 patients with NS in Japan, across 55 hospitals. It included 155 patients with Minimal Change Disease (MCD), 148 patients with membranous nephropathy (MN), 38 patients with Focal Segmental Glomerulosclerosis (FSGS), and 33 patients with other types of inflammation of the small filtering structures in the kidney. Among these diseases, we compared how often proteinuria (too much protein in the urine) was cured and came back. We also compared how often patients died, had kidney failure, or had other serious problems. The most common cause of death was being hospitalized for an infection. We compared this cause among the different diseases using statistical methods. We found that treatment to suppress the immune system was given to 339 patients. For patients with MCD, MN, FSGS, there was more than a 75% chance the disease was completely cured within 3 years. The most common side effect of treatments suppressing the immune system was diabetes. In each year, a person had a 71 in 1000 chance of this happening. Death from any cause, about half of which caused by infections, was more common than kidney failure, especially in patients with MCD and MN. MCD was more associated with hospitalization for infections than MN. Patients with MCD and MN were more likely to die, especially from infections, than to have kidney failure. We also conclude that doctors should pay more attention to infections in patients with NS." +"Background: Little population-based data exist about adults with primary nephrotic syndrome. Methods: To evaluate kidney, cardiovascular, and mortality outcomes in adults with primary nephrotic syndrome, we identified adults within an integrated health care delivery system (Kaiser Permanente Northern California) with nephrotic-range proteinuria or diagnosed nephrotic syndrome between 1996 and 2012. Nephrologists reviewed medical records for clinical presentation, laboratory findings, and biopsy results to confirm primary nephrotic syndrome and assigned etiology. We identified a 1:100 time-matched cohort of adults without diabetes, diagnosed nephrotic syndrome, or proteinuria as controls to compare rates of ESKD, cardiovascular outcomes, and death through 2014, using multivariable Cox regression. Results: We confirmed 907 patients with primary nephrotic syndrome (655 definite and 252 presumed patients with FSGS [40%], membranous nephropathy [40%], and minimal change disease [20%]). Mean age was 49 years; 43% were women. Adults with primary nephrotic syndrome had higher adjusted rates of ESKD (adjusted hazard ratio [aHR], 19.63; 95% confidence interval [95% CI], 12.76 to 30.20), acute coronary syndrome (aHR, 2.58; 95% CI, 1.89 to 3.52), heart failure (aHR, 3.01; 95% CI, 2.16 to 4.19), ischemic stroke (aHR, 1.80; 95% CI, 1.06 to 3.05), venous thromboembolism (aHR, 2.56; 95% CI, 1.35 to 4.85), and death (aHR, 1.34; 95% CI, 1.09 to 1.64) versus controls. Excess ESKD risk was significantly higher for FSGS and membranous nephropathy than for presumed minimal change disease. The three etiologies of primary nephrotic syndrome did not differ significantly in terms of cardiovascular outcomes and death. Conclusions: Adults with primary nephrotic syndrome experience higher adjusted rates of ESKD, cardiovascular outcomes, and death, with significant variation by underlying etiology in the risk for developing ESKD.","Nephrotic Syndrome (NS) is a combination of symptoms relating to the kidneys. There is not much information about how NS exists in the population. We looked at kidney health, heart disease, and death in adults within Kaiser Permanente of Northern California that had symptoms of NS between 1996 and 2012. Kidney specialists looked at medical records to confirm NS and determined causes. For comparison, we also found a group of adults with no diabetes, NS, or proteinuria (too much protein in the urine) through 2014. This group was to compare rates of kidney failure, heart disease, and death using statistical methods. We confirmed 907 patients with NS. Of these, 655 definitely had either Focal Segmental Glomerulosclerosis (FSGS), Membranous Nephropathy (MN), or Minimal Change Disease (MCD). Another 252 were presumed to have one of these. The average age of the patients was 49, and 43% were women. Adults with NS had about 20 times the rate of kidney failure compared to people with no NS. They also had about two and a half times the rate of heart-related chest pain, three times the rate of heart failure, almost twice the rate of stroke, two and a half times the rate of blood clots, and 34% higher rate of death. The extra risk for kidney failure was much higher for FSGS and MN than for disease presumed to be MCD. The three causes of NS did not have significant differences in heart disease and death. In conclusion, adults with NS have higher rates of kidney failure, heart disease, and death. The risk of kidney failure depended significantly on which underlying disease caused the NS symptoms." +"Nephrotic syndrome (NS) encompasses a variety of disease processes leading to heavy proteinuria and edema. Minimal change disease (MCD) remains the most common primary cause of NS, as well as the most responsive to pharmacologic treatment with often minimal to no chronic kidney disease. Other causes of NS include focal segmental glomerulosclerosis, which follows MCD, and secondary causes, including extrarenal or systemic diseases, infections, and drugs. Although initial diagnosis relies on clinical findings as well as urine and blood chemistries, renal biopsy and genetic testing are important diagnostic tools, especially when considering non-MCD NS. Moreover, biomarkers in urine and serum have become important areas for research in this disease. NS progression and prognosis are variable and depend on etiology, with corticosteroids being the mainstay of treatment. Other alternative therapies found to be successful in inducing and maintaining remission include calcineurin inhibitors and rituximab. Disease course can range from recurrent disease relapse with or without acute kidney injury to end-stage renal disease in some cases. Given the complex pathogenesis of NS, which remains incompletely understood, complications are numerous and diverse and include infections, electrolyte abnormalities, acute kidney injury, and thrombosis. Pediatricians must be aware of the presentation, complications, and overall long-term implications of NS and its treatment.","Nephrotic syndrome (NS) includes a variety of underlying diseases that lead to serious proteinuria (too much protein in the blood) and edema (fluid buildup). Minimal change disease (MCD) is still the most common cause of NS, and is the most responsive to treatment with drugs, often with little or no chronic kidney disease. Other causes of NS include focal segmental glomerulosclerosis, which follows MCD, and secondary causes, including diseases outside the kidneys, infections, and drugs. The initial diagnosis relies on signs and symptoms observed by a doctor. However, urine and blood tests, kidney tissue samples, and genetic testing are also important for diagnosis. This is especially true for NS not caused by MCD. Additionally, signs of disease in blood and urine have become important areas for research in this disease. The outcomes of NS and the way it progresses can vary and depend on the underlying disease. Corticosteroids are the main treatment. Alternative treatments that have been found to work include calcineurin inhibitors (a class of drugs that suppress the immune system) and rituximab (Rituxan). The course of the disease can range from continuing to come back, with or without serious kidney damage, to kidney failure in some cases. Since the origin of NS is complicated and not completely understood, there are many associated problems. These include infections, electrolyte problems, serious kidney damage, and blood clots. Pediatricians should know about how NS appears and the associated problems and long-term issues of NS and its treatment." +"Children with nephrotic syndrome (NS) have a number of potential risk factors for the development of acute kidney injury (AKI) including intravascular volume depletion, infection, exposure to nephrotoxic medication, and renal interstitial edema. This study was aimed to determine the incidence of AKI in children hospitalized with a relapse of NS and its short-term outcome. This prospective observational study was conducted from February 2017 to January 2018 at a tertiary care teaching hospital. A total of 54 children and adolescents (1-18 years) hospitalized with a diagnosis of NS and relapse with/or without other complications were enrolled. Clinical data and examination were recorded. AKI was defined using the Kidney Disease Improving Global Outcomes (KDIGO) serum creatinine criteria and Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (p-RIFLE) classification. Children who developed AKI during the first two weeks of hospitalization were followed up till recovery or six weeks whichever was earlier to determine the outcome and factors predisposing to AKI. The mean age of the study population was 59.5 months and 35 (64.8%) patients were male. Of the 54 patients hospitalized, 42 (77.8%) were admitted with infection-associated relapses while 22.2% of children had relapse alone. Diarrhea and spontaneous bacterial peritonitis were the most common infections (26.1% each) followed by urinary tract infections in 19% and pneumonia in 14.3%. Twenty-three (42.6%) children developed AKI according to the KDIGO definition and 27 (50%) using the pRIFLE classification. Fourteen (60.9%) had stage 2 AKI while 21.7% had stage 3 AKI. Infections [odds ratio (OR) 1.24] and use of angiotensin-converting enzyme inhibitors (ACEI) (OR 2.3) were the most common predisposing factors for AKI. The mean recovery time for AKI was 7.34 days. Development of AKI was associated with prolonged hospital stay (12.57 vs.8.55 days P <0.01) and delayed recovery. At the end of follow-up all children recovered from AKI. The incidence of AKI in children hospitalized with complications of NS is high. While the occurrence of these AKI episodes may appear transient, a recurrence of such episodes may be detrimental to the long-term outcome of children with NS. Infections and the use of ACEI during relapses are risk factor for the occurrence of AKI.","Nephrotic Syndrome (NS) is a combination of kidney-related symptoms. Children with NS are at risk for serious kidney damage for a number of reasons. These include too little blood, infection, medications, and swelling in the kidneys. The aim of this study was to find out how often serious kidney damage happens in children that had NS come back, and the short-term outcome of that damage. This study followed people over time and was conducted from February 2017 to January 2018 at a teaching hospital with highly specialized care. We enrolled a total of 54 children and adolescents who were hospitalized with a diagnosis of NS that came back, with or without associated problems. We recorded health-related information. To figure out what puts children more at risk for serious kidney damage, we followed up with children who had this problem during the first two weeks of hospitalization. We continued following up with them either until they recovered or until six weeks, whichever was earlier. The average age of people in the study was 59.5 months. Thirty-five of the patients (65%) were male. Out of the 54 patients that were hospitalized, 42 had returning NS that was associated with infections. Twenty-two percent of children had returning NS only. The most common infections were diarrhea and bacterial infections of the peritoneum, the lining of the abdominal cavity. The next most common were urinary tract infections and pneumonia. Twenty-three or 27 children developed serious kidney damage, depending on the criteria used. The most common factors that increased risk of serious kidney damage were infections and the use of ACE inhibitors. The average time for recovery from the serious kidney damage was about 7 days. Serious kidney damage was associated with longer hospital stays and delayed recovery. At the end of the followup, all children recovered from the kidney damage. Children hospitalized with problems associated with NS have high rates of serious kidney damage. These instances of serious kidney damage may seem to come and go, but happening repeatedly may cause long-term problems for children with NS. Infections and the use of ACE inhibitors increases the risk of serious kidney damage." +"Background: Although venous thromboembolism is a well-known complication of nephrotic syndrome, the long-term absolute and relative risks of arterial thromboembolism, venous thromboembolism, and bleeding in adults with nephrotic syndrome remain unclarified. Methods: In this matched cohort study, we identified every adult with first-time recorded nephrotic syndrome from admissions, outpatient clinics, or emergency department visits in Denmark during 1995-2018. Each patient was matched by age and sex with 10 individuals from the general population. We estimated the 10-year cumulative risks of recorded arterial thromboembolism, venous thromboembolism, and bleeding accounting for the competing risk of death. Using Cox models, we computed crude and adjusted hazard ratios (HRs) of the outcomes in patients with nephrotic syndrome versus comparators. Results: Among 3967 adults with first-time nephrotic syndrome, the 1-year risk of arterial thromboembolism was 4.2% (95% confidence interval [CI] 3.6-4.8), of venous thromboembolism was 2.8% (95% CI 2.3-3.3), and of bleeding was 5.2% (95% CI 4.5-5.9). The 10-year risk of arterial thromboembolism was 14.0% (95% CI 12.8-15.2), of venous thromboembolism 7.7% (95% CI 6.8-8.6), and of bleeding 17.0% (95% CI 15.7-18.3), with highest risks of ischemic stroke (8.1%), myocardial infarction (6.0%), and gastrointestinal bleeding (8.2%). During the first year, patients with nephrotic syndrome had increased rates of both arterial thromboembolism (adjusted HR [HRadj] = 3.11 [95% CI 2.60-3.73]), venous thromboembolism (HRadj = 7.11 [5.49-9.19]), and bleeding (HRadj = 4.02 [3.40-4.75]) compared with the general population comparators after adjusting for confounders. Conclusion: Adults with nephrotic syndrome have a high risk of arterial thromboembolism, venous thromboembolism, and bleeding compared with the general population. The mechanisms and consequences of this needs to be clarified.","Blood clots are a well-known problem associated with Nephrotic Syndrome (NS), a group of kidney-related symptoms. However, the risks of blood clots and bleeding in adults with NS is not clear. This study looked at groups of similar people with and without disease. In it, we found every adult that had NS recorded for the first time from 1995 to 2018 at admissions, outpatient clinics, and emergency department visits in Denmark. Each patient was matched by age and sex with 10 individuals from the general population. We estimated the 10-year risk of recorded blood clots and bleeding, accounting for risk of death. Using a statistical model, we calculated how likely the patients were to have certain outcomes compared to the general population. Among 3,967 adults with first-time NS, the risk of having a blood clot in an artery within one year was 4%. The risk of a blood clot in a vein in the same time was 3%, and the risk of bleeding was 5%. Within 10 years, the risk of a blood clot in an artery was 14%, the risk of a blood clot in a vein was 8%, and the risk of bleeding was 17%. The highest bleeding risks were of stroke, heart attack, and gastrointestinal bleeding. During the first year, patients with NS had higher rates of blood clots in arteries, blood clots in veins, and bleeding than the people from the general population. In conclusion, adults with NS have a higher risk of blood clots, both in arteries and veins, and bleeding compared to the general population. We still need to figure out how this happens and what the consequences are." +"Background: Steroid resistant nephrotic syndrome (SRNS), while uncommon in children, is associated with significant morbidity. Calcineurin inhibitors (CNIs) remain the first line recommended therapy for children with non-genetic forms of SRNS, but some children fail to respond to them. Intravenous (IV) cyclophosphamide (CTX) has been shown to be effective in Asian-Indian children with difficult to treat SRNS (SRNS-DTT). Our study evaluated the outcome of IV CTX treatment in North American children with SRNS-DTT. Methods: Retrospective review of the medical records of children with SRNS-DTT treated with IV CTX from January 2000 to July 2019 at our center. Data abstracted included demographics, histopathology on renal biopsy, prior and concomitant use of other immunosuppressive agents and serial clinical/laboratory data. Primary outcome measure was attainment of complete remission (CR). Results: Eight children with SRNS-DTT received monthly doses (median 6; range 4-6) of IV CTX. Four (50%) went into CR, 1 achieved partial remission and 3 did not respond. Three of the 4 responders had minimal change disease (MCD). Excluding the 1 child who responded after the 4th infusion, the median time to CR was 6.5 (range 0.5-8) months after completion of IV CTX infusions. Three remain in CR at a median of 8.5 years (range: 3.7-10.5 years) after completion of CTX; one child relapsed and became steroid-dependent. No infections or life-threatening complications related to IV CTX were observed. Conclusions: IV CXT can induce long term remission in North-American children with MCD who have SRNS-DTT.","Steroid Resistant Nephrotic Syndrome (SRNS) is a group of kidney-related symptoms that cannot be treated with steroids. Though it is not common in children, it is associated with many serious health problems. Immune system suppressing drugs called Calcineurin Inhibitors (CNIs) are the preferred treatment for children with SRNS that is not inherited. However, some children do not respond to these drugs. Another drug called Cyclophosphamide (CTX), given by IV, has been shown to be effective in Asian-Indian children with SRNS that is difficult to treat (SRNS-DTT). Our study looked at the outcome of IV CTX treatment in North American children with this disease. The study was a review of previous medical records of children with SRNS-DTT treated with IV CTX from January 2000 to July 2019 at our center. From these records, we looked at demographics, kidney tissue samples, and the use of drugs to suppress the immune system. We also looked at notes from office visits and lab results recorded over time. The main outcome that we measured was complete reversal of the disease. We found that 8 children with SRNS-DTT were given monthly doses of IV CTX. Four were completely cured, one was partially cured, and three did not respond to the treatment. Three of the four patients that were cured had a particular type of SRNS that was caused by Minimal Change Disease (MCD). Except for the one child who responded to treatment after the 4th dose, the average time to reverse the disease was about six and a half months after completing all the IV CTX doses. Three of the patients are still cured at an average of 8 and a half years after completing the CTX treatment. One child had the disease come back and had to continue taking steroids indefinitely. No infections or other life-threatening problems relating to IV CTX were seen. In conclusion, in North American children, Cyclophosphamide (CTX) given by IV can completely cure SRNS that is difficult to treat and is caused by Minimal Change Disease (MCD)." +"Chylothorax is an uncommon and serious clinical condition, typically induced by trauma, either postsurgical or accidental injury, but the mechanism of chylothorax caused by nephrotic syndrome is still unclear. Here, we report a case of primary nephrotic syndrome with membranous nephropathy (MN) in a 66-year-old man who presented with severe chylothorax. The chylothorax was managed by intercostal chest tube drainage, subcutaneous injection of enoxaparin, and treatment with anti-inflammatory agents and diuretics. After treatment, the patient's pleural effusion decreased, and the chyle gradually became clear. We discuss the causes of MN with chylothorax. We considered that the hypoproteinemia changed the permeability of mucous membranes and lymphatic vessels, leading to leakage of chylous particles and chylous pleural effusion formation. Chylothorax may also have been caused by severe tissue edema, edema of the lymphatic walls, and increased pressure, resulting in increased permeability or rupture of the lymphatic wall, and leakage of chylous fluid into the thoracic cavity. Because of its rarity, we hope this case report will improve clinicians' understanding of MN complications in primary nephrotic syndrome and provide suitable treatment options for future clinical reference.","Chylothorax is an uncommon and serious medical condition where fluid from the lymphatic system builds up around the lungs. It is typically caused by serious damage to the body, either after surgery or an accident. However, we don�t know how a cluster of kidney-related symptoms called Nephrotic Syndrome (NS) causes chylothorax. In this article we describe a case of NS with a kidney disease called Membranous Nephropathy (MN) in a 66 year old man with severe chylothorax. The chylothorax was kept under control with a drainage tube inserted into the chest, injections of a drug called enoxaparin, and treatment with anti-inflammatory drugs and diuretics, which increase urine production. After treatment, the fluid around the lungs decreased and became clear. We will talk about the causes of MN with chylothorax. We thought that maybe too little protein in the blood allowed fluid from the lymphatic system to leak through tissues and cause the buildup around the lungs. The chylothorax may also have been caused by severe swelling and increased pressure. This could have caused fluid to seep through or rupture the walls of lymph vessels (which are similar to blood vessels) and leak into the chest cavity. Since MN is rare, we hope this case report will help doctors to understand problems associated with MN in patients that have NS, and that it will provide treatment options for doctors in the future."