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Standard versus limited colon resection for high risk T1 colon cancer. A matched case-control study.
BACKGROUND AND AIMS: The National Comprehensive Cancer Network (NCCN) recommends a colectomy in presence of high risk T1 colon polyps considering the risk of incomplete lymph node dissection or presence of residual disease. We evaluated the outcomes of segmental versus standard colon resection for high risk T1 colon cancers, in order to demonstrate if segmental colectomy (SegCR) allows same short-term and oncological results compared to standard radical colectomy (StaCR). METHODS. A matched case-control study on patients who had undergone segmental versus standard colon resection was performed. One-hundred and two patients with high risk T1 colon cancer after endoscopic polypectomy, divided in 2 homogeneous groups of 51 cases, were analyzed and intra-operative, post-operative and oncological data were compared. RESULTS. Segmental colectomy allowed less operative time and intra-operative blood loss compared to StaCR (p < 0.001). Hospital stay after SegCR was shorter compared to StaCR (p < 0.001). No differences were found in terms of overall morbidity and mortality rates. Five-year actuarial overall, disease-free and disease-specific survival after StaCR were similar to SegCR (87%, 96% and 95% vs. 88%, 97% and 94%, respectively, p = 0.51, p=0.33, p=0.78). CONCLUSIONS. According to our findings, SegCR can be a valid alternative to StaCR for high risk T1 colon polyps. Segmental colectomy allows better peri-operative outcomes compared to StaCR ensuring the same oncological long-term outcomes.
Circulating tumor cells count predicts survival in colorectal cancer patients.
BACKGROUND AND AIMS: Data on the potential of circulating tumor cells (CTC) count in predicting overall survival (OS) in patients with colorectal cancer are timely and worthy of interest. This study aimed to evaluate the prognostic role of CTC count in both localized and metastatic colorectal cancer patients. METHODS: Consecutive patients with histological diagnosis of colorectal cancer were enrolled. CTC count was performed, by using a quantitative immunofluorescence method, at baseline (T0) and 1 month following start of chemotherapy (T1). A CTC count <2 was considered negative, whilst a CTC level >/= 2 was positive. Overall survival was calculated accordingly. RESULTS: A total of 75 colorectal cancer patients were enrolled, including 54 stages I-III and 21 stage IV patients. Overall, 21 (28%) patients had a positive CTC count at baseline, and it was significantly associated with a worse prognosis as compared to a negative status (OS: 36.2 vs. 61.6 months; P = 0.002). CTC count remained positive after chemotherapy in 22.4% of the patients and it was an independent prognostic factor of OS (P = 0.03; Hazard Ratio: 3.55; 95% CI: 1.1-11.5). CONCLUSIONS: This study found that the presence of CTCs is associated with a reduced survival in colorectal cancer patients. Further studies aimed at testing such a predictive value in early stage colorectal cancer are awaited.
Rapid fecal calprotectin level assessment and the SIBDQ score can accurately detect active mucosal inflammation in IBD patients in clinical remission: a prospective study.
BACKGROUND AND AIMS: Mucosal healing is an important predictor of disease-related outcome in patients with inflammatory bowel disease (IBD) patients, including those in clinical remission. However, colonoscopy is an invasive procedure and many patients decline repeated endoscopic examinations. We aimed to assess whether noninvasive biomarkers could accurately detect endoscopic mucosal inflammatory activity in IBD patients in clinical remission. METHODS: We conducted a prospective observational cohort study on IBD patients in clinical remission at Colentina Hospital, Bucharest. Clinical activity was assessed using the Mayo score and Crohn's Disease Activity Index (CDAI), quality of life was assessed using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Serum C-reactive protein (CRP) and fecal calprotectin (FC) levels were determined. All patients underwent ileo-colonoscopy to assess mucosal inflammatory activity. RESULTS: 48 patients were included in this study, with 67% showing endoscopic disease activity. SIBD questionnaire and FC performed well as noninvasive markers of intestinal inflammation (AUROC 0.78 and 0.77, respectively), while CRP could not accurately predict endoscopic disease activity. Fecal calprotectin levels > 30 microg/g showed a 93% sensitivity and a 50% specificity for detecting inflammatory changes of the mucosa while a combined test using FC > 30microg/g and a SIBDQ score < 6 achieved 81.2% sensitivity and 75% specificity, respectively, in detecting active endoscopic disease. CONCLUSION: Fecal calprotectin and SIBDQ have good diagnostic accuracy in detecting mucosal inflammatory changes in IBD patients in clinical remission. Combining simple, noninvasive tests such as the SIBDQ and FC levels appears to be a practical method for monitoring disease activity in these patients, possibly reducing the need for repeat endoscopic examinations.
Mucosal expression of basic fibroblastic growth factor, syndecan 1 and tumour necrosis factor-alpha in Crohn's disease in deep remission under treatment with anti-TNFalpha antibodies.
BACKGROUND AND AIMS: Both inflammation and fibrosis may be detected in Crohn's disease (CD). The molecular pattern of Basic Fibroblastic Growth Factor (bFGF) and Syndecan-1 (SD1) expression is altered in stenosing CD, but we do not know what the behaviour of this teamwork factor is in CD in deep remission under treatment with anti-TNFalpha antibodies. Our aim was to compare the expression of bFGF, SD1 and TNF-alpha in patients with CD in deep remission under treatment with Infliximab (IFX) or Adalimumab (ADA) and a control group of patients with active CD. METHODS: We assessed the expression of bFGF, SD1 and TNF-alpha in 10 patients with active CD and in 28 patients with CD in sustained deep remission for at least 6 months. All patients underwent surveillance colonoscopy with biopsies, while receiving maintenance therapy with IFX or ADA. Analysis was conducted by real-time reverse transcriptase PCR (RT-PCR) in biopsy samples. RESULTS: We found that bFGF, SD1 and TNF-alpha were significantly reduced under treatment with anti-TNFalpha versus controls (p=0.000). bFGF and SD1 expression were similar between IFX and ADA patients (p=0.335 and p=0.289, respectively), while TNF-alpha was significantly under-expressed in ADA patients (p=0.008). CONCLUSIONS: bFGF, SD1 and TNF-alpha are significantly reduced in CD patients in deep remission under treatment with anti-TNFalpha, likely as an expression of optimal control of inflammation. The significance of the TNF-alpha under-expression in patients under treatment with ADA with respect to those under treatment with IFX should be elucidated in further studies.
Analysis of promoter methylation, polymorphism and expression profile of cytotoxic T-lymphocyte-associated antigen-4 in patients with gastric cancer.
BACKGROUND AND AIM: Cytotoxic T lymphocyte-associated antigen-4 (CTLA4) is a crucial immune-checkpoint receptor regulating T-cell activation. The current study was carried out to evaluate the function of CTLA4 gene in patients with gastric cancer. METHODS: The methylation of CTLA4 gene promoter was evaluated by methylation-specific polymerase chain reaction (MSP) technique using 85 paraffin-embedded gastric cancer tissue samples and normal tissue on the tumor margins as control tissue samples. Expression analysis was performed on paraffin-embedded tissue samples (25 each of cancerous and normal tissues) using Real-time PCR. RESULTS: Statistically significant differences were observed between the tumor and margin-cell areas with respect to promoter methylation status (OR = 4.829, 95% CI: 2.46-9.48, p < 0.001) and CTLA4 expression profile (mean +/- SD = 7.56 +/- 17.35, p = 0.04). CONCLUSION: To the best of our knowledge, the current study is the first one highlighting the association between promoter hypermethylation of CTLA4 gene, decreased CTLA4 expression, and increased risk of gastric cancer.
Use of Nonsteroidal Anti-inflammatory Drugs in Colorectal Surgery: Do the Risks Cast a Shadow on the Benefits?
Nonsteroidal anti-inflammatory drug (NSAID) use is recognized as a key component of the Enhanced Recovery After Surgery protocols and is systematically recommended in colorectal surgery to optimize perioperative care. However, a red flag about this practice has been raised because clinical studies have recently pointed out an increased risk of anastomotic leak after colorectal surgery following NSAID administration. Therefore, we used the Bradford Hill criteria to examine this potential relationship and concluded that use of perioperative NSAIDs in colorectal surgery should be evaluated carefully and on an individual basis considering the potentially increased risk of anastomotic leak and its consequences.
Disseminating hypnosis to health care settings: Applying the RE-AIM framework.
Hypnosis is a brief intervention ready for wider dissemination in medical contexts. Overall, hypnosis remains underused despite evidence supporting its beneficial clinical impact. This review will evaluate the evidence supporting hypnosis for dissemination using guidelines formulated by Glasgow and colleagues (1999). Five dissemination dimensions will be considered: Reach, Efficacy, Adoption, Implementation, and Maintenance (RE-AIM). REACH: In medical settings, hypnosis is capable of helping a diverse range of individuals with a wide variety of problems. EFFICACY: There is evidence supporting the use of hypnosis for chronic pain, acute pain and emotional distress arising from medical procedures and conditions, cancer treatment-related side-effects and irritable bowel syndrome. ADOPTION: Although hypnosis is currently not a part of mainstream clinical practices, evidence suggests that patients and healthcare providers are open to trying hypnosis, and may become more so when educated about what hypnosis can do. IMPLEMENTATION: Hypnosis is a brief intervention capable of being administered effectively by healthcare providers. MAINTENANCE: Given the low resource needs of hypnosis, opportunities for reimbursement, and the ability of the intervention to potentially help medical settings reduce costs, the intervention has the qualities necessary to be integrated into routine care in a self-sustaining way in medical settings. In sum, hypnosis is a promising candidate for further dissemination.
A Longitudinal Examination of the Moderating Effects of Symptoms on the Relationship between Functional Competence and Real World Functional Performance in Schizophrenia.
BACKGROUND: Many individuals with schizophrenia experience remission of prominent positive symptoms but continue to experience impairments in real world functioning. Residual negative and depressive symptoms may have a direct impact on functioning and impair patients' ability to use the cognitive and functional skills that they possess (competence) in the real world (functional performance). METHODS: 136 individuals (100 men, 36 women) with schizophrenia were classified as having primarily positive symptoms, primarily negative symptoms, primarily depressive symptoms, or undifferentiated symptom profiles. Performance based measures of cognition and adaptive and interpersonal functional competence were used, along with ratings of real world behavior by high contact clinicians. Assessments were performed at baseline and at an 18-month follow-up. RESULTS: The relationships between neurocognition and capacity / performance were not moderated by symptom group ps > .091; neurocognition predicted capacity and performance for all groups ps < .001. The relationship between adaptive competence and adaptive performance was moderated by symptom group, ps < .01, such that baseline competence only predicted future performance ratings for participants with primarily positive or undifferentiated symptoms, and not for individuals with primarily negative or depressive symptoms. This same moderation effect was found on the relationship between interpersonal competence and interpersonal performance, ps < .002. CONCLUSIONS: Residual negative and depressive symptoms are distinct constructs that impede the use of functional skills in the real world. Depressive symptoms are often overlooked in schizophrenia but appear to be an important factor that limits the use of functional ability in real world environments.
A novel, online social cognitive training program for young adults with schizophrenia: A pilot study.
BACKGROUND: Pervasive social cognition deficits are evident early in the course of schizophrenia and are directly linked to functional outcome, making them an important target for intervention. Here, we tested the feasibility of use, and initiated the evaluation of efficacy, of a novel, neuroplasticity-based online training program (SocialVille) in young adults with schizophrenia. METHODS: Schizophrenia patients (n=17) completed 24 hours of online SocialVille game play either from home or at a clinic, over a 6-10 week period. We examined training feasibility, gains on the SocialVille exercises relative to matched healthy controls (n=17), and changes on measures of social cognition, social functioning, global functioning and motivation. RESULTS: Subjects adhered to training requirements, and rated SocialVille in the medium to high range in satisfaction, enjoyment, and ease of use. Subjects demonstrated significant, large improvements on the speeded SocialVille tasks, and small to moderate improvements on the working memory tasks. Post-training performance on the SocialVille tasks were similar to initial performance of the healthy controls. Subjects also showed improvements on standard measures of social cognition, social functioning, and motivation. No improvements were recorded for emotion recognition indices on the MSCEIT, or on quality of life scales. CONCLUSION: This study provides an initial proof of concept for online social cognition training in schizophrenia. This form of training demonstrated feasibility and resulted in within-subject gains in social functioning and motivation. This pilot study represents a first step towards validating this training approach; randomized controlled trials, now underway, are designed to confirm and extend these findings.
ENDOTHELIN-1 SYTEM ACTIVITY IN ADULTS WITH BORDERLINE HIGH LDL-CHOLESTEROL.
BACKGROUND: Modest elevations in plasma low-density lipoprotein (LDL)-cholesterol have been shown to confer a significant increase in cardiovascular risk. Endothelin (ET)-1 is a vasoconstrictor peptide with proatherogenic properties. The experimental aim of this study was to determine whether ET-1 system activity is elevated in adults with borderline high LDL-cholesterol, independent of other cardiometabolic abnormalities. METHODS: Forearm blood flow (FBF; plethysmography) responses to intra-arterial infusion of ET-1, selective ETA receptor blockade (BQ-123), and non-selective ETA/B blockade (BQ-123 + BQ-788) were determined in 40 middle-aged and older adults (45-70 years): 20 with optimal/near optimal LDL-cholesterol (<3.4 mmol/L) and 20 with borderline-high LDL-cholesterol (3.4-4.1 mmol/L). RESULTS: Both groups demonstrated a similar, non-significant (~10%) reduction in FBF to ET-1. BQ-123 and BQ-123+788 elicited a modest, but significant, increase in FBF (~15-20%) in each group. However, there were no group differences in the FBF responses to either selective ETA or non-selective ETA/B receptor antagonism. CONCLUSION: Borderline-high LDL-C is not associated with increased ET-1 mediated vasoconstrictor tone. Disrupted ET-1 system activity may not contribute to the increased cardiovascular risk burden with borderline-high LDL-cholesterol.
Burden Among Male Alzheimer's Caregivers: Effects of Distinct Coping Strategies.
Focusing on the understudied, increasing population of male Alzheimer's disease (AD) caregivers, the purpose of this study was to identify their likelihood of utilizing 3 coping strategies (task focused, emotion focused, and avoidance focused) and to examine the effects of each coping strategy on caregiving burden. Data were collected from 138 male AD caregivers in southern United States, including geographically proportional representation of African Americans in the sample. Stepwise regression revealed effects of each coping strategy on caregiving burden, controlling for demographics. The sample reported high burden. Task focused was the highest reported coping strategy. Yet, regression models indicated no significant effect of task-focused coping on burden outcomes. Emotion-focused and avoidance-focused coping each showed significant proportional effects on burden. Implications suggest that emotion- and avoidance-focused coping among male AD caregivers may be maladaptive, that is, reinforcing burden. Male AD caregivers may benefit from more task-focused coping, such as planning and active problem solving.
Personalizing Behavioral Interventions Through Single-Patient (N-of-1) Trials.
Behavioral interventions are typically studied with the use of a conventional between-subject randomized controlled trial (RCT) design. In this design, the effect of an intervention on one group of patients is compared with the effect of a control condition on another group of patients, such that a between-subject change is tested. A between-subject design has an underlying assumption that there is a homogenous treatment effect for a behavioral intervention, drug or psychotherapy, and that the way the intervention operates in the study that will tend to operate in the same way in many other patients. We review some of the philosophical and practical problems with the use of this design when a clinician is attempting to decide on a course of behavioral treatment aimed at within-subject change in patients who are likely to have heterogeneous or unique responses to behavioral treatment. We also review the biases inherent in our current clinical practice model, which does not use any empirical data collection or design for testing if a treatment is useful, and also in the conventional between-subject personalized medicine RCT designs. We propose increased use of single-patient (also known as N-of-1) trials that employ within-subject designs, in cases where treatment response is heterogeneous-as is the case for most psychological and behavioral treatments. Limitations of such designs include that they can only be used when the treatment is potentially reversible, the patient can act as their own control, and the outcome can be measured repeatedly. Increased use of within-subject trials may address in many more instances the more clinically relevant question of how a specific patient will respond to a specific treatment, and could introduce a more harmonious scientific approach into the way we treat our patients. We have incorporated a case presentation that illustrates the complexities of applying evidence drawn from these different designs to selecting and evaluating treatments for the behavioral issues commonly faced by clinicians and patients.
Nanomedicine in the Management of Microbial Infection - Overview and Perspectives.
For more than 2 billion years, microbes have reigned on our planet, evolving or outlasting many obstacles they have encountered. In the 20th century, this trend took a dramatic turn with the introduction of antibiotics and vaccines. Nevertheless, since then, microbes have progressively eroded the effectiveness of previously successful antibiotics by developing resistance, and many infections have eluded conventional vaccine design approaches. Moreover, the emergence of resistant and more virulent strains of bacteria has outpaced the development of new antibiotics over the last few decades. These trends have had major economic and health impacts at all levels of the socioeconomic spectrum - we need breakthrough innovations that could effectively manage microbial infections and deliver solutions that stand the test of time. The application of nanotechnologies to medicine, or nanomedicine, which has already demonstrated its tremendous impact on the pharmaceutical and biotechnology industries, is rapidly becoming a major driving force behind ongoing changes in the antimicrobial field. Here we provide an overview on the current progress of nanomedicine in the management of microbial infection, including diagnosis, antimicrobial therapy, drug delivery, medical devices, and vaccines, as well as perspectives on the opportunities and challenges in antimicrobial nanomedicine.
Intratumoral pseudoaneurysms in hepatocellular carcinoma: do they occur de novo without any prior intervention? A tertiary care center experience of 6 years.
BACKGROUND: Intratumoural pseudoaneurysms (ITPA) within hepatocellular carcinomas (HCC) usually arise as postprocedural complications of endovascular therapies or surgical procedures. Their de novo presence in HCC without any prior interventions has not been adequately described in medical literature. PURPOSE: To evaluate and quantify the presence of intratumoural pseudoaneurysms (ITPA) within hepatocellular carcinomas (HCC) prior to any intervention. MATERIAL AND METHODS: Retrospective cross-sectional review of 519 patients with HCC at a tertiary care university hospital with the purpose to evaluate and quantify the presence of ITPA present prior to any therapy. Patients' baseline data along with viral marker status, alpha fetoprotein (AFP) levels, imaging findings, and any prior treatment provided were recorded. Multi-detector computed tomography (MDCT) scans of selected patients were reviewed for presence of any ITPA and their incidence was calculated. RESULTS: ITPAs without any prior therapy were found in 5% (25/519) of patients with HCC. Seventeen of 25 (68%) patients had liver cirrhosis while eight of 25 (32%) patients were non-cirrhotic on imaging. Multiple ITPAs were seen in 44% (11/25) of patients. Eight percent (2/25) of patients had pseudoaneurysm-associated hemorrhage, 20% (5/25) had lung metastasis, 12% (3/25) had portal vein thrombosis, 8% (2/25) had hepatic vein thrombosis, and 16% (4/25) had peritumoral hematoma. The incidence of de novo ITPAs occurring in patients with HCC without any prior therapy or intervention was 0.24%. CONCLUSION: These cases provide a unique insight into an additional feature of HCC and usefulness of recognizing the ITPAs on imaging studies. Although de novo ITPAs in HCC are uncommon, occurring with an incidence rate of 0.24%, their presence in hypervascular hepatic lesion may point towards the diagnosis of HCC. Additionally, they should be accounted for in management planning as they can lead to complications of rupture and hemorrhage.
Structure-activity analysis of a CFTR channel potentiator: Distinct molecular parts underlie dual gating effects.
The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) is a member of the ATP-binding cassette transporter superfamily that functions as an epithelial chloride channel. Gating of the CFTR ion conduction pore involves a conserved irreversible cyclic mechanism driven by ATP binding and hydrolysis at two cytosolic nucleotide-binding domains (NBDs): formation of an intramolecular NBD dimer that occludes two ATP molecules opens the pore, whereas dimer disruption after ATP hydrolysis closes it. CFTR dysfunction resulting from inherited mutations causes CF. The most common CF mutation, deletion of phenylalanine 508 (DeltaF508), impairs both protein folding and processing and channel gating. Development of DeltaF508 CFTR correctors (to increase cell surface expression) and potentiators (to enhance open probability, Po) is therefore a key focus of CF research. The practical utility of 5-nitro-2-(3-phenylpropylamino)benzoate (NPPB), one of the most efficacious potentiators of DeltaF508 CFTR identified to date, is limited by its pore-blocking side effect. NPPB-mediated stimulation of Po is unique in that it involves modulation of gating transition state stability. Although stabilization by NPPB of the transition state for pore opening enhances both the rate of channel opening and the very slow rate of nonhydrolytic closure, because of CFTR's cyclic gating mechanism, the net effect is Po stimulation. In addition, slowing of ATP hydrolysis by NPPB delays pore closure, further enhancing Po. Here we show that NPPB stimulates gating at a site outside the pore and that these individual actions of NPPB on CFTR are fully attributable to one or the other of its two complementary molecular parts, 3-nitrobenzoate (3NB) and 3-phenylpropylamine (3PP), both of which stimulate Po: the pore-blocking 3NB selectively stabilizes the transition state for opening, whereas the nonblocking 3PP selectively slows the ATP hydrolysis step. Understanding structure-activity relationships of NPPB might prove useful for designing potent, clinically relevant CFTR potentiators.
Systematic review research on needle/syringe programs and opiate substitution programs in low- and middle-income countries.
Persons who inject drugs (PWID) are at an elevated risk for human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection. In many high-income countries, needle and syringe exchange programs (NSPs) have been associated with reductions in blood-borne infections. However, we do not have a good understanding of the effectiveness of NSP in low/middle-income and transitional-economy countries. A systematic literature review based on PRISMA guidelines was utilized to collect primary study data on coverage of NSP programs and changes in HIV and HCV infection over time among PWID in low- and middle-income and transitional countries (LMICs). Included studies reported laboratory measures of either HIV or HCV and at least 50% coverage of the local injecting population (through direct use or through secondary exchange). We also included national reports on newly reported HIV cases for countries that had national level data for PWID in conjunction with NSP scale-up and implementation. Studies of 11 NSPs with high-coverage from Bangladesh, Brazil, China, Estonia, Iran, Lithuania, Taiwan, Thailand, and Vietnam were included in the review. In five studies, HIV prevalence decreased (range -3% to -15%) and in three studies HCV prevalence decreased (range -4.2% to -10.2%). In two studies, HIV prevalence increased (range +5.6% to +14.8%). HCV incidence remained stable in one study. Of the four national reports of newly reported HIV cases, three reported decreases during NSP expansion, ranging from -30% to -93.3%, whereas one national report documented an increase in cases (+37.6%). Estimated incidence among new injectors decreased in three studies, with reductions ranging from -11/100 person years at risk to -16/100 person years at risk. While not fully consistent, the data generally support the effectiveness of NSP in reducing HIV and HCV infection in low/middle-income and transitional-economy countries. If high coverage is achieved, NSP appear to be as effective in LMICs as in high-income countries. Additional monitoring and evaluation research is needed for NSPs where reductions in HIV/HCV infection among PWID are not occurring in order to identify and correct contributing problems.
Emerging drug problems in Asia.
This session, "Emerging Drug Problems in Asia," focused on emerging drug problems in Asia. Dr. Juana Tomas-Rossello discussed "East and Southeast Asia: Emerging Drug Problems and Response" and Dr. Wei J. Chen discussed "Ketamine Use among Regular Tobacco and Alcohol Users as Revealed by Respondent Driven Sampling in Taipei: Prevalence, Expectancy, and Users' Risky Decision Making."
The Living Heart Project: A robust and integrative simulator for human heart function.
The heart is not only our most vital, but also our most complex organ: Precisely controlled by the interplay of electrical and mechanical fields, it consists of four chambers and four valves, which act in concert to regulate its filling, ejection, and overall pump function. While numerous computational models exist to study either the electrical or the mechanical response of its individual chambers, the integrative electro-mechanical response of the whole heart remains poorly understood. Here we present a proof-of-concept simulator for a four-chamber human heart model created from computer topography and magnetic resonance images. We illustrate the governing equations of excitation-contraction coupling and discretize them using a single, unified finite element environment. To illustrate the basic features of our model, we visualize the electrical potential and the mechanical deformation across the human heart throughout its cardiac cycle. To compare our simulation against common metrics of cardiac function, we extract the pressure-volume relationship and show that it agrees well with clinical observations. Our prototype model allows us to explore and understand the key features, physics, and technologies to create an integrative, predictive model of the living human heart. Ultimately, our simulator will open opportunities to probe landscapes of clinical parameters, and guide device design and treatment planning in cardiac diseases such as stenosis, regurgitation, or prolapse of the aortic, pulmonary, tricuspid, or mitral valve.
Dyspnoea management in acute coronary syndrome patients treated with ticagrelor.
The occurrence of dyspnoea in acute coronary syndrome (ACS) patients has always been considered a challenging diagnostic and therapeutic clinical scenario. P2Y12 platelet receptor inhibitors (i.e., clopidogrel, prasugrel and ticagrelor) are currently the cornerstone of treatment of ACS patients. Thus, in the last few years, the potential association between ACS and dyspnoea has also become more challenging with the increasing use of ticagrelor in these patients due to its beneficial effects on ischaemic event prevention and mortality, since ticagrelor can induce dyspnoea as a side effect. The present article is intended to review the current literature regarding dyspnoea occurrence in ACS patients, especially those treated with ticagrelor, and to propose ticagrelor-associated dyspnoea management recommendations based on current knowledge.
The correlation between the amplitude of Osborn wave and core body temperature.
INTRODUCTION: Several reports illustrate an inverse correlation between the Osborn wave (J wave) amplitude and core body temperature. We attempted to study the strength of this correlation. METHODS: We reviewed all articles reporting hypothermic J waves from 1950-2014 for patient demographics, core body temperature in Celsius ( degrees C), amplitude of the J wave in millimeters (mm), lead with the highest amplitude of J wave, presence of acidosis, PO2, electrolytes and outcome. In cases with more than one electrocardiogram (ECG), the respective core body temperature and J wave amplitude of each ECG were recorded. The main study outcome is to evaluate the correlation between the J wave amplitude and core body temperature in the admission ECG. We have also examined the strength of this relationship in cases with more than one ECG. We attempted to find the most frequent lead that recorded the highest amplitude of the J wave in addition to the correlation between the amplitude of J wave and pH. RESULTS: We found 64 articles comprising a total of 68 cases. When analyzing only cases with more than one reported ECG, there was a strong inverse correlation (r= - 0.682, p<0.001) between J wave amplitude and body temperature: however, when analyzing admission ECG of all cases, the correlation was only moderate (r= - 0.410, p<0.001). The lead with the highest amplitude of the J wave was V4 (44% of the cases, p<0.001) followed by V3 (23.7% of the cases, p<0.001). CONCLUSION: The amplitude of the J wave in the admission ECG of hypothermic patients may not accurately predict the core body temperature.
How to use: nutritional assessment in neonates.
Adequate nutrition and growth during the neonatal period are important, especially for preterm infants, for whom there is evidence of poor nutrient intakes and growth, and this has important implications for their health in later life. Increased nutritional support while on the neonatal intensive care unit has been shown to improve growth, but such support is not universally available. Being able to carry out and interpret a nutritional assessment is therefore an important skill for paediatricians caring for neonates. This article aims to explain how to use nutritional assessment in neonates and provides some tools to make this process as straightforward as possible.
Temporal changes in land cover types and the incidence of malaria in Mangalore, India.
BACKGROUND: Malaria contributes to 881000 deaths worldwide annually and India is a major contributor in the region. This study aimed at detecting land cover changes and assesses their relationship with the burden of malaria in Mangalore taluk of southern India. METHODOLOGY: Landsat TM images were obtained from the U.S. Geological Survey data repository. The statistics for the malaria incidences in the region were obtained from the National Vector Borne Diseases Control Program division of the State of Karnataka. The images were preprocessed, classified and change detection statistics were employed for major land cover types. RESULTS AND CONCLUSIONS: An increase in the urban land cover by 20% with a reduction in the mountainous terrain by 34.7% and vegetation by 38.7% was noted between the years 2003 and 2005. The annual incidence of malaria increased five-fold from 203 to 1035/100000 population during the period. This study demonstrates the application of publicly available remote sensed data as a cost effective approach to study the agent, host and environment relationships in resource scarce settings which would provide valuable information planning and policy making at regional levels.
Nonlinear and Stochastic Dynamics in the Heart.
In a normal human life span, the heart beats about 2 to 3 billion times. Under diseased conditions, a heart may lose its normal rhythm and degenerate suddenly into much faster and irregular rhythms, called arrhythmias, which may lead to sudden death. The transition from a normal rhythm to an arrhythmia is a transition from regular electrical wave conduction to irregular or turbulent wave conduction in the heart, and thus this medical problem is also a problem of physics and mathematics. In the last century, clinical, experimental, and theoretical studies have shown that dynamical theories play fundamental roles in understanding the mechanisms of the genesis of the normal heart rhythm as well as lethal arrhythmias. In this article, we summarize in detail the nonlinear and stochastic dynamics occurring in the heart and their links to normal cardiac functions and arrhythmias, providing a holistic view through integrating dynamics from the molecular (microscopic) scale, to the organelle (mesoscopic) scale, to the cellular, tissue, and organ (macroscopic) scales. We discuss what existing problems and challenges are waiting to be solved and how multi-scale mathematical modeling and nonlinear dynamics may be helpful for solving these problems.
Interpersonal Emotion Regulation Model of Mood and Anxiety Disorders.
Although social factors are of critical importance in the development and maintenance of emotional disorders, the contemporary view of emotion regulation has been primarily limited to intrapersonal processes. Based on diverse perspectives pointing to the communicative function of emotions, the social processes in self-regulation, and the role of social support, this article presents an interpersonal model of emotion regulation of mood and anxiety disorders. This model provides a theoretical framework to understand and explain how mood and anxiety disorders are regulated and maintained through others. The literature, which provides support for the model, is reviewed and the clinical implications are discussed.
L-Proline catalyzed one-step synthesis of 4,5-diaryl-2-1,2,3-triazoles from heteroaryl cyanostilbenes via [3+2] cycloaddition of azide.
Use of a novel reagent has been established for the synthesis of a series of 4,5-diaryl-2H-1,2,3-triazoles (6a-i and 9a-e) from cyanostilbene analogs of benzo[b]thiophene, benzo[b]furan and indole, catalyzed by L-proline via Lewis base-catalyzed one-step [3+2]cycloaddition of azide. This method provides an efficient, simple and environmentally benign procedure that affords good yields and relatively short reaction times.
RADIATION SAFETY CONSIDERATION DURING INTRAOPERATIVE RADIATION THERAPY.
Using in-house-designed phantoms, the authors evaluated radiation exposure rates in the vicinity of a newly acquired intraoperative radiation therapy (IORT) system: Axxent Electronic Brachytherapy System. The authors also investigated the perimeter radiation levels during three different clinical intraoperative treatments (breast, floor of the mouth and bilateral neck cancer patients). Radiation surveys during treatment delivery indicated that IORT using the surface applicator and IORT using balloons inserted into patient body give rise to exposure rates of 200 mR h-1, 30 cm from a treated area. To reduce the exposure levels, movable lead shields should be used as they reduce the exposure rates by >95 %. The authors' measurements suggest that intraoperative treatment using the 50-kVp X-ray source can be administered in any regular operating room without the need for radiation shielding modification as long as the operators utilise lead aprons and/or stand behind lead shields.
Chevron formation of the zebrafish muscle segments.
The muscle segments of fish have a folded shape, termed a chevron, which is thought to be optimal for the undulating body movements of swimming. However, the mechanism shaping the chevron during embryogenesis is not understood. Here, we use time-lapse microscopy of developing zebrafish embryos spanning the entire somitogenesis period to quantitate the dynamics of chevron shape development. Comparing such time courses with the start of movements in wildtype zebrafish and analyzing immobile mutants, we show that the previously implicated body movements do not play a role in chevron formation. Further, the monotonic increase of chevron angle along the anteroposterior axis revealed by our data constrains or rules out possible contributions by previously proposed mechanisms. In particular, we find that muscle pioneers are not required for chevron formation. We put forward a tension-and-resistance mechanism involving interactions between intra-segmental tension and segment boundaries. To evaluate this mechanism, we derive and analyze a mechanical model of a chain of contractile and resisting elements. The predictions of this model are verified by comparison to experimental data. Altogether, our results support the notion that a simple physical mechanism suffices to self-organize the observed spatiotemporal pattern in chevron formation.
Immunization of mice with live-attenuated late liver stage-arresting P. yoelii parasites generates protective antibody responses to pre-erythrocytic stages of malaria.
Understanding protective immunity against malaria is essential for the design of an effective vaccine to prevent the large number of infections and deaths caused by this parasitic disease. To date, whole parasite immunization with attenuated parasites is the most effective method to confer sterile protection against malaria infection in clinical trials. Mouse model studies have highlighted the essential role that CD8+ T cells play in protection against pre-erythrocytic stages of malaria; however there is mounting evidence that antibodies are also important in this stage. Herein, we show that experimental immunization of mice with Pyfabb/f-, a genetically attenuated rodent malaria parasite that arrests late in the liver stage, induced functional antibodies that inhibited hepatocyte invasion in vitro and reduced liver stage burden in vivo. These antibodies were sufficient to induce sterile protection from challenge by P. yoelii sporozoites in the absence of T cells in 50% of mice when sporozoites were administered by mosquito bite, but not by intravenous injection. Moreover, among mice challenged by mosquito bite, a higher proportion of BALB/c mice than C57BL/6 mice developed sterile protection (62.5% and 37.5%, respectively). Analysis of the antibody isotypes induced by immunization with Pyfabb/f- showed that overall, BALB/c mice developed an IgG1 biased response, whereas C57BL/6 mice developed an IgG2b/c biased response. Our data demonstrate for the first time that antibodies induced by experimental immunization of mice with a genetically attenuated rodent parasite play a protective role during the pre-erythrocytic stages of malaria. Furthermore, they highlight the importance of considering both the route of challenge and the genetic background of the mouse strains used when interpreting vaccine efficacy studies in animal models of malaria infection.
Goal-directed learning and obsessive-compulsive disorder.
Obsessive-compulsive disorder (OCD) has become a paradigmatic case of goal-directed dysfunction in psychiatry. In this article, we review the neurobiological evidence, historical and recent, that originally led to this supposition and continues to support a habit hypothesis of OCD. We will then discuss a number of recent studies that have directly tested this hypothesis, using behavioural experiments in patient populations. Based on this research evidence, which suggests that rather than goal-directed avoidance behaviours, compulsions in OCD may derive from manifestations of excessive habit formation, we present the details of a novel account of the functional relationship between these habits and the full symptom profile of the disorder. Borrowing from a cognitive dissonance framework, we propose that the irrational threat beliefs (obsessions) characteristic of OCD may be a consequence, rather than an instigator, of compulsive behaviour in these patients. This lays the foundation for a potential shift in both clinical and neuropsychological conceptualization of OCD and related disorders. This model may also prove relevant to other putative disorders of compulsivity, such as substance dependence, where the experience of 'wanting' drugs may be better understood as post hoc rationalizations of otherwise goal-insensitive, stimulus-driven behaviour.
The 30-year wait for treatment of an acutely painful knee.
A 63-year-old retired man presented to our clinic reporting a severely painful, localised knee pain present for around 30 years and associated with a spontaneous palpable lump. He was prompted to seek medical advice at this point because his symptoms were exacerbated when his young grandchildren bumped into the knee. While radiographs were unhelpful, ultrasonography revealed a well-defined, subcutaneous soft tissue mass at the anterior aspect of the knee. Surgical excision was performed as a day case. Histological examination of the mass showed a glomus tumour. This patient had suffered for many years as a result of this painful mass but full resolution of his pain occurred immediately after excision.
Fatal Waterhouse-Friderichsen syndrome due to Serotype C Neisseria meningitidis in a young HIV negative MSM (men who have sex with men).
Waterhouse-Friderichsen syndrome (fulminant meningococcaemia) is a fulminating infection, often leading to mortality in a matter of hours. In the past 3 years there has been a rise in cases of Neisseria meningitis in the men who have sex with men (MSM) population in the USA and sporadic cases over the world especially in those who are HIV positive. We describe a case of a 34-year-old Caucasian man who presented with acute fulminant meningococcaemia, which proved fatal over a period of hours. This case report emphasises the need for further vigilance, prompt diagnosis and treatment of fulminant meningococcaemia without signs of meningitis especially in the MSM population and the need to expand vaccination recommendations of Meningococcaemia in the MSM population across the USA in both HIV positive and negative males.
Late-onset methotrexate-induced pneumonitis with neutrophilia in bronchoalveolar lavage fluid.
A 61-year-old woman being treated with methotrexate (MTX) 8-10 mg/week and prednisolone 2.5 mg/day for rheumatoid arthritis presented with a 1-week history of increasing fever and dry cough. The patient deteriorated with administration of antibiotics. Chest CT scan showed bilateral diffuse ground-glass opacities. Analysis of bronchoalveolar lavage fluid (BALF) revealed marked neutrophilia (65.2% of total cells). The specimen from transbronchial lung biopsy showed a non-specific interstitial pneumonia pattern. Following withdrawal of the MTX, her pulmonary infiltration, clinical symptoms and laboratory findings gradually improved. Therefore, she was diagnosed as having MTX-induced pneumonitis. Lymphocytosis in BALF has been identified as a characteristic of MTX-induced pneumonitis, particularly in late onset of this disease. However, the BALF in our patient was neutrophilic. Although neutrophilia in BALF of patients with drug-induced pneumonitis is usually associated with poor outcome, rare cases of good outcome do exist.
AS, DISH or something else?
A 68-year-old farmer presented with progressively worsening pain in multiple joints associated with stiffening for 9 months. Locomotor examination revealed grossly restricted movement of the axial skeleton. There were no neurological deficits. Radiological evaluation demonstrated diffuse bone densification and extraspinal calcification with bony ankylosis reminiscent of ankylosing spondylitis. Laboratory tests subsequently yielded the true diagnosis. The patient was counselled accordingly and started on appropriate therapy.
CT diagnosis of an iatrogenic bile duct injury.
Bile duct injuries are a recognised complication of cholecystectomy and a number of options exist for their evaluation. A 44-year-old woman presented with a suspected biliary leak 11 days following an open cholecystectomy. Her medical history was significant for biliopancreatic diversion 2 years previously. An ultrasound scan demonstrated a perihepatic collection but no dilation of the biliary tree was observed. The patient's surgical history and the lack of biliary dilation precluded an endoscopic retrograde cholangiopancreatography or percutaneous transhepatic cholangiography, and she could not undergo an MR cholangiopancreatography due to claustrophobia. A CT cholangiogram was performed and clarified the location of the injury, facilitating operative identification and repair of the bile duct. CT cholangiography performed as a dynamic procedure is useful as a means of identifying bile duct injuries.
The biology of radiosurgery and its clinical applications for brain tumors.
Stereotactic radiosurgery (SRS) was developed decades ago but only began to impact brain tumor care when it was coupled with high-resolution brain imaging techniques such as computed tomography and magnetic resonance imaging. The technique has played a key role in the management of virtually all forms of brain tumor. We reviewed the radiobiological principles of SRS on tissue and how they pertain to different brain tumor disorders. We reviewed the clinical outcomes on the most common indications. This review found that outcomes are well documented for safety and efficacy and show increasing long-term outcomes for benign tumors. Brain metastases SRS is common, and its clinical utility remains in evolution. The role of SRS in brain tumor care is established. Together with surgical resection, conventional radiotherapy, and medical therapies, patients have an expanding list of options for their care. Clinicians should be familiar with radiosurgical principles and expected outcomes that may pertain to different brain tumor scenarios.
Nebivolol, But Not Metoprolol, Lowers Blood Pressure in Nitric Oxide-Sensitive Human Hypertension.
Nebivolol, unlike other selective beta1-receptor blockers, induces vasodilation attributable to increased NO bioavailability. The relative contribution of this mechanism to the blood pressure (BP)-lowering effects of nebivolol is unclear because it is normally masked by baroreflex buffering. Autonomic failure provides a unique model of hypertension devoid of autonomic modulation but sensitive to the hypotensive effects of NO potentiation. We tested the hypothesis that nebivolol would decrease BP in these patients through a mechanism independent of beta-blockade. We randomized 20 autonomic failure patients with supine hypertension (14 men; 69+/-2 years) to receive a single oral dose of placebo, nebivolol 5 mg, metoprolol 50 mg (negative control), and sildenafil 25 mg (positive control) on separate nights in a double-blind, crossover study. Supine BP was monitored every 2 hours from 8:00 pm to 8:00 am. Compared with placebo, sildenafil and nebivolol decreased systolic BP during the night (P<0.001 and P=0.036, by mixed-effects model, maximal systolic BP reduction 8-hour postdrug of -20+/-6 and -24+/-9 mm Hg, respectively), whereas metoprolol had no effect. In a subanalysis, we divided patients into sildenafil responders (BP fall >20 mm Hg at 4:00 am) and nonresponders. Nebivolol significantly lowered systolic BP in sildenafil responders (-44+/-13 mm Hg) but not in nonresponders (1+/-11 mm Hg). Despite lowering nighttime BP, nebivolol did not worsen morning orthostatic tolerance compared with placebo. In conclusion, nebivolol effectively lowered supine hypertension in autonomic failure, independent of beta1-blockade. These results are consistent with the hypothesis that NO potentiation contributes significantly to the antihypertensive effect of nebivolol.
Prenatal Hypoxia Leads to Increased Muscle Sympathetic Nerve Activity, Sympathetic Hyperinnervation, Premature Blunting of Neuropeptide Y Signaling, and Hypertension in Adult Life.
Adverse conditions prenatally increase the risk of cardiovascular disease, including hypertension. Chronic hypoxia in utero (CHU) causes endothelial dysfunction, but whether sympathetic vasoconstrictor nerve functioning is altered is unknown. We, therefore, compared in male CHU and control (N) rats muscle sympathetic nerve activity, vascular sympathetic innervation density, and mechanisms of sympathetic vasoconstriction. In young (Y)-CHU and Y-N rats ( approximately 3 months), baseline arterial blood pressure was similar. However, tonic muscle sympathetic nerve activity recorded focally from arterial vessels of spinotrapezius muscle had higher mean frequency in Y-CHU than in Y-N rats (0.56+/-0.075 versus 0.33+/-0.036 Hz), and the proportions of single units with high instantaneous frequencies (1-5 and 6-10 Hz) being greater in Y-CHU rats. Sympathetic innervation density of tibial arteries was approximately 50% greater in Y-CHU than in Y-N rats. Increases in femoral vascular resistance evoked by sympathetic stimulation at low frequency (2 Hz for 2 minutes) and bursts at 20 Hz were substantially smaller in Y-CHU than in Y-N rats. In Y-N only, the neuropeptide Y Y1-receptor antagonist BIBP3226 attenuated these responses. By contrast, baseline arterial blood pressure was higher in middle-aged (M)-CHU than in M-N rats ( approximately 9 months; 139+/-3 versus 126+/-3 mm Hg, respectively). BIBP3226 had no effect on femoral vascular resistance increases evoked by 2 Hz or 20 Hz bursts in M-N or M-CHU rats. These results indicate that fetal programming induced by prenatal hypoxia causes an increase in centrally generated muscle sympathetic nerve activity in youth and hypertension by middle age. This is associated with blunting of sympathetically evoked vasoconstriction and its neuropeptide Y component that may reflect premature vascular aging and contribute to increased risk of cardiovascular disease.
Effect of Hypoglycemia on Brain Structure in People With Type 2 Diabetes: Epidemiological Analysis of the ACCORD-MIND MRI Trial.
OBJECTIVE: The effect of hypoglycemia related to treatment of type 2 diabetes mellitus (T2DM) on brain structure remains unclear. We aimed to assess whether symptomatic severe hypoglycemia is associated with brain atrophy and/or white matter abnormalities. RESEARCH DESIGN AND METHODS: We included T2DM participants with brain MRI from the Action to Control Cardiovascular Risk in Diabetes-Memory in Diabetes (ACCORD-MIND) trial. Symptomatic severe hypoglycemia was defined as blood glucose <2.8 mmol/L or symptoms resolved with treatments that required the assistance of another person or medical assistance (hypoglycemia requiring assistance [HA]). Standardized brain MRI was performed at baseline and at 40 months. Total brain volume (TBV) and abnormal white matter (AWM) volume were calculated using an automated computer algorithm. Brain MRI scans of hypoglycemic participants were also reviewed for local disease. RESULTS: Of the 503 T2DM participants (mean age, 62 years) with successful baseline and 40-month brain MRI, 28 had at least one HA episode during the 40-month follow-up. Compared with participants without HA, those with HA had marginally significant less atrophy (less decrease in TBV) from baseline to 40 months (-9.55 [95% CI -15.21, -3.90] vs. -15.38 [95% CI -16.64, -14.12], P = 0.051), and no significant increase of AWM volume (2.06 [95% CI 1.71, 2.49] vs. 1.84 [95% CI 1.76, 1.91], P = 0.247). In addition, no unexpected local signal changes or volume loss were seen on hypoglycemic participants' brain MRI scans. CONCLUSIONS: Our study suggests that hypoglycemia related to T2DM treatment may not accentuate brain pathology, specifically brain atrophy or white matter abnormalities.
Immunoglobulin E plays an immunoregulatory role in lupus.
The (patho)physiological role of IgE in nonallergic inflammatory diseases is not well understood. Here, we explored the effect of IgE deficiency on the inflammatory response in FcgammaRIIB-deficient mice as well as in mice carrying both a deletion of FcgammaRIIB and the chromosomal translocation of Y-linked autoimmune acceleration (Yaa) that hastens and results in a more aggressive lupuslike disease in these mice. The findings show that deficiency of IgE delays disease development and severity as demonstrated by reduced autoantibody production and amelioration of organ pathologies. This was associated with decreased numbers of plasma cells and reduced levels of IgG2b and IgG3. Unexpectedly, the loss of IgE also caused a striking decrease of immune cell infiltration in secondary lymphoid organs with a marked effect on the presence of dendritic cells, monocytes, neutrophils, and eosinophils in these organs and decreased activation of basophils. The presence of autoreactive IgE in human systemic lupus erythematosus subjects was also associated with increased basophil activation and enhanced disease activity. These findings argue that IgE facilitates the amplification of autoimmune inflammation.
Short-term changes in hormonal profiles after laparoscopic ovarian laser evaporation compared with diagnostic laparoscopy for PCOS.
STUDY QUESTION: Which reproductive endocrine changes are attributed exclusively to laparoscopic ovarian drilling in polycystic ovarian syndrome (PCOS)? SUMMARY ANSWER: Laser evaporation-specific endocrine effects were the prevention of an immediate increase in inhibin B and a sustained decrease in testosterone, androstenedione and anti-Mullarian hormone (AMH). WHAT IS KNOWN ALREADY: All ovarian drilling procedures result in reproductive endocrine changes. It is not known which of these changes are the result of ovarian drilling and which are related to the surgery per se. STUDY DESIGN, SIZE, DURATION: This prospective controlled study was performed at an outpatient academic fertility clinic. Between 2007 and 2010, a total of 21 oligo- or amenorrheic PCOS patients were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Included were oligo- or amenorrheic PCOS patients with all three of the Rotterdam criteria and luteinizing hormone (LH) >6.5 U/l. All PCOS patients had an indication for diagnostic surgery due to subfertility. There were 12 PCOS patients who chose to undergo ovarian laser evaporation (CO2 laser, 25 W, 20 times/ovary) and 9 PCOS who chose a diagnostic laparoscopy only (controls). Reproductive endocrinology was measured before, and until 5 days after, surgery, and four gonadotrophin-releasing hormone (GnRH) 'double pulse' tests were included. The main outcome measures were changes in reproductive endocrinology and pituitary sensitivity/priming to GnRH after laser evaporation compared with diagnostic laparoscopy only. MAIN RESULTS AND THE ROLE OF CHANCE: In the first hours after surgery, both groups showed an increase in LH, follicle stimulating hormone, estrogen and a decrease in testosterone, androstenedione, AMH and insulin growth factor-1 (P < 0.05). Inhibin B increased in the laparoscopy only group (P < 0.05). In the first days after surgery, testosterone, androstenedione and AMH remained at lower than baseline levels exclusively in the laser group (P < 0.05). Pituitary sensitivity/priming to GnRH was not altered after either laser evaporation or laparoscopy only. LIMITATIONS, REASONS FOR CAUTION: The limitations of this study are the short follow-up period and the relatively small groups. WIDER IMPLICATIONS OF THE FINDINGS: The strength of this study is the integrally measured endocrine profiles in combination with an optimal control group of PCOS patients undergoing diagnostic laparoscopy only. Interestingly, most of the immediate endocrine changes after laser evaporation could be related to the surgical context and not to the ovarian drilling procedure itself. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the Foundation of Scientific Research in Obstetrics and Gynaecology and the study medication, Lutrelef, was donated by Ferring, The Netherlands, Hoofdorphe There were no conflicts of interests mentioned by the authors.
Lipid profiles and ovarian reserve status: a longitudinal study.
STUDY QUESTION: Is there any association between ovarian reserve status and lipid profile changes? SUMMARY ANSWER: Women with lower ovarian reserve might be susceptible to higher cardiovascular risks, especially lipid disturbances, even during their reproductive life span. WHAT IS KNOWN ALREADY: The risk of developing cardiovascular disease (CVD) in women increases after menopause, but the association between ovarian reserve status and CVD is not known. STUDY DESIGN, SIZE AND DURATION: This longitudinal study was conducted on 1015 participants of Tehran Lipid and Glucose Study, an ongoing population based cohort study with 12 years follow-up. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 1015 women who were aged 20-50 years and met our eligibility criteria. Their ovarian reserve status was identified according to their age-specific AMH levels, calculated using the exponential-normal 3-parameter model. At the time of recruitment, 268, 233, 256 and 258 subjects were in the first, second, third and fourth quartiles of age-specific AMH, respectively. The cardiovascular risk factors of these groups were compared. MAIN RESULTS AND THE ROLE OF CHANCE: Anthropometric measurements, lipid profiles and mean systolic and diastolic blood pressures in the first and fourth AMH quartiles did not differ at the initiation of the study. Total cholesterol (TC) net changes per year were incremental in the first AMH quartile but not in the fourth quartile (P < 0.001). According to the generalized estimating equation (GEE), after adjustment for age, BMI, time interaction and menopause status, the changes across time in TC, LDL and HDL were varied according to the age-specific AMH status. LIMITATIONS, REASONS FOR CAUTION: A potential limitation is that development of cardiovascular risk is a major long-term event that needs decades of follow-up from birth to death; hence further studies with longer follow-up times are needed. WIDER IMPLICATIONS OF THE FINDINGS: We provide the insight that women with lower ovarian reserve might be susceptible to developing cardiovascular risk factors, particularly lipid disturbances, even during their reproductive life span. STUDY FUNDING/COMPETING INTERESTS: This study was funded by Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: Not applicable.
Laser-assisted zona pellucida thinning does not facilitate hatching and may disrupt the in vitro hatching process: a morphokinetic study in the mouse.
STUDY QUESTION: Does laser-assisted zona thinning of cleavage stage mouse embryos facilitate hatching in vitro? SUMMARY ANSWER: No, unlike laser zona opening, zona thinning does not facilitate embryo hatching. WHAT IS KNOWN ALREADY: Artificial opening of the zona pellucida facilitates hatching of mouse and human embryos. Laser-assisted zona thinning has also been used for the purpose of assisted hatching of human embryos but it has not been properly investigated in an animal model; thinning methods have produced inconsistent clinical results. STUDY DESIGN, SIZE, DURATION: Time-lapse microscopy was used to study the hatching process in the mouse after zona opening and zona thinning; a control group of embryos was not zona-manipulated but exposed to the same laser energy. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eight-cell CB6F1/J mouse embryos were pooled and allocated to three groups (n = 56 per group): A control group of embryos that were exposed to a dose of laser energy focused outside the zona pellucida (zona intact); one experimental group of embryos in which the zona pellucida was opened by complete ablation using the same total number of pulses as the control group; a second experimental group of embryos in which the zona pellucida was thinned to establish a smooth lased area using the same number of pulses as used in the other two groups. The width of the zona opening was 25 mum and width of the thinned area was 35 mum. Development was monitored by time-lapse microscopy. Overall treatment differences for continuous variables were analyzed by analysis of variance and pairwise comparisons using the Student t-test allowing for unequal variances, while for categorical data, a standard chi-squared test was utilized for all pairwise comparisons. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of complete hatching was 33.9% in the control group, 94.4% after zona opening, and 39.3% after zona thinning (overall group comparison, P < 0.0001). Overall, 60.7% of the zona-thinned embryos did not complete the hatching process and remained trapped within the zona; when they did hatch, they did not necessarily hatch from the zona-thinned area. Hatching in about one-third of the zona-intact embryos began with breaches at multiple sites by small groups of cells. Likewise, 53.6% of zona-thinned embryos had multiple breaches, always involving an area outside the thinned zone. Zona opening decreased multiple breaching and led to blastocyst escape an average of 14 h earlier than zona-thinned embryos and 5.5 h before control embryos (P = 0.0003). LIMITATIONS, REASONS FOR CAUTION: The experiments presented here were limited to in vitro experiments performed in the mouse. Whether human embryos would behave the same way under similar circumstances is unknown. We postulate that zona thinning is not beneficial in human embryos. WIDER IMPLICATIONS OF THE FINDINGS: The experiments demonstrate that zona thinning is not equivalent to zona opening for assisted hatching. The study provides reason for systematic reviews of assisted hatching trials to take the method of assisted hatching into consideration and not combine the results of zona thinning and zona opening procedures. STUDY FUNDING/COMPETING INTERESTS: Institutional funds were used for the study. No competing interests are declared.
Using cluster analysis to identify a homogeneous subpopulation of women with polycystic ovarian morphology in a population of non-hyperandrogenic women with regular menstrual cycles.
STUDY QUESTION: Can cluster analysis can be used to identify a homogeneous subpopulation of women with polycystic ovarian morphology (PCOM) within a very large population of control women in a non-subjective way? SUMMARY ANSWER: Identification and exclusion of the cluster corresponding to women with PCOM from controls improved the diagnostic power of serum anti-Mullerian hormone (AMH) level and follicle number per ovary (FNPO) in discriminating between women with or without polycystic ovary syndrome (PCOS). WHAT IS KNOWN ALREADY: There is disagreement as to whether women with PCOM should be excluded from the control population when establishing FNPO and AMH diagnostic thresholds for the definition of PCOS and how to identify such women. It has been demonstrated that cluster analysis can detect women with PCOM within the control population through a set of classifying variables among which the most relevant was AMH. The adequacy of this approach has not been confirmed in other clinical settings. STUDY DESIGN, SIZE, DURATION: This was a retrospective study using clinical and laboratory data derived from the computerized database. The data were collected from March 2011 to May 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study included 893 patients referred for routine infertility evaluation and treatment. The patients were divided into three groups: (i) the control group (n = 621) included women with regular menstrual cycles and no signs of hyperandrogenism (HA), (ii) the full-blown PCOS group (n = 95) consisted of women who were diagnosed as having PCOS based on the presence of both HA and oligo/amenorrhoea (OA), (iii) the mild PCOS group included women with only two items of the Rotterdam classification, i.e. PCOM at ultrasonography according to the FNPO threshold of 12 or more and either OA (n = 110) or HA (n = 67). MAIN RESULTS AND THE ROLE OF CHANCE: After exclusion of women with PCOM from the controls, the AMH threshold of 28 pmol/l with specificity 97.5% and sensitivity 84.2% [area under the curve (AUC) 0.948 (95% confidence interval (CI) 0.915-0.982)] and FNPO threshold of 12 with specificity 92.5% and sensitivity 83.2% [AUC 0.940 (95% CI 0.909-0.971)] for identifying PCOS were derived from the receiver operating characteristic curve analysis. The AMH threshold of 28 pmol/l had the same specificity for discriminating the mild and the full-blown PCOS phenotypes from controls. LIMITATIONS, REASONS FOR CAUTION: There was no selection bias other than being evaluated for infertility treatment, however, this could also be considered as a limitation of the study as these women may not necessarily be a representative sample of the general population. The study demonstrated that serum AMH has intrinsically a very high potency to detect women with PCOM within a control group. However, the AMH threshold is specific for this method and clinical setting. WIDER IMPLICATIONS OF THE FINDINGS: AMH threshold value for the definition of PCOM is method specific and cannot be universally applied. This study confirmed the results of previous studies that cluster analysis can identify women with PCOM within the very large control population without using a predefined diagnostic threshold for FNPO, and that AMH can detect women with PCOM with a high specificity. The exclusion of PCOM women from the controls by using a cluster analysis should be considered when establishing reference intervals and decision threshold values for various parameters used to characterize PCOS. STUDY FUNDING/COMPETING INTERESTS: The authors have no funding/competing interest(s) to declare.
Outcomes for patients with the same disease treated inside and outside of randomized trials: a systematic review and meta-analysis.
BACKGROUND: It is unclear whether participation in a randomized controlled trial (RCT), irrespective of assigned treatment, is harmful or beneficial to participants. We compared outcomes for patients with the same diagnoses who did ("insiders") and did not ("outsiders") enter RCTs, without regard to the specific therapies received for their respective diagnoses. METHODS: By searching the MEDLINE (1966-2010), Embase (1980-2010), CENTRAL (1960-2010) and PsycINFO (1880-2010) databases, we identified 147 studies that reported the health outcomes of "insiders" and a group of parallel or consecutive "outsiders" within the same time period. We prepared a narrative review and, as appropriate, meta-analyses of patients' outcomes. RESULTS: We found no clinically or statistically significant differences in outcomes between "insiders" and "outsiders" in the 23 studies in which the experimental intervention was ineffective (standard mean difference in continuous outcomes -0.03, 95% confidence interval [CI] -0.1 to 0.04) or in the 7 studies in which the experimental intervention was effective and was received by both "insiders" and "outsiders" (mean difference 0.04, 95% CI -0.04 to 0.13). However, in 9 studies in which an effective intervention was received only by "insiders," the "outsiders" experienced significantly worse health outcomes (mean difference -0.36, 95% CI -0.61 to -0.12). INTERPRETATION: We found no evidence to support clinically important overall harm or benefit arising from participation in RCTs. This conclusion refutes earlier claims that trial participants are at increased risk of harm.
Raised levels of immunoglobulin G, A and M are associated with an increased risk of total and cause-specific mortality: the Vietnam Experience Study.
BACKGROUND: Immunoglobulins (Ig) are essential for combating infectious disease. However, high levels are associated with a range of diseases and/or poor health behaviours, such as autoimmune diseases, chronic infection, HIV and excessive alcohol consumption. In the present analyses, we extend this body of work by examining whether higher levels of serum Ig G, A and M are associated with increased mortality risk. METHODS: Participants were 4255 Vietnam-era, former US army personnel (the Vietnam Experience Study). From military service files, telephone interviews in 1983 and a medical examination in 1986, sociodemographic, and health data were collected. Contemporary morning fasted blood samples were taken from which IgG, IgA and IgM concentrations were determined. Mortality surveillance over 15 years gave rise to deaths ascribed to all-causes, cardiovascular disease mortality, all cancers combined mortality, external cause and 'other' causes (predominantly comprising deaths due to infectious disease). Cox proportional hazard models were utilised to compute HRs per SD increase in Ig which were first adjusted for age and then additionally adjusting for a range of candidate confounders. RESULTS: In multiply adjusted analyses, in general, the higher the immunoglobulin concentration, the greater the risk of death. Thus, IgA (HR=2.0 95% CI 1.47 to 2.73), IgM (HR=1.5 95% CI 1.11 to 1.91) and IgG (HR=5.8 95% CI 3.38 to 9.95) were positively related to all-cause mortality. Corresponding results for 'other' causes of mortality were 4.7 (2.64 to 8.19), 3.5 (2.29 to 5.45) and 33.4 (15.13 to 73.64). CONCLUSIONS: In the present study, high levels of Ig are associated with an elevated risk of death from total and 'other' causes, mainly infectious disease. High levels of Ig, particularly IgG, may signal subclinical disease.
Did Changes in Drug Reimbursement After the Medicare Modernization Act Affect Chemotherapy Prescribing?
PURPOSE: The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (MMA) decreased fee-for-service (FFS) payments for outpatient chemotherapy. We assessed how this policy affected chemotherapy in FFS settings versus in integrated health networks (IHNs). PATIENTS AND METHODS: We examined 5,831 chemotherapy regimens for 3,613 patients from 2003 to 2006 with colorectal cancer (CRC) or lung cancers in the Cancer Care Outcomes Research Surveillance Consortium. Patients were from four geographically defined regions, seven large health maintenance organizations, and 15 Veterans Affairs Medical Centers. The outcome of interest was receipt of chemotherapy that included at least one drug for which reimbursement declined after the MMA. RESULTS: The odds of receiving an MMA-affected drug were lower in the post-MMA era: the odds ratio (OR) was 0.73 (95% CI, 0.59 to 0.89). Important differences across cancers were detected: for CRC, the OR was 0.65 (95% CI, 0.46 to 0.92); for non-small-cell lung cancer (NSCLC), the OR was 1.60 (95% CI, 1.09 to 2.35); and for small-cell lung cancer, the OR was 0.63 (95% CI, 0.34 to 1.16). After the MMA, FFS patients were less likely to receive MMA-affected drugs: OR, 0.73 (95% CI, 0.59 to 0.89). No pre- versus post-MMA difference in the use of MMA-affected drugs was detected among IHN patients: OR, 1.01 (95% CI, 0.66 to 1.56). Patients with CRC were less likely to receive an MMA-affected drug in both FFS and IHN settings in the post- versus pre-MMA era, whereas patients with NSCLC were the opposite: OR, 1.60 (95% CI, 1.09 to 2.35) for FFS and 6.33 (95% CI, 2.09 to 19.11) for IHNs post- versus pre-MMA. CONCLUSION: Changes in reimbursement after the passage of MMA appear to have had less of an impact on prescribing patterns in FFS settings than the introduction of new drugs and clinical evidence as well as other factors driving adoption of new practice patterns.
Phase I/II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Patients With Locally Advanced or Metastatic Breast Cancer.
PURPOSE: Glycoprotein NMB (gpNMB), a novel transmembrane protein overexpressed in 40% to 60% of breast cancers, promotes metastases in animal models and is a prognostic marker of a poor outcome in patients. The antibody-drug conjugate glembatumumab vedotin consists of a fully human anti-gpNMB monoclonal antibody, conjugated via a cleavable linker to monomethyl auristatin E. Glembatumumab vedotin is generally well tolerated, with observed objective responses in advanced melanoma. This is, to our knowledge, the first study of glembatumumab vedotin in breast cancer. PATIENTS AND METHODS: Eligible patients had advanced/metastatic breast cancer with at least two prior chemotherapy regimens, including taxane, anthracycline, and capecitabine. A standard 3+3 dose escalation was followed by a phase II expansion. Immunohistochemistry for gpNMB was performed retrospectively for patients with available tumor tissue. RESULTS: Forty-two patients were enrolled. Dose-limiting toxicity (DLT) consisted of worsening neuropathy at 1.34 mg/kg. After excluding patients with baseline neuropathy more than grade 1, no DLT occurred through 1.88 mg/kg (the phase II dose). The phase II primary activity end point was met (12-week progression-free survival [PFS12] = 9 of 27 patients; 33%). Sixteen of 19 (84%) patients tested had gpNMB-positive tumors. At the phase II dose, median PFS was 9.1 weeks for all patients, 17.9 weeks for patients with triple-negative breast cancer (TNBC), and 18.0 weeks for patients with gpNMB-positive tumors. Two patients had confirmed partial responses; both had gpNMB-positive tumors and one had TNBC. CONCLUSION: Glembatumumab vedotin has an acceptable safety profile. Preliminary evidence of activity in treatment-resistant metastatic breast cancer requires confirmation, such as the phase II randomized trial (EMERGE) that also examines the relationship between activity and gpNMB distribution/intensity.
Multi-Institutional Study of Post-Transplantation Cyclophosphamide As Single-Agent Graft-Versus-Host Disease Prophylaxis After Allogeneic Bone Marrow Transplantation Using Myeloablative Busulfan and Fludarabine Conditioning.
PURPOSE: The clinical safety and efficacy of intravenous busulfan and fludarabine (IV Bu/Flu) myeloablative conditioning as well as graft-versus-host disease (GVHD) prophylaxis with high-dose, post-transplantation cyclophosphamide (PTCy) have been demonstrated independently in several single-institutional studies. We hypothesized that combining these two promising approaches in a multi-institutional study of human leukocyte antigen (HLA) -matched bone marrow transplantation would provide low rates of severe acute and chronic GVHD, low toxicity, and effective disease control. PATIENTS AND METHODS: Ninety-two adult patients (median age, 49 years; range, 21 to 65 years) with high-risk hematologic malignancies were enrolled at three centers (clinical trial No. NCT00809276). Forty-five patients received related allografts, and 47 received unrelated allografts. GVHD prophylaxis was solely with PTCy at 50 mg/kg/day on post-transplantation days +3 and +4. RESULTS: The cumulative incidences of grades 2 to 4 acute, grades 3 to 4 acute, and chronic GVHD were 51%, 15%, and 14%, respectively. Nonrelapse mortality (NRM) at 100 days and 1 year were 9% and 16%, respectively. With a median follow-up period of 2.2 years, the 2-year disease-free survival (DFS) and overall survival (OS) rates were 62% and 67%, respectively. Donor relatedness did not affect NRM, DFS, or OS. Patients in complete remission (CR) without evidence of minimal residual disease (MRD) had markedly better DFS (80%) and OS (80%) than patients in CR with MRD or with active disease at the time of transplantation (DFS, P = .0005; OS, P = .019). CONCLUSION: This multi-institutional study demonstrates that PTCy can be safely and effectively combined with IV Bu/Flu myeloablative conditioning and confirms PTCy's efficacy as single-agent, short-course GVHD prophylaxis for both acute and chronic GVHD after bone marrow transplantation from HLA-matched donors.
p16 Protein Expression and Human Papillomavirus Status As Prognostic Biomarkers of Nonoropharyngeal Head and Neck Squamous Cell Carcinoma.
PURPOSE: Although p16 protein expression, a surrogate marker of oncogenic human papillomavirus (HPV) infection, is recognized as a prognostic marker in oropharyngeal squamous cell carcinoma (OPSCC), its prevalence and significance have not been well established in cancer of the oral cavity, hypopharynx, or larynx, collectively referred as non-OPSCC, where HPV infection is less common than in the oropharynx. PATIENTS AND METHODS: p16 expression and high-risk HPV status in non-OPSCCs from RTOG 0129, 0234, and 0522 studies were determined by immunohistochemistry (IHC) and in situ hybridization (ISH). Hazard ratios from Cox models were expressed as positive or negative, stratified by trial, and adjusted for clinical characteristics. RESULTS: p16 expression was positive in 14.1% (12 of 85), 24.2% (23 of 95), and 19.0% (27 of 142) and HPV ISH was positive in 6.5% (six of 93), 14.6% (15 of 103), and 6.9% (seven of 101) of non-OPSCCs from RTOG 0129, 0234, and 0522 studies, respectively. Hazard ratios for p16 expression were 0.63 (95% CI, 0.42 to 0.95; P = .03) and 0.56 (95% CI, 0.35 to 0.89; P = .01) for progression-free (PFS) and overall survival (OS), respectively. Comparing OPSCC and non-OPSCC, patients with p16-positive OPSCC have better PFS and OS than patients with p16-positive non-OPSCC, but patients with p16-negative OPSCC and non-OPSCC have similar outcomes. CONCLUSION: Similar to results in patients with OPSCC, patients with p16-negative non-OPSCC have worse outcomes than patients with p16-positive non-OPSCC, and HPV may also have a role in outcome in a subset of non-OPSCC. However, further development of a p16 IHC scoring system in non-OPSCC and improvement of HPV detection methods are warranted before broad application in the clinical setting.
Cognitive Function After the Initiation of Adjuvant Endocrine Therapy in Early-Stage Breast Cancer: An Observational Cohort Study.
PURPOSE: This report examines cognitive complaints and neuropsychological (NP) testing outcomes in patients with early-stage breast cancer after the initiation of endocrine therapy (ET) to determine whether this therapy plays any role in post-treatment cognitive complaints. PATIENTS AND METHODS: One hundred seventy-three participants from the Mind Body Study (MBS) observational cohort provided data from self-report questionnaires and NP testing obtained at enrollment (T1, before initiation of ET), and 6 months later (T2). Bivariate analyses compared demographic and treatment variables, cognitive complaints, depressive symptoms, quality of life, and NP functioning between those who received ET versus not. Multivariable linear regression models examined predictors of cognitive complaints at T2, including selected demographic variables, depressive symptoms, ET use, and other medical variables, along with NP domains that were identified in bivariate analyses. RESULTS: Seventy percent of the 173 MBS participants initiated ET, evenly distributed between tamoxifen or aromatase inhibitors. ET-treated participants reported significantly increased language and communication (LC) cognitive complaints at T2 (P = .003), but no significant differences in NP test performance. Multivariable regression on LC at T2 found higher LC complaints significantly associated with T1 LC score (P < .001), ET at T2 (P = .004), interaction between ET and past hormone therapy (HT) (P < .001), and diminished improvement in NP psychomotor function (P = .05). Depressive symptoms were not significant (P = .10). CONCLUSION: Higher LC complaints are significantly associated with ET 6 months after starting treatment and reflect diminished improvements in some NP tests. Past HT is a significant predictor of higher LC complaints after initiation of ET.