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trec-ct-2022-36

A 47-year-old woman comes to the clinic complaining of dizziness. She also has occasional nausea and ringing in her right ear. The patient also has difficulty hearing while holding her phone to the left ear, although hearing in her right ear is normal. The dizziness improves spontaneously, and she feels fine between episodes. Past medical history is notable for hypothyroidism and low vit D level, for which she is using Levothyroxine and Vit D pearl. She does not use tobacco or drink alcohol. Physical examination shows sensorineural hearing loss in the left ear. She has only one-man sexual partner and menopaused 2 years ago.

trec-ct-2022-37

A 47-year-old man comes to the office due to weight gain and fatigue. He is not able to lift heavy objects or climb stairs. Family history is positive for DM type 2 and HTN in his father. Blood pressure is 165/90 mm Hg and pulse is 85/min. On physical examination, there is symmetric proximal muscle weakness of the upper and lower extremities. Fasting plasma glucose level is 138 mg/dL and 24-hour urinary cortisol is twice the upper normal limit. Further evaluation reveals that high-dose, but not low-dose, dexamethasone suppresses serum cortisol levels. Serum ACTH levels are high-normal. This patient's findings are consistent with endogenous Cushing Syndrome.

trec-ct-2022-38

A 60-year-old man comes to the clinic complaining of hand tremor that started few months ago. It is most bothering when he wants to drink from a glass or pour from a bottle. He does not smoke, but drinks occasionally. He recently started consuming more alcohol as his tremor subsides somewhat when he drinks small amounts of alcohol. Family history is significant for similar problems in his mother. Vital signs are normal and the patient has no other medical conditions. Neurologic examination shows bilateral tremor in the upper extremities. The diagnosis of essential tremor is confirmed.

trec-ct-2022-39

A 55-year-old white woman comes for a routine checkup. She has no significant medical history and does not use tobacco, alcohol, or illicit drugs. The patient's only medication is an over-the-counter multivitamin. Family history is notable for a hip fracture in her mother. Blood pressure is 130/80 mm Hg and pulse is 112/min. She has occasional back pain and lives a sedentary lifestyle with the BMI of 24 Kg/m2. Plain X-ray of the spine shows mild compression fracture at the level of T10. X-ray absorptiometry studies demonstrate abnormally low bone density in the lumbar vertebrae and T-score values below -2.5, which confirms the diagnosis of osteoporosis.

trec-ct-2022-40

A 23-year-old female has prolonged oral bleeding immediately after a tooth extraction. Despite several interventions, the bleeding persists for hours and stops only after desmopressin (DDAVP) administration. The patient has heavy menstrual cycles each month. She has no other medical problems and takes no medications. Her mother and grandmother have also had excessive bleeding during menstrual period. Review of systems is positive for mild bruising on his legs. Laboratory findings reveal a normal platelet count and an abnormal ristocetin cofactor assay, as well as CB <= 0.30 IU/mL and FVIII:C <= 0.40 IU/mL.

trec-ct-2022-41

A 61-year-old man comes to the emergency department complaining of an acute vision disturbance. He had an episode of vision disturbance in the right eye that occurred suddenly and resolved spontaneously in 15 minutes. He also has right jaw pain while chewing. He also complains of fatigue and hip muscle aches over the last several months. The patient has a history of mild hyperlipidemia that has been controlled by diet and lifestyle modifications. On examination, his blood pressure is 130/70 mm Hg and pulse is 66/min. Neurological examination is unremarkable. Visual examination is also normal. ESR is 103 mm/h. Temporal artery biopsy shows multinuclear giant cells and internal elastic membrane fragmentation.

trec-ct-2022-42

A 9-year-old girl is brought to the office for evaluation of short stature and overweight body habitus. The patient's mother and father are 170 cm and 181 cm tall, respectively. On physical examination, the patient's height is in the 5th percentile of her age. Other findings include low-set ears, a high arched palate, a webbed neck, and cubitus valgus. Chromosomal analysis reveals a 45, XO karyotype.

trec-ct-2022-43

A 27-year-old woman comes to the dermatology clinic with skin rash and oral ulcers. The rashes are mildly itchy. The patient has no other medical conditions and takes no medications. Vital signs are normal. On examination, there are pink papules symmetrically distributed over the anterior surfaces of the shins and ankles. There are some white ulcerated papules on her buccal mucosa. She is in relationship with her boyfriend and has only one sexual partner. Her boyfriend uses condoms. She smokes 1 to 2 cigarettes a day and drinks a beer daily. Biopsy reveals prominent hyperkeratosis with a thickened granular layer. There is an infiltration of mononuclear cells in the superficial dermis that involves the overlying epidermis. The rete ridges have a sawtooth appearance.

trec-ct-2022-44

A 48-year-old man comes to the office complaining of heartburn and acid reflux. He has taken over-the-counter antacids but sees no relief. Other medical history is unremarkable. The patient does not use tobacco, alcohol, or illicit drugs. Vital signs are within normal limits. BMI is 31 kg/m2. Physical examination is positive for mild tenderness in upper stomach. Chest x-ray shows an air-fluid opacity behind the heart. A barium swallow study reveals approximately 1/3 of the stomach herniating through the esophageal hiatus.

trec-ct-2022-45

A 15-week-old infant brought to the clinic for the follow up. The infant has flat facies, small ears, a single palmar crease, and upward slanting eyes. He was born on 39th week to a 39-year-old woman who didn't have prenatal care. The medical record confirms the trisomy of chromosome 21 (Down syndrome). The infant is otherwise healthy.

trec-ct-2022-46

The patient is a 38-year-old man with cough and body ache that started 3 days ago. He had fever and chills at the beginning and has low grade fever at the time of visit. He feels tired and sleepy. His body ache and myalgia get better after using Tylenol. The PCR test for Covid is positive. His vital signs are within normal limits with a body temperature of 37.9 C. There is no lymphadenopathy or white exudates in the pharynx.

trec-ct-2022-47

A 41-year-old woman comes to the dermatology clinic complaining of facial redness, especially on her forehead and cheeks. She noticed that the redness gets worse in the summer and after sun exposure. She is otherwise healthy. On physical examination, she has multiple papules and pustules present on her forehead, cheeks, and nose on a background of erythema and telangiectasias. There are no other lesions or nodules. The patient is married and has 2 children who are 5 and 9 years old. She has IUD and doesn't wish to have more kids. She does not smoke or drink alcohol. Her vital signs are normal, and BMI is 21.

trec-ct-2022-48

A 20-year-old man comes to the emergency due to bleeding after a tooth extraction. The bleeding has persisted for approximately 30 minutes despite constant direct pressure. He is a known case of Hemophilia type A treated with FVIII. Blood pressure is 95/60 mm Hg and pulse is 105/min. His weight is 70 Kg. Family history is positive for Hemophilia type A in his maternal uncle. He also has a lipoma on his left arm which he plans to remove surgically. His FVIII activity is 40%.

trec-ct-2022-49

A 50-year-old woman comes to the clinic complaining of difficulty swallowing both liquids and solid foods, as well as occasional cough while eating. She also has difficulty lifting her arms above her head and getting up from a chair. The weakness seems to get worse gradually. The patient has no prior medical problems and takes no medications. Vital signs are normal. Physical examination shows an erythematous rash on the upper eyelids. There are some red papules over joints of her hands. The rest of the physical examination is unremarkable. Antinuclear antibodies, anti-Jo-1 antibodies and anti-MDA5 antibody are positive. Muscle biopsy shows perifascicular inflammation and atrophy of the fascicle and surrounding blood vessels.

trec-ct-2022-50

A 70-year-old man comes to the office accompanied by his wife. The patient has experienced progressive memory loss over the last years. He needs help with some of his routine activities, such as paying bills. The patient's wife says, "He used to be such an independent person, but now he needs help with many things, even finding direction to home!" Medical history includes hypertension, hyperlipidemia, and type 2 diabetes mellitus. Family history includes Alzheimer disease in his father. MRI reveals diffuse cortical and hippocampal atrophy. The diagnosis of AD is made using the National Institute on Aging and the Alzheimer's Association (NIA-AA) criteria.

pmc-7665777-1

This 60-year-old male was hospitalized due to moderate ARDS from COVID-19 with symptoms of fever, dry cough, and dyspnea. We encountered several difficulties during physical therapy on the acute ward. First, any change of position or deep breathing triggered coughing attacks that induced oxygen desaturation and dyspnea. To avoid rapid deterioration and respiratory failure, we instructed and performed position changes very slowly and step-by-step. In this way, a position change to the 135° prone position () took around 30 minutes. This approach was well tolerated and increased oxygen saturation, for example, on day 5 with 6 L/min of oxygen from 93% to 97%. Second, we had to adapt the breathing exercises to avoid prolonged coughing and oxygen desaturation. Accordingly, we instructed the patient to stop every deep breath before the need to cough and to hold inspiration for better air distribution. In this manner, the patient performed the breathing exercises well and managed to increase his oxygen saturation. Third, the patient had difficulty maintaining sufficient oxygen saturation during physical activity. However, with close monitoring and frequent breaks, he managed to perform strength and walking exercises at a low level without any significant deoxygenation. Exercise progression was low on days 1 to 5, but then increased daily until hospital discharge to a rehabilitation clinic on day 10.

pmc-7665777-2

A 39-year-old man was hospitalized due to an increasingly reduced general health condition, after persistent fever and dry cough for 2 weeks. The patient initially needed 4 L/min of oxygen, had a rapid and shallow breathing pattern at rest and became severely breathless during minor physical activities. In the beginning, physical therapy focused on patient education about dyspnea-relieving positions, the importance of regular mobilization, and deep-breathing exercises. However, it quickly became evident that his anxiety from fear of dying and worries about his future aggravated his dyspnea and vice versa. The patient was so dyspneic, anxious, and weak that he was barely able to walk to the toilet. To counter this vicious circle, the physical therapist actively listened to the patient, explained why he was experiencing breathlessness, and tested suitable positions to relieve his dyspnea. He seemed to benefit from the education and the relaxing breathing exercises, as seen on day 2, when his respiratory rate could be reduced from 30 breaths/min to 22 breaths/min and his oxygen saturation increased from 92% to 96% on 4 L/min oxygen after guiding him through some deep-breathing exercises. Over the next days, his dyspnea and anxiety started to alleviate and he regained his self-confidence. Therapy was progressively shifted to walking and strength training and the patient rapidly advanced to walk 350 m without a walking aid or supplemental oxygen before his discharge home.

pmc-7665777-3

One week after a positive COVID-19 result this 57-year-old male was admitted to the ICU because of oxygen desaturation (70%) with worsening tachypnea and dyspnea. Physical therapy started immediately after ICU admission. We found a highly dyspneic patient with a high breathing frequency and significant symptom exacerbation from the slightest effort. With hands-on physical therapy guidance, the patient managed to achieve a 135° prone position and to perform deep-breathing exercises resulting in an increase in oxygen saturation from 88% to 96%. Intensive physical therapy and positioning was continued along with 6 to 12 L/min of oxygen therapy over the next days and intubation was avoided. The major challenges in achieving a prone position were the patient’s profoundly reduced respiratory capacity and the high risk of exacerbating his symptoms. However, standard ICU monitoring enabled safe implementation at an individually adapted pace to allow sufficient time for convalescence. After 3 days with this regime, he could be transferred to the normal ward, where physical therapists carried on his rehabilitation with walking and strength training. The patient’s severe instability remained a challenge. Nevertheless, 9 days after ICU admission, the patient was able to leave the hospital as a pedestrian.

pmc-7665777-4

This 69-year-old male was admitted to the ICU after a dry cough for 2 weeks, oxygenation was poor and computer tomographic imaging showed typical COVID-19 pneumonia. Initially the patient received lung-protective ventilation and targeted sedation, but was otherwise stable. Treatment interventions included passive range of motion and positioning including passive mobilization into a side-edge position (). Over the next days, the patient deteriorated with hemodynamic instability and severe ARDS leading to intermittent prone positioning and continuous renal replacement therapy. The role of physical therapists during proning was to ensure correct joint positioning and pressure prophylaxis to prevent secondary complications such as nerve lesions, contractures, or pressure ulcers. Nevertheless, the long duration and repeated positioning resulted in a small pressure ulcer on the patient’s forehead. After tracheostomy, passive range-of-motion exercises, and passive side-edge mobilization were slowly resumed, whereby asynchronous ventilation and hemodynamic instability remained 2 major problems leading to further sedation and relaxation, thus inhibiting any active participation. After 24 days in the ICU, the patient scored 1/50 points on the Chelsea Critical Care Physical Assessment Tool (CPAx) and showed severe signs of muscle loss. The patient died soon after withdrawal of life support.

pmc-7665777-5

This 57-year-old male was admitted to the ICU with dyspnea, heavy dry cough, and fever 6 days after testing positive for COVID-19. Initially, he was able to exercise and sit in a chair with a physical therapist, but progressive respiratory failure necessitated intubation and proning. The patient had large amounts of bronchial mucus and required regular suctioning along with respiratory therapy. Secretions were assessed with pulmonary auscultation (presence of crackles) and by analyzing expiratory flow on the ventilator (sawtooth pattern). When suctioning failed to improve these clinical signs, 1 to 2 physical therapists used manual airway clearance techniques. The goal of these techniques was to sufficiently increase expiratory flow for effective airway clearance while avoiding alveolar collapse. To achieve this, manual compressions on the chest and abdomen were performed with just enough intensity to modify expiratory flow. After extubation, the patient was still unable to effectively clear his mucus due to weak cough. He continued to need intensive manual airway clearance techniques, nasal rinsing to induce cough and to help expectoration as well as upper and lower airway suctioning. To this end, the patient was treated up to 6 times per day/night. Additional physical therapist interventions included passive range of motion, assisted exercising, and mobilization. At the time of writing, the patient was still in the ICU without ventilatory support.

pmc-7665777-6

This 52-year-old male tested COVID-19 positive 4 days after the beginning of a dry cough, fever, and head and limb pain. One day later, he was hospitalized with exertional dyspnea. He was diagnosed with pneumonia that developed into moderate ARDS needing mechanical ventilation and intermittent dialysis. After extubation, oxygenation was stable with 2 to 3 L/min of oxygen. However, the patient was disoriented and could not communicate verbally. His global weakness (CPAx 11/50) was accompanied by oral and pharyngeal weakness and paresthesia. Spontaneous swallowing frequency and tongue control were severely reduced, and the patient showed insufficient protection from aspiration. This was confirmed by a specialized physical therapist with the Gugging Swallowing Screen, which confirmed severe dysphagia with 2/20 points. He was treated nil by mouth and received dysphagia therapy such as intensive oral stimulation, facilitation of swallowing, and training of protection mechanisms. After initial agitation and disorientation, the patient started to communicate in single-word phrases, but dysphagia continued to be severe with massive oral and pharyngeal dry saliva residuals that compromised his paresthesia and required regular mouth care. Over the next days, the patient managed to swallow pureéd food and mildly thick fluids under supervision, although cough strength was still weak (Gugging Swallowing Screen 13/20, CPAx 30/50). Nevertheless, he continued to progress and became capable of independent food ingestion (Gugging Swallowing Screen 20/20, CPAx 39/50) before his discharge to a rehabilitation clinic 25 days after admission.

pmc-7665777-7

Paramedics found this 59-year-old female with dyspnea and an oxygenation of 65% on room air and performed immediate tracheal intubation. Moderate ARDS with reduced lung compliance was diagnosed and treated with deep sedation, neuromuscular blocking agents, and prone positioning. On day 14, a trial of sitting on the edge-of-bed (SOEB) was performed, while she was still intubated and under pressure support ventilation. SOEB required 3 physical therapists to maintain the position, but resulted in a significant increase in her level of consciousness and collaborative state. The next day, she was able to hold her head and sit for about 15 minutes with 2 therapists. Her muscle strength indicated ICU-acquired weakness, with a Medical Research Council sum-score (MRC-SS) of 40/60; still she continued with small but consistent improvements and started to participate actively in physical therapy sessions. She was encouraged to mobilize herself with exercises against gravity and was actively transferred to a chair each day with the help of 2 physical therapists. She was successfully extubated, but presented postextubation dysphagia. The physical therapy team closely monitored her for secretion management and cough stimulation and continued her physical rehabilitation. On day 19, she started to walk with a walking aid, although at this point oxygen desaturation during exercise training became evident (89% with 3 L/min of oxygen). After 25 days, she was transferred to the institution’s rehabilitation facilities, where a battery of tests indicated persistent physical function impairment (MRC-SS 52/60, physical function ICU test score17 9/12, Timed Up & Go 23 seconds, short physical performance battery 4/12).

pmc-7665777-8

This 33-year-old female patient had typical COVID-19 symptoms such as high fever, dry cough, headache, and dyspnea about 1 week before ICU admission. She was intubated and proned due to rapid respiratory deterioration. For the following 6 days, her situation was unstable, and physical therapy consisted of prone positioning and prevention of secondary damage. From day 7 onwards, she started to improve rapidly and could be mobilized passively into a side-edge position. After extubation, she presented postextubation dysphagia and severe ICU-acquired weakness (MRC-SS 36/60). She also suffered from pronounced delirium and anxiety and said repeatedly that she had been abducted and that she believed she had to die. She seemed to feel threatened by us and it was difficult to calm her down. Due to the pandemic measures of the Swiss government, hospital visits were not generally allowed, but because her anxiety was limiting her rehabilitation, her husband was granted an exceptional permission to visit her. This seemed to give the patient a short sense of security, and she started to participate in some basic functional activities (CPAx 21/50). Nevertheless, the delirium did not resolve upon her transfer to a peripheral acute hospital.

pmc-7665777-9

This 66-year-old male patient was admitted to the hospital due to an ischemic left-hemispheric stroke in addition to a dry cough and fever. He tested positive for SARS-CoV-2 the following day but continued to deteriorate resulting in severe ARDS, intubation, and ICU admission. Despite repeated proning, gas exchange did not improve sufficiently and the patient was placed on veno-venous extracorporeal membrane oxygenation for 7 days. After sedation was stopped, the patient continued to be somnolent and unable to communicate or to follow commands. Physical therapy therefore focused on perception training, movement exercises, airway-clearing techniques, dysphagia therapy, and mobilization. A first SOEB trial had to be discontinued due to hemodynamic instability. Instead, the patient was positioned in a side-edge position (), which he tolerated better and where an intensive exercise training including trunk and head control was conducted. Nevertheless, muscle tone and strength remained severely reduced, particularly on his hemiplegic side, and a second SOEB trial failed again. Physical therapy was also limited because of reduced self-activity and suspected impaired perception and visual acuity. Consequently, occupational therapy was involved to create a basis of communication, to support functional initiation of upper limb movements, and to integrate perception-training into activities of daily living. Currently, the patient tolerates spontaneous breathing trials, shows signs of being alert during therapy, but cannot communicate. He is hemodynamically stable, even in an SOEB position, but remains functionally dependent (CPAx 6/50).

pmc-7665777-10

A 66-year-old male started to present symptoms of fever, dyspnea, coughing, asthenia, lack of appetite, nausea, and vomiting. He was admitted to the acute care unit for observation and oxygen therapy, but his oxygen requirements constantly increased due to moderate ARDS. After 12 days of deep sedation, neuromuscular blocking agents, and proning with daily passive range of motion, the patient finally started to initiate active movements and was passively transferred to a chair. However, due to a persisting difficult weaning status, probably related to respiratory muscle weakness, tracheostomy was performed [ventilator settings: pressure support 10 cmH2O, positive end-expiratory pressure (PEEP) 8 cmH2O]. Subsequently, the patient showed significant improvement in his physical functions with active SOEB, chair-transfer with the help of 2 physical therapists, and active in-bed cycling against resistance for 20 minutes (). The strategy was to increase pressure support (by 5 cmH2O) during efforts to reinforce exercise training effects, unloading respiratory muscles. This strategy along with a highly collaborative patient culminated in his rapid improvement in physical function (MRC-SS 58/60, physical function ICU test score 10/12, walking distance 10 m), although he was still experiencing fatigue, inspiratory muscle weakness (maximal inspiratory pressure of −45 cmH2O) and dysphagia upon his transfer to a step-down unit.

pmc-7665777-11

This 77-year-old male patient was transferred to our ICU 1 week after his COVID-19 diagnosis due to continuing respiratory decompensation requiring intubation. Following the acute phase, with intermittent proning, the patient continued to be hemodynamically unstable and was difficult to wean. Rehabilitation proved challenging under these conditions, and physical therapists had to reevaluate and adapt their interventions daily according to his condition. After 2 weeks, he was tracheotomized and started to improve very slowly. One week after tracheostomy, the patient was able to speak for the first time after a cuff-down trial and with the help of a speaking valve. But the patient spoke only a few words with us and it was often difficult to involve him in exercises. Two days later, he was able to communicate with his relatives via video telephony. This was a very emotional moment for everyone involved, but it improved his communication and he was able to express to his wife that he had no strength left to continue. However, through the family’s active participation in his early rehabilitation process, they were able to reinforce his confidence and motivation. He was discharged to a rehabilitation clinic severely weak (MRC-SS 40/60) and functionally impaired (CPAx 22/50), but continued to progress in slow steps.

pmc-8674153-1

A 45-year-old female was brought in by ambulance after collapsing at home secondary to a hypoglycemic event (capillary blood glucose of 1 mmol/L with paramedics). She had a history of restrictive AN, binge-purge behaviour, and an old traumatic brain injury, leaving her with memory problems. She was well known to mental health services, having been admitted multiple times to eating disorder centres for nasogastric feeding. She had never smoked in her life and denied any alcohol intake. The patient was on ferrous fumarate, fexofenadine, fluoxetine, ibuprofen, lansoprazole, quetiapine, supplemental vitamins, regular morphine (modified release), and gabapentin. On admission, her blood pressure was 106/85 mmHg, respiratory rate was 20 breaths/minute, heart rate was 64 beats/minute, temperature was 35.1 °C, and capillary blood glucose was 6 mmol/L. Her weight on admission was 37.3 kg (body mass index [BMI] = 12.6). On examination, she was clearly malnourished, cachexic, and dehydrated. The rest of the clinical examination was normal, as shown in Table . Her chest radiograph showed patchy consolidations in the right middle and lower lobes (Figure ). She was prescribed appropriate antibiotics. She was refusing treatment and was deemed to lack the capacity to make that decision. Therefore, Section 5(2) under the Mental Health Act was put in place. She was commenced on oral supplements as per guidance from the dietitian, and then switched to nasogastric feeding. On the night of the second day, she had an episode of decreased consciousness, bradypnoea (RR-6), and hypotension (83/64). Her blood sugar level was 6.6 mmol/L. After receiving Naloxone, her symptoms improved, and her opiates were discontinued. The following day she mentioned right upper quadrant pain. Blood tests showed worsening liver enzymes, as shown in Table . An abdominal ultrasound was performed on the fourth day of admission, which showed multiple small calculi and biliary debris, with gallbladder oedema, and a small amount of peri-cholecystic fluid (Figure ). She was treated for cholecystitis with amoxicillin, clavulanic acid, and clarithromycin, which led to improvement in her inflammatory markers in the following days. She underwent an inpatient magnetic resonance cholangiopancreatography (MRCP) to rule out intra-biliary pathology, which was negative. Subsequently, she was referred to surgeons for consideration of elective laparoscopic cholecystectomy once deemed fit. She had a protracted and difficult admission. Due to the coronavirus disease 2019 pandemic, her transfer to an Eating Disorders Unit proved difficult. By the fourth week of admission, her liver enzymes had improved, as can be seen in Table . Nasogastric feeding was successfully weaned as her weight improved. She was discharged on day 51 to an Eating Disorders Unit weighing 56.4 kg (BMI = 18.1) from her admission weight of 37.3 kg (BMI = 12.6).

pmc-8674153-2

A 29-year-old male was brought to the hospital by ambulance after collapsing at home. He was found to be bradycardic and hypoglycaemic with a capillary blood glucose level of 2.3 mmol/L. He had a history of eating and anxiety disorders and was not on any regular medications. On admission, his weight was 37.3 kg (BMI = 11.6). His blood pressure was initially un-recordable but subsequently was recorded to be 104/72 mmHg. His capillary blood glucose level was 4.7 mmol/L, and his Glasgow Coma Scale score was 15/15. On examination, he was noted to be severely malnourished and cachexic. The rest of the clinical examination was normal. LFTs were very abnormal, as shown in Table . Since admission, he seemed to lack insight. Due to problems keeping him compliant with medication and intravenous glucose, he had a number of hypoglycaemic events in the first two days of admission. The following day, he was deemed not to have the capacity. He underwent Mental Capacity Assessment and Deprivation of Liberty Safeguards. He was ultimately placed under Mental Health Act 5(2) and was started on nasogastric feeding. His liver enzymes worsened further after the introduction of nasogastric feeding, but we were reassured by a normal non-invasive liver screen and ultrasound. His condition, liver tests, and liver synthetic function improved over the course of his 24-day admission (Table ), but his stay was associated with difficult behaviour. He was eventually discharged to an Eating Disorders Unit.

pmc-8674405-1

A 36-year-old G4P2 premenopausal woman with a family history of colorectal, hepatobiliary cancers felt an abnormal right breast lump. Diagnostic mammogram and ultrasound showed a hypoechoic lesion in the upper outer quadrant of right breast measuring 14 mm x 13 mm x 18 mm and 5 x 4 mm satellite lesion is noted 6 mm inferior to the dominant mass, BI-RADS 5 highly suggestive of malignancy. Due to concern for multifocal disease, MRI breast with without contrast was done and it showed 2.3 x 1.1 x 2.7 cm irregular-shaped, heterogeneous mass with irregular margins in the upper outer quadrant of right breast, 7 cm from the nipple, 1.2 cm from the skin and there was an additional mass measuring 8 mm x 4 mm x 1.6 cm at 12:00 along with 4 mm lesion, 7 mm from the nipple at 10:00 (Figures (a) and (b)). Right breast biopsy from the dominant lesion showed invasive mammary carcinoma with features of both lobular and ductal carcinoma, Nottingham histological grade 2, estrogen receptor 90%, progesterone receptor 100%, HER2 2+ by IHC but negative by FISH, Ki-67 50%. Status post right breast simple mastectomy and axillary lymph node evaluation. Surgical pathology showed a multifocal invasive mammary carcinoma of the breast with ductal and lobular features, size of largest invasive carcinoma was 55 mm, size of additional invasive foci was 1.5 mm, Nottingham histological grade 2 of 3, low to intermediate nuclear grade DCIS without central necrosis measuring at least 6 mm, margins uninvolved, one benign sentinel lymph node. Pathological staging (m)pT3 (sn)N0. Oncotype DX breast recurrence score of 16 (for patients <50 years of age, benefit from chemotherapy 1.6%). Genetic testing did not reveal any clinically significant mutations. The patient has received adjuvant PMRT 5000 cGy dose, 25 fractions along with 1000 cGy scar boost. Based on TEXT/SOFT data ovarian suppression could be considered in patients with high-risk features. The patient's tumor was multifocal, and the largest lesion measured 5.5 cm. The patient elected against surgical menopause. The patient was started on ovarian suppression with goserelin 3.6 mg every 28 days along with letrozole 2.5 mg once daily. Sixteen months after initiation of ovarian suppression patient started having a regular menstrual cycle while on goserelin. No medication interaction or missed doses were noted. The patient's BMI was 41.1 and BSA was 2.19 m2. Estradiol was 92 pg/mL and follicle-stimulating hormone (FSH) was 4.3 mIU/mL in the premenopausal range. Few prior case reports showing failure of goserelin ovarian ablation in a premenopausal woman were reported. Given high-risk disease, discussed benefit of continued ovarian suppression plus AIs versus tamoxifen alone, and discussed the role of oophorectomy which results are reliable and prompt reduction in circulating estrogens. The patient was hesitant and wished to wait before the oophorectomy. She was started on triptorelin 3.75 mg IM once every 28 days.

pmc-8674458-1

The patient was a 62-year-old male with a past medical history of liver cirrhosis secondary to hepatitis C, tobacco use, and post-stent coronary artery disease, who initially came to the hospital for elective left and right heart catheterization as a pre-transplant evaluation. Physical examination showed abdominal distension and diffuse tenderness with the presence of prominent superficial abdominal veins. A computed tomography (CT) scan of the abdomen with contrast was obtained immediately. The CT showed an occlusive thrombus of the IVC extending from the renal veins to the level of the cavoatrial junction. Thrombus was also observed in the portal vein, and multiple subcutaneous varicosities were found. Initially, a plan was made to start the patient on anticoagulation, but because of the patient’s history of advanced cirrhosis, large esophageal varices on recent endoscopy, and thrombocytopenia, we concluded that the patient was not a candidate for anticoagulation. Given that the patient had significant abdominal distention with pain that did not improve even after therapeutic paracentesis; we inserted a stent in the IVC to relieve the patient’s pain as a palliative procedure to improve his quality of life. Right internal jugular (IJ) and right femoral vein accesses were obtained for the procedure. A 6F pigtail diagnostic catheter was advanced from the right IJ to the right atrium, and contrast was injected into the right atrium that showed an occluded IVC at the junction of the right atrium. Another pigtail catheter was advanced through the right femoral vein and an inferior venogram was performed that showed the IVC was 100% occluded 2 cm above the renal veins (Figures , ). A Glidewire advantage was advanced through the right femoral vein but was unable to cross the 100% occluded IVC. Then, a 7-French Swan-Ganz catheter was tried and was successfully advanced through the IVC all the way to the right atrium. A Swan wire was inserted through the Swan-Ganz catheter. Then, a multipurpose catheter was advanced over the Swan wire into the right atrium, and the Swan-Ganz wire was successfully replaced with a Glidewire Advantage (Figure ). Initially, a 9 × 80 Mustang balloon was used to perform the IVC ballooning; after IVC ballooning; however, the inferior venogram showed no flow to the IVC, which was still 100% occluded. Then, a 22 × 70 mm Wallstent was advanced via the right femoral vein to the right atrial side. The stent was deployed with a considerable waist in the mid area (Figure ). After stent placement, an 18 × 60 Boston Scientific esophageal balloon was successfully used to post-dilate the stent (Figure ). The final venogram (Figures , ) and digital subtraction imaging mode showed excellent flow in the IVC to the right atrium. Small clots floating around at the lower edge of the stent above the renal artery were successfully removed with a 7-Fr snare. Usually, if IVC occlusion is of thrombosis in etiology anticoagulation is advised after venous stent placement, since our patient had an advanced liver failure with elevated INR, anticoagulation was not started [].

pmc-8674685-1

We report a case of a 45-year-old woman, a non-smoker, treated for type II diabetes under insulin and primary hyperparathyroidism. Her medical history dates back to 2006 with an infiltrated nodule associated with ulcers that grew gradually in her right thigh. The patient underwent surgery with an anatomopathological study. Skin biopsy objectified ulcerated epidermotropic dermo-hypodermal tumor proliferation whose morphological appearance and immunohistochemical data are in favor of LCH. Langerhans cells present positivity of the anti-PS100 antibody, anti-CD1a antibody, and anti-Ki67 antibody (60%), and negativity of the anti-CD68 antibody. The patient subsequently received 25 sessions of radiotherapy followed by six courses of chemotherapy with a low dose of oral methotrexate. After these treatments, skin lesions are stable. In 2020, the patient complained of an increase in skin lesions, with the appearance of several infiltrating nodules, scaling, crusted papules, and ulcerated plaques. The patient received chemotherapy as single-system LCH (SS-LCH) based on methotrexate, associated with prednisone and vinblastine, with the obtainment of stable response and limited regression of the lesions. After two courses, the patient was lost to follow-up. One year later, the oncologist referred the patient to the hematology department for a major increase in skin lesions, with the appearance of new ones on her thigh. Dermatological examination found ulcers and necrotic lesions, purplish, well-limited, of variable size, not painful, not warm to the skin, and localized to the right thigh. The mucous membranes and integuments were unharmed (Figure ). Furthermore, the examination found an afebrile, obese patient (body mass index (BMI) at 44.8). Abdominal and cardiovascular examinations were unremarkable. The physical examination did not find any tumoral syndromes, and the patient did not present have B signs (fever, weight loss, and night sweats). A complete assessment was carried out in favor of a cutaneous location without visceral involvement. A CT scan of the chest and abdomen was normal. Extensive investigation revealed no systemic involvement, central nervous system (CNS) evaluation was not done, serum thyroid hormone levels were normal, endocrine workup was performed, including cortisolemia, and parathormone assessment were done in favor of primary hyperparathyroidism. A skin biopsy was performed. The microscopic examination revealed a cutaneous tissue with an infiltrate of large cells involving the dermis and realizing an epidermotropism. The infiltrate was composed of atypical cells with abundant, pale eosinophilic cytoplasm, irregular and elongated or lobed nuclei with prominent nuclear grooves and folds, fine chromatin, and indistinct nucleoli. Multinucleated giant tumor cells, high cytonuclear atypia, and marked nuclear pleomorphism were seen. The mitotic figures were increased. The neoplastic cells also showed a mixed inflammatory background with variable numbers of reactive lymphocytes, plasma cells, benign histiocytes, and eosinophils associated (Figure ). The immunohistochemical stains had shown a diffuse strong and heterogeneous positivity for CD1a and S100 and variable positivity for CD45. All other markers studied were negative, including CD68, cytokeratins (AE1/AE3), and melanocytic marker (MelanA). The Ki-67 proliferation index was high (50%) (Figure ). In the light of microscopic and phenotypic results, the diagnosis of Langerhans cell sarcoma was confirmed. The patient did not receive any maintenance therapy and she received only two courses of chemotherapy; consequently, the patient was included in the LCH protocol as single-system LCH (SS-LCH), and she received the same chemotherapy combining prednisone (60 mg / m2), high-dose of methotrexate (5000 mg/m2), and vinblastine (10 mg/m2). The evolution was favorable after five cycles of chemotherapy with significant regression of lesions in the thigh without the appearance of any new lesions (Figure ).

pmc-8675570-1

We describe the case of a 55-year-old male who presented to the emergency department via emergency medical services for the chief complaint of sudden onset shortness of breath that woke him from his sleep just prior to arrival. He reported three days of non-radiating lumbar back pain and two episodes of non-bloody emesis leading up to this event. His medical history included hypertension and type 2 diabetes mellitus. His current medications were metformin, amlodipine, losartan, and atenolol. Initial vital signs revealed heart rate (HR) 75, respiratory rate (RR) 29, blood pressure (BP) 119/62, and oxygen saturation 99% on 2L nasal cannula. Temperature was 36.3°C. Physical examination was significant for an ill-appearing male patient who was anxious and tachypneic. He also had significant work of breathing with retractions and abdominal breathing. Lungs were clear to auscultation, with no wheezing, rhonchi, or rales. Abdominal exam revealed mild epigastric tenderness with no rebound, guarding, or palpable pulsatile mass. No costovertebral angle (CVA) tenderness or midline tenderness was elicited. Neurological exam revealed no focal deficits. Due to his presentation and multiple comorbidities we had significant concern for the possible acute coronary syndrome, dissection, sepsis, or pulmonary embolism. Blood work including complete blood count (CBC), comprehensive metabolic panel (CMP), lactic acid, troponin, urine analysis (UA) was ordered. CT-angiogram of his chest, abdomen, and pelvis was also ordered. Complete blood count revealed a white blood cell count of 20.4 x 103/uL, hemoglobin of 11.2 g/dL, and platelet count of 376 x 103/uL. Comprehensive metabolic panel was significant for a sodium of 145 mmol/L, potassium 6.1 mmol/L, chloride 100 mmol/l, bicarbonate <7 mmol, blood urea nitrogen (BUN) 67 mg/dl, creatinine 14.7 mg/dL, calcium 9.1 mg/dL, and glucose of 165. Troponin I was <0.012 ng/mL. Initial lactic acid was recorded at 13.9 mmol/L. An arterial blood gas revealed severe anion gap metabolic acidosis with a pH of 6.9, pCO2 of 22.3 mmHg, pO2 of 105.5 mmHg, HCO3 of 5.3 meq/L, and a Base Excess of -24.8 mmol/l. The patient was anuric at this time. Initial EKG showed normal sinus rhythm (NSR), nonspecific ST abnormalities, vent rate 73, QTC 471. The CT scan revealed an obstructing stone at the left proximal ureteropelvic junction (Figures , ) and at the right ureterovesical junction (Figure ), with resultant bilateral hydronephrosis (Figure ). While in the ED the patient progressively became hypotensive and was given broad-spectrum antibiotics, Vancomycin and Cefepime, due to concern for sepsis and aggressive fluid resuscitation was initiated. The patient did not respond to fluid resuscitation and was started initially on Levophed. In addition, the patient received 100 mL of 8.4% sodium bicarbonate and 2 grams of calcium gluconate for severe metabolic acidosis and hyperkalemia. Due to the expected clinical decline, the patient was intubated in the emergency department. Critical Care, Nephrology, and Urology were consulted emergently in the ED. After initial stabilization, the patient was taken for immediate bilateral percutaneous nephrostomy (PCN) placement by Interventional Radiology (IR) and placement of a trialysis catheter for initiation of hemodialysis afterward. Urinalysis from the PCN revealed hematuria, but no evidence of infection. After successful placement of bilateral PCN, the patient was transferred to the intensive care unit (ICU) in critical condition. He was maintained on multiple vasopressors consisting of combinations of norepinephrine, vasopressin, epinephrine, and phenylephrine along with stress dose hydrocortisone. Repeat blood gas and labs revealed a worsening metabolic and lactic acidosis with a repeat pH of 6.7 and a lactic acid of 15.9. The patient was started on hemodialysis with a high bicarbonate dialysate for emergent clearance of hyperkalemia and refractory acidosis. After hemodialysis, the patient’s pH was 7.1, despite a worsening lactic acidosis of 17.0 mmol/L. Overnight the patient was converted to continuous venous-venous hemodialysis, a form of continuous renal replacement therapy (CRRT). Within 24 hours the patient’s acidemia corrected and blood pressure stabilized allowing for a de-escalation of vasopressors. A repeat chemistry revealed recovering renal function along with urine production in the nephrostomy tubes. On hospital day 3, the patient was successfully extubated, weaned off all vasopressors, and CRRT was stopped. Blood and urine cultures taken prior to dialysis were negative after five days. On hospital day 6, Urology performed a cystoscopy with bilateral ureteral stent placement and removal of bilateral percutaneous nephrostomy tubes. On hospital day 8, the patient had made a remarkable recovery from being critically ill. His creatinine was 1.5, BUN 27, and he was discharged home with urology follow-up in 1-2 weeks.

pmc-8675571-1

A 58-year-old Caucasian (American) male with an unremarkable past medical history presented for evaluation of nausea, vomiting, and a 30-pound weight loss over the past two months at our hospital. He also reported dark-colored urine and intermittent episodes of hemoptysis during the same period. Specifically, he stated that his symptoms started four days after receiving his second dose of the mRNA-1273 (Moderna) vaccine for COVID-19. His first dose taken three weeks earlier was well tolerated. He denied any flank or abdominal pain, melena, fever, cough, hematuria, urinary frequency or urgency, and trauma. He denied smoking. Vital signs were stable upon admission. Physical examination was insignificant for any lower extremity pitting edema, petechiae, or rash. The patient was not on any medication prior to his hospitalization. Laboratory analysis was remarkable for serum creatinine of 4.1 mg/dL (0.8-1.4 mg/dL) along with hematuria and sub-nephrotic proteinuria of 1796 g/24 hours (<150 mg/24 hours). Our differential diagnosis at this point was wide including all nephritic syndromes given AKI, hematuria and proteinuria. All serological workup was subsequently sent. C-ANCA (anti-neutrophil cytoplasmic antibodies) were elevated 160 AU/mL (20-25 AU/mL) and anti-proteinase 3 (anti-PR3) antibodies were also elevated >100 EU/ mL (normal <3.5 EU/mL) (Table ). Immunohistochemical staining for the SARS-CoV-2 spike protein was not performed. All previous routine laboratory parameters including urinalysis were within normal range. He underwent computed tomography (CT) scan of the chest for evaluation of hemoptysis that showed a right upper lobe consolidation and moderate bilateral pleural effusion. The renal ultrasound was unremarkable. Renal biopsy was subsequently performed and showed acute, pauci immune, focal necrotizing, and diffuse crescentic glomerulonephritis (Figures , ). The patient was diagnosed with anti-PR3-associated ANCA glomerulonephritis. He received intense immunosuppression with plasma exchange x 5 cycles, intravenous prednisone 1 gram x 3 doses followed by prednisone 60 mg daily, cyclophosphamide x 2 doses, and rituximab x 4 doses. The patient achieved remission after 10 weeks of diagnosis with a resolution of symptoms and improvement in renal function with a creatinine of 1.5 mg/dl. He is following in our nephrology office regularly since discharge.

pmc-8675572-1

A 67-year-old Caucasian female presented to our hospital with a chief complaint of persistent bright red blood per rectum. Her medical history was significant for hypertension, hyperlipidemia, diabetes mellitus type 2, coronary artery disease with three prior myocardial infarctions, recurrent cerebrovascular accidents requiring anticoagulation with warfarin, gastroesophageal reflux disease, asthma, and endometrial cancer status post radiation therapy. Fifteen months prior to the current presentation, the patient was noted to have a grade 1 endometrial adenoma but was not considered a good surgical candidate due to multiple comorbidities. Vaginal hysterectomy was considered but due to her long and narrow vagina, this option was deferred initially. Her only treatment option was radiation therapy and brachytherapy. She eventually underwent total abdominal hysterectomy with bilateral salpingo-oopherectomy due to continued pelvic pain. The patient denied any prior history of gastrointestinal (GI) bleeding. Her bleeding was described as one large episode of bright red blood per rectum associated with blood clots. She denied any abdominal pain, nausea, vomiting, diarrhea, constipation, or melena. The most recent colonoscopy was performed four months ago and revealed three diminutive polyps in the transverse colon with pathology confirming tubular adenoma. Her physical examination was significant for mild left-sided abdominal tenderness but was otherwise unremarkable. Rectal examination was notable for nonbleeding hemorrhoids and no visible blood. Blood work revealed white blood cells of 14.3k/uL (normal range 4.3-10.0 k/uL) and hemoglobin of 9.6 g/dL (normal range 11.8-14.8 g/dL), which is similar to the patient’s baseline. Creatinine was slightly elevated to 1.2 and blood urea nitrogen was elevated to 39. International normalized ratio was 2.0. Due the large volume of hematochezia and presence of anemia, the patient was admitted to the hospital and underwent a colonoscopy, which revealed a large, fungating, friable, and ulcerated nonobstructing mass in the sigmoid colon. The mass was noncircumferential, measured 4 cm in length, and was located 15-19 cm from the anal verge (Figures , ). Biopsies were obtained with cold forceps for histology and the proximal and distal margins of the mass were tattooed. Histology showed invasive and moderately differentiated carcinoma without visible goblet cells. Given the patient’s history of endometrial cancer, immunohistochemistry was performed and was consistent with an endometrial (endometrioid subtype) primary. Pan-computed tomography was negative for any obvious distant disease. The tumor marker carcinoembryonic antigen level was normal as well. The patient subsequently underwent surgical resection of the affected colon followed by radiation therapy. At a follow-up visit one year later, the patient was doing well without active GI complaints.

pmc-8675574-1

A 71-year-old African American female with a medical history of hypertension, type 2 diabetes mellitus, stage 3 chronic kidney disease, and osteoarthritis initially presented to the emergency room with intermittent bilateral hand tingling and numbness, which was gradual in onset over months. Her symptoms were associated with seeing red spots and experiencing a burning sensation in the bottom of her feet. She was concerned because she was having difficulty picking up objects due to her hand symptoms. Her basic lab work was unremarkable, and she was provided gabapentin and magnesium oxide with close follow-up with her primary care physician. At follow-up, she complained of one to two months of unsteady gait as well as increased confusion. Her reported medications included losartan and metformin. Physical exam revealed normal pupils with reaction and accommodation (3mm diameter bilaterally), no cranial nerve deficits, normal strength throughout, and normal reflexes throughout except for diminished reflexes in the bilateral knees and ankles. She endorsed blurry vision; no ophthalmologic exam was performed, but she was able to read a name badge from one foot away. She additionally was found to have decreased vibratory and proprioception in a stocking pattern as well as a wide-based and unsteady gait. To investigate further, tests for thyroid-stimulating hormone (TSH), folate, B12, and rapid plasma regain (RPR) titer were ordered. Her TSH, folate, and B12 levels were within normal limits, but her RPR titer was reactive at 1:1. A subsequent reflex Treponema pallidum particle agglutination (TP-PA) test was reactive. She was told to go to the hospital for further workup and treatment. Further questioning revealed that she had had two sexual partners in her life, both ex-husbands. However, she noted that her husbands committed adultery several times and that she was not currently sexually active; her last sexual encounter occurred several years ago. She endorsed that she did not notice any ulcers or skin lesions, and she had not been treated for syphilis. During hospitalization, she received a lumbar puncture that revealed a negative venereal disease research laboratory (VDRL) test result. Her glucose level (61 mg/dL) and white blood cell level (3 x 109/L) were normal, but her CSF protein level was markedly elevated at 156 mg/dL. Due to her exposure history, a constellation of symptoms, RPR titer with positive TP-PA, and protein elevation in her CSF, our infectious disease colleagues believed that she contracted syphilis earlier in life from one of her husbands and was never treated. The decision was made to start treatment with intravenous (IV) penicillin (24 million units, continuous infusion) for two weeks. At follow-up, her vision had improved and she no longer had sensory symptoms in her hands. Her gait was somewhat improved, but still unsteady, and she still had burning pain in her feet. Her physical exam showed improvement in sensation in hands and improved gait; all other neurological exam was unchanged. It was thought that neuropathy in feet could have been due to poorly controlled diabetes; although, no formal nerve conduction study was pursued.

pmc-8675577-1

Our patient is a 78-year-old male with a past medical history of cutaneous T-cell lymphoma/mycosis fungoides (on regular outpatient extracorporeal photopheresis), type II diabetes mellitus, atrial flutter on Xarelto, and sick sinus syndrome on dual-chamber pacemaker, presented to the hospital with right upper quadrant abdominal pain. The patient was a former smoker and denied any alcohol use. In the emergency department, he was hemodynamically stable. Laboratory workup was significant for abnormally elevated liver function tests including aspartate aminotransferase/alanine aminotransferase (AST/ALT) of 204/188 U/L, alkaline phosphatase (ALP) of 550 U/L, and total bilirubin of 2.5 mg/dL. Ultrasound of the abdomen was negative for any focal liver or gallbladder lesions. There was no evidence of intrahepatic or extrahepatic biliary duct dilation. Hepatobiliary iminodiacetic acid (HIDA) scan was normal, and hence cholecystitis was ruled out. CT abdomen and pelvis and CT angiography of the chest were negative for acute pathology. As the patient had a pacemaker, magnetic resonance cholangiopancreatography (MRCP) could not be performed. Further laboratory evaluation for elevated liver enzymes, including viral hepatitis panel, thyroid-stimulating hormone (TSH), iron panel, antinuclear antibody (ANA), anti-mitochondrial antibody, alpha-1-antitrypsin antibody, anti-smooth muscle antibody, and ceruloplasmin was negative. Given that the patient has a history of cutaneous T-cell lymphoma, the important differential diagnosis included leukemic infiltration of the liver and adverse reaction to the prior chemotherapy. However, the patient received only a short course of the chemotherapeutic regimen mogamulizumab (due to insurance issues), and hence it was unlikely to cause this current clinical picture. Subsequently, a percutaneous liver biopsy was performed to confirm the diagnosis, which showed replacement of the normal liver parenchymal cells by high-grade tumor cells with a high nuclear-cytoplasmic ratio (Figures -). The tumor cells showed positive immunohistochemical staining for cytokeratin AE1/AE3, cytokeratin 20 (CK20), synaptophysin, chromogranin, and negative for CK7, caudal type homeobox transcription factor 2 (CDX-2), and thyroid transcription factor 1 (TTF-1) (Figures -). All these features were suggestive of metastatic Merkel cell carcinoma. There was no evidence of leukemic infiltrates. As the patient had no evidence of MCC involvement of the skin, he was diagnosed with metastatic MCC of the liver of unknown primary. Hematology/Oncology and Dermatology was consulted. Considering the medical comorbidities, the patient and family opted for comfort care measures and were discharged home.

pmc-8675578-1

A 24-year-old healthy woman presented with difficulty breathing and dissatisfaction with her facial appearance. She had a history of childhood trauma resulting in nasal septum deviation and external nasal deformity. Four months after a successful and uneventful septorhinoplasty, she presented to the emergency department with blunt nasal trauma resulting in a septal hematoma, which was drained successfully; the patient was discharged with no adverse sequelae. Four months later, the patient sustained nasal trauma again, this time accompanied by clear nasal discharge, raising suspicion of cerebrospinal fluid (CSF) leak. The patient was discharged after managing the nasal injury, as the CT brain showed an intact cribriform plate with no evidence of a CSF leak. Ten days later, she presented at the emergency department with dizziness and an unstable gait. She also had complaints of paresthesia for the past two months, beginning in her right hand and progressing to the right shoulder, arm and leg, associated with some difficulty in the execution of movements in the first and second finger of the right hand. Her right leg was quite stiff with difficulty in walking. On close inquiry, she gave history of pain in the right eye and double vision many months back, which had resolved spontaneously. Examination showed a positive Romberg’s and Lhermitte’s sign, with right-sided sensory impairment. Magnetic resonance imaging (MRI) of the brain, cervical and thoracic spine demonstrated demyelinating lesions in the brain and cervical segment of the spinal cord (Figure ). Some of the lesions demonstrated enhancement on post gadolinium administration sequences, suggestive of active demyelinating diseases like MS. A lumbar puncture was performed which demonstrated the presence of oligoclonal bands in the CSF. The diagnosis of MS was confirmed by a neurologist and treatment was initiated. The initial neurological symptoms have largely vanished with only persistent light paresthesia in the right hand. Two years later she has had no new symptoms and continues with the same medication with good tolerance.

pmc-8675583-1

A 64-year-old Caucasian male smoker with a horseshoe kidney with a history of open pyelolithotomy 18 years ago, presented to King Abdulaziz Medical City in mid-2020 with a report from another hospital stating that he developed gross hematuria six months prior, which was treated as a urinary tract infection. A CT of the abdomen and pelvis was performed in that hospital, showing a horseshoe kidney with severe left hydronephrosis and enlarged retroperitoneal lymph nodes, with the largest one located in the posterior part of the left renal artery measuring 4.7 × 3.5 × 2.6 cm. Additionally, there were multiple stones (Figures , , ). Urine culture was performed and revealed that various organisms were isolated (10-100,000 CFU/ml). Urinalysis showed a small amount of blood with a moderate presence of leukocytes and a trace protein. At the end of 2020, the patient underwent magnetic resonance imaging (MRI). The MRI showed a horseshoe kidney with chronic hydronephrosis of the left kidney and a large mass within it centrally with further satellite lesions, which all likely represent UC and associated lymphadenopathy along the para-aortic chain (Figure ). Additionally, a finding of chronic pancreatitis was noted with dilated duct and stone, for which the patient was referred to the gastroenterology department. Furthermore, a bone scan and chest CT were performed, and no significant abnormality or metastasis was found. After a couple of days, the patient presented to the emergency department with non-radiating progressive lower abdominal and left colicky flank pain for three days with hematuria and constipation with fullness. The patient denied any history of fever or vomiting. There were no other genitourinary symptoms, scrotal pain, or change in the level of consciousness. Vital signs were measured and were as follows: blood pressure, 151/71 mmHg; heart rate, 109; respiratory rate, 20; and temperature, 37.1℃. The weight of the patient was 48.4 kg, and height was 166 cm. The chest was clear, while the abdomen was tender over the left side and the left flank area. Lab results were obtained (Table ). Urine culture was performed and showed more than 100,000 CFU/ml of Staphylococcus aureus being isolated. Abdomen and pelvis CT was performed to rule out any intra-abdominal collections, but it was negative. The urology team was consulted for his chief complaint, as his case is already known to them. On examination, they found that the abdomen was soft with lower left quadrant tenderness. They concluded that the pain was less likely to be from the left kidney as the CT findings were stable. Furthermore, based on the urine culture result, the patient was prescribed Bactrim and was given an appointment for admission a week later to perform a flexible ureteroscopy with biopsy. After one week, the patient underwent ureteroscopy with cytology and culture based on his MRI findings. Cystoscopy and retrograde pyelography showed normal bilateral ureters. However, the left kidney was severely dilated, and cloudy urine was noticed from the left ureteric orifice. Thus, culture and cytology were taken; then, a double-J (DJ) stent was inserted (Figure ). Urine culture was positive for S. aureus, and the patient was already on Bactrim. The urine cytology result was negative for high-grade UC, but benign urothelial cells, squamous cells, inflammatory cells, and red blood cells were present. Furthermore, since cancer could not be excluded, the patient was discharged and given an appointment for a left nephroureterectomy. After two weeks, the patient presented to the emergency room complaining of left flank pain for five days with hematuria and constipation. The urology team was again consulted and suspected urinary tract infection at the site of the double J stent. Thus, the patient was admitted, given antibiotics, and was planned for the open left radical nephroureterectomy the following day. The surgery was successfully performed, and samples were sent to the histopathology department. Macroscopic examination showed a fairly-circumscribed, bulging, gray-white mass located mainly in the renal pelvis and mostly replacing the entire kidney. It measured 14 cm in maximum dimension. The mass cut sections were homogenous with areas of necrosis, with a stent present (Figure ). The mass is away from margins and Gerota’s fascia by 2 cm. The remaining kidney parenchyma showed dilated cystic spaces containing multiple brownstones. Furthermore, the resected left renal hilum lymph node measured 7 cm in maximum dimension. Microscopically, the tumor showed urothelial carcinoma of the renal pelvis with dysplasia in the background. In addition, the tumor had a predominance of sarcomatoid differentiation. Furthermore, foci of squamous formation containing keratin formation, and other foci of glands with mucinous and goblet cells lining were seen. The tumor was focally extending to the perinephric fat. Margins were negative; however, the ureteric margin showed dysplasia. The left renal hilum lymph node was positive for metastatic carcinoma. The final diagnosis based on the examination was UC of the renal pelvis with sarcomatoid differentiation (70%) and unusual histological differentiation including squamous (25%), and glandular (<5%) (Figure ). In addition, there was no outside pathology confirmation done. Immunohistochemistry profile was positive for CK7, epithelial membrane antigen (EMA), vimentin, and focally for smooth muscle antigen (SMA). However, it was negative for desmin, cytokeratin (AE1/3), and GATA-3 (Figure ). According to the American Joint Committee on Cancer (AJCC), the pathological stage is pT3N2Mx. After a couple of days, the patient underwent a cystourethrogram, and there was no leak. The patient was eventually discharged in good health the next day and was given an appointment. The plan of the oncology team was to start adjuvant chemotherapy and perform positron emission tomography-CT (PET-CT) for the suspicious distant lymphadenopathy. In addition, CT, cystoscopy, and urine cytology were supposed to be done regularly. However, the patient missed the appointment, so the current status of the patient is unknown.

pmc-8675589-1

A 47-year-old Caucasian male with a history of an aortic valve replacement, Factor V Leiden anomaly, migraines, and a competitive cycling hobby presented with new paracentral blind spots in the right eye following a fishing trip in Florida on August 28, 2014. The patient reported that the vision loss began during a fishing trip when he became dehydrated and had not resolved. He described three to four similar events that occurred previously following episodes of extreme physical activity, however, all resolving. On presentation in 2016, visual acuity was 20/20 in both eyes. No fundus abnormalities were noted. Amsler grid testing revealed two scotomas about 1 and 4 degrees superior nasal to fixation in the right eye. Spectral-domain OCT imaging also revealed several hyperreflective bands in the middle retina of the right eye (Figure ). In Figure , the hyporeflective lesions seen at the border of the fovea inferior temporal and slightly further out were consistent with his subjective superior nasal scotomas on Amsler grid testing. Spectral-domain OCT findings of PAMM were corroborated with the Chief of the Retinal Service at the New York Eye and Ear Infirmary. The patient was diagnosed with findings consistent with PAMM. At that time, no treatment was given. While diagnostic measures were not taken during this patient’s first few described episodes, it was thought that the previous episodes were also consistent with PAMM, given their similar presentation on the Amsler grid testing and symptomatology. In mid-2018, the patient presented with a left-sided visual scotoma that had developed following a recent episode of febrile gastroenteritis. Treatment started with niacinamide OTC minerals, which helped initially over 30-40 minutes. After consulting with his cardiologist, nitroglycerin was prescribed but not taken. The patient was treated with 325 mg of aspirin and 200 mg of ibuprofen every 4 hours, with minimal relief. Aspirin and ibuprofen were administered because they are anti-inflammatory and blood thinners. The scotoma improved over the course of the next week but did not fully resolve. A permanent small scotoma remained. In 2019, the patient began to experience similar symptoms after vigorous exercise. The patient was treated with 0.4 mg nitroglycerin sublingually previously prescribed by his cardiologist. Within 45 minutes, the visual scotoma improved, and within a few hours, it completely resolved. Since this occasion, the patient experienced two subsequent episodes of the development of visual scotomas, both resolving within minutes of the administration of sublingual nitroglycerin. The patient described the lesions as permanent obstructions in the field of vision. They appear as small opaque structures, with a purple hue. The structures blend into the background without a distinct outline. The right eye lesions seen in Figure appeared at about 11 o’clock in the field of the patient's vision and did not move.

pmc-8675591-1

The patient was a 68-year-old female with a G3P2 (G, gravidity; P, parity) pregnancy history who had undergone a pancreatoduodenectomy of the pancreas to remove a tumor (adenocarcinoma) of the duodenal papillae at our hospital five years ago. She underwent computed tomography (CT) during the postoperative follow-up and was suspected of having an ovarian tumor (Figure ); thus, she visited our Department of Obstetrics and Gynecology. Transvaginal ultrasound showed a mass with abundant internal blood flow in the bladder mucosa (Figure ). Although the patient had no urinary tract symptoms, an examination by a urologist was deemed necessary. Accordingly, the patient was referred to the Department of Urology, and urinalysis and urine cytology were performed because early-stage bladder cancer was suspected. Urinalysis showed no hematuria, but urine cytology showed dysmorphic cells that were indicative of a tumor. Cystoscopy revealed a stalked papillary tumor at the apex of the posterior wall of the bladder. Transurethral resection of bladder tumor was performed the following month. A 2-cm papillary tumor was found at the apex of the bladder (Figure ), and the lesion was resected, followed by intravesical chemotherapy administration. The pathological diagnosis revealed that the removed mass was a non-muscle-invasive bladder tumor (transitional cell carcinoma, stage 0a). At the three-month postoperative follow-up, no recurrence was noted. Postoperative CT examination has not yet been performed.

pmc-8675592-1

A 54-year-old Caucasian female, without significant past medical history, unvaccinated for COVID-19 presented with shortness of breath, cough, myalgias, nausea, vomiting, diarrhea, and fevers a week starting with headache. Upon initial evaluation in the emergency room, vital signs were as follows: blood pressure (BP) was 115/77 mmHg, heart rate (HR) was 103 beats per minute (bpm), temperature was 99.0°F, and oxygen saturation was 84% on room air. Lab work showed nasopharyngeal swab positive for SARS-CoV-2, elevated D-dimer (772 ng/mL), elevated international normalized ratio (INR) (1.3), hyperglycemia (117 mg/dL), hyponatremia (130 mmol/L), hypokalemia (3.3 mmol/L), hypochloremia (91 mmol/L), elevated liver enzymes (aspartate aminotransferase {AST}: 157 U/L, alanine aminotransferase {ALT}: 87 U/L), elevated N-terminal pro b-type natriuretic peptide (NT-proBNP) (508 pg/mL), and elevated troponin (13 ng/L). Chest x-ray showed bilateral infiltrates. CT chest with contrast showed bilateral pneumonia. The patient was admitted to the telemetry unit and started on ceftriaxone, azithromycin, dexamethasone, and remdesivir. Initial EKG on admission showed sinus tachycardia and left axis deviation with HR of 101 bpm (Figure ). After three days of remdesivir, EKG was repeated and showed sinus bradycardia with nonspecific intraventricular conduction delay, with HR of 57 bpm (Figure ). Third day after discontinuing remdesivir, the patient developed a transient arrhythmia noted on telemetry which resolved within a few seconds. This prompted nurse to get an EKG which showed normal sinus rhythm (Figure ). Potassium levels were low initially and after repletion potassium normalized on day two of hospital stay. Magnesium levels were normal throughout the hospital stay.

pmc-8675592-2

A 54-year-old Hispanic female with a past medical history of type 2 diabetes mellitus, unvaccinated for COVID-19 presented with shortness of breath, cough, and pleuritic chest pain for four days. Upon initial evaluation in the emergency room, vital signs were as follows: BP was 118/63 mmHg, HR was 80 bpm, temperature was 103.1°F, and oxygen saturation was 91% on room air. Lab work showed nasopharyngeal swab positive for SARS-CoV-2, leukopenia (WBC: 3.8x103/uL), elevated D-dimer (514 ng/mL), hyperglycemia (126 mg/dL), elevated liver enzymes (AST: 224 U/L, ALT: 175 U/L), elevated c-reactive protein (CRP) (129.8 mg/L), and elevated respiratory procalcitonin (0.26 ng/mL). Chest x-ray showed patchy bilateral lung opacities. CT chest with contrast showed moderate bilateral pulmonary infiltrates. The patient was admitted to the telemetry unit and started on ceftriaxone, azithromycin, and dexamethasone. EKG on admission showed normal sinus rhythm with HR of 80 bpm (Figure ). The day following admission, the patient was started on remdesivir. After two doses of remdesivir, the patient developed severe sinus bradycardia with HR of 30-40 bpm, and remdesivir was discontinued (Figure ). She continued to have bradycardia with HR of 45-60 bpm persistently throughout the hospitalization. Potassium and magnesium levels stayed within normal limits for this patient throughout the hospital stay.

pmc-8675594-1

A 59-year-old female, current smoker with 20 pack-years history, with a past medical history only significant for hypertension, gradually developed anorexia, nausea, fatigue, and weight loss. She initially presented to the emergency department with left flank pain and on CT scan of the abdomen was found to have diffuse osteosclerotic lesions in visualized bones. She was then followed up in primary care clinic where workup for an occult malignancy was initiated. There was no palpable mass or axillary adenopathy on breast examination. She had multiple mammograms in the past, some of which had shown suspicious architecture, which was followed up with multiple breast ultrasounds that had revealed benign findings. Mammogram was repeated and was reported benign with BI-RADS 2. Nuclear bone scan was unremarkable. CT chest revealed no pulmonary lesions but there were small mediastinal, submental, and axillary lymphadenopathy and several subcutaneous lesions on the back (one of which was excised and showed inclusion epidermal cyst). Multiple myeloma workup was negative. While the workup was ongoing, the patient started to experience lower back pain associated with weakness of lower extremities, numbness, tingling, and balance issues. She developed constipation as well as urinary incontinence. MRI of the brain and spine redemonstrated similar bony lesions in vertebrae, and also revealed abnormal leptomeningeal enhancement in the brainstem extending along the entire spinal cord (Figure ). Due to this finding, the patient was admitted to the hospital for further workup. Her mentation was normal. Deep tendon reflexes were absent in lower extremities, Babinski was positive bilaterally, and gait was ataxic. Strength was overall 5/5 in upper extremities and 4/5 in lower extremities. Sensations to touch, pain, temperature, and vibration were normal. Cranial nerve examination was normal, and cerebellar signs were absent. Her thyroid-stimulating hormone was normal. Lumbar puncture showed increased protein (1187 mg/dL) and white blood cells 43 cells/uL (lymphocytes 70%, monocytes 30%) in CSF. CSF cytology was negative for carcinoma and showed numerous lymphocytes but the negative finding could also have been due to delay in processing the specimen. Peripheral blood flow cytometry revealed monoclonal B cell lymphocytosis, non-CLL type. Infectious workups including human immunodeficiency virus, rapid plasmin reagent, Epstein-Barr virus, herpes simplex virus, cytomegalovirus, lyme, and cryptococcal antigen were negative. Finally, right iliac bone biopsy was done that revealed metastatic adenocarcinoma, GCDFP-15 and GATA-3 positive, indicative of breast carcinoma. Estrogen (ER) positive (90%), progesterone (PR) positive (40%), human epidermal growth factor receptor 2 (HER-2)/neu non-amplified IHC 1+, and Ki-67 10%. Tumor markers CA 15-3, CA 27.29, and carcinoembryonic antigen were raised at 85 U/mL, 84.2 U/mL, and 7.1 ng/mL, respectively. She was started with letrozole initially with dexamethasone taper, followed by palliative radiation therapy. The radiation was given to lumbosacral spine with 30 Gy in 10 fractions, which improved her lower back pain. After completion of the radiation therapy, abemaciclib was added to letrozole as the systemic therapy. She showed excellent response to the treatment and her previously seen leptomeningeal enhancements are no longer seen in the follow-up scans (Figure ). She does continue to have sclerotic changes in her bones; however, she deferred from bone-targeted therapy. The patient has been on abemaciclib and letrozole for about two years, her neurological symptoms have improved, and now she has a good quality of life. She is able to walk half a mile on flat ground and is able to perform light household chores.

pmc-8675595-1

A 33-year-old female with no prior medical comorbidities, who recently gave birth to a healthy girl child four months ago, was brought to the emergency department with sudden onset weakness of both upper and lower limbs that started four days prior and rapidly progressed to a state of quadriplegia. She was conscious and obeyed simple commands with eyes and mouth; however, she had severe dysarthria. She had bilateral facial palsy and bulbar palsy. She had flaccid, hyporeflexic, pure motor quadriplegia with limbs showing only a subtle withdrawal flicker to pain. MRI of the brain revealed hyperintensity in the central pons in diffusion-weighted images (Figure ), T2-weighted images (Figure ), and fluid-attenuated inversion recovery (FLAIR) images (Figure ) without abnormal contrast enhancement (Figure ), consistent with central pontine myelinolysis (CPM) (Figure ). The biochemical analysis showed hypernatremia while the remaining electrolytes were normal. The rest of the blood workup was unremarkable. Relatives denied an antecedent history of hyponatremia with rapid correction. The patient was started on sodium correction and was given five days intravenous (IV) pulse methylprednisolone 1 g/day to stabilize the blood-brain barrier. The patient recovered significantly to normal power. She was then considered to have idiopathic hypernatremic osmotic demyelination and was discharged with a modified Rankin Scale score (mRS) of 0. One year later, she presented to the neurology department with a one-week history of generalized fatigue, diffuse myalgias, and three days history of rapidly progressive weakness of all four limbs making her wheelchair-bound one day before the presentation. Her initial vital signs were unremarkable. She was noted to have a pure motor flaccid symmetric quadriparesis with proximal more than distal weakness and generalized hyporeflexia. Clinical examination of other systems was normal. Nerve conduction studies (NCS) done on day three of onset of weakness demonstrated reduced compound muscle action potential (CMAP) amplitudes of bilateral tibial and peroneal nerves with absent F waves and H reflexes. CMAP of tested nerves in upper limbs showed preserved amplitudes with normal distal latency and absent F waves. There were no conduction blocks. The sensory conduction study of all the tested nerves in all four limbs was normal. Cerebrospinal fluid (CSF) analysis did not show albumin-cytological dissociation. Therefore, acute motor axonal neuropathy (AMAN) variant of Guillain-Barré syndrome (GBS) or hypokalemia-related electrophysiological abnormalities were considered. A basic metabolic panel revealed severe hypokalemia (potassium 2.2 mEq/L). Arterial blood gas (ABG) and 24-hour urine analysis showed metabolic acidosis, consistent with renal tubular acidosis type-1 (distal). Autoimmune workup was positive anti-SSA/Ro autoantibodies. The biopsy of the minor salivary gland was pathognomonic. The patient was diagnosed with pSS according to the new classification criteria proposed by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). Overall clinical, electrical, and biochemical data suggest the presence of renal tubular acidosis with secondary hypokalemia-related quadriparesis due to pSS. The patient was given intravenous (IV) potassium supplementation through a peripheral vein at a rate not exceeding 10 mEq/hour and subsequently was shifted to oral liquid formulation in the form of a syrup. Oral sodium bicarbonate supplementation was given at a dose of 1 mEq/kg/day for renal tubular acidosis. With potassium correction, there was a rapid recovery in the power of all four limbs within 24 hours of admission. The patient was initiated on 1 mg/kg/day of oral prednisolone and was referred to a rheumatologist for further management. She remained asymptomatic on her six-month follow-up.

pmc-8675596-1

A 67-year-old female with a past medical history of chronic obstructive pulmonary disease and history of long-term tobacco abuse, who recently quit smoking, presented with shortness of breath, cough, myalgias, and malaise for one week. The patient had received two doses of Pfizer COVID vaccine, with the second dose in February 2021. In the ER, her vital signs were blood pressure (BP) 120/71, heart rate (HR) 78 bpm, respiratory rate (RR) 20 breaths/min, oxygen saturation 85% on room air, and afebrile. Laboratory assessment on admission is in Table . Nasopharyngeal swab for SARS-CoV-2 was positive. Chest X-ray on admission shows mildly patchy bibasilar pulmonary infiltrates and a calcified pulmonary nodule in the mid-right lung (2.0 cm) (Figure ). The patient was admitted to the general medical ward and started on 6 L per minute of supplemental oxygen via nasal cannula, remdesivir, dexamethasone, furosemide, azithromycin, and enoxaparin for venous thromboembolism prophylaxis. Despite multiple measures, the patient did not improve, requiring more aggressive management. Repeat chest X-ray showed slight interval improvement of bilateral pulmonary infiltrates and needed 4-5 L per minute via nasal cannula (Figure ).

pmc-8675596-2

A 58-year-old female with no significant past medical history presented with shortness of breath, fever, and cough for three days. The patient received two doses of the COVID vaccine, with the second dose in May 2021. In the ER, her vital signs were BP 105/96, HR 131 bpm, RR 20 breaths/min, oxygen saturation of 96% on room air, and febrile with a temperature of 102.0°F. Laboratory assessment is in Table . Nasopharyngeal swab for SARS-CoV-2 was positive. CT chest on admission shows no acute infiltrate and nonspecific nodules (Figure ). The patient was admitted to the general medical ward and started on antibiotics, dexamethasone, and remdesivir. The patient developed worsening hypoxia on Day 2, and CT chest showed widespread airspace disease throughout the lungs (Figure ). The patient required 4-5 L per minute via nasal cannula.

pmc-8675596-3

An 84-year-old female with a past medical history of hypertension presented with weakness, dry cough, and shortness of breath for four days. The patient had received two doses of the COVID vaccine, with the second dose in March 2021. In the ER, her vital signs were BP 133/93, HR 103 bpm, RR 22 breaths/min, oxygen saturation of 96% on 40 L per minute of supplemental oxygen via high-flow nasal cannula, and afebrile. Laboratory assessment is in Table . Nasopharyngeal swab for SARS-CoV-2 RNA was positive. Chest X-ray on admission shows worsening right pleural effusion with new opacity obscuring the lower two-third of the right lung and a new pleural-based opacity in the left upper lobe (Figure ). CT chest with contrast shows large right pleural effusion and associated right basilar consolidation and abdominal ascites. The patient was admitted to the telemetry unit and started on methylprednisolone, piperacillin-tazobactam, remdesivir, and baricitinib. The patient clinically deteriorated on Day 2 and was transferred to the intensive care unit for thoracentesis and possible intubation. Thoracentesis removed 1.95 L of bloody, serosanguineous fluid obtained, with partial resolution of the effusion (Figure ). On Day 3, the patient developed septic shock, florid renal failure, and lethargy and was started on intravenous fluids and norepinephrine drip. Chest X-ray showed near-complete opacification of bilateral lung fields and subsequently was intubated. On Day 4, tense ascites were noted and the patient underwent paracentesis, which removed 4.25 L of bloody, serosanguinous fluid. Renal replacement therapy started. The patient was deemed to have a guarded prognosis with multiorgan failure.

pmc-8675596-4

A 48-year-old male with a past medical history of type 2 diabetes mellitus and end-stage renal disease on hemodialysis presented with shortness of breath for three days. The patient was transferred from an outside facility where he was found to be hypoxic, saturating 79% on room air, chest X-ray showing infiltrates, and a positive nasopharyngeal swab for SARS-CoV-2 RNA. The patient had received two doses of the COVID vaccine, with the second dose in March 2021. Upon arrival to the general medical ward, the patient's vital signs were BP 132/79, HR 84 bpm, RR 18 breaths/min, oxygen saturation of 100% on 2-4 L per minute of supplemental oxygen via nasal cannula, and afebrile. Laboratory assessment is in Table . The patient was quickly weaned to room air, with SpO2 of 94-98%; hence, only supportive care was provided for COVID-19. On Day 1, the patient was found to have a right foot wound infection and was started on intravenous vancomycin and piperacillin-tazobactam. On Day 2, the patient was found to be hypoxic, put on 5 L per minute of supplemental oxygen via nasal cannula, and started on dexamethasone and remdesivir. Because of end-stage renal disease, the patient did not qualify for baricitinib. On Day 4, the patient required 10 L per minute of supplemental oxygen via high-flow nasal cannula, which he needed until Day 12, when we could start weaning down the supplemental oxygen over the next 3-4 days until Day 15 to room air. On Day 17, the patient was put back on 2 L per minute of supplemental oxygen via a nasal cannula which quickly escalated to 15 L on a nonrebreather mask within 2-3 hours, requiring the patient to get transferred to the intensive care unit on Day 18. At this time, he was put on bilevel positive airway pressure (BiPAP) with 40 L per minute of supplemental oxygen. Chest X-ray showed extensive diffuse airspace infiltrates, which significantly worsened from one week prior (Figure ). He was dialyzed without improvement from a respiratory standpoint and then intubated on Day 19. Subsequently, the patient was restarted on dexamethasone and broad-spectrum antibiotics despite completing 14 days' worth previously.

pmc-8675599-1

A 23-year-old Caucasian male with a history of exercise-induced asthma presented to the emergency department complaining of left-sided chest pain which started two days after receiving the second dose of the mRNA-1273 Moderna vaccine. The patient described the pain as sharp, intermittent with radiation to the left upper back and left arm with 10/10 severity and worsening with deep inspiration. Fever and chills were also present. The patient did not report any recent history of tick bites, upper respiratory symptoms, paroxysmal nocturnal dyspnea (PND), orthopnea, arthralgias or rashes. On physical examination the patient was in no distress, with normal vital signs, normal S1/S2 heart sounds without any murmurs, rubs, or gallops and no jugular vein distention (JVD). There was no palpable tenderness of the chest wall. The lungs were clear to auscultation. There was no pitting edema in the lower extremities. Diagnostic testing revealed elevated troponin T of 475ng/L (<22ng/L) which trended upward reaching a peak of 910ng/L (<22ng/L). Initial electrocardiogram (ECG) showed right axis deviation with left posterior fascicular block without any ST elevations as well as premature atrial contractions (PACs) in trigeminy (Figure ). A bedside ultrasound showed trace pericardial effusion. CT angiography (CTA) of the chest was negative for pulmonary embolism (PE). Lyme serology, antinuclear antibodies (ANA) and respiratory viral panel were negative and thyroid stimulating hormone (TSH) was normal. Pertinent leukocytosis of 11.09 K/ul (3.8-10.5 K/Ul) with absolute neutrophil count of 8.09 K/uL, elevated erythrocyte sedimentation rate (ESR) of 37mm/hr (0-15mm/hr), c-reactive protein (CRP) of 11.6mg/L (<4.0mg/L). Urine toxicology was positive for recreational marijuana drug use but negative for cocaine use. Transthoracic echo (TTE) revealed abnormal motion and increased thickening of the septal wall with preserved ejection fraction (EF) of 65% and normal diastolic function (Video ). Trace pericardial effusion was also noted. Based on the patient’s clinical presentation, ECG, cardiac markers and TTE findings a presumptive diagnosis of peri-myocarditis was made. We did not pursue cardiac MRI since the patient had clinically improved within 48 hrs. He received aspirin 325 mg once followed by indomethacin 50mg twice a day and discharged on day three to complete a total of two weeks indomethacin and three months of colchicine 0.6mg daily. Complete resolution of his symptoms, normalization of troponins and ECG, was demonstrated within two weeks during follow up. At his 60-day follow-up visit, TTE confirmed resolution of the wall motion abnormality and pericardial effusion and he remains completely symptom free at 128 days.

pmc-8675801-1

A 35-year-old male presented with a foreign body in his left ear caused by a trauma to the left parietal area by a fishhook. The patient was in a boat on a fishing trip when the fishhook accidentally pierced his upper neck behind the left auricle and pierced the auricle of the left ear. On examination, the patient was conscious and oriented and no bleeding, swelling, hematoma or bruises were noticed. Vital measurements and systemic review revealed normal findings. The patient received an intramuscular injection of 0.5 mL tetanus toxoid adsorbed vaccine and was referred for surgical assessment and foreign body removal. Under local anesthesia, the triple needle fishhook was removed and cut by a bone nipper from left pinna and post-auricular area (Figure ). The lacerated wound was stitched by 05 Ethilon suture, left mastoid dressing was applied and the patient was discharged after prescribing per-oral cefuroxime and diclofenac for five days. Two weeks later, the patient returned to the hospital for follow-up. On examination, left pinna and post-auricular area were normal. However, a small, non-tender, firm 2 x 2 mm subcutaneous swelling was noticed below the ear lobule. Amoxicillin/clavulanate and diclofenac sodium were prescribed, and the patient was discharged. In the follow-up visit two months after the injury, the patient was assessed for a localized small, non-tender, 2 x 2 mm parotid swelling at the angle of mandible on the left side. The swelling appeared after the removal of the foreign body two months ago and did not get resolved. Ultrasound (US) of the neck showed a linear hypoechoic focus in the superficial parotid gland extending to the subcutaneous tissue (Figure ). The presence of scar or granulation tissue was suspected and no focal mass lesions were detected. In addition, a few oval-shaped, non-specific cervical lymph nodes were noted with preserved fatty hilum and a short axis diameter of 0.8 cm. Magnetic resonance imaging (MRI) confirmed the presence of a post-traumatic scar and granulation tissue involving the superficial part of the left parotid gland and extending to the subcutaneous soft tissue (Figure ). The presence of bilateral non-specific lymph nodes was noted in both cervical regions.

pmc-8676056-1

An 18-year-old male patient presented to the emergency department with right hip pain for two weeks. Examination revealed pain and mild to moderate tenderness in the right hip joint. The range of motion was decreased, and trying to initiate movement caused severe pain to the extent that the patient could not walk for gait assessment. Past history revealed similar but less severe episodes for the last four years. There was no history of fever, skin rash, or acne. His inflammatory laboratory investigations, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), were within the normal limits. X-rays of the pelvis and right thigh were unremarkable except for a small lucency in the right greater trochanteric region (Figure ). Subsequently, an MRI of the right thigh showed trochanteric bursa effusion and right hip joint synovitis (Figures , ). Non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol were started for the management, and the patient showed excellent improvement for the first three months. He remained well for four months, after which he developed swelling of the right sternoclavicular joint. X-ray of the joint and laboratory investigations were found to be normal (Figure ). Due to the previous history of the right hip joint, the lesion was investigated further with MRI (Figures , , ). A patchy area of hyperintensity on T2 and hypointensity on T1 images close to the sternoclavicular junction was observed. On post-contrast images, there was a mild accentuated heterogeneous enhancement. Traces of fluid was also noted in the joint space, and marrow edema was seen along the articular margin and body of the sternum. MRI also showed subcutaneous edema and changes related to cellulitis in the overlying soft tissues. Clinical history and imaging data were suggestive of SAPHO syndrome. The patient was again started on paracetamol and NSAIDs based on the excellent previous response. At the one-month follow-up, the swelling was found to have improved. The patient was continued on the therapy and his symptoms resolved within three months.

pmc-8676056-2

A 35-year-old male patient presented with a six-month history of pain in the anterior chest and neck. His pain initially had been mild but had become severe in the last three weeks. He was afebrile and did not have any constitutional symptoms. On examination, marked tenderness of the right sternoclavicular joint was noted. Initial laboratory investigations, tuberculosis workup, and chest X-rays were unremarkable. However, further study with MRI revealed subchondral bone marrow edema and enhancement involving the medial end of the right clavicle. In addition, mild effusion of the right sternoclavicular joint and surrounding soft-tissue edema was also seen (Figure , ). Given the patient's radiological and clinical findings, suspicion of SAPHO syndrome was raised. He was given an initial trial of paracetamol and NSAIDs and he showed remarkable improvement on his monthly follow-up visits. Though a biopsy was offered, the patient refused to undergo one and has shown no relapse to date thanks to the dramatic response to NSAIDs.

pmc-8677335-1

A previously healthy 49-year-old female with a past medical history of well-controlled hypertension and body mass index (BMI) of 30.37 kg/m2 presented to the emergency department with altered mental status, abdominal pain, hematemesis, and hypotension. According to family, the patient complained of abdominal pain earlier that morning and was later found at home minimally responsive and recurrently vomiting blood. In the emergency department, the patient’s vitals included a blood pressure of 94/50 mmHg, a temperature of 87.1 Fahrenheit, and a respiratory rate of 34 breaths per minute. The patient was intubated for airway protection. She received 5L of fluid as well as one unit of packed red blood cells for suspected large fluid volume loss. Esophagogastroduodenoscopy was performed and was remarkable for a Mallory-Weiss tear with portohypertensive gastropathy. This was thought to be caused by the repeated vomiting reported by her family. CT scan showed peripancreatic edema and fat stranding, consistent with acute pancreatitis (Figure ). A repeat CT scan was done to evaluate the progression of her pancreatitis, which showed worsening pancreatitis with developing ascites. Labs were remarkable for a glucose up to 955 mg/dL, hemoglobin A1c (HgbA1c) of 13.7%, and a triglyceride level up to 1608 mg/dL (Table ). The patient was then placed on an insulin drip for her significantly elevated blood glucose. After her glucose normalized, she was continued on an insulin drip until her triglycerides dropped below 500 mg/dL. The patient was then downgraded to the general medical floor and discharged after being able to tolerate a regular diet without significant pain or discomfort.

pmc-8690961-1

A 53-month-old Sudanese female presented with progressive bilateral breast enlargement and accelerated growth since the age of 9 months. Her family had sought medical advice several times in different primary health care facilities and were reassured. She had no vaginal bleeding and no pubic or axillary hair. Examination showed a well-looking girl, vitally stable with normal blood pressure. Her weight was 17 kg (50th centile) and height 108 cm (90th centile) using the Centers for Disease Control and Prevention growth chart. Mid-parental height was 175 cm and predicted adult height was 167 cm using the JM Tanner formula. No previous documented follow-up growth data were available. Her Tanner staging was A1, P1, and B3. She had reddish mucoid vagina. She had no clitoromegaly, acne, hirsutism, or palpable abdominal mass (Table ). Left wrist X-ray revealed a bone age of 8 years. The hormonal evaluation using fluorometric enzyme immunoassay showed basal luteinizing hormone of 3.1 mIU/L, which increased to 8.8 mIU/L 45 minutes post-gonadotrophin-releasing hormone stimulation. Elevated levels of estradiol E2 29,000 pg/ml (5–15 pg/ml), and dehydroepiandrosterone sulfate 90 ng/mL (2.3 ng/mL), with normal early morning cortisol level 16 ng/mL (7–28 ng/mL). Due to financial difficulties, we did not measured the follicular-stimulating hormone level. Abdominal ultrasound revealed a right-sided hypoechoic suprarenal mass, an ovarian volume of 1.8 cm3, uterine volume of 3 cm3, and endometrial thickness of 1.2 cm. The abdominal CT scan showed a 25 × 22 mm well-defined rounded focal lesion with a smooth outline, at the level of the right adrenal gland with homogeneous attenuation, HU-7 on a noncontrast scan, and no evidence of local tissue invasion (Fig. ). The left adrenal gland and ovaries were normal. Brain magnetic resonance imaging was done to exclude a central cause of precocious puberty and was normal. Complete hemogram, liver, and renal functions were normal. A diagnosis of an estrogen-secreting right adrenocortical tumor was made, and we referred the patient to surgery. During laparotomy a 3 cm diameter tumor in the right adrenal gland was completely excised. The histopathological examination showed well-circumscribed tumor forming nests with trabeculae and sheets of polygonal cells with eosinophilic cytoplasm. The tumor was not infiltrating the capsule, with no mitosis, atypia, or necrosis (Wieneke index score = 0). Findings suggestive of benign adrenal cortical adenoma. The postoperative evaluation revealed normal cortisol and dehydroepiandrosterone sulfate. Estradiol E2 40 pg/mL was consistent with secondary central precocious puberty, so the patient was started on monthly gonadotrophin-releasing hormone agonist, with a regular follow-up plan for the possibility of recurrence of adrenal adenoma. Six months after the operation, the patient was well and compliant to monthly gonadotrophin agonist injections. She showed partial regression of her secondary sexual characters and a growth velocity of 5 cm/year. The abdominal CT scan was normal with no evidence of recurrence.

pmc-8691080-1

A 66-year-old male with back pain and cough for two weeks was admitted to the First Hospital of Jiaxing on 8 August 2019. A thoracic computed tomography (CT) scan revealed that the malignant tumor on the left upper lobe was complicated by distal obstructive inflammation, the enlargement of the left hilar and mediastinal lymph nodes, and the multiple bone metastases on 25 August 2019 (Fig. A). Immunohistochemical (IHC) results of the posterior iliac bone marrow biopsy specimen showed the positive expression of CD3, CD20, CD34, CD235a, and NPO, and the negative CD61 expression. IHC results of an endoscopic biopsy specimen of the bronchial mucosa on the upper left lobe showed the positive expression of TTF1, CK7, NapsinA, Ki67, CK, and EMA, and the negative expression of CK5/6, P40, CgA, Syn, and CD45 on 6 September 2019. Histopathologic observations showed infiltration of atypia cells in mucosal and fibrous tissues. The detection tools of pathology and cytology included automatic IHC staining (BenchMark XT, Roche, The United States), digital slice scanner, image analysis software (Pannoramic 250, 3DHistech, Hungary), and microscope (Eclipse Ci-S, Nikon, Japan). Finally, the patient was diagnosed with stage IVb lung adenocarcinoma combing with bone metastases. To seek potential therapeutic opportunities, the FFPE tissue and control sample (white blood cell) of the patient were detected using a 733-gene NGS panel in a College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) certificated lab. Sequencing reads were mapped against the hg19/GRCh37 genome, and duplicate reads were removed, followed by variants calling in targeted regions using an in-house developed bioinformatics algorithm. The algorithm utilized a filtering model containing background error correction, strand bias, base quality, mapping quality, short tandem repeat regions, and low-quality mapping ratio 25 []. The NGS analysis results indicated that the patient had an EGFR exon 19 p.L747_S752del somatic mutation with an allelic fraction of 73.19% and TP53 p.H179L germline mutation. Besides, the whole chromosome 7 and 5q deletion were detected using NGS-based copy number variation (CNV) analyses (Fig. ), which were classical abnormalities associated with MDS. According to the clinical inquiry, the patient was a farmer by occupation, which means that he has long been exposed to certain chemicals such as pesticides, fertilizers, and solvents containing benzene. In addition, he smoked for 40 years. Taking all these findings together, we suspected the patient with secondary MDS. The results of the physiological blood indexes and the bone marrow aspiration test showed a decrease of platelet counts and the elevation of myelocyte counts. The proportion of blast was 5%, and the morphology of the cells presented the characteristics of MDS, which further confirmed our speculation (Fig. and Additional file : Fig. S1). In terms of treatment, the EGFR-positive mutation patient was administered with gefitinib starting from 20 August 2019. Due to decreasing platelet counts, azacitidine was administrated for four courses of treatment. However, the thrombocytopenia had not been significantly improved, and the size of the maximal tumor in the lung lesion did not decrease after seven months’ treatment (Fig. B). On 10 April 2020, a pathological report showed the infiltration of poorly differentiated cancer cells into the fibrous tissue. IHC results suggested the neuroendocrine tumor, in which small cell carcinoma and atypical carcinoid tumor accounted for about 40% and 60%, respectively. On 7 April and 28 April 2020, considering positive PD-L1 expression and high tumor mutation burden (TMB) in the tissue sample, the patient was administrated with toripalimab (a PD-1 inhibitor) and bevacizumab. Platelet counts returned to near-normal levels gradually, and the tumor lesion shrank obviously (Fig. ). It was concluded that the patient reached a partial response (PR) (Fig. C). The progression-free survival was four months.

pmc-8692721-1

A 22-year-old male presented in the emergency department with acute onset of swelling and redness over the right side of the neck and chest wall for the last three days. He had features of septicemia such as drowsiness or Glasgow Coma Scale score of 11/15, respiratory rate of 26 breaths per minute, pulse rate of 130 beats per minute, blood pressure of 84/56 mmHg, and urine output of 15 mL/hour. He had no history of chronic disease, drug reaction, trauma, unknown bite, or significant familial disease. Blood investigations revealed low hemoglobin of 7.6 g/dL, raise leukocyte count of 28000/mm3, low albumin of 2.2 g/dL, raised serum creatinine of 2.23 mg/dL, serum urea of 174 mg/dL, and low sodium of 125 mEq/L. Serological markers including erythrocyte sedimentation rate (95 mm/hour) and procalcitonin (25.2 ng/mL) were higher. X-ray of the chest was grossly normal (Figure ), and contrast-enhanced computed tomography (CECT) of the neck revealed irregular, well-defined, hypodense, non-enhancing area in the right parotid gland with extension into the neck spaces, larynx, and subcutaneous planes (Figure ). CECT of the chest revealed mild effusion in bilateral pleural space secondary to acute infection and no evidence of lymphadenopathy or osteomyelitis (Figures , ). Ziehl-Neelsen (ZN) staining from pleural fluid was negative for acid-fast bacillus (AFB bacilli). The patient was managed in the intensive care unit with ventilator support due to acute respiratory distress syndrome. He was diagnosed with acute progressive necrotizing fasciitis with multiple organ dysfunction syndromes due to an unknown cause of septicemia. He underwent multiple aggressive debridements of the neck and chest wall (Figure ). The cartridge-based nucleic acid amplification test (CBNAAT) and ZN staining revealed positive mycobacteria and AFB bacilli for pathological tissue. Therefore, the pus collected in the parotid region and neck space was likely secondary to tubercular infection. A split-thickness graft was applied in multiple fractions after three weeks of anti-tubercular chemotherapy. The patient had a long hospital stay due to the difficult location and complexity of the ulcer over the neck. He was followed up for six months in good clinical condition after discharge.

pmc-8693491-1

A 41-year-old Japanese woman presented to our clinic with a 4 month history of bilateral groin pain and right buttock pain. Her right hip was more painful than her left hip. There was no history of trauma, alcohol abuse, or steroid use. Her medical history included iron-deficiency anemia diagnosed 2 years earlier, after which she had been on iron supplements. She had no fracture episodes, including fragility fractures. Her height, body weight, and body mass index were 155 cm, 42 kg, and 18.7 kg/m2, respectively. She was able to walk for approximately 10 minutes without a stick, albeit at a slow speed. Limitations in the passive motion of her bilateral hip joint were observed thus: flexion, 100°, internal rotation 5°, external rotation 15°, and abduction 20°, on both sides. She was able to perform a straight-leg raise of the right limb with substantial pain. The neurovascular status of both lower extremities was intact. The Japanese Orthopaedic Association scoring system for the evaluation of hip-joint function (JOA hip score) was 46 points for her right hip and 56 points for her left hip. The score was based on a total of 100 points, comprising 40 for pain, 20 for range of motion, 20 for the ability to walk, and 20 for activities of daily living []. Standard radiographs of both hips (Fig. a–c) demonstrated no characteristic findings such as the crescent sign, sclerotic band pattern, and collapse of the femoral head, and no joint space narrowing was seen in either femoral head. MRI of both hips (Fig. d, e) presented a low signal line in the subchondral region of the femoral head in the T1 weighted image and high signal region in almost all of the femoral head in the short tau inversion recovery (STIR). The oblique axial views of the proton density-weighted image showed a low-signal sinuous line in the anteromedial region of the femoral head (Fig. ). Dual-energy X-ray absorptiometry (DEXA) values were low in both femoral necks. Bone mineral density was 0.909 g/cm2 (T-score –0.9, Z-score −0.8) in the lumbar spine, 0.594 g/cm2 (T-score −1.8, Z-score −1.4) in the right femoral neck, and 0.529 g/cm2 (T-score −2.4, Z-score −2.0) in the left femoral neck. Laboratory findings were as follows: C-reactive protein (CRP) 0.03 mg/dl (normal range: 0–0.5 mg/dl); alkaline phosphatase 608 IU/l (40–150 IU/l); calcium 9.0 mg/dl (8.4–10.2 mg/dl); albumin 4.4 g/d (3.9–4.9 g/d); and hemoglobin 9.7 g/dl (12–16 g/dl). Bone turnover markers were as follows: tartrate-resistant acid phosphatase 5b (TRACP-5b) 463 mU/dl (premenopausal normal range: 120–420 mU/dl) and total procollagen type 1 N-terminal propeptide (Total P1NP) 72.7 ng/ml (26.4–98.2 ng/ml). We diagnosed bilateral osteonecrosis of the femoral head and classified it as stage 1 in both femoral heads, according to the Association Research Circulation Osseous (ARCO) classification []. The patient was instructed not to take as much weight as possible using sticks on the right side. Her symptoms improved immediately. However, 6 months later, her symptoms increased slightly without any traumatic episodes. Radiographic findings indicated almost no change (Fig. a–c). However, a slight signal change in the medial subcapital region was observed in the MRI scan (Fig. d, e). Her pain gradually increased thereafter, and 10 months after her first visit, walking became difficult. The JOA hip score decreased to 34 points in both hips; still, no changes could be observed in the radiograph (Fig. a–c). MRI of both hips showed a nondisplaced subcapital fracture on the medial side of both femoral necks, with bone marrow edema around the fracture (Fig. d, e). Because the cause of the fractures was not identified, the DEXA and bone turnover markers were measured again, and 25-hydroxy (OH) vitamin D was measured for the first time. All DEXA values decreased. The bone mineral density was 0.849 g/cm2 (T-score −1.5, Z-score −1.2) in the lumbar spine, 0.527 g/ cm2 (T-score −2.4, Z-score −2.1) in the right femoral neck, and 0.490 g/cm2 (T-score −2.7, Z-score −2.4) in the left femoral neck. TRACP-5b level increased to 607 mU/dl, and total P1NP decreased to 52.7 ng/ml. Her 25(OH) vitamin D level was 11.1 ng/dL and she was diagnosed with vitamin D deficiency. Based on the above results, our diagnosis was bilateral stress fracture of the femoral neck secondary to osteonecrosis of the femoral head. The patient underwent internal fixation of both hips with sliding hip screws (Dual SC screw system; Kisco, Kobe, Japan) to stabilize the stress fractures. In addition, the reaming performed before inserting of the sliding hip screw served as core decompression for the femoral heads [, ]. The specimens obtained from the reaming were examined histologically. Definitive findings of osteonecrosis such as bone marrow necrosis and loss of osteocyte nuclei in the femoral heads were observed (Fig. ). Postoperative radiographs showed no evidence of displacement of the fractures (Fig. ). We administered eldecalcitol 0.75 μg per day orally for vitamin D deficiency, and daily subcutaneous injections of teriparatide acetate. In the immediate postoperative period, the patient began to bear weight as tolerated with the use of an assistive device bilaterally. One month postoperatively, she was able to walk without pain and used a cane part time. She eventually regained full walking ability without a cane 3 months after surgery. Furthermore, her JOA hip score improved to 90 points in both hip joints at 5 months after surgery. Radiographs showed no evidence of recurrent stress fracture in the femoral neck or progression of osteonecrosis (Fig. ). Sequential oblique axial MRI showed that the necrotic region of the femoral head had decreased 5 months after surgery (Fig. ).

pmc-8693492-1

A 14-year-old male adolescent presented to the emergency department with subfebrile temperatures for 1 week and localized pain in his right popliteal fossa for 3 days. Prior to the onset of these symptoms, he had been immobilized for several days following a minor sports injury. The adolescent had no permanent medication and no prior medical history except for an asymptomatic ATD diagnosed at the age of six by functional antithrombin assay (antithrombin activity of 57%, age adapted reference: 77–125%). Since at that time, there were no clinical signs of thrombosis, the diagnosis of ATD did not lead to any therapeutic consequences. Screening for ATD at this early age had been carried out on parental request, as his mother was diagnosed with ATD in her early adulthood. Interestingly, his mother now reported that she had very recently been diagnosed with IVCA (preexisting chromogenic test results showed an antithrombin activity of 50% for the mother, the age adjusted reference range being 80 to 130%). The coexistence of other hereditary thrombophilic disorders in our patient and his mother (protein S deficiency, protein C deficiency, factor V Leiden mutation, prothrombin-mutation, antiphospholipid syndrome) was ruled out by respective laboratory analyses. Laboratory blood analysis in the emergency department showed markedly elevated D-dimers of 25 mg/l FEU (reference: < 0.5 mg/l FEU) and of C-reactive protein (CrP) of 184 mg/l (reference < 5 mg/l). Antithrombin activity on admission was reduced to 61% (age adjusted reference 83–118%). A vascular ultrasound examination upon admission confirmed the clinically suspected thrombosis of the right lower extremity involving the external iliac, common and superficial femoral as well as the popliteal vein. The ultrasound examination of the left lower extremity veins did not give evidence of thromboses upon admission. The patient was treated with continuous infusion of unfractionated heparin at a therapeutical dose including several bolus administrations and antithrombin (4000 IE within the first 36 h) was substituted reaching levels in the target range between 80 and 100%. Subsequent monitoring of the activated partial thromboplastin time (aPTT) showed an insufficient response to heparin treatment (aPTT was 29 s before the administration of heparin and did not exceed a maximum value of 33.6 s during heparin treatment). The anticoagulative therapy was therefore switched to direct thrombin inhibition by argatroban at a dose of 1.5–2.0 μg/kg/min, which led to target aPTT values of 50–60s. Due to the elevated CrP levels and subfebrile temperatures, empirical antibiotic treatment with intravenous cefuroxim was initiated. A magnetic resonance imaging (MRI) scan on day three confirmed a complete DVT of the right lower extremity, and now additionally extended thromboses of the left lower extremity and thrombosis of both iliac vessels. Furthermore, it revealed an occlusion of the inferior vena cava (IVC) with prominent venous lumbar collaterals, suggestive of IVCA. Surrounding the lumbar vertebrae, several of these collaterals appeared to be fully thrombotic, which was confirmed by angiography (Fig. A). The following day, a catheter-directed local thrombolysis using recombinant tissue plasminogen activator (rt-PA) at a daily dose of 0.25 mg/kg was initiated in both extremities and carried out for a total of 48 h. For the right leg, an additional ultrasound-accelerated thrombolysis using the EKOS® system was performed. During hospitalization, the anticoagulative therapy was switched from argatroban to the vitamin K antagonist phenprocoumon with a target International Normalized Ratio (INR) of 2.0–2.5. Oral anticoagulation will most likely be continued lifelong due to the combination of extended multilocal thromboses with underlying ATD, as well as IVCA, which in itself is a risk factor for thrombosis. The patient was discharged on day eight after hospital admission. An ultrasound examination upon discharge showed full recanalization of the femoral and iliac veins of both legs. During a routine follow-up 1 week later, the patient presented free of any clinical complaints. However, despite continued oral anticoagulation since hospital discharge, vascular ultrasound now revealed extended re-thrombosis of both the right and left pelvic axis and the right lower extremity, thus leading to a second hospital admission and re-induction of therapy with both intravenous antithrombin and catheter-directed thrombolysis. Recanalization of the right lower extremity and pelvic axis was subsequently achieved, whereby IVC occlusion was confirmed (Fig. B). However, the left pelvic vessels remained thrombotic even after 5 days of catheter-directed thrombolysis. Surprisingly, one of the angiographies allowed for location of the occluded area of the IVC by rendezvous-technique between the superior and inferior vena cava, which prior to this had been thought to be atretic (Fig. C). The vessel was successfully recanalized using balloon dilation and subsequent stenting (Fig. D). Throughout the clinical stay, the patient’s oral anticoagulation with phenprocoumon was intensified to a new target INR of 2.5–3.0 in order to prevent re-thrombosis. The patient was discharged from hospital on day seven after admission. Regular follow-up examinations at our outpatient clinic did not give evidence for any new thrombotic events to date (time since first occurrence of thrombosis was 9 months). Concerning the thrombotic left iliac vessels, a follow-up angiographic intervention relying on special equipment was performed, but recanalization could not be achieved. Fortunately, the IVC of the patient’s mother could also be recanalized by angiographic intervention.

pmc-8693538-1

The patient is a 68-year-old retired male, born in Aloag and resident of Tambillo (a rural locality in the vicinity of the capital of Ecuador, Quito). His medical history was significant only for being a heavy smoker until 2016 (with a calculated 20 pack-year), copious alcohol consumption every 15 days until 2010 and a myocardial infarction in 2015, successfully treated with stenting, acetylsalicylic acid and atorvastatin, a medication that he continues until this day. There is no family history of cancer or other pathologies of interest. In February 2020, he presented dysesthesias in the right hemithorax associated with pain and a mass-like sensation in the same region. This prompted a visit to his local healthcare center (part of the public health network) where a chest CT scan was ordered in March 2020 revealing a solitary pulmonary mass located in the right inferior lobule with an invasion of both the pleura and thoracic wall. However, due to the beginning of the COVID-19 pandemic in Ecuador, all further studies were suspended for two to three months, resulting in a significant delay of the biopsy, which was undertaken on May 17, 2020. The histopathological study reported a neuroendocrine carcinoma. The patient was subjected to a thoracotomy and inferior pulmonary lobectomy on June 7, 2020 and was afterward treated with four cycles of chemotherapy consisting of cisplatin and etoposide until November of the same year. In December, the patient presents with neurologic symptoms consisting of loss of balance, ataxic gait, headaches, and nausea, prompting the necessity of a brain MRI. The study revealed a mass on the right lobe of the cerebellum (2.66 x 2.61 x 2.48cm) with perilesional edema, compressing the fourth ventricle. A progression of his primary lung cancer was diagnosed, the original chemotherapy regimen was suspended and replaced with adjuvant Temozolomide maintenance therapy, and he is referred to the radiotherapy service for WBRT with 20 Gy divided into five fractions, which improved his symptoms. However, in March 2021, the patient comes to our hospital’s radiotherapy department to request a second opinion due to the reappearance of his neurological symptoms (loss of balance, headaches, nausea, dizziness, and photophobia). The physical examination is relevant for a Glasgow Coma Scale of 15, oriented in time, place, and person, incapacitating ataxic gait (the patient needs to be mobilized in a wheelchair), and severe photophobia requiring the constant use of sunglasses. The rest of the neurological examination is normal including cranial nerves, reflexes, and somatosensory function. Relevant prognostic indexes were calculated and included the Karnofsky Performance Scale (KPS) of 80%, and the Graded Prognostic Assessment (GPA), specific for patients with brain metastasis, of 3. A CT scan of the thorax, abdomen and pelvis was obtained, on February 22, 2021, in order to detect any new tumoral or metastatic activity; however, none was found (Figures -). Therefore, a follow-up MRI was ordered on February 23, 2021, which revealed two intra-axial lesions on the right cerebellar hemisphere and near the right lateral ventricle, respectively (Figures -). Due to the aforementioned clinical and imaging findings, radio-surgical management of the disease with 21Gy, in one fraction, delivered with a linear particle accelerator (LINAC), TrueBeam® (Varian Medical Systems, Inc., Palo Alto, CA) was offered to the patient; immobilization was performed with a thermoplastic mask and Precise Bite mouthpiece (Solstice™ SRS Immobilization System, Orange City, IA); treatment simulation was done on the CT images and volume definition was performed in the contrasted T1 MRI with SPACE sequence; Gross tumor volume (GTV) was defined as the signal enhancing hyperintense tumoral regions observed on MRI and planning target volume (PTV) was prolonged 1mm in all directions. Dosimetric planning was based on HyperArc (Varian Medical System) which is a relatively new isocentric VMAT technique developed specifically for non-coplanar, multileaf collimator (MLC)-based stereotactic radiotherapy with automated treatment optimization and dose delivery; the clinical and dosimetric planning can be found in Figures -. Dosage and organ constraints, evaluation of the iso-dosage curve goals as well as the evaluation of the Paddick index were performed in accordance with published guidelines [,]. Before treatment, we administer a 16mg intramuscular deposit dexamethasone injection in order to reduce the risk of cerebellar tonsil herniation due to the important edema from the cerebellar metastasis. Tomographic images obtained with the Cone Beam CT system, integrated into the LINAC, showed a complete (100%) correlation of the images obtained during simulation and planning. Finally, the effective time of treatment was of four minutes. Treatment was delayed as per the patient’s request for more time to consider and on April 5, 2021, the procedure was finally performed without complications and in an outpatient setting. A follow-up was programmed 15 days after treatment at which the patient presented significant clinical improvement (absence of headaches, nausea, dizziness, photophobia, and normal balance and gait). There was no evidence of radiation toxicity, and the cognitive function was normal. A control MRI on July 17, 2021, showed a clear reduction in the size of both lesions as well as complete resolution of the mass effect produced by the cerebellar mass; a comparison of the pre- and post-treatment scans can be found in Figures -. At the moment, the patient remains in continuous follow-up, with the last reported telephonic follow-up, on September 2, 2021, in which the patient reported being asymptomatic and carrying out all of his regular day-to-day activities without any limitations.

pmc-8693539-1

A 68-year-old female patient was admitted to the hospital on December 2, 2020, due to being “anxious and easily frightened for 3 months, psychomotor retardation, and affected by urinary incontinence for half a month.” The patient had no mental illness before and developed symptoms 3 months before admission. These included waking up early, being nervous and afraid for no apparent reason, and being fearful of leaving the house. The patient was upset, sensitive, and cried occasionally. In addition, the patient needed walking support (e.g., hands on the wall) at home to prevent falling. The patient had been hospitalized at a local mental health center 2 months prior to the present admission, where she was diagnosed with “GAD.” She received paroxetine (20 mg/d), tandospirone (30 mg/d), and oxazepam (15 mg/d). Her symptoms improved, and so she was discharged. She reported that she took the medications regularly according to the instructions. However, half a month prior to admission at our hospital, the patient experienced a relapse characterized by anxiety, fear, small steps while walking, reluctance to come out of her home, speaking less, and being slow to respond, as well as urinary incontinence. In addition, her social skills declined significantly, and the patient could not take care of herself independently. The patient had been diagnosed with type-II diabetes 4 years previously. No other comorbidities were reported. The patient had no abnormalities in her personal history, menstrual history, marriage and childbirth history, or family history. Physical examination after admission revealed she had normal limb muscle strength and tone. The finger-to-nose, rapid alternating movement, heel-to-shin tests, and Romberg’s sign were normal. However, her gait was not stable and she took small steps. She was negative for pathological signs and meningeal irritation. In a psychological assessment, the patient exhibited clear consciousness, disorientation to place and time, passivity during interactions with few answers to questions, no hallucinations or delusions, a decline in memory and cognition; and a reduction in daily physical activities and energy levels. She felt distraught with a slight tremor in her hands. Her level of thyroid-stimulating hormone (TSH) was 6.280 µIU/mL (0.270-4.200); and she was normal for total T3, total T4, free T3, and free T4. Her level of anti-thyroglobulin antibody (anti-Tg) was 235.60 IU/mL (<115.00), and that of anti-thyroid peroxidase antibody (anti-TPO) was 238.70 IU/mL (<34.00). A color Doppler ultrasound showed diffused thyroid lesions with nodular changes (nodules in the right lobe of the thyroid). Both a CT examination (Figure ) and an MRI (Figure ) of the head showed brain atrophy and leukoaraiosis. A chest CT and pelvic ultrasonography were normal. EEG recordings revealed diffuse slow waves. No epileptic activity or extreme delta brush was observed. The patient’s Hamilton Anxiety Scale (HAMA) score was 22, indicating moderate anxiety. Her Hamilton Depression Scale (HAMD) score was 13, indicating a likelihood of depression. Her Mini-Mental State Examination (MMSE) score was 14, indicating dementia. The differential diagnosis was as follows: 1) rapidly progressive dementia, 2) type-II diabetes, and 3) subclinical hypothyroidism. After admission, the patient was treated with venlafaxine (75 mg/d) and oxazepam (15 mg/d). She showed a rapidly progressive decline in cognitive function, emotional dysregulation, paroxysmal body shaking, slow performance, abnormal gait, constipation, and urinary incontinence. However, the reason for the rapidly progressive dementia was unknown. Thus, lumbar puncture and cerebrospinal fluid examination were performed with the following results: cerebrospinal fluid glucose: 6.30 mmol/L (2.50-4.50); protein: 0.87 g/L (0.15-0.45); and anti-glutamate receptor (NMDA) ratio: 1:3.2 (IgG). Based on these results, the diagnosis was changed to AE. Accordingly, the patient was transferred to the neurology department and treated with immunoglobulin (IVIG, 20 g/d via intravenous infusion for 5 days) and methylprednisolone (1000 mg/d via intravenous infusion for 3 days). The dosage of methylprednisolone was dropped by half every 3 days (till 48 mg/d) and was given orally. After treatment, the patient showed a gradual recovery in cognitive and emotional function, her body shaking disappeared, and her gait was stable. Her EEG was normal. Both medications were stopped gradually. The patient was discharged 24 days after administration and had resumed a normal life without relapse at a 6-month follow-up.

pmc-8693546-1

A 44-year-old female with a history of asthma, essential hypertension, class 3 obesity, depression, and poor social and economic background was intermittently followed during the previous four years for persistent cutaneous candidiasis with intertrigo in the inframammary, inguinal, and lower abdominal regions (Figure ). She had been treated with topical antifungal, oral fluconazole and oral itraconazole with no improvement, which was believed to be because of poor hygiene and questionable therapeutic compliance. A worsening in the skin rash with exudate, pruritus, and a change to a violaceous colour, with scaly papules and vesicles (Figures , ) led to the performance of a skin biopsy which revealed (Figure ) orthokeratotic hyperkeratosis in the epidermis with areas of parakeratosis and, in the papillary dermis, there was an infiltrate of cells with eosinophilic cytoplasm and reniform nuclei that showed positive CD1a and S100 proteins on the immunohistochemistry and negative CD163 (Figure ). The patient denied constitutional, musculoskeletal, neurological, or urinary complaints. She underwent a complete blood count, complete metabolic panel, brain magnetic resonance imaging (MRI), thoracic-abdominal-pelvic computed tomography (CT), and bone scintigraphy. Brain MRI depicted mild chronic microvascular changes in the white matter, unchanged from a prior study. CT demonstrated a thickening of the renal pelvis (4 mm) in the right kidney with a slight urothelial dilation (Figure ). The rest of the exams did not reveal further organ involvement. After considering the skin histology, the extensive cutaneous involvement, and the infiltrative urothelial involvement, it was evident this was a multi-system process. A consultation with Hematology/Oncology, led to induction treatment with prednisolone and vinblastine-based chemotherapy. At six weeks of chemotherapy, there was a partial regression of the skin lesions (Figure ) and a resolution of the urothelium lesion in imaging exam (CT). The disease was in continuous regression and considering the extension of affected skin tissue a second round of chemotherapy with prednisolone and vinblastine was administered for six weeks. There was a resolution of all the lesions following this second round, and the patient underwent maintenance therapy consisting of administrating mercaptopurine daily and prednisolone/vinblastine every three weeks during 12 months, staying in remission (Figure ). Six months after the end of maintenance therapy the patient had a recurrence of the disease and started second-line chemotherapy with clofarabine and cytosine arabinoside (ARA-C). The patient did not comply with the treatment and the disease progressed. As a result of skin ulceration, she developed skin and soft tissue infection that evolved into septic shock and did not survive despite intensive care support.

pmc-8693547-1

A 72-year-old male, known hypertensive on medication, non-smoker, no family history of cancer presented with complaints of pain in the right hip with difficulty in walking in January 2019. On evaluation, a pathological fracture was found at the neck of the right femur. Magnetic resonance imaging of the spine was done, which revealed osteophyte complexes at C3-C4, C4-C5, C5-C6 vertebrae causing narrowing of neural foramina. Multiple T2-hyperintense lesions in lung parenchyma were an incidental finding. Upon further evaluation with positron emission tomography-computed tomography (PET-CT) scan of the whole body, mass in the apex of the right lung, right hilum, mediastinal lymph node, soft tissue wall thickening in the proximal stomach along with multiple liver and bone metastases were found. Upper gastrointestinal (GI) endoscopy revealed a proximal gastric growth from which a biopsy was taken. Histopathology showed poorly differentiated adenocarcinoma. A provisional diagnosis of carcinoma stomach with distant metastasis was reached. But immunohistochemistry came out to be positive for thyroid transcription factor-1 (TTF-1) and cytokeratin-7 (CK-7), while negative for cytokeratin 20 (CK-20) (Figures -). So, a possibility of metastasis from a lung primary was considered. It was confirmed by a biopsy from the lung mass that revealed adenocarcinoma as the histopathology. On immunohistochemistry, it was positive for TTF-1 and CK-7 while negative for CK-20 and synaptophysin. Analysis for anaplastic lymphoma kinase, epidermal growth factor receptor, and receptor tyrosine kinase 1 were all negative but programmed death ligand 1 (PD-L1) tumor proportion score (TPS) was 90%. So, the final diagnosis was adenocarcinoma lung with multiple lung, liver, femur, as well as gastric metastases. For the pathological fracture, he underwent fixation by intramedullary nailing followed by palliative external beam radiotherapy 8 Gy in a single fraction. He received 10 three-weekly cycles each of Inj. pembrolizumab 200 mg as intravenous infusion and Inj. denosumab 120 mg subcutaneously from March 2019 to September 2019. An interim PET-CT scan done after four cycles of immunotherapy in June 2019 showed a near-complete metabolic response (Figures -). After 10 cycles, Inj. pembrolizumab was discontinued as the patient was unwilling to continue due to personal reasons. He was then started with chemotherapy, Inj. pemetrexed 500 mg/m2 and Inj. bevacizumab 15 mg/kg in October 2019. Following this, the patient developed grade 1 maculopapular rash, pedal edema, and grade 2 diarrhea, which were managed conservatively. After that the patient did not opt for the continuation of chemotherapy. The next visit of the patient was in February 2021 with complaints of cough and breathlessness. On re-evaluation with PET-CT scan, progressive disease was found in the primary site (Figures , ). Palliative radiotherapy of 30 Gy in 10 fractions to the primary lesion was delivered through anteroposterior and posteroanterior portals of 10 megavolt energy each in April 2021 via linear accelerator (Elekta-Versa HD) which was tolerated well (Figure ). In June, the patient developed an altered sensorium and contrast-enhanced magnetic resonance imaging of brain revealed multiple brain metastases for which the patient received palliative whole-brain radiotherapy of 30 Gy in 10 fractions over two weeks from the same linear accelerator. His condition further deteriorated, and in July, the patient succumbed to disease progression.

pmc-8693548-1

A 90-year-old male was found in his home slumped to his right side and unable to be awakened. Paramedics calculated an 8/15 Glasgow Coma Scale (GCS) score, which remained the same on admission. On presentation to the hospital, the patient had left facial droop, bilateral pinpoint pupils, and right-sided weakness. The National Institutes of Health Stroke Scale (NIHSS) score on admission was 26, suggesting a severe stroke. All other observations on admission were non-revealing, including vital signs, biochemical tests, and systems review. The patient’s neurological medical history included two previous transient ischemic attacks and suspected dementia. Other past medical history included chronic obstructive pulmonary disease, hypertension, abdominal aortic aneurysm repair, stage 3 chronic kidney disease, adult polycystic kidney disease, hypercholesterolemia, and aortic valve sclerosis. He was an ex-smoker of unknown pack-years and prior to admission was living independently. Initial head CT performed only showed chronic small vessel disease with periventricular leukoaraiosis, consistent with his age. Thrombolysis was initiated with an intravenous tissue-plasminogen activator, however, the patient’s GCS declined to 6/15 approximately 40 minutes after the start of thrombolysis. A repeat head CT was performed, again showing no acute findings. To prevent further deterioration, a decision to monitor the patient’s condition conservatively was made. Over the next few days, the patient remained very somnolent. When the patient was able to awaken, he was only capable of responding to simple commands. Speech and language therapists noted that fatigue was limiting conversations, with the patient speaking with imprecise articulation and at a low volume. Occupational therapists concurred that the patient was poorly engaged during sessions, while physiotherapists classified this patient as having limited rehabilitation potential. Stroke was finally confirmed upon a third head CT several days after admission, which showed bilateral thalamic infarcts. Other findings included hyperdensity at the basilar tip and left posterior cerebral artery, likely due to wall calcification of vessels. An MRI revealed bilateral hyperintensities in the thalami, consistent with acute bilateral thalamic stroke, with small left parietal cortical infarction (Figure ). Imaging also confirmed the arterial location of the infarction, a single branch of the pre-communicating (P1) segment of the left posterior cerebral artery known as the artery of Percheron (AOP). Over the next month, the patient participated in multidisciplinary rehabilitation sessions. He had a gradual return of physical function and with it, his sense of humor returned, much to the delight of his family and the attending staff. He was unable to care for himself independently and was eventually discharged to a care home. Six months later, he was mobile with a walking stick and had a reasonable quality of life. One year after the initial presentation to the hospital, he passed away from an intercurrent chest infection.

pmc-8693695-1

A 47-year-old male with a past medical history notable for hypertension on metoprolol succinate, morbid obesity, and pre-diabetes presented to the emergency department (ED) with a chief complaint of generalized weakness. The patient tested positive for COVID-19 and exhibited mild unspecified respiratory symptoms. He was subsequently discharged home to recover in isolation per the CDCs COVID-19 response protocols. One week later, the patient returned to the ED for ongoing symptoms and was admitted requiring supplemental oxygen for hypoxia. Upon admission to the hospital, the patient was noted to have difficulty standing and ambulating. Two days into his inpatient stay, the patient developed urinary retention issues requiring intermittent catheterization. Three days later, he developed facial weakness and numbness. The clinical diagnosis of GBS was suspected and subsequent EDX studies reported AIDP. The patient was treated with a five-day course of intravenous immune globulin (IVIG). Three days after the completion of his IVIG treatment, the patient noted improvement with right upper extremity anti-gravity strength. The patient was transferred to inpatient rehabilitation with significant proximal lower extremity weakness. The bilateral upper extremities demonstrated slight weakness. The bilateral lower extremities demonstrated a significant loss of strength, 1/5 dorsiflexion, and 3/5 plantar flexion bilaterally. The patient also reported diminished sensation to light touch in bilateral upper extremities in all dermatomes. His blood pressure upon rehabilitation admission was 110/73 mmHg. Prior to hospitalization, the patient was independent with mobility and all activities of daily living. Upon evaluation in the inpatient rehabilitation, the patient was at a significant functional decline from baseline, requiring dependent assistance with toileting hygiene, showering, upper body dressing, lower body dressing, footwear management, rolling left and right, and all transfers. The patient was unable to ambulate due to his level of impairment. In inpatient rehabilitation, the patient completed three hours total of physical, occupational, and speech therapy per day five days a week with exercises aimed to improve balance, mobility, activities of daily living, fine motor skills, cognition, and breath support. After completing four weeks of inpatient therapy, the patient was independent with supine to sit, upper and lower body dressings, and rolling right and left in bed. He required minimal assistance to lift the left lower extremity into the bed and moderate assistance with wheelchair-to-bed transfers and bed mobility. He was able to stand with the assistance of his spouse and by using significant reliance on bilateral upper extremity support on a walker for stability and offloading lower extremities. He required a power wheelchair for mobility and was unable to transfer in and out of the car thereby requiring a wheelchair van for transportation. Final muscle strength grading was not documented. His blood pressure remained stable throughout his stay on metoprolol succinate and was 121/65 mmHg on discharge.

pmc-8693699-1

This is a case of a 4-year-old male who was brought to our clinic with complaints of four-day history of constipation, dry cough, vomiting, high fever (104 °F), abdominal pain with bloating, headache, and rash. The patient’s symptoms started gradually with fatigue, loss of appetite, muscle aches, cough, bloated abdomen, and poor oral intake, prior to presenting to the hospital. The parents assumed it was stomach flu, and so managed their child’s symptoms with Tylenol and soups. However, the patient continued to have constipation, abdominal discomfort, and eventually maculo-papular rashes on the head, face, and extremities erupted (Figure ). On day 1, upon admission to the hospital, IV fluid with 0.9% normal saline solution was started, due to signs of dehydration, bradycardia, and hypotension. Norepinephrine was also administered. Lab samples (stool, urine, and blood) were collected for analysis, and abdominal ultrasound was ordered which showed clumps of worms in the jejunum which explained the constipation our patient had (Figure ). Stool test for helminth (stained with bile) showed rounded 45-78 micrometer long thick-shelled eggs indicative of roundworm infestation (Ascaris lumbricoides). Blood test came back positive for typhoid DNA and increased level of eosinophils with relatively high leukocytes. The rest of the complete blood count (CBC) was normal including a chest X-ray. Following day 2 of in-hospital admission, the patient’s condition remained unstable due to high fever (102 °F), vomiting, and fatigue. Antibiotics were initiated with ceftriaxone, antipyretics, albendazole, and more IV fluids. Finally on day 3, the patient’s symptoms improved clinically, although body rashes persisted. CBC had normalized, and he was later discharged home with one week prescription of azithromycin and albendazole. The patient was also prescribed antihistamine cream to help stop the itching from the rash.

pmc-8694018-1

The patient was a 31-year-old male, a right-hand-dominant construction worker who was referred to our plastic surgery unit from a local minor injuries unit. He complained of pain in his left ring finger, following an inadvertent injury with a spray gun containing Newton 103-S (a type of liquid cement). The patient had been wearing protective gloves at the time of injury. He had no past medical history, took no regular medications, and had no allergies. The patient had been given tetanus immunisation by the referring hospital. He had a plastic surgery review approximately three hours post-injury. On examination, his left ring finger was swollen, erythematous with necrotic skin on the volar aspect of the finger (Figure ). There was no evidence of distal vascular compromise and the dorsal skin was well-perfused. He had a complete loss of sensation in the distribution of the ulnar digital nerve; however, the radial digital nerve was clinically intact. There was decreased range of movement at both the proximal interphalangeal joint (PIPJ) and distal interphalangeal joint (DIPJ). The palmar skin was not involved. Blood results and observations were within normal ranges. No X-rays were taken at the time of presentation. Broad-spectrum IV antibiotics were commenced, and the patient was taken to theatre for urgent debridement and washout under general anaesthetic. The initial surgical approach consisted of Bruner incisions. Significantly hardened concrete was identified in the subcutaneous tissues (Figure ). It was evident that skin and subcutaneous tissues were non-viable and were debrided, improving access. The pH of the wound was 8.5, in keeping with the alkaline substance injected; irrigation continued until pH returned to 7. The ulnar digital artery was thrombosed, but the radial digital artery was patent. The concrete had penetrated the flexor sheath, surrounding both flexor tendons. Subsequent flexor sheath washout from A1 to A5 confirmed that both tendons were in continuity but had undergone surface changes secondary to contact with the concrete. A second look was performed at 48 hours; the distal digit remained viable with the flexor tendons appearing healthy. Tendon glide was impeded by friction within the flexor sheath. Access incision was made into the palm, which revealed further cement material. The passive range of movement was reassessed, which confirmed PIPJ and DIPJ to be in good condition. Further debridement of devitalised soft tissue resulted in a large defect of almost the full length of the volar aspect of the ring finger exposing the intact flexor apparatus pulleys and tendons (Figure ). The patient was counselled extensively regarding ongoing management, which principally consisted of either reconstruction of the volar soft tissue defect or potential amputation through the middle phalanx. He was counselled that the reconstructive option would result in a stiff and potentially insensate finger but could preserve length, while amputation might provide a faster recovery and better overall functional outcome. The patient opted for reconstruction and preservation of as much length of the digit as possible. At one week from the initial injury, a cross-finger flap from the ipsilateral middle finger was performed, reconstructing the volar soft tissue defect (Figure ). The patient was discharged with oral antibiotics. After three weeks, the flap was divided and inset. However, the patient developed a wound infection five weeks after reconstruction, necessitating further washout and IV antibiotics. At four months post-injury, the digit had an active range of movement of 20-84 degrees at the metacarpophalangeal joint (MCPJ); both PIPJ and DIPJ were in fixed 30 degrees of flexion. The protective sensation was maintained in the radial aspect of the digit, and the patient did not develop issues with pain subsequently. He was followed up via telephone consultation at 18 months postoperatively, and he reported that he had no functional limitations on daily activities, and was back to work. The skin overlying the volar defect of the ring finger and grafted area on the dorsum of the middle finger has healed well (Figures , ).

pmc-8695605-1

A 46-year-old male patient was admitted to the hospital with intermittent back pain and chest tightness for 2 weeks. The patient works in ozone disinfection. Prior to symptom onset, he had a history of acute ozone inhalation. He recalled smelling something more pungent than usual for several days. Before coming to our hospital, he had not undergone any treatment. In addition, he denied any history of chest trauma. He had suffered from hypertension for over a decade and was treated with oral nifedipine and metoprolol. However, medication poorly controlled his blood pressure. The highest recorded systolic blood pressure with treatment was 180 mmHg. His blood pressure upon admission was 148/91 mmHg. An echocardiogram revealed a left SVA that ruptured into the left-ventricular myocardium, forming an echo-lucent cavity (). The left-ventricular wall had thickened resulting in uncoordinated motion and reduced systolic function. Moreover, moderate eccentric aortic regurgitation was also noted. Furthermore, CT angiograms better captured a large, left-ventricular, IPA arising from a small perforation in the left SVA (). The adjacent left ventricle and interventricular septum were compressed. With CMR examination, late gadolinium enhancement (LGE) clearly demonstrated the left-ventricular IPA with distal thrombus and a linear enhancement of the IPA wall, compatible with myocardial fibrosis (). Subsequently, the patient underwent surgery where the perforation was sutured and repaired, and the left aortic valve was lengthened with pericardial patches. Three weeks after surgery, a follow-up echocardiogram demonstrated the cessation of the abnormal blood flow in the left sinus of Valsalva ().

pmc-8695686-1

Patient 1: A 64-year-old man with a left inferior visual field deficit and headache. The CT angiography showed a left superior carotid-ophthalmic aneurysm (4 × 5 mm) ().

pmc-8695686-2

Patient 2: A 43-year-old woman with subarachnoid hemorrhage, classified as Fisher I, Hunt, and Hess II. In the digital 3D angiographic reconstruction multiple aneurysms are observed: a right M1 aneurysm and a right superior carotid-ophthalmic aneurysm ().

pmc-8695756-1

A 77-year-old woman was hospitalized in the cardiology department due to atrial fibrillation. Contraindications were excluded, and atrial fibrillation (AF) ablation was performed on an optional schedule. However, abdominal contrast-enhanced computed tomography (CT) scan found a circular and low-density lesion in the Segment 4 of the liver with unclear border, approximately 15 mm× 12 mm in size, which was mild progressive enhanced in the arterial phase and portal phase. HCC was suspected, but no hepatic cirrhosis and history of hepatitis (). Tumor markers, including CEA, CA199, CA125, AFP, were within normal range, hepatitis panel was negative, and hepatic function was normal. To confirm the diagnosis, the patient underwent further examinations. Abdominal magnetic resonance imaging (MRI) disclosed one nodule in the segment 7, one nodule in the segment 5, and two nodules in the segment 4 of the liver (4, 6, 17, and 6 mm in diameter), respectively. The larger one was located in the segment 4 of liver, with hypointense on T1-weighted images (T1WI) and hyperintense on T2-weighted images (T2WI), which showed significant enhancement on the arterial phase and slight washout on the portal phase. In the delayed phase, the edge of the tumor was underscored as a circular enhancement which is unsimilar to the enhancement method of dynamic CT. It showed a significant restriction of diffusion on diffusion weighted images (DWI) and apparent diffusion coefficient (ADC). Other lesions in segments 7 and 5 showed the same hemodynamic characteristics as the tumor in segment 4 (). Based on MRI findings, it is considered as tumorous lesions of the liver. For further differential diagnosis, the patient underwent positron emission tomography-computer tomography (PET-CT) examination, founding that the segment 4 of liver had a slightly low-density lesion with increased uptake of 18F-fluoro-deoxy-glucose (FDG), and SUVmax of early and delayed enhancement imaging was 4.81 and 5.24, respectively. The detention index was 8.9%. However, the lesions in segments 7 and 5 of the liver showed no significant increase in FDG uptake (). As all images suggested HCC, the medial segment of the liver was finally surgically removed. Surgical removal of a piece of left medial lobe of liver tissue, about 6 cm × 4 cm × 2.5 cm in size, the cut surface shows an expanded lumen structure, and a gray-white mass in the liver parenchyma. The size is about 2.5 × 2cm, part of the boundary is unclear, and the texture is soft. The HE-stained sections under low-power microscope showed that massive lymphoid tissues proliferated in the lesion and formed massive lymphoid follicles, and the peripheral lymphoid tissues of the lesion grew around the small bile ducts, but no clear lymphoepithelial lesions were seen. The interfollicular area is dominated by small lymphocytes, and many plasma cells can be seen. In the lymphatic tissue, there were homogeneous red-stained collagen-like deposits around some small blood vessels. Immunohistochemical results were as follows: Bcl-2(−), Bcl-6(germinal center +), CD10(germinal center +), CD20(+), CD23(+), CD3(+), Ki-67(germinal center +), CD5(+), CyclinD1(−), TDT(−), kappa/lambda ratio about 2:1. EBV negative by qRT-PCR method (). A genetic study of the immunoglobulin heavy chain (IgH) clonality on the DNA of tumor tissues was performed using capillary electrophoresis method, which was reported previously (). The results showed that no clonal IgH gene rearrangement was detected: IGH (−), IGK (−), IGL (−). Therefore, the possibility of extranodal marginal-zone lymphoma (MALT) was ruled out, and the final diagnosis was RLH. Combined with imaging, pathology, and clinical manifestations, the clinical diagnosis was multifocal RLH in the liver. Three months after the operation, a re-examination of the abdominal ultrasound showed no signs of recurrence.

pmc-8695790-1

Patient 1 was a 45-year-old right-handed woman, who sought treatment for a depressive episode. The current episode onset was placed after a switch from sertraline to vortioxetine due to unbearable side effects (nausea and headache). She suffered from her first depressive episode at the age of 25, then alternating depressive and hypomanic episodes, which led clinicians to a diagnosis of BD-II. The patient has also been suffering from EDs since her adolescence: she was diagnosed with anorexia nervosa at the age of 13; she then shifted to a bulimic eating pattern, with binge episodes followed by purging behaviors. This phase lasted for 10 years, followed by a complete remission until the age of 38. At this age she developed BED. Once a week or more she used to wake up at night and eat everything she could find in the fridge, including raw food. After these episodes she used to feel guilty and nauseated, but she did not show purging behavior anymore. She felt very uncomfortable due to either the loss of control or her weight gain. Her private psychiatrist then diagnosed her with BED, but apparently, she did not receive any psychological or pharmacological specific support. In the following years she had alternating periods of remission with periods of active disease. She denied alcohol or other psychoactive substances consumption. In the 2 months previous to our study, she had gained 12 kg, with 3–4 binge episodes per week on average. She denied medical comorbidities. When she first came to our attention, her therapy was the following: lamotrigine (150 mg daily), vortioxetine (20 mg daily). She was suffering from a depressive episode defined as mild according to the Hamilton Rating Scale for Depression (HAMD) and moderate according to the Montgomery-Åsberg Depression Rating Scale (MADRS) ().

pmc-8695790-2

The second patient we are reporting is a 28-year-old right-handed woman, who came to our attention for a severe depressive episode. Her psychopathological onset is placed 10 years ago; she developed her first depressive episode with comorbid panic attacks. From that moment the patient has alternated phases of depression with sporadic episodes of elation, thus a sign of hypomanic episodes, which led clinicians to a diagnosis of BD-II. Her depressive phases used to have a seasonal pattern, with autumn or winter worsening. When she came to our attention (November 2020), the current episode had been lasting for 3 months, according to her seasonal pattern. She reported low consumption of alcohol in social circumstances and sporadic use of cannabis in her adolescence. Regarding her ED, binging behaviors were reported to happen from the first diagnosis of depression, with various degrees of intensity and severity, and appeared to be more intense in depressive phases. Binge eating episodes during depressive phases used to be daily. No compensatory behaviors were ever observed. Notably, her first BED diagnosis was given in our center during her last depressive episode, as she had always been trying to hide her eating behaviors, even with physicians. Along with the current depression, she referred almost daily binge eating: after her dinner she used to go out and then buy and rapidly eat large amounts of high-fat food. This used to cause both physical and psychological distress. In her past pharmacological history, many pharmacological therapies had been prescribed (i.e., valproate, fluoxetine, citalopram, venlafaxine, and bupropione) and when she came to our attention her therapy was clomipramine (150 mg daily) and pregabalin (225 mg daily). Her depressive symptoms at baseline were severe according to both MADRS and HAMD ().

pmc-8695792-1

Patient 1: A 65-year-old male was diagnosed with AML in January 2020 with the manifestation of leukocytosis, thrombocytopenia and anaemia. BM aspiration revealed a hypercellular BM with 50% blasts. Flow cytometry showed the immunophenotype of myeloid blasts. Cytogenetics revealed a complex karyotype, and a molecular panel identified aberrations in ASXL1, CEBPA, JAK2, and RUNX1. None of the 41 gene fusions were detected by using multiple RT–PCR assay (). Therefore, AML with adverse risk was diagnosed according to genetic risk stratification (). After one course of induction treatment with the IA regimen [idarubicin 12 mg/m2 day1-3, cytarabine 100 mg/m2 continuous infusion day1-7.], the patient achieved complete remission with minimal residual disease as low as 5.8x10-4 by flow cytometry analysis. Genetic analyses showed that all gene mutations were negative. Subsequently, the patient refused bone marrow transplant for financial reasons. He received one course of the IA regimen and 3 courses of the high-dose Ara-c (HiDAC) regimen [cytarabine 2 g/m2 over 3 h every 12 h on day1–3.] as consolidation therapies. However, the remission duration only lasted for 11 months. In November 2020, relapsed BM morphology was detected, with 17.5% blasts concurrent with molecular aberration recurrence. Therefore, relapsed AML was diagnosed. Initially, venetoclax combined with azacitidine [VA, venetoclax once daily (100 mg day1, 200 mg day2, 400 mg day3-28) and azacitidine 75 mg/m2 day1-7.] was administered as a salvage therapy, an effective regimen recommended for the treatment of R/R AML patients who are ineligible for intensive salvage chemotherapy, but progressive disease was observed. Then, his treatment plan switched to a chidamide combined with venetoclax plus azacitidine regimen [chidamide 5 mg daily day1-7, venetoclax 100 mg day1, 200 mg day2, 400 mg day3-21; azacitidine 75 mg/m2 daily day1-7.], and CR was achieved after one course of therapy. The patient treatment process is shown in . After 3 months of follow-up, unfortunately, the patient gave up further treatment and passed away due to disease progression. The overall survival time was 1.5 years from first diagnosis.

pmc-8695792-2

Patient 2: A 57-year-old male was diagnosed with AML in July 2016. Investigation revealed a pancytopenia. BM examination showed a hypercellular marrow with 65% myeloid blasts. Flow cytometry analysis showed the immunophenotype of myeloid blasts. Cytogenetics revealed del () (q22q36), and a molecular panel identified aberrations in DNMT3A and IDH2. The patient achieved CR after 1 cycle of the IA regimen [idarubicin 12 mg/m2 day1-3, cytarabine 100 mg/m2 continuous infusion day1-7.] and received 6 courses of the HiDAC regimen [cytarabine 2 g/m2 over 3 h every 12 h on day1–3.] as consolidation therapies while not adopting allogeneic haematopoietic stem cell transplantation. The patient experienced his first relapse 2 years after first remission with a 9% immature cell level in the BM and was treated with the CAG [cytarabine 10 mg/m2 every 12 h, day1-14; aclarubicin 5-7 mg/m2, daily on day1-8; and concurrent use of G-CSF 200 µg/m2/day.] regimen for 3 cycles, resulting in a second CR in March 2019. A second relapse occurred 20 months later. The patient began the VA regimen [venetoclax once daily (100 mg day1, 200 mg day2, 400 mg day3-28) and azacitidine 75 mg/m2 day1-7.], but no response was observed after 2 courses of therapies. Finally, the patient received a chidamide combined with venetoclax plus azacitidine regimen [chidamide 5 mg daily day1-7, venetoclax 100 mg day1, 200 mg day2, 400 mg day3-21; azacitidine 75 mg/m2 daily day1-7.] as salvage therapy as described above. The patient achieved his third CR. Treatment process is shown in . There were no infectious complications observed with the combination, and the duration of neutropenia was 10 days. After 1 month of follow-up, the patient remains in CR and is preparing for transplantation.

pmc-8695792-3

Patient 3: A 60-year-old female was diagnosed with AML in December 2020. BM examination showed a hypercellular marrow with 32% myeloid blasts. A molecular panel identified aberrations in RUNX1. Karyotype was normal. All patient baseline characteristics at diagnosis and treatment characteristics are shown in . For induction therapy, the patient received the VA [venetoclax once daily (100 mg day1, 200 mg day2, 400 mg day3-28) and azacitidine 75 mg/m2 day1-7.] regimen and achieved CR after one course. Subsequently, she continued two courses of VA as consolidation therapy, but progressive disease was observed during the second course, with 67% blasts in BM. Then, a chidamide combined with venetoclax plus azacitidine regimen [chidamide 5 mg daily day1-7, venetoclax 100 mg day1, 200 mg day2, 400 mg day3-21; azacitidine 75 mg/m2 daily day1-7.] was given. After one course, the patient obtained CR. Treatment process is shown in . During the whole course, no severe adverse events occurred. After 1 month of follow-up, the patient remains in CR at the time of writing.

pmc-8695846-1

A 54-year-old Caucasian male patient was referred to our institution, initially with the diagnosis of a T-cell lymphoma, not otherwise specified, which was refractory to two courses of chemotherapy (CHOEP: cyclophosphamide, doxorubicine, vincristine, etoposide and prednisolone). At presentation an erythroderma involving >90% of the integument was predominant (). Computer tomography (CT) scans showed enlarged axillary, inguinal and cervical lymph nodes. The complete blood counts showed a leukocytosis of 24,300/µl. Flow cytometry of the pb revealed 11,664 Sézary cells/µl with CD4+CD7- phenotype and with a CD4:CD8 ratio of 85.5. Flow cytometry of the bone marrow aspirate confirmed CD30 positivity with expression of 7% in Sézary cells. Polymerase chain reaction of pb confirmed the clonality in T-cell receptor beta and gamma showing monoclonal Vβ-β2 and two clonal Vγ1-8-Jγ1.1 and 2.1 rearrangements. While conventional cytogenetics showed a normal male karyotype, fluorescent in situ hybridization (FISH) detected the deletion of chromosome 17p in 22 of 200 interphases with deletion of TP53 gene. Immunohistochemistry of both trephine biopsy () and skin histology revealed infiltrations with Sézary cells (). The skin histology also confirmed CD30 positivity with 5-10%, and the diagnosis was revised to SS. The diagnosis was thus revised to Sézary Syndrome in Stage IVA (pT4 Nx M0 B2) according to the updated classification of International Society for Cutaneous Lymphomas (ISCL) and the European Organization of Research and Treatment (EORTC) (). Subsequently, successive therapies with 3,000,000 IU interferon alpha three times weekly for 6 months, combined with 10 mg/m2 methotrexate (MTX) and 19 courses ECP including bexarotene showed no improvement. Six months prior to alloHSCT an antibody-conjugate treatment with brentuximab vedotin (BV) was administered. The patient received five courses, which led to an improvement of skin lesions and their reduction to about 30% of body surface. CT scans showed no further progression of the lymph nodes, the CD4:CD8 ratio was 76.7 with 63.5% Sézary cells in the flow-cytometry, confirming stable disease according to the EORTC and ISCL classification (, ). Due to preexisting comorbidities, we performed an alloHSCT from an unrelated HLA identical (10/10) and cytomegaly virus matched (recipient and donor IgG positive) 30 year old male donor with non-myeloablative conditioning (fludarabine 30 mg/m² body surface area on d-4 to -2 and total body irradiation with 2 Gy on day -1) followed by infusion of pb stem cells (). Immunosuppression consisted of cyclosporine A from d-1 (blood target level 200 ng/ml) and mycophenolate mofetil (3x1000 mg per day). The patient received a total of 6.6x106 CD34+ cells/kg body weight, 1.1x108 CD3+ cells/kg body weight and 0.2x108 CD16+ cells/kg body weight. In the absence of acute graft-versus-host disease (GvHD), mycophenolate-mofetil was tapered 500 mg every 14 days from day 40 and discontinued on day 74 while cyclosporine A was tapered from day +56 and discontinued on d+196. The restaging on day +30 and +90 after alloHSCT showed residual infiltration of SS cells in the FACS analysis of the bone marrow (13 and 5% of all WBC, respectively) and chimerism of 70 and 93% on sorted CD3+ cells. The CT scan on day +90 after alloHSCT confirmed the persistent lymphadenopathy. On day + 172 after alloHCT a complete hematological remission (CR) with no infiltration of SS in bone marrow trephine biopsy, 100% chimerism on sorted CD3 positive cells from bone marrow aspirate and normal pb CD4:CD 8 ratio was documented, thus confirming graft-vs-Sézary effect (). The CT scan showed no lymph node enlargements. The inspection of the skin revealed no suspect lesions. After discontinuation of immunosuppression the patient developed chronic GvHD of the ocular mucosa and the liver according to national institutes of health (NIH) criteria () on day 277 and required immunosuppressive treatment with intermediate dosage of methylprednisolone, cyclosporine A and mycophenolic acid. The immunosuppression could have been slowly tapered to 720 mg mycophenolic acid b.i.d, 5 mg prednisolone and autologous plasma eye drops as previously described (, ). Furthermore, since September 2021 ruxolitinib was added to the GvHD treatment (). Currently, 1215 days after alloHSCT the patient is in continuous complete remission of SS, having active ocular chronic GvHD.

pmc-8695924-1

The first case was that of a 37-year-old man. At admission, the patient was diagnosed with septic shock, previous total cystectomy with ileal bladder replacement, urinary retention with pyuria, chronic renal insufficiency stage V, and neurogenic bladder. In addition, the patient’s vital signs were unstable, and noradrenaline and phenylephrine were required to maintain blood pressure after fluid resuscitation. Blood culture analyses were negative. Escherichia coli [extended spectrum beta-lactamase (ESBL) +], Enterococcus avium, and Enterococcus faecium were detected in the drainage fluid of the ileostomy. The antibiotic regimen at admission was 1000 mg meropenem q12 h ivgtt combined with vancomycin (loading dose on D1 of 1500 mg and maintenance dose of 1000 mg on D2). CVVH was also administered. From D7, the patient’s condition tended to be stable, and the CVVH frequency was reduced to every other day. On D9, puncture and catheterization of left subphrenic effusions were conducted under the guidance of B-ultrasound. Escherichia coli (ESBL+) and Enterococcus avium were identified in the drainage fluid. The intra-abdominal infection improved and the function of organs other than the kidney returned to normal. On D22, the culture of drainage fluid was negative, thus vancomycin and meropenem were stopped. On D26, the patient was transferred out of the intensive care unit and resumed routine hemodialysis.

pmc-8695924-2

The second case was that of a 93-year-old woman. Her diagnosis at admission included a gallstone, acute attack of chronic cholecystitis, biliary pancreatitis, septic shock, and multiple organ dysfunction syndrome. The surgeons performed endoscopic retrograde cholangiopancreatography to relieve the biliary obstruction. The growth of Escherichia coli (ESBL +) and Enterococcus faecium was observed in bile bacterial culture during ultrasound-guided cholecystostomy. Blood cultures were positive for Escherichia coli (ESBL +). Mechanical ventilation and CVVH were performed at admission. The initial antibiotic treatment regimen comprised 500 mg imipenem/cilastatin q12 h ivgtt and 1,250 mg vancomycin ivgtt. Starting on D2, the patient was administered 750 mg vancomycin QD ivgtt. On D5, the patient was treated with CVVH again because of oliguria and elevated creatinine. On D7, blood culture tests were negative, thus imipenem/cilastatin was switched to piperacillin-tazobactam, and vancomycin was continued. On D14, the drainage fluid culture was negative and the patient was transferred to the general surgery department for further treatment. On D21, antimicrobial treatment was discontinued.

pmc-8696155-1

A 5-year-old boy initially presented with headache, right eye pain, and vomiting, to a rural district hospital in the State of Sabah, East Malaysia on Borneo island. The boy also experienced difficulty in walking, blurring of vision, and fluctuating consciousness 1 month before admission. There was a significant (but unquantified) loss of weight and anorexia. He completed his bacille Calmette-Guerin (BCG) vaccination but missed all scheduled shots after his first birthday because of poor family support. On examination, a Glasgow Coma Scale (GCS) of 9 was documented (E2V2M5) with left lateral strabismus. The pupils were unequal (4 mm/3 mm) and sluggish. Power in all four limbs was 4/5 (Medical Research Council scale) with normal reflexes. Babinski was downgoing, and Kernig's sign was not elicited. The boy was transferred to our center for further evaluation and treatment. Non-contrast CT brain showed acute hydrocephalus with cerebral edema. Subsequently, an external ventricular drain was inserted. Intra-operatively, the opening pressure was high, and outflowing cerebrospinal fluid (CSF) was clear and colorless. Magnetic resonance imaging of the brain revealed diffuse enhancing nodular leptomeningeal thickening, especially at the basal cisterns (). No intra-axial lesion was present. Small non-enhancing cystic lesions were seen along the leptomeningeal surface (), and no restricted diffusion was depicted. A diagnosis of tuberculous meningitis was considered, and an extensive TB workup was undertaken. The positive results from that battery of tests were a high erythrocyte sedimentation rate (ESR) of 90 mm/h and elevated CSF protein with normal CSF glucose levels. Otherwise, the Mantoux test was negative, and the blood, CSF, and CSF TB cultures showed no organism. The CSF for acid-fast bacilli as well as CSF GeneXpert were also negative. CSF latex agglutination was negative for streptococcus Group B, haemophilus influenzae, streptococcus pneumoniae, neisseria meningitidis, and escherichia coli. Both gastric lavage for acid fast bacilli stain and gastric lavage for GeneXpert were negative. Smear-negative TB was considered after reviewing the biochemical and imaging findings. Using the Composite Reference Standard (CRS) criteria, this child was classified as probable TB (). A standard anti-TB regimen was started consisting of isoniazid, rifampicin, pyrazinamide, and ethionamide. Intravenous dexamethasone was prescribed during the first 2 weeks of admission and was subsequently changed to oral administration. The boy's condition improved considerably after 14 days, and he was well enough to undergo a comprehensive ophthalmology examination. He had a visual acuity of 1/60 in the right eye, and there was no light perception in the left eye. A positive right afferent pupillary defect was detected. Ophthalmoscopy showed normal macula bilaterally. Both his parents were screened and found to be negative for TB. He was discharged well after a 4-week hospital stay. One month later, he presented again with vomiting, unsteady gait, and anorexia. The follow-up MR brain study revealed exuberant nodular leptomeningeal enhancement that was more extensive than the initial study (). Also, the previously seen cystic lesions have increased in size and number (). MR spectroscopy (single voxel placed at the thickened tentorium cerebelli) showed a markedly elevated choline:creatine ratio of 4.34 and absence of a singlet peak at 3.8 ppm (). A biopsy sample was obtained and sent for histopathological examination (HPE). Transcranial approach at the right Keen's point was used to obtain the biopsy sample. The patient incidentally needed a revision of his external ventricular shunt at that time, so dural tissue was obtained via the Burr hole just prior to the shunt revision. Histopathological examination (HPE) revealed a moderately cellular neoplastic proliferation with background desmoplastic and myxoid changes seen from the hematoxylin and eosin (H&E) stain slides (). The cells were fairly monomorphic with mild nuclear pleomorphism displaying enlarged round to oval nuclei with fine chromatin and inconspicuous nucleoli (). Occasional mitosis was seen (). The Ki-67 proliferation rate was high, accounting for about 80% (). Immunohistochemical (IHC) studies showed that the tumor cells were positive for S100 and synaptophysin (). Given these findings, the boy was diagnosed with DL-GNT. A family conference was held to counsel the parents on possible treatment options. The parents decided to opt for palliative treatment. The patient succumbed to the illness 3 months later, 22 weeks in total, after diagnosis.

pmc-8696182-1

A 1.9-year-old girl was referred to our hospital on March, 2016 due to 4-day fever and cough, with no pertinent past medical history. Physical examination revealed temperature 37.4°C, heart rate 120 beats/min, respiration 50 times/min, blood pressure 90/60 mm Hg, and transcutaneous oxygen saturation 92% without oxygen administration, fatigue, and depressions in suprasternal fossa, supraclavicular fossa, and intercostal space. She developed hypoxemia, so the reservoir mask of 6 l/min was utilized for ventilatory support. The right lung showed diminished breath sounds. Cardiovascular, nervous system, extremities, antinuclear antibodies (ANAs), and extractable nuclear antigens (ENAs) examinations were normal. Routine blood tests showed the following results: hemoglobin (Hb) 118 g/l, white blood cell (WBC) 7.83 × 109/L, neutrophils (N) 53.3%, lymphocytes (L) 40.4%, and C-reactive protein (CRP) 156 mg/l. Arterial blood gas analysis revealed a pH of 7.48, partial pressure of carbon dioxide in artery (PaCO2) of 42 mm Hg, partial pressure of oxygen in artery (PaO2) of 50 mm Hg, base excess (BE) of 6.9 mmol/l, and oxygenation index of 238. Pulmonary CT suggested consolidation with atelectasis in the middle lobe of right lung (). Electrocardiogram indicated sinus rhythm with blunt T wave of part of the lead, visible in double peak. The patient received cephalothin for anti-infection at admission. On 2nd day, due to pneumonia complicated with atelectasis in her CT scan, the first fiberoptic bronchoscopy (FB) was used to relieve atelectasis and obtain respiratory samples for bacteriologic, cytologic, and histologic detection. On 3rd day, the titer of MP-immunoglobulin M (IgM) was 1:160 and then azithromycin and methylprednisolone were applied for anti-inflammation. On 5th day, due to persistent fever, aggravated cough, and lesions on chest radiography progressed after conventional anti-infective therapy, the second FB was performed and found plastic bronchitis in the airway (). Bronchoalveolar lavage (BAL) fluid (BALF) was negative in other microorganism, except MP-DNA up to 5.1 × 108 copies/ml. MP resistance mutation site 2063/2064 showed positive. No other etiological evidence was found in body fluid or secretions. On 9th day, the body temperature returned to normal level and the clinical symptoms and imaging improved. On 14th day, the blood oxygen turned to normal and stopped oxygen inhalation. The titer of MP-IgM was increased to 1:10240. She was discharged on the 17th day. However, on 24th day, she had sudden high fever. Because she was still not getting better after 3-day conventional anti-infective therapy and persistent consolidations in X-ray, the third FB was used on 27th day on outpatient department and removed bronchial casts. Her temperature was normal on the next day and the chest X-ray on the 30th day had great improvement (, ). She did not present any discomfort within 60 days.

pmc-8696182-2

A 2.4-year-old girl was hospitalized on October, 2015 due to 3-day persistent fever and cough, without underlying disease. Reservoir mask of 10 l/min was utilized for ventilatory support. Due to pulmonary CT suggested inflammatory consolidation with atelectasis, the first FB was used for treatment and etiological diagnosis. After 2 days of cephalothin and azithromycin treatment, she still had fever and cough and developed hypoxemia. Arterial blood gas revealed a pH of 7.44, PaCO2 of 45 mm Hg, PaO2 of 52 mm Hg, and oxygenation index of 247. Then, nasal high-flow oxygen of 10 l/min was adopted and methylprednisolone was applied for anti-inflammation. Physical examination revealed temperature 38.3°C, heart rate 135 beats/min, respiration 45 times/min, blood pressure 85/50 mm Hg, transcutaneous oxygen saturation 93% without oxygen administration, fatigue, flaring of nares, and decreased respiratory sound in the left lung. Cardiovascular, nervous system, extremities, ANA, and ENA examinations were normal. The routine blood tests indicated Hb 118 g/l, WBC 6.25 × 109/L, N 55.3%, L 37.6%, and CRP 26 mg/l. On day 4, pulmonary CT suggested inflammatory consolidation accompanied with left pleural effusion (). Fiberoptic bronchoscopy and pathological results revealed fibrinoid formation in the left upper lobe and lower lobe, indicating plastic bronchitis (). BAL fluid was negative in etiological, except for MP-DNA and Epstein Barr (EB)-DNA up to 1 × 108 copies/ml and 4.8 × 105 copies/ml, respectively. MP resistance mutation site 2063/2064 was also positive. No other etiological evidence was found in body fluid and secretions. Hypokalemia (K 3.28 mmol/l) and dysfunction of blood coagulation () occurred during disease. On 5th day, chest radiography showed increased patchy shadows in the left lung (). Therefore, the second PB was performed to relieve bronchial casts. After administration with methylprednisolone of 10 mg/kg/d and gamma globulin of 2 g/kg, body temperature returned to normal and anoxia was improved on the 6th day. The methylprednisolone was applied for 11 days. She was discharged on the 12th day and the titer of MP-IgM was increased by eight times on the 14th day (). In the follow-up, she still had cough on the 18th day. On the 48th day, the chest X-ray turned to normal ().

pmc-8696182-3

A 4.3-year-old boy was admitted on April, 2016 due to 5-day fever and cough. He was in good health and had never been to hospital. Two days before admission, pulmonary CT from other hospital suggested inflammatory consolidation with atelectasis. Therefore, the first FB was performed to etiological diagnosis and atelectasis treatment on admission. FB revealed fibrinoid formation in the right upper lobe. After 2 days of treatment of cephalothin and azithromycin, the condition worsened and hypoxemia developed. Arterial blood gas revealed PaCO2 43 mm Hg, PaO2 56 mm Hg, and oxygenation index 266. Then, reservoir mask of 6 l/min was adopted for ventilatory support. Physical examination revealed temperature 38.0°C, heart rate 135 beats/min, respiration 32 times/min, blood pressure 90/60 mm Hg, and transcutaneous oxygen saturation 90% without oxygen administration, fatigue, and decreased respiratory sound in the right lung. Cardiovascular, nervous system, extremities, ANA, and ENA examinations were normal. Routine blood tests showed Hb 132 g/l, WBC 12.2 × 109/L, N 73.3%, and L 27.1%. The biochemical examination revealed a result of aspartate aminotransferase (AST) 2,031 U/L, alanine transaminase (ALT) 1,595 U/L, lactate dehydrogenase (LDH) 2,673 U/L, creatine kinase-MB (CK-MB) 41 U/L, triglyceride 1.33 mmol/l, procalcitonin (PCT) 1.56 ng/ml, CRP 38.8 mg/l, and ferritin 4,355 ng/ml. MP-DNA reaching 1 × 108 copies/ml in BAL fluid and MP resistance mutation site 2063/2064 were positive and MP-DNA of hydrothorax was 3.2 × 105 copies/ml. On the 2nd day, pulmonary CT suggested substantial pulmonary consolidation in the upper and middle lobes of the right lung accompanied by significant effusion (). Due to persistent fever and significant elevation on blood inflammatory indicators, an additional methylprednisolone of 10 mg/kg/d was added for anti-inflammation and it was applied for 14 days. B-ultrasound showed that the maximum depth of pleural effusion was about 70 mm. Then, thoracentesis was performed and 300 ml of light yellow liquid was drained. Due to plastic casts in the airway and persistent consolidations in X-ray, FB was performed on the 3rd day and 6th day again. His temperature returned to normal and blood oxygen improved on 7th day. On 9th day, B-ultrasound showed no pleural effusion. The chest X-ray was normal and the titer of MP-IgM was increased by eight times on the 14th day. This patient had a fever for a total of 7 days after admission and discharged with azithromycin (oral) on the 15th day (). No other etiological evidence was found in body fluid and secretions. She was followed-up without any discomfort on the 22nd and 52nd day.

pmc-8696256-1

A 61-year-old male was diagnosed with de novo metastatic melanoma in January 2020 after presenting with sudden onset left upper limb dyspraxia and confusion. Comorbidities included hemochromatosis and a distant history of meningococcal meningitis. Magnetic resonance imaging (MRI) brain demonstrated a large right parietal lesion. Computed tomography (CT) and positron emission tomography (PET) scan revealed left upper and lower lobe lung lesions, solitary liver lesion, and base of skull lesion. Histopathology confirmed BRAF/NRAS wild-type metastatic melanoma. He proceeded with resection of the right parietal lobe metastases in February followed by ipilimumab (3 mg/kg)/nivolumab (1 mg/kg) commencing in March (). MRI brain on the April 3 demonstrated intracranial recurrence with PET/CT confirming stable extracranial disease. A redo craniotomy was performed on April 8, complicated by the development of cerebral abscess and ventriculitis requiring burr hole and drainage. Cultures confirmed corynebacterium acnes and he commenced intravenous (IV) Cephalothin for a total of 12 weeks. Six weeks following his last dose of immunotherapy and while on IV antibiotics for his cerebral abscess, the patient developed severe peripheral edema, dyspnea, and tachycardia. Electrocardiograph (ECG) demonstrated sinus tachycardia, left axis deviation, and right bundle branch block. Transthoracic echocardiogram (TTE) revealed a new circumferential pericardial effusion with early signs of tamponade. Serial troponins remained normal, and cardiac MRI showed no evidence of myocarditis. A diagnosis of ICI-induced pericarditis with associated pericardial effusion was made. The patient was commenced on aggressive diuresis, colchicine 500 mcg daily and ibuprofen 500 mg three times daily. The active decision to withhold high-dose corticosteroids was made given the patient’s concomitant cerebral abscess. He was monitored with weekly echocardiograms by the treating cardiologist with gradual resolution of the pericardial effusion over 4 weeks. Immunotherapy was discontinued. In June 2020, the patient had a further recurrence of brain metastases. A third resection followed by stereotactic radiosurgery to the cavity were completed at that time. Seven months following cessation of immunotherapy, the patient presented with sudden onset aphasia, left lower limb myoclonic jerks, and confusion. Further history revealed that the patient had developed subtle behavioral changes in the weeks prior. CT brain and angiogram showed no evidence of acute cerebrovascular event, infection, or intracranial disease progression. Laboratory results showed a normal CRP (0.7 m/L) and mild hyponatremia (129 mmol/L). An MRI brain revealed T2/FLAIR hyperintensity in the right mesotemporal lobe with differentials including encephalitis or postictal changes (). Electroencephalogram (EEG) demonstrated lateralizing periodic discharges from the right temporal region. Empirical acyclovir was commenced following a lumbar puncture that demonstrated a mild elevation of protein 0.62 g/L, normal white cell count, negative bacterial/fungal cultures, and negative viral PCR panel. Despite up titration of antiepileptics, the patient continued to deteriorate with increasing confusion, fluctuating level of consciousness, persistent dysphasia, and development of visual hallucinations. Autoimmune encephalitis and antineuronal antibody panels were normal. ICI-induced encephalitis was considered the most likely diagnosis and methylprednisolone 500 mg IV/day was initiated, continued for 3 days, and followed by 2 days of 250 mg IV/day. There was a rapid and remarkable improvement in symptoms following steroid administration. A repeat EEG showed resolution of lateralizing periodic discharges from the right temporal region. He was discharged on 80 mg oral prednisone, which was slowly weaned over 2 months. The patient has continued on surveillance since cessation of immunotherapy in April 2020. His most recent imaging in March 2021 demonstrated an ongoing near-complete response of his metastatic melanoma. His pericarditis has not recurred with significant but partial neurological recovery from his grade 4 encephalitis.

pmc-8697878-1

A six-year-old, 9.7 kg, male Cavalier King Charles spaniel was referred to the Cardiology Unit of the Veterinary Teaching Hospital of the University of Bologna with a two-month history of severe exercise intolerance associated with a syncopal episode. Clinical signs had developed during a local wave of COVID-19 approximately two weeks after the family of its owner had manifested symptoms of this viral disease and their positivity to SARS-CoV-2 had been confirmed by the local Health authority. Despite the dog’s clinical condition, evaluation at our institution was postponed and performed only after two months from the occurrence of the aforementioned signs due to the COVID-19 illness and related quarantine of the owners. The dog had been previously evaluated by the primary veterinarian several times since he was a puppy, as regular examinations were performed approximately every six months. Previous medical history was unremarkable and no cardiac problems had been identified at earlier examinations. The patient was an indoor dog that was being fed a high-quality balanced commercial diet. He had no known exposure to toxic agents or medications and was current on vaccinations and parasite prevention. Upon presentation, cardiac auscultation revealed a grade II/VI left apical systolic murmur; the heart rate was 136 beats/min and the cardiac rhythm was regular. The femoral pulse was strong and synchronous with the heartbeat. Non-invasive systolic arterial blood pressure, assessed by a high-definition oscillometric device (petMAP graphic, Ramsey Medical, Inc., Tampa, USA), was 166 mmHg. Given the patient’s anxiety during physical examination, the pressure value was primarily interpreted as situational hypertension. Respiratory rate was mildly accelerated (44 breaths/min), likely due to the dog’s emotional stress, but lung auscultation was within normal limits. The remainder of the physical examination were unremarkable. Thoracic radiographs revealed mild generalised enlargement of the cardiac silhouette (vertebral heart scale 11.5, breed-specific reference interval 10.60 ± 0.50 []), with no obvious lung parenchymal abnormalities (). Sinus rhythm was observed on a six-lead surface electrocardiogram (Cube ECG, Cardioline S.p.A., Caverano, Italy) (). A transthoracic echocardiography was also performed by a board-certified cardiologist (GR) using an ultrasound unit (iE33 ultrasound system, Philips Healthcare, Monza, Italy) equipped with phased-array transducers (3–8 and 1–5 MHz) and continuous electrocardiographic tracing (, ). This showed LV volume overload and global systolic dysfunction without concomitant left atrial dilation (). Although the mitral valve leaflets were structurally and functionally normal, a mild mitral regurgitation with central jet was present. In light of the aforesaid findings, the valve insufficiency was hypothesized to be functional and due to the dilated cardiomyopathy (DCM) phenotype. No other echocardiographic abnormalities were identified. Results of routine blood work, including complete blood count, serum chemistry and coagulation profile (prothrombin time, activated partial thromboplastin time, fibrinogen and antithrombin), were unremarkable. In light of the DCM phenotype, further laboratory tests included a thyroid profile and assessment of the serum concentration of cardiac troponin I (cTnI, IMMULITE 20000, Siemens, Erlangen, Germany). The former test ruled out hypothyroidism as a possible cause of LV systolic dysfunction (thyroxine 29.5 nmol/L, hospital reference interval [HRI] 13–51 nmol/L; thyroid stimulating hormone 0.12 ng/mL, HRI 0.03–0.38 ng/mL), while the latter unveiled MI (0.19 ng/mL, HRI < 0.15 ng/mL) [,]. The dog was started on pimobendan (Vetmedin, Boehringer Ingelheim, Ingelheim amRhein, Germany) at a dose of 0.25 mg/kg orally every 12 h, and several blood samples were collected with the aim of submitting them for investigation of infections responsible for MI. Initially, serological tests for Borrelia burgdorferi, Dirofilaria immitis, Anaplasma phagocytophilum, Ehrlichia canis, Leishmania infantum, Toxoplasma gondii and Bartonella henselae infection were performed (SNAP 4Dx, IDEXX Laboratories, Inc., Westbrook, U.S.A.; MegaFLUO LEISH, Vetefarma S.r.l., Cuneo, Italy; MegaFLUO TOXOPLASMA Gondii, Vetefarma S.r.l., Cuneo, Italy; Indirect immunofluorescence performed as described by Fabbi et al. []), yielding negative results. Given the family history as well as the ongoing and still unexplained MI, further serum samples were subsequently submitted for SARS-CoV-2 investigation [,]. Different serological assays were performed (using samples collected on the same day) to detect antibodies against the S and the N proteins of SARS-CoV-2. More in detail, specific neutralizing antibodies against the receptor binding domain of the spike protein were determined in serum samples using the SARS-CoV-2 surrogate virus neutralisation test (sVNT, GenScript cPass™ SARS-CoV-2 Neutralisation Antibody Detection Kit, GenScript Biotech Co., Ltd., Leiden, Netherlands) following the manufacturer’s instructions (positivity: ≥30% inhibition). Furthermore, SARS-CoV-2 neutralization assay (VNT) was performed as described by Rijkers et al. [] (positivity: titers ≥1/10). Lastly, a commercial multispecies enzyme-linked immunosorbent assay (ELISA; EradikitTM COVID19-Multispecies, In3Diagnostic, Turin, Italy; positivity: >20%) was performed. Pending serological results, no other therapies were prescribed in addition to pimobendan, but exercise restriction was recommended. Within two weeks, results from serological assays became available. All tests yielded a positive result (). In light of such findings, approximately two weeks from presentation, another control was performed to recheck the clinical, cardiological and serological condition of the dog, and to obtain nasopharyngeal and rectal swabs for SARS-CoV-2 genome detection (using a real-time polymerase chain reaction (PCR) targeting E gene, as previously described by Corman et al. []). The owner reported an improvement in exercise tolerance and no further syncopal episodes. Physical evaluation was unremarkable, with the only exception being the heart murmur, which maintained unchanged characteristics. Echocardiography demonstrated a mild improvement of LV systolic function, although a DCM phenotype and a functional mitral regurgitation were still present, thus explaining the persistence of the heart murmur (). Blood samples were collected to monitor the antibodies against SARS-CoV-2 as well as the serum concentration of cTnI. All serologic assays were still positive () and cTnI was still over the HRI (0.17 ng/mL). SARS-CoV-2 molecular analysis yielded a negative result. Therapy as well as instruction at home were unchanged, and another recheck was planned within three weeks. At that control, although the clinical and echocardiographic findings were stable compared to the previous examination, and two serological tests were still positive (i.e., sVNT and VNT), cTnI was normalised (0.09 ng/mL) and ELISA yielded a negative result for SARS-CoV-2 (). The dog continued to receive pimobendan and be revaluated regularly over the following weeks, showing a good clinical condition, stable echocardiographic parameters and a cTnI within the HRI. He is still alive and doing well at the time of manuscript writing (9 months from the occurrence of clinical signs and 7 months from the first evaluation at our institution).

pmc-8697958-1

In the first week of April 2021, one 11-month-old female PI calf (Brown breed) was identified in a herd of Apulia region, Italy, that consisted of 99 Alpine Brown cattle, all under the age of 1 year, including 91 lactating cows. The herd adheres to the compulsory eradication plans for tuberculosis, brucellosis and bovine leucosis and to the voluntary eradication plan for BVDV. The PI animals are destined to be slaughtered. The PI calf was taken to the Veterinary Hospital of the Department of Veterinary Medicine of the University of Bari, Italy, for a diagnostic confirmation of BVDV PI and for clinical and hematological assessments to be shown to students of the Veterinary Medicine degree course. A week before arrival, the calf was clinically examined on the farm of origin and subjected to virological and bacteriological investigations. To this purpose, nasal swabs (NSs) collected from both nasal cavities with a dry sterile swab, a fecal swab (FS) collected directly from the rectum with a similar dry sterile swab and EDTA-treated blood and serum samples were collected to monitor the health of the calf and the concomitance of other viral and/or bacterial infections. In particular, NS, FS and EDTA-treated blood were tested in RT-qPCR for BCoV, BVDV, bovine respiratory syncytial virus (BRSV), bovine parainfluenza virus (BPiV), bovine adenovirus (BAdV), bovine herpesvirus type 1 (BoHV-1), Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis. The serum sample was tested for antibodies detection using the ELISA test (Svanovir® BVDV-Ab, Boehringer Ingelheim Svanova, Uppsala, Sweden) and the neutralization test for BVDV and BoHV-1, respectively. The collected samples were immediately transported on ice to the laboratory of Infectious Diseases of the Department of Veterinary Medicine of Bari (Italy) and stored at −80 °C (NS, FS) and at RT (blood samples) before processing. The calf, which arrived on 12 April 2021 (T0), was immediately hospitalized in the Infection Diseases Unit of the Veterinary Hospital in a separate room and subjected to clinical examinations on the day of arrival and then two times a day during the entire period of hospitalization (Italian Ministry of Health authorization n. 0017484-DGSAF-MDS-P). To minimize the stress and discomfort, the calf was kept in a pen with straw bedding, was fed a commercial concentrate twice daily and had access to haylage and water ad libitum. The facility was closed for other animals and had restricted admission for people. A trained animal technician and a veterinarian monitored the calf at least two times a day. To enter the animal room area, the investigators undressed and put on work clothes and boots. The presence of the following clinical signs was noted down: rectal temperature, pain and depression, nasal discharge, polypnea, coughing and diarrhea. Two days after arrival (T1), the calf showed hyperthermia (39.8 °C) and, consequently, NS, FS, EDTA-treated blood and serum samples were collected to monitor its health status and to assess the presence of concomitant virological/bacteriological infections. The presence of BVDV was confirmed in the blood, NS and FS, and BCoV was contextually detected in the NS. As a consequence, stool samples, NSs, serum samples and EDTA-treated blood were collected weekly up to 60 days (T60) until BCoV test were negative.

pmc-8698328-1

The first patient is a 53-year-old male with a long history of paroxysmal atrial fibrillation. He had some cardiovascular risk factors, including high blood pressure that had been well controlled for 5 years on a therapy with ACE inhibitor. He did not suffer from other relevant comorbidities, except for sleep apnea syndrome on home nocturnal ventilatory support. He had his first episode of paroxysmal atrial fibrillation six years before and he started oral anticoagulation with dabigatran (CHA2DS2-VASC score 1) and antiarrhythmic therapy, initially with Flecainide and then with Amiodarone. Despite this, he had been admitted several times to the emergency room due to irregular heartbeat episodes and other symptoms, such as palpitations and shortness of breath. The arrhythmic recurrences often required electrical or pharmacological cardioversions to control the symptoms. The patient was then referred to our clinic because of the gradual worsening of his symptoms. The arrhythmic episodes lasted several hours, with spontaneous resolution, crippling him in his daily life. Considering his young age, the absence of cardiac structural alterations, and the inefficacy of the rhythm control strategy, AF ablation was proposed to the patient. At admission into the ward, the patient was overweight (body mass index was 38 kg/m2) and the electrocardiogram showed a normal sinus rhythm, while the pre-procedure echocardiography revealed dilated left atrium (left atrial volume 43 mL/m2) and the ejection fraction of the left ventricle of 55%. We started the procedure by performing a bipolar map of the right atrium with a ThermoCool SmartTouch™ SF (Biosense Webster, Johnson & Johnson Medical S.p.a., Irvine, CA, USA) ablation catheter. First, we delineated the inferior and superior vena cava, and the coronary sinus, and we tagged in yellow the His potential (A). Next, we carefully reconstructed the interatrial septum and, finally, to precisely define the fossa ovalis (FO), we set the color range on the bipolar map to 0.25–0.75 mV and we tagged in light blue all the fragmented and low voltage signals, which are typical of the FO area [] (A). The FO location was further confirmed by the ICE and the CartoSound® module (Biosense Webster, Johnson & Johnson Medical S.p.a., Irvine, CA, USA). A 10F Soundstar™ Ultrasound catheter was advanced in the right atrium and pointed at the FO. Thanks to the CartoSound® module, it was possible to mark the contours of the FO location and to visualize them on the 3D EAM previously obtained (B). In addition to the FO, using ICE and the CartoSound® module, it was possible to assess and to reconstruct the structures of the left atrium (left atrial appendage, pulmonary veins, and esophagus). Next, a single transseptal puncture was performed using the bidirectional guiding sheath VIZIGO™ (8.5F) and a transseptal needle (standard Brockenbrough needle 98 cm from Abbott, St. Paul, MN, USA). Since the sheath is visible on the Carto 3® EAM system, it was possible to place it in the superior vena cava (3 to 4 cm above the cavoatrial junction) without any use of fluoroscopy. At this point, the guidewire was removed and the transseptal needle with the stylet was gently inserted and advanced through VIZIGO™, avoiding pushing the needle over the tip of the sheath. In this step, the needle and the sheath were held in the fingers between 4 and 6 o’clock. The needle and the sheath were pulled back caudally, visualizing the VIZIGO™ sheath with the 3D EAM system until it reached the level of the coronary sinus and the tip of the dilator inside the sheath placed in the FO. From this location, the VIZIGO™ sheath was pushed and placed on the FO under the guidance of the EAM system and confirmed by ICE imaging (C). When the sheath was in the right position, the transseptal needle was advanced to perform the puncture. Live tracking of the distal part of the needle on the 3D EAM system was possible thanks to an Alligator clip lead wires (FIAB Spa, Florence, Italy) connected to the distal portion of the needle (see ). Both the transseptal sheath and the needle should be advanced for 1–2 cm in the left atrium (LA). Then, holding the needle, the sheath was advanced over the needle. Finally, the needle and the dilator were kept steady, and the sheath was advanced over the dilator. The transseptal sheath was deaired and a 0.032 inch guidewire was advanced toward the left superior pulmonary vein under ICE guidance. After a successful transseptal puncture, the ThermoCool SmartTouch™ SF catheter was advanced through the VIZIGO™ sheath into the left atrium to perform a fast anatomical mapping and PVI following the CLOSE protocol []. With the help of the VIZIGO™ steerable sheath, we performed ablations with good contact and stability, leading to fast and effective PVI. There were no complications during the entire procedure. The procedure time was 100 min, radiofrequency time was 20 min, and, finally, the fluoroscopy time was 00:00 min:s. The patient was followed up 3 months after the procedure with an outpatient visit and electrocardiographic-Holter monitoring, which did not register any AF episode. After a 9 months follow-up, the patient presents no more symptoms, is not taking any antiarrhythmic drugs, and does not have recurrences of AF. He is taking apixaban 5 mg twice a day and ACE inhibitor drug for blood pressure control.

pmc-8698328-2

A 46-year-old male was referred to our clinic due to a long history of persistent atrial fibrillation. He had arterial hypertension and diabetes mellitus under good pharmacological control. He also had microcythemia due to a thalassemic trait. The atrial fibrillation was discovered seven years earlier with an electrocardiogram performed during a routine medical examination. The patient was asymptomatic for palpitations, irregular heartbeat, or other cardiological symptoms. An echocardiogram was performed without showing any pathological feature and oral anticoagulation with Dabigatran (CHA2DS2-VASC score 2) was started. After four weeks of therapy, electrical cardioversion was performed with effectiveness in restoring sinus rhythm. An antiarrhythmic therapy with Flecainide 100 mg twice daily was also initiated. The patient did not undergo further medical checks during the following five years, when, during a cardiological visit, the recurrence of the arrhythmia was discovered. The patient mentioned reduction in daily normal activity due to asthenia. An echocardiography exam showed a left atrial indexed volume of 36 mL/m2 and a left ventricular ejection fraction of 47%. AF ablation through PVI was proposed. At admission, the electrocardiogram showed AF. To perform an accurate anatomical reconstruction of the right and left atrium and a high-density voltage map, the multi-electrode mapping (MEM) catheter Pentaray™ (Biosense Webster, Johnson & Johnson Medical S.p.a., Irvine, CA, USA) was used. As in the previous case, we started by mapping the right atrium to define the inferior and superior vena cava, the His location, and the coronary sinus (A). Next, a decapolar catheter was inserted in the coronary sinus under 3D EAM guidance. Again, we mapped the FO looking for fragmented and low-voltage signals. However, this time, using the Pentaray™ catheter, we were able to achieve a higher signal resolution and to easily discriminate between a low-voltage and fragmented signal area, although the patient was in AF. Moreover, using the Pentaray™ catheter, we were able to acquire a detailed map in a shorter time (5 min with Pentaray™ catheter vs. 10 min with Thermocool SmartTouch™ SF catheter in the previous case). Again, based on the 3D EAM and under ICE guidance, a single transseptal puncture was performed with the VIZIGO™ sheath and the transseptal needle, both visible on the 3D EAM system (B,C). The transseptal puncture procedure followed the same steps already described in the previous case (video of the puncture is available in the ). The Pentaray™ catheter was then advanced in the left atrium through the VIZIGO™ sheath and a detailed fast anatomical mapping of the chamber and the veins was obtained (). The VIZIGO™ steerable sheath was extremely useful to map all the left atrium structures and veins very quickly. Moreover, using ICE imaging and the CartoSound® module, we could identify important structures, such as the pulmonary veins (A) and the esophagus (B), and to co-register the ultrasound images with the fast anatomical map obtained with CARTO 3®. The Pentaray™ catheter was then replaced by the ThermoCool SmartTouch™ SF catheter to perform PVI following the CLOSE protocol []. Again, with the help of the VIZIGO™ steerable sheath, we performed ablations with good contact and stability, leading to a fast and effective PVI. As in the previous case, the entire procedure was performed without fluoroscopy and without complications (procedural time was 110 min, radiofrequency time was 19 min, and fluoroscopy time was 00:00 min:s). The patient was followed up 3 months after the procedure with an outpatient visit, echocardiogram, and electrocardiographic-Holter monitoring, which did not register any AF episode. The echocardiogram showed a normal left ventricular ejection fraction (65%) and the patient mentioned that there was not a reduction in normal daily activities. After 6 months follow-up, the patient is taking low dose of flecainide (50 mg twice per day), apixaban 5 mg twice per day and has not recurrences of AF.

pmc-8698451-1

A 20-year-old Caucasian male (1.75 m tall and 76 kg (BMI 24.8)), was admitted to the medical department for persistent hyperpyrexia, severe sore throat, dyspnea, and impaired consciousness with stupor. Persistent symptoms started at home 4 days before and he assumed clarithromycin as empiric antibiotic therapy. The physical examination showed jaundice, dry mucous membranes, pharyngeal hyperemia in the tonsillar region and soft palate, and left laterocervical lymphadenopathy. He was tachypneic (respiratory rate of 30 breaths per minute) and the peripheral oxygen saturation (SpO2) in room air was 92%. The abdominal palpation revealed hepatosplenomegaly. The laboratory tests showed a white blood count (WBC) of 8000 cells/mcL with 74% neutrophils, thrombocytopenia (platelet count of 31,000/mcL), total bilirubin 5.8 mg/dL, C-Reactive Protein (CRP) 43 mg/L, creatinine 0.9 mg/dL, AST 150 UI/L, ALT 79 UI/L. The nasopharyngeal swab testing for SARS-CoV-2 was negative (RT-PCR). Blood cultures were carried out upon admission and a full-body computer tomography (CT) was performed on the second day of hospitalization. The CT showed ground glass bilateral pulmonary alterations, pericardial effusion, mediastinal lymphadenopathy, and hepatosplenomegaly (). The neck CT scan with intravenous contrast evidenced a 5.4 cm retropharyngeal abscess with associated thrombosis of the left anterior jugular vein (). On the second day of hospitalization, the microbiology laboratory communicated the early identification of Fusobacterium necrophorum grown in blood cultures by MALDI-TOF (Matrix Assisted Laser Desorption Ionization Time-of-Flight) spectrometry -Vitek ®MS Blood cultures performed at admission and on the second day and collected in standard anaerobic blood culture bottles were positive (). The association of retropharyngeal abscess with thrombosis of the anterior jugular and involvement of other organs systemically and the microbiology led to the diagnosis of Lemierre’s syndrome. Despite empirical antibiotic therapy with piperacillin/tazobactam (18 g/day, continuous infusion), there was a rapid worsening of the clinical conditions with further impairment of the respiratory failure and severe hemodynamic alterations (mean arterial pressure (MAP) constantly <65 mmHg). This picture suggested a progression towards a septic shock status. Consequently, the patient was referred to the Intensive Care Unit (ICU). A multimodal approach was the core of the ICU management of Lemierre’s septic syndrome. It included source control, antibiotic therapy, anticoagulant therapy, hemodynamic support, and continuous renal replacement therapy (CRRT) (). The source control was planned in a sterile environment. Under general anesthesia, the patient underwent an explorative puncture of the retropharyngeal abscess and surgical tracheostomy for airway protection. Unfortunately, although the procedure revealed purulent material, surgeons were unable to collect suitable samples for microbiological testing. At ICU admission, the patient showed a clinical and radiological picture of acute lung injury and the need for deep sedation (propofol, remifentanil, and clonidine), and mechanical ventilation through protective ventilation (tidal volume 6 mL/kg and driving pressure < 15 cmH2O) and high FiO2 (80%). The sequential organ failure assessment (SOFA) score was 12, predicting a high mortality rate (50%) []. About antibiotic therapy, metronidazole (500 mg q8hr, intravenously) was added to piperacillin/tazobactam (started empirically at hospital admission). This antibiotic therapy was based on anecdotal clinical evidence because, due to the lack of cards for antimicrobial susceptibility testing of anaerobes in the laboratory, the antibiogram was not performed. Hemodynamic support was based on the synergic association of norepinephrine and the non-adrenergic vasopressor argipressin (also known as arginine-vasopressin or anti-diuretic hormone) (EMPRESSIN® AOP Orphan Pharmaceutical Group) starting with norepinephrine at 0.3 mcg/kg/min and argipressin at 0.03 IU/min to maintain a MAP > 65 mmHg and lactic acid < 2 mmol/L. On day 2, the drug synergism allowed the rapid reduction of the norepinephrine and argipressin dosages (0.1 mcg/kg/min and 0.025 IU/min, respectively) (). On the same day (day 2), there was an enhancement in the clinical conditions, and the biomarkers of inflammation and organ failure improved (). Despite the adequate MAP (>65 mmHg), from the 3rd to the 6th day of ICU admission, there was a new worsening of the clinical status. It featured anemia (worse value 6.8 g/dL) without evidence of a hemorrhagic source. The hemodynamic monitoring (Edwards EV1000™ device) showed a hyperdynamic septic state (Cardiac Output 15 L/min, Systemic Vascular Resistance 300 dynes/seconds/cm). Due to the worsening of the sepsis-related organ damage, on the 8th day, hydrocortisone (200 mg/day) was added to argipressin and norepinephrine. This approach led to a paramount hemodynamic improvement. From the 8th day of hospitalization, there was a progressive reduction of the dose of both vasoconstrictors until the suspension of norepinephrine, on day 9, and argipressin, on day 12 of ICU stay. Moreover, there was an important decrease in the Sequential Organ Failure Assessment (SOFA) score (from 12 on ICU admission to 7 on day 9). The worsening of the clinical status and the anemia were associated with bilirubin and cytokines rise. The inflammatory response was treated by 4 cycles of continuous hemofiltration (from 4th to 7th day). At the end of the procedure, there was an unexpected rise in D-dimers and in bilirubin values, up to 15.3 mg/dL (10th day), as well as hyperpyrexia. Nevertheless, these findings improved within 24 h. Heparin therapy was administered throughout the entire stay according to thrombocytopenia (enoxaparin 6000 U/day at the beginning and 4000 U twice a day after normalization of the platelet count) monitoring D-dimer values and avoiding intravascular coagulopathy. On the 9th day, a chest tube was placed for the drainage of lung pleural effusion and a new CT was carried out. It showed a persistence of the known injuries of the lungs, liver, and spleen despite the paramount improvements of laboratory and clinical values, as well as the normalization of hemodynamic parameters at monitoring. The patient was discharged to the ward on the 17th day to continue the antibiotic therapy and the rehabilitation program. After the discharge to the rehabilitation care unit, the young man was in good health condition. At the first follow up, performed 15 days after ICU admission, the CT scan showed better lungs ventilation, absence of retropharyngeal abscess, laterocervical lymphadenopathy, and internal jugular thrombosis. Hepatosplenomegaly and some cavitary lungs lesions were found. Another thoracic CT scan was performed after 3 months. It demonstrated an improvement of both the lung lesions and hepatosplenomegaly.

pmc-8698474-1

A 34-year-old male presented with a 6 mm bluish nodule, slowly growing on his forehead. An excisional biopsy was performed, which revealed a pigmented lesion with rare mitotic figures and multiple microscopic satellites, extending into fat (Clark level V) to a depth of at least 4 mm (). Sentinel lymph node biopsy was negative for neoplasm. Immunohistochemical stains for Melan-A and HMB-45 were diffusely reactive and -catenin showed non-specific cytoplasmic staining. Ki-67 demonstrated a low proliferative index (<5% in tumor cells). Four-color in situ hybridization was performed to rule out melanoma which showed normal results. Fusion analysis for 104 using targeted RNA sequencing related genes did not reveal any gene rearrangements including PRKCA and PRKAR1A. Targeted mutation analysis for over 50 cancer-related genes showed GNA11 c.626A>T p.Q209L oncogenic mutation. Finally, whole-genome DNA methylation profiling and t-Distributed Stochastic Neighbor Embedding (t-SNE) cluster analysis were performed as described above. Genome-wide copy number profiles determined from the DNA methylation data failed to reveal significant copy cumber changes (A). t-SNE cluster analysis matched our case to the group of melanocytomas (B). Methylation profiling of tumors offers highly efficient and reliable information for classification of tumors and future studies aiming to explore the optimal use of this technique will warrant improved diagnostic and management approaches for pigmented lesions when there is a concern for malignancy.

pmc-8698542-1

A 61-year-old woman with confirmed COVID-19 was admitted to a different hospital with a productive cough experienced for a few days. She required invasive assisted ventilation shortly after admission. Her medical history included rheumatoid arthritis, obstructive sleep apnea, and arterial hypertension. Because of progressive severe acute respiratory distress syndrome (ARDS), the patient was transferred to our tertiary care hospital for kinetic therapy (prone positioning for at least 12 h per day) and continuous renal replacement therapy (CRRT) due to oliguric acute kidney injury (AKI) (A). Because of progressive hypoxemia, venovenous ECMO therapy was initiated 13 days after admission to our hospital (A). Subsequently, nasopharyngeal swabs and tracheal aspirates tested negative for SARS-CoV-2. After tracheotomy and weaning, ECMO therapy and invasive assisted ventilation were no longer required, but the patient still needed intermittent renal replacement therapy (IRRT) (A). During the course of the disease, the patient developed laboratory signs of liver injury during ECMO therapy before the clinical appearance of jaundice with elevated bilirubin levels, but sustained synthetic liver function reflected by the international normalized ratio (INR) and serum albumin measurements (B–E). A diagnosis of SSC-CIP was confirmed by endoscopic retrograde cholangiopancreatography (ERCP), showing intraductal filling defects in the intrahepatic bile ducts due to biliary casts. In addition, the patient received drugs that have previously been associated with SSC, including amoxicillin-clavulanate, and ketamine sedation [,,]. Plasma levels of bilirubin and ammonia gradually increased after that, with stable liver synthesis reflected by normal values of the international normalized ratio (INR) without substituting coagulation factors (D,E). Nevertheless, the patient developed progressive nausea, vomiting, weakness, and exhaustion as the disease progressed. Hepatic encephalopathy was treated with lactulose and rifaximin, but clinical symptoms worsened (A). Based on these observations, hemadsorption using the CytoSorb hemoperfusion device (CytoSorbents Europe, Berlin, Germany) was used in combination with IRRT (6 treatments within 7 days and 8–12 h per session). In this patient with SSC following ECMO therapy and severe COVID-19, hemadsorption successfully eliminated bilirubin, ammonia, and C-reactive protein (CRP) levels, while serum albumin levels remained stable (A). Direct comparison revealed that bilirubin was less efficiently eliminated by hemadsorption by 33% and 56% after 2 and 6 treatments, respectively (B) compared to ammonia by 65% and 74% after 2 and 6 treatments, respectively (C). During successful elimination of bilirubin and ammonia, clinical symptoms of nausea, vomiting, weakness, and exhaustion improved. Following a continuation of IRRT but termination of hemadsorption therapy, bilirubin (32.2 mg/dL) and ammonia levels (208 g/dL) increased again, worsening clinical symptoms within 20 days. The patient suddenly died due to cardiac arrhythmia before liver transplantation evaluation was initiated.

pmc-8698877-1

A patient of Ukrainian origin (UKR29) was born after the first normal pregnancy (39 week of gestation) from a healthy 27 year old mother and 32 year old father. At birth, the child was registered as a male. Birth weight was 3500 g and length was 53 cm. At the age of two months, the patient was examined due to hypospadias and bilateral cryptorchidism. At that time hormonal analysis was performed. At the age of 14 months a comprehensive examination, such as karyotyping, urological examination (including gonadal and pelvic ultrasound and MRI investigation) and hormonal analysis (including testosterone synthesis stimulation test) were performed. The patient’s psychological development was normal. Neither signs of Wilms’ Tumour nor renal anomalies were found in the patient. Informed consent was obtained from the patient’s parents. Ethical approval for this study was obtained from the Committee on Bioethics of the Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, protocol No. 2 (30 April 2013).

pmc-8699357-1

A 15-year-old male patient presented to the neurology department at our institution with severe Tourette syndrome and comorbid anxiety and depression. The patient’s parents reported that tic onset had occurred when the patient was 9 years of age, when the patient began to exhibit a vocal tic (throat grunting). Motor tics developed at 11 years of age. The tics had worsened over the following three years, at which point the patient developed coprolalia. The patient presented to our movement disorders clinic with severe coprolalia and near-continuous simple and complex motor tics. The patient’s tics were noted to significantly limit his activities of daily living, including self-feeding, self-care, social interaction, and school attendance. Attempts to type were unsuccessful, resulting only in repeated hits to the keyboard interrupted by motor tics. At the time of the initial consultation, the patient had been unable to attend school for over 8 months. He ex-pressed significant feelings of isolation and previous suicidal ideation 6 months prior to consultation. The patient displayed occasional self-injurious tic behavior, including lip/tongue biting and hitting himself in the arm and/or chest. Coprolalia was suggestible and triggerable, with frequency greater than 1/min, concurrent with complex motor tics. Multiple attempts at medical therapy included trials of escitalopram, benztropine, clonazepam, clonidine, sertraline, haloperidol, risperidone, guanfacine, and aripiprazole, all of which failed to decrease tic frequency for more than 4 weeks, at any dose administered. Escalation rate, maximum dose, duration, and concomitant medications were adjusted carefully to ensure that the failure of medical therapy was confirmed by an adequate medication trial. After treatment with a single dose of haloperidol, the patient had an acute dystonic reaction requiring hospitalization. Dystonia at that time was diagnosed by a pediatric movement disorder specialist (TDS) based on published criteria [,]. Haloperidol treatment was discontinued, and dystonia was resolved. Given his lack of response to multiple medications and the severity of symptoms pre-venting activities of daily living including education, DBS surgery was discussed with the patient and his family. Since the optimal DBS target for Tourette syndrome is not known, we recommended use of a staged procedure with implantation of test leads at multiple possible targets []. The patient and his family consulted with neurosurgery (JKC, MAL) and elected to proceed with implantation of temporary depth electrodes at 12 sites and an anticipated hospitalization for testing of approximately 4–7 days. The presurgical work-up included neuroimaging and laboratory studies, which demonstrated no abnormalities or contraindications to surgical intervention. The patient’s mental health counselor expressed no contraindications. He was off all medications at the time of testing.

pmc-8699387-1

A 60-year-old female patient with a medical history of hypertension came to our attention because of several neurological deficits that had developed over the last few years, significantly impairing her daily life. Four years earlier, she developed sudden weakness and hypoesthesia of the right hand. The symptoms resolved in a few days and no specific diagnostic tests were performed. Two months later, she developed hypoesthesia and weakness of the right lower limb. On neurological examination at the time, she had spastic gait, ataxia, slight pronation of the right upper limb and bilateral Babinski sign. Brain MRI showed extensive white matter hyperintensities (WMHs), so leukodystrophy was suspected. However, these WMHs were located bilaterally in the corona radiata, basal ganglia, the anterior part of the temporal lobes and the medium cerebellar peduncle (A–D), and were highly suggestive of CADASIL. Genetic testing was performed, showing heterozygous mutation of the NOTCH3 gene (c.994 C<T; exon 6). The diagnosis of CADASIL was confirmed and antiplatelet prevention therapy was started. Since then, her clinical conditions remained stable, and the lesion load was unchanged at follow-up brain MRIs for 4 years until November 2020, when the patient was diagnosed with COVID-19 after a PCR nasal swab. The patient developed only mild respiratory symptoms, not requiring hospitalization or any specific treatment. Fifteen days after the COVID-19 diagnosis, she suddenly developed aphasia, agraphia and worsened right upper limb motor deficit, but she did not seek medical attention. Some days later, she reported these symptoms to her family medical doctor, and a new brain MRI was performed, showing a subacute ischemic area in the left corona radiata (E,F). Therapy with acetylsalicylic acid was switched to clopidogrel as secondary prevention, while her symptoms improved in the next few weeks. The patient underwent a carotid doppler ultrasound and an echocardiogram, which did not reveal any pathological changes. The review of the blood pressure log, both in-hospital and the personal one the patient had kept, excluded uncontrolled hypertension.

pmc-8699499-1

A 61-year-old male patient was referred for hearing rehabilitation with CI on the left side because of progressive asymmetric hearing loss (see ) and limited communication ability, restricting his professional performance as a dentist. WRS on the left side with a hearing aid was 20%, and on the right side, 50% (FMT at 65 dB SPL). Contrast-enhanced cMRI revealed an intra- and extracanalicular VS (Samii T2) (A,B). Possible treatment options before cochlear implantation included tumor removal via a retrosigmoid approach or SRS as first-line therapy. The patient decided on the first option. Intraoperatively, the vestibulocochlear and facial nerves were preserved as the functionality was monitored with electrophysiologic monitoring (neuromonitoring). cMRI demonstrated a small residual IC VS 6 months postoperatively, and the patient decided to undergo SRS before the cochlear implantation. The SRS was performed during a single session with 13 Gy (70% Isodose; Dmax 18.6 Gy). The implantation was performed successfully six weeks later. The CI was placed more posterior than usual to minimize the artifacts in postoperative MRI scans []. Six months after CI surgery, the first postoperative MRI was performed using 1.5 Tesla MR with medium bandwidth (see C,D for post-CI MRI; the VS is marked with green arrows). A,B demonstrates the patient with the Rondo 2 speech processor (images used with the patient’s approval). One month after implantation, aided WRS with CI on the left side (and masking of the right side) was 45% (FMT at 65 dB SPL) and six months later, 60%. Binaural hearing with CI on the left side and hearing aid on the right side resulted in an aided WRS of 90% (FMT) with CI only after two years. Hearing in noise was measured with the aided Oldenburg Sentence test (OLSA). One year postoperatively, this test revealed scores of −1.1 dB signal-to-noise ratio (SNR) for the left side with CI (with masking of the right ear) and −3 dB with CI and hearing aid on the right side, indicating an improvement of hearing in noise with CI.

pmc-8699499-2

A 76-year-old male complained of bilateral progressive hearing loss for approximately 35 years (see ) and recurrent acute hearing loss on both sides. He reported no tinnitus or vertigo. The patient had a profound hearing loss on the left side with an aided WRS of 20% at 65 dB SPL (FMT) and 0% on the right side with bilateral hearing aids. The hearing nerve integrity was tested with an electrode in the external auditory meatus; the patient could hear humming when the amperage of 531 µA was applied. Cranial MRI performed during evaluation for implantation revealed a multilocular schwannoma on the right side: small IC VS (T1) and a small intracochlear schwannoma (A,B). The case was discussed during the meeting of the Interdisciplinary Skull Base Board. The debated tumor treatment options included resection with a translabyrinthine approach, CyberKnife radiosurgery, or watch-and-scan. All three options were proposed and explained in detail to the patient. In addition, the patient was offered cochlear implantation on the contralateral ear with residual hearing. After presenting possible therapy options for tumor treatment and auditory rehabilitation with CI, the patient decided to treat both tumors using CyberKnife radiosurgery (13 Gy, 70% Isodose; Dmax 18.6 Gy) and opted out from cochlear implantation on the contralateral left ear. One and a half years after the CyberKnife treatment, following two cMRI examinations demonstrating stable tumor (D), the patient opted for cochlear implantation on the right side. Two years later, as he was very satisfied with the right ear’s auditory outcome, he opted for CI on the left ear. Twelve months postoperatively, the patient had an aided WRS of 35% (FMT) on the right side. He uses the CI over 10 h daily and has received the second CI two years after the first one. One year postoperatively, OLSA test revealed a 4.6 dB signal-to-noise ratio (SNR) with CI on the right side and hearing aid on the left side and 11.3 dB for the right side with CI (with masking of the left ear).

pmc-8699499-3

A 57-year-old female patient presented with IC VS on the right side with profound hearing loss after SRS. At the age of 4, she had mumps resulting in a profound sensorineural hearing loss on the left side. An earlier CI evaluation revealed a negative promontory test on the left side. In 2010, she developed hearing loss on the right side, and IC VS was detected using cMRI. SRS was performed in 2019 in a different hospital (3 × 6 Gy) to stop tumor progression and prevent further hearing loss (A: pre-therapeutic PTA). Unfortunately, the hearing loss progressed (B), and by August 2020, aided WRS with a hearing aid was 0% on the right side. Therefore, after cMRI demonstrated a stable tumor, the patient decided on hearing rehabilitation with CI on the right side. The implantation was performed in our unit in November 2020 without complications. Two months after CI, aided PTA improved remarkably (C), and the patient understood 90% of the monosyllables at 65 dB (FMT), remaining on that level six months after implantation. Hearing in noise was postoperatively measured with the aided Oldenburg Sentence test (OLSA). One year postoperatively, the patient scored 1.5 dB signal-to-noise ratio (SNR) with unilateral CI.

pmc-8699610-1

A 74-year old, right-handed female presented with anxiety and depressive symptoms to the psychiatric ED at the University Hospital of Geneva (HUG, Switzerland) in 2012, after SA by abuse of acetaminophen. Although showing depressive symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders (5th ed., DSM-V) [], the latter could not be classified as a major episode of depression (MDD). She had suffered a circumscribed ischemic stroke two years earlier, which had left her with incomplete Broca’s aphasia and dysprosody. By “incomplete” we mean two things here: (i) the fact that the severity of the speech impairment fluctuated over time, leaving the patient with better abilities on some days and worse on others, and (ii) the fact that the patient always retained some capability to express very simple words and phrases. However, due to the patient’s refusal to undergo testing with psychometric scales, we were unable to assess the severity of this deficit through the use of more objective means, such as battery scores. The examining physicians, becoming aware of the specific symptoms, retrospectively examined her file (after the consent of the patient and later of her husband), which contained all the clinical, laboratory, and imaging elements that had been collected. The patient had no family or personal history of psychiatric diseases, nor SI/SB, prior to the onset of her language impairments. Her only other somatic complaint was hypertension. Her family was very supportive and consisted of a husband, three children, and several grand-children. The patient was bilingual in Italian and French and had been working as a writer and translator. After hospitalization in a psychiatric unit, a cerebral MRI was performed, revealing a diffuse white matter high-signal hyper-intensity in the left posteroinferior portion of the frontal lobe, just anterior to motor cortex. Small white matter high-signal hyper-intensities were also located in the frontal lobe of the right hemisphere. A neuropsychological investigation was not possible because of the patient’s refusal. The patient was started on psychotropic treatment with the antidepressant sertraline (increasing the dose gradually to 50 mg/day) and, with an anxiolytic purpose, quetiapine (12.5 mg × 3 per day), a drug that with higher posology is mainly prescribed to treat bipolar disorder and schizophrenia. She was treated by a multidisciplinary team of psychiatrists, neurologists, psychologists, and speech therapists. Although the patient showed gradual improvements, both with regard to the anxious and depressive symptomatologies, we observed marked deteriorations in her psychiatric (increased anxiety and depressive symptoms) and neurological patterns (greater difficulty in finding words and more incongruent prosody) whenever she was asked to describe her situation and emotions to the best of her abilities. We also observed a marked improvement in her language expression abilities once her anxiety and depressive symptoms were controlled. The patient described feeling powerless after the onset of her language deficit, which, having been a professional a professional in the field of language, represented an immense and burdensome impairment for her, eventually leading to her SI and SA. The multidisciplinary team worked to offer her other means of expression besides language, and to mobilize her emotions by employing a range of approaches (art therapy, music therapy, psychomotricity, garden therapy, and pet therapy). Therapists attempted to elicit the activation and expression of complex emotional responses by showing her photographs, both generic and of the patient’s family, by engaging the patient in small “role-playing games” that were interesting to the patient, and by encouraging her to use words in songs that she had memorized during her youth, and to which she was emotionally and affectively linked. While SI was fluctuant initially, after 6 months the patient no longer had any SI and showed an overall improvement. She was therefore discharged and referred to an outpatient facility where she continued treatment for about one year. Then, stating that she was feeling much better, the patient decided to no longer continue her treatment and also wanted to stop attending any sessions with both psychiatrist and speech therapists, contrary to medical advice at the time. Soon after, her anxious and depressive symptoms reappeared, her language expression deteriorated, and, 6 months after stopping her outpatient treatment, the patient performed suicide by drowning in a lake.

pmc-8699826-1

The mother, 34-years old, primigravida (G0P0), underwent all recommended tests. The first-trimester morphology scan revealed normal crown-rump length, visible nasal bone, and normal nuchal translucency value. Moreover, the double marker for chromosomal aneuploidies (13, 18, and 21) indicated a low-level risk. The TORCH IgM and IgG screening showed no acute or recent infection (negative IgM), and the IgG titer was high. The woman had not been previously exposed to harmful factors that would have justified placing the pregnancy in the high-risk category. The second-trimester morphology scan performed at 22 weeks confirmed the normal development of a female fetus. However, at 33 weeks of pregnancy, the first abnormal sign was noted. The amniotic fluid quantity started to increase, leading to the diagnosis of polyhydramnios. Another visible alteration was the shape and position of the lower fetal limbs, indicating minor clubfoot and altered fetal biophysical profile. By the time the pregnancy reached 36 weeks, the biophysical variables were severely modified. The fetal heart rate monitored using the non-stress test was worrying. There were significant decelerations, abnormal fetal movement, and poor muscular tonus. Additionally, the quantity of amniotic fluid continued to rise. Cumulatively, these observations led to the decision to deliver the baby prematurely via emergency C-section, 36 weeks into the pregnancy. The C-section was uneventful, and the mother made a fast recovery, but the female newborn weighing 2200 g received an APGAR score of 3. Unfortunately, when thoroughly examined by our team, it was noticeable that the fetus’s movement, breathing, and swallowing capacity were impaired, and she was unable to sustain spontaneous breathing. The newborn was constantly and fully dependent on assisted mechanical ventilation. Her condition continued to deteriorate despite all the efforts. Unfortunately, at two months of age, the baby succumbed to respiratory failure and multiple associated complications. Based on the clinical signs and paraclinical tests, we were able to establish the following diagnostics: generalized congenital muscular atony, right diaphragmatic hernia, cerebral atrophy, neonatal anemia, bilateral varus equinus, neonatal hypocalcemia, prematurity and low birth weight, ostium secundum atrial heart defect, and tricuspid valve dysplasia. Thoracic X-rays show reduced ribcage expansion of the right hemithorax, suggestive of right diaphragmatic hernia. The transfontanelar ultrasound and head CT showed moderate cerebral atrophy, mostly in the frontal lobe. The generalized and severe muscular hypotonia was investigated using a muscular biopsy that showed no significant alterations. Both tests for aminoacidopathies and spinal muscular atrophy were negative. Serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH) were high but with a tendency to normalize. The karyotype showed a normal profile 46XX. Given the multitude of heterogenic clinical symptoms, we suspected a genetic syndrome yet to be diagnosed, so we proceeded to perform an Array Comparative Genome Hybridization (aCGH) with Single Nucleotide Polymorphism (SNP). aCGH+SNP was conducted on a blade with 4 ∗ 180,000 (180 K) samples (110.112 CGH samples, 59.647 SNP samples, 3000 replicated samples and 8121 control samples) covering the entire human genome with a spatial resolution of ~25.3 kb DNA (G4890A, design ID: 029830, UCSC hg19, Agilent). The scans were interpreted with the CytoGenomics Agilent software, using standard interpretation parameters with a SureScan Microarray Scanner. The resulting profile was abnormal: there were three areas associated with loss of heterozygosity on chromosomes 1 (q25.1–q25.3) of 6115 kb, 5 (p15.2–p15.1) of 2589 kb and 8 (q11.21–q11.23) of 4830 kb, a duplication of 1104 kb on chromosome 10 in the position q11.22, and duplication of 1193 kb on chromosome 16 in the position p11.2p11.1. Considering this abnormal genetic profile, the parental couple received genetic counseling. Furthermore, we continued to test both partners through Next Generation Sequencing (NGS) by Illumina. The results confirmed the following abnormal genetic profile; TTN (NM_001267550.1, sequencing): heterozygous variant on Chr2(GRCh37):g.179479653G>C—TTN variant c.48681C>G p.(Tyr16227*)—exon 260, heterozygous variant on Chr2(GRCh37):g.179396832_179396833del—TTN variant c.104509_104510del p.(Leu34837Glufs*12)—exon 358 (TTN: NM_001267550.1—reference sequence). The TTN variant c.48681C>G p.(Tyr16227*) creates a premature stop codon. Sanger sequencing also confirmed this variant and was classified as likely pathogenic (class 2). The TTN variant c.104509_104510del p.(Leu34837Glufs*12) creates a shift in the reading frame starting at codon 34837. The new reading frame ends in a stop codon 11 positions downstream. This variant has been confirmed by Sanger sequencing, and it is also classified as likely pathogenic (class 2) (). In light of the clinical outcomes, based on the previous unfortunate experience, the couple agreed to receive genetic counseling. The couple was advised to pursue in vitro fertilization (IVF) with preimplantation genetic testing (PGT-M). Considering the mother’s age and weight, her Anti-Müllerian hormone (AMH) serum level and antral follicle count, we used a short-antagonist ovarian stimulation (OS) protocol with 200 UI of FSH (follitropin beta) concomitantly with 150 UI of combined FSH and LH (menotropin). Ten days later, seven oocytes were retrieved through transvaginal, sonographically controlled follicle puncture. Five of them were injected through intracytoplasmic intracytoplasmatic sperm injection (ICSI), resulting in two blastocysts. The embryonic biopsy was performed on day 6 of the blastocyst stage for these two embryos (). The amplification of the entire genome was performed using the SurePlex DNA Amplification System by Illumina Inc. 2018, California US. Using the BlueFuse Multi Analysis Software (Illumina Inc. 2018, San Diego, CA, USA), all 24 chromosomes were detected euploid for embryos. The identification of the mutation TTN gene on exon 358 (father’s mutation) and exon 260 (mother’s mutation) was performed only for euploid embryos using Sanger sequencing with specific primers on ABI 3500. PCR products for both embryos were purified and sequenced in both senses with a BigDye Terminator v3.1 Cycle Sequencing Kit by Thermo Fisher Scientific. Specific primers were manually designed according to both mutations and tested afterwards using blood samples from the parents. Both embryos tested by PGT-A were euploid. One of them was a carrier of the mother’s mutation c.48681C>G p.(Tyr16227), exon 260, and the other was a wild type (WT) for both mutations (). We performed a frozen-thawed embryo transfer in the following cycle, transferring the WT euploid embryo after endometrial preparation with exogenous estrogen. The result was positive, and we confirmed the ongoing viable pregnancy via ultrasound 14 days after. Throughout the pregnancy, we performed the non-invasive double marker test (low-risk result) and fetal DNA analysis using maternal blood (low-risk result) and an invasive amniocentesis at 17 weeks of gestation, indicating a normal genetic profile. To test whether or not the second fetus presents a genetic abnormality, we extracted the DNA directly from the amniotic fluid. Targeted sequencing was performed on both DNA strands of the relevant TTN region. The reference sequence is TTN: NM_001267550.2. To exclude maternal cell contamination (MCC), we analyzed 15 STR autosomal markers plus amelogenin using the PowerPlex 16HS multiplex kit (Promega, Madison, Wisconsin, USA). Moreover, all the non-invasive ultrasound scans showed a normal growth rate and organ development. The evolution of the pregnancy was uneventful, and at 38 weeks, we carried out the C-section delivery of a healthy female baby of 2990 g, receiving an APGAR score of 9.

pmc-8699836-1

A 40-year-old male engineer, former professional rugby player, was referred to our clinic with a left heel inflammatory pain that was worsening during jogging or trailing. The symptoms started seven months before and the patient presented to a regional local hospital for investigations where a plain radiography was performed and a simple bone cyst diagnosis was suspected. Patient was recommended a break from physical activity for six months and non-steroid anti-inflammatories drugs (NSAIDS) to ameliorate pain. The pain increased gradually and he started to complain of swelling. The pain was hardly controlled with NSAIDS and non-morphinic analgesics. Our clinical examination revealed a mild tenderness in the posterior foot, including the ankle and the heel, without evidence of a palpable mass. Ankle and subtalar joint mobilities were limited. The laboratory blood tests and urine analysis results were normal. Radiography revealed a benign-appearing bone lesion of 16 × 19 mm within the anteroinferior part of the calcaneum which was well defined, radiolucent, almost entirely homogeneous with a small central sclerotic focus-“Cockade sign” [,], describing the classical appearance of a calcaneal intraosseous lipoma (). We also performed and MRI exam that showed a focal lesion, hyperintense on both T1 and T2 weighted images, and isointense with fatty tissues (a,b). There was a discreet focal attenuation in the center of the lesion, on T2* sequence, suggestive for focal calcification (c). The MRI aspect corresponded to a Milgram type II intraosseous lipoma (predominantly fatty lesions with central necrosis/calcifications/ ossifications) []. Surgery was performed and a direct lateral approach to the calcaneum was chosen. The saphenous nerve and the long peroneus tendon were reclined superiorly and distally (a). A bone window was performed immediate distally to the lateral tubercle of the calcaneum. Aggressive curettage of the lesion was carried out and the intralesional samples were send to the histopathological exam (b). The cavity was filled with a medium viscosity poly (methyl methacrylate)-based bone cement with gentamycin. No perioperative complications occurred. The histopathological exam () and immunohistochemistry (S100 and Vimentin positive) confirmed the diagnosis, a stage II Milgram intraosseous lipoma. Postoperatively, the pain subsided completely. The patient was discharged the second day after the surgery. Total weight bearing was allowed without crutches. No cast or brace was applied. Rehabilitation was conducted for two weeks in order to encourage full ankle mobilities. In the follow-up, the patient was evaluated every six weeks during the first three months and every six months until the first two years after surgery. Starting from the first postoperative consultation at six weeks, the ankle joint mobilities were normal, the patient was painless, and radiological examination showed no modifications. At the time of the last follow-up at 24 months, no modification and no recurrence were observed (a,b) and the patient returned to work six weeks after the surgery.

pmc-8699839-1

A 72-year-old white male with end-stage liver disease due to cryptogenic cirrhosis underwent a deceased-donor orthotopic liver transplantation (OLT) in 2010. The post-transplant immunosuppression (IS) regimen included tacrolimus 5 mg twice daily, prednisone 20 mg daily, and mycophenolate mofetil (MMF) 1000 mg twice daily. He remained relatively well until seven years post-transplant when he presented with right foot pain and right lower extremity swelling for a duration of 4 weeks. Doppler ultrasound showed an acute right popliteal, tibial, and peroneal deep venous thrombosis for which he was prescribed apixaban. Two months after the initiation of anticoagulation therapy, he presented with a recurrence of right lower extremity swelling, increased pain and numbness, and a new weakening of the right foot. Further history revealed progressive fatigue, dyspnea, and a 30-pound weight loss over 3 months. A computed tomography (CT) of the chest showed scattered lung nodules with multiple areas of bilateral thoracic lymphadenopathy. A positron emission tomography (PET-CT) revealed the abnormal FDG uptake of numerous, sub-centimeter bilateral pulmonary nodules (max SUV 8.4) with mediastinal (1.6 cm, max SUV 13.4), bilateral hilar, right femoral, inguinal adenopathy, and abnormal FDG uptake in a soft tissue mass adjacent to the proximal right femur (5.8 × 3.9 cm2, max SUV 11.9) (). An excisional biopsy of the soft tissue mass showed diffuse infiltration with atypical monomorphic lymphoid cells with large regions of necrosis (). By immunohistochemistry the tumor cells expressed CD3, CD4, CD30 (30%), and BCL-2, and were negative for CD5, CD8, CD10, CD20, CD21, TIA-1, perforin, T-cell receptor (TCR) gamma, and ALK-1. In situ hybridization for Epstein–Barr virus (EBV)-encoded RNA was negative and plasma EBV DNA was not detectable. The proliferation index estimated by Ki-67 staining was 70–80%. TCR gene rearrangement analysis showed a monoclonal band for both the TCR gamma and beta genes. A bone marrow biopsy showed normocellular bone marrow, with trilineage hematopoietic maturation, and no lymphoid aggregates or atypical lymphoid cells, but with a mononoclonal TCR rearrangement identical to that found in the soft tissue mass, consistent with a low-level involvement by T-cell lymphoma. He was diagnosed with stage IV CD30-positive T-cell PTLD, peripheral T-cell lymphoma (PTCL), which was not otherwise specified (NOS). At the time of the PTLD diagnosis, IS therapy consisted only of tacrolimus 1 mg twice daily. After discussion with the transplant team, the tacrolimus dose was decreased to 0.5 mg twice daily, and CHOP-21 chemotherapy was initiated. However, based on the emerging ECHELON-2 outcomes with the addition of brentuximab vedotin (BV) to an anthracycline-based chemotherapy backbone in CD30-positive PTCL, after two cycles of CHOP, the patient’s chemotherapy regimen was changed to BV-CHP [,,]. BV was dosed at 1.8 mg/kg with CHP every 3 weeks with G-CSF support, according to the published ECHELON-2 regimen [,]. Cycle 3 (BV-CHP #1) was complicated by neutropenic sepsis, and BV was reduced to 1.3 mg/kg for cycles 4–6. Cycle 4 (BV-CHP #2) was again complicated by neutropenic sepsis, and cyclophosphamide and doxorubicin dosing were reduced by 25% for the remaining cycles 5 and 6. Interim PET-CT after cycle 4 showed a complete resolution of previously seen pulmonary metastases, a decrease in the mediastinal (1.3 cm, max SUV 9.3; from pre-treatment 1.6 cm, max SUV 13.4) and hilar adenopathy, and a near complete resolution of the soft tissue mass in the right anterior thigh (2.4 × 2.3 cm2, max SUV 1.68, from pre-treatment 5.8 × 3.9 cm2, max SUV 11.9), overall consistent with a partial response (PR). End-of-treatment PET-CT after cycle 6 showed stable disease in the mediastinal (1.3 cm, max SUV 10.25) and hilar adenopathy, and no new or recurrent adenopathy, with complete resolution of the previously seen right lower extremity soft tissue mass, consistent with ongoing PR (). Maintenance therapy with single-agent BV was discussed and started, but after one BV maintenance dose he was again admitted with a neutropenic febrile episode and the patient requested to stop all therapy, as he was satisfied with the achieved response. Following completion of front-line therapy, his course was complicated by elevations of alkaline phosphatase (peak 417 U/L 3 months post-treatment initiation, from pre-treatment 97 U/L) and AST (peak 75 U/L 11 months post-treatment initiation, from pre-treatment 33 U/L) levels. ALT remained within normal limits. A liver biopsy completed 8 months after treatment initiation showed minimal lobular inflammation, but no evidence of portal inflammation, bile duct injury, or endothelitis, as seen with acute cellular rejection, and no ductopenia, as seen with chronic rejection. Due to chemotherapy-induced thrombocytopenia and an episode of duodenal ulcer bleeding, his anticoagulation was briefly interrupted and then re-initiated after endoscopy clipping and the recovery of thrombocytopenia. His known DVTs were monitored with serial Doppler ultrasound, which demonstrated a chronically dilated, thrombosed right popliteal vein with post-thrombotic venous changes, representing chronic thrombosis despite being on anticoagulation. No additional complications were observed. Neutropenia and thrombocytopenia normalized 4 months after the last dose of BV, with mild persistent anemia (8–11 g/dL). He remains alive and well 25 months since his diagnosis without clinical or radiographic evidence of progression.