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pmc-8654109-2

Another 34-year-old male patient who smoked visited the hospital with a history of fever, runny nose, and diarrhea for seven days. There was no complaint of shortness of breath or chest pains. The patient was tested for central nervous system (CNS) response and reflexes and was alert and conscious. Examination of clinical vitals parameters was performed and recorded as BP: 126/76; PR: 43; RR: 21/min; body temperature: 36.6°C; oxygen saturation (SpO2): 98%; CVS: S1+S2+0; chest bilateral vesicular breathing, and no lower limbs edema. EKG reports showed sinus bradycardia with a prolonged PR interval and QT interval; a U wave was observed in V1 (Figure ). Chest X-ray and chest CT showed unremarkable findings (Figures -). Echocardiography also revealed a normal echo study (Figure ). General clinical and blood parameters of the patients are provided in Table . Patient 2 was suspected of COVID-19 due to a non-symptomatic fever. The nasal swab of Patient 2 was tested by the same procedure as for Patient 1 and was SARS-CoV-2 positive. Treatment Both patients were admitted to the isolation room and treated conservatively without hydroxychloroquine and azithromycin. They were administered 1 mg IV atropine and showed a transient change from bradyarrhythmia to sinus rhythm.

pmc-8654114-1

A 50-year-old Indian gentleman, a known case of diabetes and an active smoker, presented with a right eye painless inferior visual field defect upon waking up from sleep. At presentation, his right and left eyes' visual acuity (VA) were 6/24 and 6/9, respectively. Anterior segment examination was unremarkable in both eyes. Fundoscopy revealed swollen right optic disc with peripapillary splinter hemorrhage (Figure ). Humphrey visual field (HVF) showed right inferior altitudinal scotoma. Computed tomography of the brain and orbit proceeded to rule out compressive lesions. Thus, a diagnosis of right eye NAION was made. Three months later, he complained of a worsening visual field of the right eye. VA remained static with the right eye (VA 6/24) and left eye (VA 6/9). Examination showed right eye relative afferent pupillary defect (RAPD) with impaired red saturation and light brightness. His right optic disc was pale; however, the left was hyperemic and swollen with peripapillary splinter hemorrhage (Figure ). HVF showed right eye tunnel vision while the left eye displayed inferior arcuate scotoma (Figure ). The patient was admitted for further investigations and was co-managed by the neuro-medical team. The visual evoked potential test was suggestive of right optic neuropathy. Serum glucose and serum hemoglobin A1c (HbA1c) levels were elevated, measuring 13.9 mmol/L and 9.1%, respectively. Serum total cholesterol (4.6 mmol/L) and low-density lipoprotein (LDL) cholesterol (2.1 mmol/L) were normal, but triglyceride level was high (3.3 mmol/L). Full blood count, erythrocyte sedimentation rate (2 mm/hour), and C-reactive protein (0.7 mg/dL) were all within normal limits. Serum anti-aquaporin-4, anti-nuclear antibodies, rheumatoid factor, and infective screening tests were negative. However, magnetic resonance imaging revealed suspicious enhancement of both intra-orbital optic nerves suggestive of bilateral optic neuritis. Diagnosis of bilateral atypical optic neuritis was made. The patient was loaded with intravenous methylprednisolone 1 g/day for five days and subsequently oral steroid in tapering doses along with topical brimonidine tartrate 0.2%. At the end of one month, his VA remained static and fundoscopy showed left eye resolving optic disc swelling. Despite that, his left eye's visual field progressively deteriorated to inferior altitudinal scotoma (Figure ). Subsequently, we performed a lumbar puncture test, and the result was unremarkable. Repeated MRI of the spine and brain showed no focal enhancing lesion. Upon further history taking, the patient revealed that he had a history of taking phosphodiesterase type 5 (PDE5) inhibitor (tadalafil) on and off over the past year. Hence, we diagnosed him with bilateral sequential NAION, and he was co-managed with the endocrine team to optimize his diabetic status. His subsequent visual field remained static with right eye tunnel vision and left eye inferior altitudinal scotoma (Figure ).

pmc-8654133-1

We present the case of a 30-month-old male who was brought to the family medicine clinic with a complaint of abdominal bloating and persistent diarrhea after every feeding for four months. His stools were foul-smelling and occurred more than four times a day. The diarrhea was associated with a failure to gain weight. The parents reported that the child has a normal appetite with no history of vomiting or feeding intolerance. There was no history of fever, night sweats, rash, cough, or joint pain. The child did not have any recent sick contact. The patient was seen by several general practitioners for the same complaint, but no diagnosis was obtained. The patient had an unremarkable past medical history. He did not have any previous hospital admissions. He had no history of previous surgeries. He does not take any medications and was not known to have any food or drug allergies. Regarding the perinatal history, the child was full term with a birth weight of 3.5 kg. The labor and delivery were unremarkable for any complications. The child was up to date with his vaccination schedule. Regarding the developmental history, the child reached the developmental milestones at the appropriate ages, and there was no parental concern regarding his development. The social history was noncontributory. There was no history of diseases running in the family. The child was not born of a consanguineous marriage. Upon examination, the child was awake and alert and did not appear sick. No dysmorphic features were noted. The patient was below the second standard deviations for weight and height. He appeared pale, and there was no scleral icterus. His vital signs were as follows: heart rate of 90 bpm, blood pressure of 80/52 mmHg, respiratory rate of 22 bpm, and temperature of 36.8°C. Abdominal examination revealed a soft and non-tender abdomen with no organomegaly and had normal bowel sounds. Neurological examination, including hearing and vision tests, was normal. No evidence of muscle wasting was noted. The cardiorespiratory examination was unremarkable. The initial laboratory investigation revealed a hemoglobin level of 14.1 g/dL, leukocyte count of 5100/µL, and platelet count of 370,000/µL. Liver enzymes were mildly elevated. The total protein was 2.9 g/dL. His random glucose level was normal. Stool analysis, including routine culture, ova, and parasite testing, was negative. Stool testing for reducing substances yielded negative results. The remainder of the laboratory evaluations is summarized in Table . Because of the clinical and laboratory findings, the patient was referred to the pediatric gastroenterology center for further investigation. The patient underwent upper endoscopy, which showed no abnormal gross findings. However, mild duodenal inflammation was evident in the histopathological examination of the obtained specimen. The patient underwent a 72-hour fecal fat collection, which indicated the presence of fat malabsorption. Subsequently, the fecal pancreatic elastase level was measured as 20 fecal μg/g. Such findings were consistent with exocrine pancreatic dysfunction. To exclude the possibility of cystic fibrosis as the underlying etiology of malabsorption, a chloride sweat test was performed and yielded negative results. A dedicated abdominal computed tomography scan to evaluate the pancreas for any structural abnormalities was performed. The scan demonstrated complete replacement of the pancreatic parenchyma by fatty tissue (Figure ). The suggested differential diagnoses by the radiologist for the fatty replacement of the pancreas included cystic fibrosis, Shwachman-Diamond syndrome, and Johanson-Blizzard syndrome. The blood sample of the patient was sent for genetic analysis. The diagnosis of Shwachman-Diamond syndrome was established as the analysis revealed a mutation in the SBDS gene (Table ). The detected mutation was previously reported in the literature []. The patient was treated with pancreatic enzyme replacement therapy. After two months of follow-up, the parents reported that the patient had significant improvement in diarrhea. A weight gain was observed. Since the patient did not have any history of bleeding or recurrent infections, treatment with granulocyte colony-stimulating factor was not offered.

pmc-8654134-1

A 27-year-old male patient was admitted to a high-complexity institution due to a five-day clinical picture consisting of additive, symmetrical polyarticular pain, located in the wrists, knees, and left shoulder without other associated symptoms. The joint pain was continuous, permanent, and of great intensity that caused limitation of movement, mainly in the hands. In the systems review, no urinary or gastrointestinal symptoms were documented before the onset of joint symptoms. As the only relevant antecedent, he referred mild respiratory infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed by reverse transcription-polymerase chain reaction the month before hospitalization. The initial clinical examination confirmed the presence of bilateral carpal synovitis, left suprapatellar synovitis, and synovitis of the sternoclavicular joints (Figures , , ). Magnetic resonance imaging of the different compromised anatomical compartments was performed, presenting as additional findings the presence of bursitis of the lateral collateral ligament of the left lower limb and a peritendinous inflammatory process of the triangular fibrocartilage in the right wrist. Mild lymphopenia associated with a marked elevation of acute-phase reactants was documented in laboratory studies. Differential diagnoses of infectious etiology were sought, including a positive fourth-generation HIV enzyme-linked immunosorbent assay with a subsequent CD4 count of 98 cells/mm3 and a viral load of 459,000 copies/mL. Treatment with prednisolone at a dose of 1 mg/kg and sulfasalazine (1 g per day) was initiated and no significant improvement in joint symptoms was noted despite sequential changes from disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and leflunomide. Subsequently, the patient achieved a complete joint response when antiretroviral therapy (abacavir, dolutegravir/lamivudine) was initiated, thereby achieving a response to therapy resulting in gradual reduction of glucocorticoid doses and tapering to maintenance therapy solely with sulfasalazine. The description of the most representative laboratory studies upon admission and during hospitalization is shown in Table .

pmc-8654136-1

A 43-year-old-male with no known medical problems presented from an outside hospital with concern for intraabdominal hemorrhage. He was in an MVC three weeks prior and presented with complaints of right upper quadrant abdominal pain, left-sided chest pain, nausea, and vomiting. A CT scan showed fluid in the lesser sac, suggestive of pancreatic hemorrhage, so he was transferred to the University of Kentucky Medical Center for further management (Figure ). Interventional radiology was consulted, and celiac angiogram showed an arterio-portal fistula in the liver which was embolized with 900 um particles Embozene (Palo Alto, CA: Varian Medical Systems, Inc.), as well as a few tiny rounded foci of contrast enhancement in the spleen which was managed conservatively without embolization (Figure ). Following the procedure, the patient developed an elevated white blood cell (WBC) count and increased abdominal distension. A repeat CT scan four days later showed an increase in the size of the lesser sac hematoma and a pseudoaneurysm in the anterior spleen (Figure ). Surgery was discussed with the patient, which he elected against and preferred to leave the hospital. He returned to the hospital two weeks later with decreased appetite, melena, hematochezia, abdominal pain, and weakness. He was found to be anemic with a hemoglobin of 6.4 g/dL (down from 7.8 g/dL). CT scan and angiographic images revealed worsening diffuse multifocal parenchymal perfusion abnormalities and innumerable punctate foci of contrast pooling in the spleen, compatible with high-grade splenic injury and the Seurat spleen angiographic sign (Figures , ). Coil embolization of the splenic artery was performed with postembolization angiography showing no anterograde flow through the splenic artery, significantly decreased opacification of the previously noted intraparenchymal pseudoaneurysms, and opacification of the spleen via collaterals (Figure ). CT scan one month later revealed normal splenic parenchyma, with a persistent hematoma anterior and superior to the spleen (Figure ). The patient continued to have a complicated hospital course and was found to have multiple myeloma confirmed with a bone marrow biopsy specimen. He, unfortunately, passed away just over a month later due to complications from multiple myeloma.

pmc-8654137-1

A 15-year-old girl presented with chronic complaints of nasal obstruction and hyposmia on the left side. The patient had nasal obstruction symptoms for 6 months; before which she was asymptomatic. She was taking self-administered medications without relief. She had no history of maxillo-facial surgery or trauma in the past. She had no relevant family history or congenital anomalies. Upon clinical examination of the nose, there was a bump along the floor of the left nasal cavity, and her intraoral dentition appeared normal. A plain radiograph of the paranasal sinus and nasal cavity was performed which showed a radiopaque focus in the left nasal cavity (Figure ). The CT scan of paranasal sinuses showed a tooth-like bony structure with a pulp cavity in the hard palate extending into the left inferior nasal cavity and a deviated nasal septum with convexity to the left (Figures -); a shape resembling a canine with a relatively smaller size. Orthopantomogram showed a tooth-like radiopaque structure (white arrow) (Figure ). A three-dimensional computed tomography (3D CT) scan showed a tooth-like structure in the left nasal cavity (Figure ). This intranasal tooth was supernumerary. Mild mucosal thickening was noted in the bilateral maxillary and sphenoid sinuses. No tooth-like structures were found on the right side. All other teeth appeared normal. The patient had complete resolution of nasal obstruction and hyposmia following endoscopic removal of the ectopic intranasal tooth.

pmc-8654142-1

A 56-year-old woman underwent laparoscopic bilateral salpingo-oophorectomy by the gynecological team. The patient has a history of total abdominal hysterectomy 20 years prior for endometriosis. Therefore, adhesions were obscuring the anatomy of the left ureter during her later surgery. In the early postoperative days, there was mild pain at the left iliac fossa and was managed with paracetamol and oral morphine. In the early period, there was no flank pain and no costovertebral angle tenderness. One week later, the patient presented to the emergency department with severe left iliac fossa pain associated with nausea and vomiting. Her investigations were within normal range, stable renal function, and normal inflammatory markers. Contrast CT showed extravasation of the contrast at the level of the left renal pelvis (Figure ) and ureteric dilatation down to the pelvic ureter (Figure ). Considering the recent pelvic surgery, immediate diagnosis of left ureteric iatrogenic injury was concluded, and the patient was managed initially with urgent CT-guided nephrostomy insertion. The patient was in pain and an adequate nephrostogram was not performed during nephrostomy insertion. Therefore, three weeks posttraumatic injury, the patient underwent a proper antegrade nephrostogram. The contrast extravasated into the peritoneal cavity and there was no contrast passing into the distal left ureter (Figures , ). Therefore, a diagnosis of complete transection of ureteric injury was suspected. The nephrostomy was left in situ and the patient was planned for reconstructive surgery. Eleven weeks posttraumatic injury, the patient was admitted for her planned surgery. Prior to the surgery, left retrograde study was performed and surprisingly the contrast went up to the left kidney with only annular stricture at the level of the injury (Figures , ). Therefore, a decision was taken for ureteroscopic dilatation of the stricture. The ureteroscopy showed a small annular stricture, less than 0.5 cm, that was passed easily over the safety guidewire and a ureteric stent, size 8 French, was inserted successfully.

pmc-8654143-1

A 76-year-old female with a past medical history of hypertension presented to the emergency department with persistent forehead swelling two months after recovering from COVID-19 infection. The patient was diagnosed with COVID-19 pneumonia in Egypt and completed a six-week course of dexamethasone. Per family, she also received multiple antibiotics during this time, the names and courses of which were unknown. She subsequently developed progressively tender frontal scalp swelling. Initial evaluation with otorhinolaryngology (ENT) in Egypt showed mucor-like organisms on pathology. She then came to the United States and was admitted for further evaluation. Her CT head showed evidence of multifocal sinusitis with breach of the inner and outer tables of the right frontal sinus with dural enhancement (Figure ). The CT scan also confirmed dehiscence of the inner table (Figure ). She was then empirically started on a course of Amphotericin for post-COVID mucormycosis. The patient underwent surgical debridement of significant underlying purulence with intraoperative cultures growing extended-spectrum beta-lactamase-producing Escherichia coli and methicillin-resistant Staphylococcus aureus. Due to these culture results, the patient was initiated on vancomycin and meropenem with minimal improvement in edema. She underwent repeat surgical debridement two weeks later with cultures redemonstrating previously identified bacteria with rare Pseudomonas aeruginosa growth as well. The patient endorsed moderate improvement in frontal scalp tenderness following this debridement. She was thus discharged home on a six-week course of IV vancomycin through a peripherally inserted central catheter, PO levofloxacin, and PO posaconazole, with a plan to continue the latter until fungal cultures were finalized. Two weeks later, she presented to the outpatient clinic with new-onset generalized weakness. Initial workup revealed profound hypokalemia (potassium of 1.5 mEq/L; normal range 3.4-5.3 mEq/L) and acute kidney injury (creatinine of 3.03 mg/dL from baseline of 1.20 mg/dL; normal range 0.65-1.00 mg/dL) likely due to vancomycin-related renal derangements and potassium wasting due to posaconazole. The patient was admitted for fluid resuscitation and switched from vancomycin to daptomycin upon discharge to prevent further renal impairment. As all her fungal cultures were negative and no fungal forms were seen on pathology, posaconazole was discontinued. The patient was able to complete her course of treatment, though it was complicated by mild creatine kinase elevation due to daptomycin. Repeat MRI at the end of her antibiotic course demonstrated decreased soft tissue thickening along the anterior skull base and superior nasal cavity with improvement in mucosal thickening involving maxillary sinuses, sphenoid sinuses, and residual ethmoid air cells (Figure ). However, two weeks later, the patient complained of persistent frontal tenderness and was noted to have new periorbital swelling. Due to frontal sinus sequestrum formation and worsening of symptoms soon after antibiotics were stopped, the patient was recommended to undergo craniectomy to achieve definitive source control. She also had to be restarted on daptomycin and meropenem while awaiting surgery.

pmc-8654144-1

A 29-year-old male was brought to the emergency department following a car accident. It was reported that the wheel of a 5-ton water tanker rolled over his lower body as he was stepping into a car. Workup revealed a Glasgow Coma Scale (GCS) score of 15 with a pulse rate of 80 beats per minute and blood pressure of 90/60 mmHg. There was profuse bleeding due to a perineum injury. No fractures of the skull, cervical spine, and pelvis were detected in the X-rays. Urinary catheterization was performed without difficulty and there was no hematuria. No internal bleeding was seen during the abdominal ultrasound. The patient was immediately taken to the operating theatre for injury assessment after the replacement of fluid and blood. Operative Findings and Procedure While the patient was placed in the lithotomy position, the anterior displacement of the anus could be seen with a circular skin defect surrounding the region. The anus looked normal. There was a remaining 1 cm of normal perianal skin with no actual skin loss. Digital and proctoscopy examination showed an intact anorectum and its surrounding sphincters. Whereas exploring the wound revealed complete disruption of the posterior pelvic floor with lateral extensions into both gluteal regions and the right thigh. In addition, a hand could be passed behind the rectum and into the sacral promontory. The case was associated with extensive venous bleeding with the absence of major arterial tears. It was managed by the insertion of multiple packs along with partial closure of the skin defect. A small incision was made to perform a defunctioning sigmoid colostomy. No intra-abdominal bleeding was reported. The packs were removed two days later without any bleeding complications. A total of 22 units of blood were required during the first 48 hours of admission. Figures , show the site of injury before and after treatment, respectively. Progress Continuous follow-up examinations were done during the following months of the accident. Seven examinations under anesthesia were performed. The skin was not closed completely at the site of the procedure. Consequently, it was decided not to reallocate the anorectum to a further posterior direction and the wound was left open. Initially, infection of deep injury recess was found and debridement and daily cleaning with betadine was performed. In later stages, as the wound became clean, saline dressings were substituted and the wound healed by granulation. The defect was reduced to an area of 4 x 2 cm after four months of the procedure and was contracted towards the coccyx. Anterior to this, the anus felt normal on digital examination with a good sphincter tone and squeeze. Physiological tests were done to test the sphincter function and sensation. Manometry showed the resting sphincter pressure of around 30 cmH2O. This increase in squeeze pressure was due to a combination of contraction of the puborectalis and gluteal muscles. The presence of rectal sensation was noted but not quantified. Defecography was assessed using a defecation proctogram. It revealed a normal anorectum that was displaced towards the pubic bone. Furthermore, although he was able to evacuate barium paste from the rectum, the anorectal angle did not widen during straining at the angle of 90°. Anyhow, there was no abnormal descent of the rectum on straining. Five months after the surgical procedure, the perineal wound healed, and the colostomy was closed. The patient was able to pursue normal defecation without any episodes of major or minor incontinence. In the following follow-up visit, the patient expressed satisfactory defecation and micturition without incontinence.

pmc-8654144-2

A 44-year-old female patient had a car accident and she was thrown out from the car landing on a hard rock on her buttocks. In the district hospital, she was found to have a partial laceration of the posterior perineum surrounding an intact anorectum. The bladder, urethra, and pelvis were not injured. A sigmoid colostomy was performed and then she was transferred to a tertiary hospital. She had a crescent-shaped wound surrounding the anus from the three to nine o’clock position. In addition, the anus was displaced forward towards the vagina. Digital and proctoscopy examinations showed an intact anorectum and surrounding sphincters. Progress In this case, the patient's wound was subject to identical conservative management procedures as in the previously mentioned case. However, the patient was discharged from the hospital earlier as it was determined that she had adequate support from a daughter who has adequate experience in nursing. As the patient's wound was clean and in its proliferation stage of healing, the patient was instructed to perform daily irrigation using handheld bidets. She was scheduled for follow-up appointments every three weeks, which she attended punctually. Consequently, the proper management of the wound caused it to be superficial and reduced to 1 x 2 cm after five months of the procedure, with no infections. The defecation portogram performed in a follow-up appointment revealed an anteriorly displaced anus with an anorectal angle of 70°; this angle only widened to 90° on straining, and while evacuation occurred, it was incomplete. However, no atypical rectum descent was noticed, and the patient reported complete evacuation in the toilet after the examination. Seven months post-injury, the colostomy was closed, and five days after stoma closure, the patient reported normal bowel movement with no incontinence experienced and was subsequently discharged. Fifteen months post-injury, a follow-up report noted complete healing of the wound with adequate defecation. However, the patient reported the occasional need to use glycerin suppositories. Moreover, the patient's regime of treatment resulted in there being no fecal impaction. Figures , show the site of injury before and after treatment, respectively.

pmc-8654145-1

A 25-year-old woman was admitted due to complaining of difficulty in swallowing. She was the youngest of the five siblings, also a non-smoker and non-drinker. She was a child of a consanguineous marriage as her father and mother are cousins. Furthermore, when she was five years old, she was diagnosed with Fanconi anemia. To confirm the diagnosis of FA, we communicated with the related university hospital for the records of the patients 20 years ago. They approved the diagnosis of FA with some peripheric blood sample studies without giving details. They had offered bone marrow transplantation, which the parents had not approved of. She had no major symptoms for 20 years, and the disease was under control. But the patient did not go to regular hospital check-ups. The patient's first notable characteristic was growth retardation manifested by short stature, microcephaly, and microphthalmia. Afterward, she had swallowing difficulty for the last two years and had lost around 10 kg in the last six months. The patient was referred to the gastroenterology department due to swallowing problems. In the endoscopic examination, stenosis was observed in the hypopharynx that restricts the passage of the scope follows through. Positron emission tomography (PET-CT) scan showed multiple lymphadenopathies in the bilateral deep cervical lymph nodes (standardized uptake value [SUV] max: 8.8), and prominent pathological 18F-Florodeoksiglukoz (FDG) involvement beginning from the right-side oropharynx to the proximal esophagus (SUV max: 8.5) (Figure ). The patient underwent endoscopy, tumoral formation in the hypopharynx leading to only 3 mm passage opening was detected. As a result of punch biopsy and pathological examination, squamous cell carcinoma of the hypopharynx was revealed. The patient was diagnosed with T3N2cM0 hypopharyngeal cancer, and due to locally advanced disease, surgery was not considered; finally, she opted for curative radiotherapy (RT) with concomitant cetuximab chemotherapy. The RT of the patient was planned on a helical Tomotherapy system (Figure ), including primary tumour and bilateral neck lymph nodes. At the beginning of RT, the complete blood count was near-normal, with only mild leukopenia (white blood count is 3,8x10^3cells/uL). Cetuximab loading dose could not be administered due to urgent treatment needs. Consequently, the first cetuximab dose 350 mg/m2 with RT was initiated. The remaining maintenance dosage was scheduled as 250 mg/m2 but could not be administered due to a sudden drop in blood count (white blood count to 0.48x10³cells/uL) after four days of initial cetuximab and 10 days of RT. Her treatment was terminated due to progressive cytopenia (Table ), after receiving 21.2 Gy in 10 days for primary lesion. A peripheral blood smear was investigated, and it was concordant with severe pancytopenia as no atypical cells with rare leukocytes and platelets. To secure hematological recovery, G-CSF was initiated, erythrocyte and platelet transfusion was administered when necessary. Despite the daily G-CSF utilization, there was no significant change in blood counts. Moreover, the patient's dysphagia was worsened and a nasogastric tube was placed for feeding, in addition to parenteral nutritional support. Despite receiving nasal oxygen, the patient's condition worsened, on the 30th day of the start of radiotherapy, and her oxygen saturation regressed, and she was intubated. The patient died 40 days after radiotherapy begin due to respiratory failure and sepsis.

pmc-8654339-1

A four-year-old, previously healthy boy weighing 24 Kg, from Dhaka, was admitted with a four-day history of a high continued fever. He also complained of suffering abdominal pain, loose motions, and emesis for two days. He had no history of flu-like symptoms, cough, or respiratory distress in the past month. There was a history of close contact with a COVID-19 patient (within one month of the illness). He had no history of dengue. On examination, he was found febrile (temperature 102°F), tachypneic, and tachycardic with unrecordable blood pressure. Auscultation of lungs revealed bilateral crepitations with good air entry. The abdomen was distended, flanks were full with mild, diffuse abdominal tenderness. Initial investigations showed dengue NS1 Ag positive and rt-PCR for SARS-CoV-2 negative, thrombocytopenia, positive C-reactive protein, altered coagulation profiles (Table ). The chest X-ray (CXR) initially revealed bilateral pulmonary infiltrations. He was treated for dengue shock syndrome with plasma leakage with intravenous (IV) ceftriaxone, inotropes, and colloids. On the 5th and 6th day of fever, he developed petechial rashes on both extremities, cheilosis, and an erythematous rash over the trunk (Figure ). The patient also developed a cough and respiratory distress, oxygen saturation (SpO2) by pulse oximeter was found to be 96% with 5L/min oxygen through a face mask. Repeat CXR revealed bilateral inflammatory lesions with pleural effusion. The ECG was normal. However, echocardiography revealed dilated coronary arteries, left main coronary artery (LMCA, +3.0 standard deviation, SD), left coronary artery (LCA, +2.5 SD) with the loss of distal tapering and mild left ventricular (LV) dysfunction (ejection fraction [EF] 52%) (Figure ). Initial serum ferritin, N-terminal-pro hormone B-type natriuretic peptide (NT-pro-BNP), D-dimer, serum troponin I were markedly raised (as shown in Table ). The anti-SARS-CoV-2 antibody (IgG) test came back positive on the seventh day of fever. A pediatric cardiologist was consulted, and we administered one dose of intravenous immunoglobulin (IVIG) 2 g/Kg, along with enoxaparin 2 mg/Kg for five days. Thereafter, oral prednisolone and aspirin were added. Meanwhile, the patient became afebrile, and the rash faded. His general condition improved with a gradual return of appetite. Three days after the IVIG, repeat tests showed decreasing serum ferritin, NT-pro-BNP, and serum troponin I. The patient was transferred to the ward after 12 days in the pediatric intensive care unit (PICU) thereafter discharged after five days with the necessary advice and follow-up appointment.

pmc-8654339-2

A previously healthy 12-year-old girl from Dhaka, weighing 55 Kg, was admitted with a four-day history of high intermittent fever, headache, arthralgia, and generalized body aches. She had an erythematous rash on her trunk, cough, and respiratory distress. She was initially admitted to another hospital, but her condition deteriorated, and she developed shock and was referred to our PICU. She had complained of flu-like symptoms within two weeks of the presenting illness. She had a history of one episode of dengue fever three years earlier but no contact history with a COVID-19 patient. On admission, the patient was conscious, febrile (temperature 104°F), tachypneic, tachycardic with unrecordable blood pressure, and prolonged capillary refill time. SpO2 by pulse oximeter was 93% in room air and 96% with 2L/min oxygen via nasal cannula. Auscultation of lungs revealed bilateral diminished air entry with coarse crepitations, pleural rub. The abdomen was distended, full flanks with diffuse mild tenderness. She tested dengue NS1 Ag positive on the second day of fever. Management for dengue shock syndrome with plasma leakage was initiated with inotropes, IV furosemide, and albumin along with IV ceftriaxone and amikacin. She was given oxygen 3L/min via a face mask. The initial investigations showed thrombocytopenia, mild hypoalbuminemia, hypocalcemia, positive C-reactive protein, altered liver function tests with coagulopathy (as given in Table ). Her chest X-ray showed bilateral pleural effusions with pneumonitis (Figure ). A bedside echocardiogram revealed a prominent LMCA (+2.54 SD), minimal pericardial effusion, mild pleural effusion, and good biventricular function (EF 77%). Her NT-pro-BNP, serum ferritin, D-dimer were significantly high but serum troponin I was normal. At this time, the patient had mucocutaneous involvement with respiratory symptoms. Her anti-SARS-CoV-2 IgG came back positive. After reviewing the laboratory reports and echocardiographic features, we consulted the pediatric cardiologist. She was treated with one dose of IVIG 2g/Kg and started on oral prednisolone and aspirin. The patient was transferred to the main ward when she began to show clinical and laboratory improvements. She was soon discharged with the necessary advice and follow-up arrangements.

pmc-8654339-3

A three-year-old girl from Dhaka, previously healthy and thriving, weighing 16 Kg, was admitted to PICU with the complaint of five days of high continued fever with diffuse, central abdominal pain, emesis, and diarrhea for the last two days. She had experienced two episodes of melena and hematemesis. She had a history of contact with a COVID-19 positive patient in the last month but had no symptoms before the present illness. There was no previous history of dengue. She had been treated in another hospital for shock, and her dengue NS1 Ag was positive on the second day of fever. On admission, the patient was febrile, with narrow pulse pressure. Her blood pressure (BP) was 60/45 mmHg with tachycardia, she had tachypnea with a SpO2 of 90% by pulse oximeter in room air, a low volume pulse, and cold extremities. Auscultation of lungs revealed diminished breath sound with crepitations bilaterally. The abdomen was distended and tender. She was diagnosed with dengue shock syndrome with plasma leakage. She was treated with inotropes, IV furosemide, colloids, and levofloxacin. She was given 5L/min oxygen via a face mask. Her initial investigations revealed thrombocytopenia, hypoalbuminemia, hypocalcemia, positive C-reactive protein, mildly raised serum procalcitonin, altered liver function, and coagulopathy (as shown in Table ). Her CXR revealed bilateral pleural effusions with pneumonitis. Echocardiography showed prominent dilated coronaries, LMCA (+2.5 SD), LAD (+2.0 SD) with loss of distal tapering and perivascular brightness, bilateral pleural effusions, a mildly dilated left ventricle with mild LV dysfunction (EF 57%) (Figure ). Cardiac enzymes showed raised serum troponin I, NT-pro-BNP with raised serum ferritin and marked increased D-dimer level. The rt-PCR for SARS-CoV-2 Ag came back negative; however, the anti-SARS-CoV-2 antibody (IgG) was sent and came positive. By the sixth day of fever, the patient had conjunctival congestion and an erythematous rash on her trunk, which gradually faded (Figure ). After consultation with cardiologists, one dose of IVIG 2g/Kg was given; thereafter, oral prednisolone and aspirin were added. Three days after the IVIG, repeat tests showed decreased serum troponin I and NT-pro-BNP. As her general condition had improved, the patient was transferred to the pediatric ward after seven days of PICU support. Thereafter she was discharged with advice and a follow-up appointment.

pmc-8654339-4

A previously healthy nine-year-old boy, weighing 37 Kg, and hailing from Dhaka, was admitted to PICU with a high, continued fever that had lasted four days. He suffered with a headache and generalized body aches for two days and diffuse abdominal cramps with diarrhea and emesis for one day. He had a history of an upper respiratory tract infection three weeks earlier but had not done an rt-PCR for SARS-CoV-2 Ag during that time. He had no obvious contact history with a COVID-19 patient and no history of dengue infection. He tested positive for dengue NS1 Ag on the third day of fever and was admitted to another hospital. After deteriorating, the patient was referred to our PICU. On admission, he had unrecordable BP, tachycardia, tachypnea, cold extremities, breath sound was absent on right side, diminished on the left chest wall with coarse crepitations, SpO2 89% in room air by a pulse oximeter. The abdomen was distended, full flanks with diffuse abdominal tenderness. He was resuscitated, and management for dengue shock syndrome with plasma leakage was started. He was given 5L/min oxygen via a face mask, IV inotropes, albumin, colloids, furosemide, imipenem, and amikacin. His blood test results included anemia, thrombocytopenia, hypoalbuminemia, marked hypocalcemia, positive C-reactive protein, raised blood urea level, mild alteration of liver functions with coagulopathy (as given in Table ). A stool occult blood test was positive. His CXR revealed pleural effusions and pneumonitis. His ECG showed sinus tachycardia. The echocardiogram performed on the second day of admission revealed minimal pericardial effusion, bilateral pleural effusions, mild LV dysfunction (EF 59%). In addition, he had high serum ferritin, D-dimer along with a slightly raised NT-pro-BNP, normal serum troponin I. Clinically, he developed an erythematous rash on his trunk with conjunctival congestion on the seventh day of fever, which warranted further anti-SARS-CoV-2 antibody testing. This came back positive on the eighth day of fever. After consultation with pediatric cardiologists, the patient was started on IV methylprednisolone at a dose of 30 mg/Kg for three days. On the ninth day of illness, the patient developed respiratory distress and became confused and aggressive. His blood pressure was still fluctuating. His SpO2 was about 88% with 7L/min oxygen (2L/min via nasal cannula, 5L/min through face mask). He was placed on mechanical ventilation. Repeat CXR showed persistent pulmonary infiltrations with pleural effusion (Figure ). A brain MRI revealed no obvious neurological abnormalities. Repeat echocardiography revealed dilated coronaries, LMCA (+2.6 SD), LAD (+2.5 SD), with loss of distal tapering, bilateral pleural effusion, mild LV dysfunction (EF 51%) (Figure ). After consulting with a pediatric neurologist and cardiologist, one dose of 2 g/Kg IVIG was given. Methylprednisolone and aspirin were added, and we closely monitored his platelet count. From the second day on ventilatory support, he began to improve and was gradually weaned from the ventilator. After 10 days of illness, his neurological complaints started resolving, repeat blood tests results were improved with gradual remission of pleural effusion. The patient was transferred to the pediatric ward after 12 days of PICU admission. He was discharged on request after five days with the necessary advice and follow-ups.

pmc-8654339-5

A nine-year-old, previously healthy, developmentally well male child, weighing 31 Kg, and hailing from Dhaka, was admitted to the PICU. He complained of high, irregular fever over the previous four days and generalized body aches, headache, abdominal cramps with emesis for the previous two days. He had a history of dengue infection two years ago and positive contact history with a COVID-19 patient one month before the illness. He tested positive for dengue NS1 Ag on the second day of fever and was admitted to another hospital. Due to respiratory distress and fluctuating blood pressure, he was referred to our PICU. On admission, the patient had low mean pressure, tachypnea, tachycardia with a cold periphery. His breath sound was diminished bilaterally and course crepitations were heard on auscultation. He was febrile with erythematous, petechial rashes on both lower limbs, and gum bleeding. His rt-PCR for SARS-CoV-2 was negative, and blood and urine cultures yielded no growth. Initial investigations revealed, thrombocytopenia, marked hypoalbuminemia, hypocalcemia, altered liver functions, coagulopathy, positive C-reactive protein, negative procalcitonin, and slightly increased blood urea. His serum ferritin, D-dimer, serum troponin I, and NT-pro-BNP were very high (as given in Table ). The CXR revealed bilateral pleural effusions with pneumonitis (Figure ). The ECG showed sinus tachycardia. Management of dengue shock syndrome with plasma leakage was started with IV inotropes, albumin, calcium gluconate, antibiotics (imipenem, levofloxacin), and furosemide. An echocardiogram was done and showed a mild pericardial effusion, prominent dilated coronaries, LMCA (+3.0 SD), LAD (+2.5 SD), bilateral pleural effusion, fair LV function. The test for SARS-CoV-2 antibody (IgG) came back positive. After evaluating his condition and consultation with pediatric cardiologists, a single 2g/Kg dose of IVIG was administered, followed by methylprednisolone, aspirin, and clopidogrel. His general condition gradually improved with improving laboratory reports. Serial CXRs showed gradually decreasing pleural effusions. He was transferred to the pediatric ward 10 days after PICU admission and was discharged with the necessary advice and follow-up plans.

pmc-8654419-1

A 67-year-old man with chief complaints of macrohematuria and an abnormally low hemoglobin level (4.8 g/dL; normal range, 13.7-16.8 g/dL) was referred to our hospital. His performance status was zero and none of any co-morbidities were identified. Whole-body computed tomography (CT) revealed left hydronephrosis, a bladder tumor on the right lateral wall, and right external iliac LN involvement (Figure ). CT revealed a bladder tumor with invasion of surrounding fibroadipose tissue on the right lateral wall (Figure ). Transurethral resection of the bladder tumor was performed after blood transfusion; histopathological diagnosis revealed high-grade UC of the bladder with muscle layer invasion. BCa was classified as clinical T3bN1M0 according to the staging system defined in the American Joint Committee on Cancer Staging Manual []. His estimated glomerular filtration rate (eGFR) was 64.57 mL/min and his renal function was maintained at a normal eGFR level during the medication for BCa. He received two combined courses of gemcitabine and cisplatin (GC; 1,000 mg/m2 gemcitabine on days 1, 8, and 15, and 70 mg/m2 cisplatin on day 2) every 21 days. To monitor the treatment effect on BCa, the patient underwent whole-body CT and pelvic MRI after every two courses of systemic therapy. After two courses with GC, CT revealed left external iliac LN involvement as a new lesion, although the BCa and right external iliac LN decreased in size. Disease progression was diagnosed according to the Response Evaluation Criteria in Solid Tumors guidelines, version 1.1 [] (Figure ). It was difficult to explain why the left external LN has enlarged even though other lesions showed a positive effect after GCarbo. One possibility could be that the UC being a heterogeneous tumor, may have unique properties in this case. As a second-line treatment, pembrolizumab (200 mg) was administered every three weeks. Grade 4 macrohematuria according to the Clavien-Dindo classification [] occurred two weeks after the administration of pembrolizumab; thus, he immediately underwent endoscopic hemostasis for the bleeding site after blood transfusion. The break-through bleeding occurred from the surface of the BCa. Thereafter, the patient received two more courses of pembrolizumab. CT findings after the administration of pembrolizumab revealed shrinking of the BCa, positive LNs, and right kidney (Figure -). Three weeks after the final dose of pembrolizumab, open RC with bilateral pelvic lymphadenectomy and bilateral ureterocutaneostomy were performed because of the possibility of palliative surgical treatment. There was firm adhesion between the right lateral wall of the urinary bladder and the pelvic floor. The adhesion around the bilateral pelvic lymph node was not identified. There have been no surgery-related complications. The pathological examination of the surgical specimen by two pathologists at our institution indicated UC, with a pathological stage of Tis without lymphovascular invasion, a negative surgical margin, and negative LN involvement (Figure -). The patient was followed up for 30 months without evidence of local recurrence or distant metastasis.

pmc-8655043-1

A 46-year-old African male with a past medical history of essential HTN presented to the emergency department with a five days history of cough, shortness of breath, diarrhea, muscle cramping, fatigue, poor oral intake and decreased urinary output. The patient was tested positive for COVID-19 one day prior to admission. On further examination, the patient was febrile, hemodynamically stable with a blood pressure of 125/57 mmHg with a mean arterial pressure of 77 mmHg, heart rate of 83 bpm, respiratory rate of 24 per minute, and oxygen saturation was 93%. The patient was adequately oxygenated on a 2 L nasal cannula. Initial lab report revealed 133 meq/L of Na, chloride 88 meq/L, potassium 6.3 meq/L, calcium 8 meq/L, creatinine 23 mg/dL, BUN 195 mg/dL, creatinine kinase 1,200 U/L, lactate dehydrogenase (LDH) 212 U/L, C-reactive protein 126.6, and elevated D-dimer 4,433 (Table ). Arterial blood gas showed bicarbonate 6 meq/L, CO2 6 mmol/L, anion gap 41 mmol/L, PH 7.17. His liver function panel was normal. Urinary analysis showed protein >600 mg/dL, blood 1+, creatinine 404.6 mg/dL, and urine protein electrophoresis was 1,735 mg. EKG findings were non-significant for hyperkalemia, Chest x-ray was negative for the acute process of viral infection (Figure ). Since the patient was dehydrated he was started on 2 L of normal saline followed by 1 g of calcium gluconate. Repeat potassium was 7.7 meq/L. Therefore, the patient was admitted to the COVID ICU followed by a nephrology consultation. Since remdisivir is not a good drug of choice in renal dysfunction, 6 mg of decadron was started and sodium bicarbonate drip was started at 150 mL/hr. Additional investigation including color Doppler ultrasound of lower extremities was done due to high D-dimer and was negative for deep vein thrombosis. Ultrasound of kidney and urinary bladder was also negative for hydronephrosis. Despite the lack of improvement in supportive treatment, the patient was scheduled for hemodialysis. Subsequently his renal function and electrolytes status improved. Creatinine decreased to 3.1 mg/dL, creatinine kinase 895 IU/L, and the anion gap trended to 15. On discharge, potassium was 4.4 meq/L, creatinine was 2.9 mg/dL and he was sent home on room air with four more days of decadron and pulmonary rehabilitation exercise was done to enhance the recovery from COVID-19 pneumonia.

pmc-8655486-1

An 83-year-old female with a history of cold agglutinin hemolytic anemia requiring transfusions, chronic anemia with hemoglobin levels between 7-8 g/dl, hypothyroidism, hypertension, deep vein thrombosis in bilateral lower extremities, and chronic lymphedema, presented with shortness of breath, cough, weakness, lightheadedness, acrocyanosis or darkening of the fingers and toes (Figure ), jaundice, and darkening of her urine. She was found to have a productive cough with yellow sputum and worsening shortness of breath for the last four days, along with progressively worsening orthopnea that required sleeping upright. However, the patient denied chest pain, worsening leg swelling, paroxysmal nocturnal dyspnea, and wheezing. On presentation, the patient was afebrile, normotensive, with a normal heart rate, but had severe hypoxia with a saturation of 88% on room air and 95% with 2 liters of oxygen administered via nasal cannula. Throughout hospitalization, her temperature ranged between 96.7 and 98.6 °F (36-37 ℃). Physical examination was remarkable for mucosal pallor, acrocyanosis, icterus of the facial skin, diffuse bilateral rhonchi on lung auscultation, and pitting edema in bilateral lower extremities below the knee. Chest X-ray showed an enlarged cardiac silhouette, perihilar vascular fullness, and bilateral interstitial prominence likely indicative of pulmonary vascular congestion. A cardiac echocardiogram found the ejection fraction to be 60-65% with mild left ventricular wall thickness and grade I diastolic dysfunction. However, B-type natriuretic peptide (BNP) levels were only mildly elevated at 571 pg/mL. Moreover, nasal swab testing for SARS-CoV-2 was positive but was negative for influenza A, influenza B, and respiratory syncytial virus. Complete blood count revealed a high white blood count of 26.8 thousand/uL (normal range: 4.0-10.8 thousand/uL), low hemoglobin of 5.8 g/dl (12.0-16.0 g/dL), low haptoglobin of 1 mg/dL (41-165 mg/dL), and high erythrocyte sedimentation rate of 110 mm/hr (0-29 mm/hr). Serum chemistry testing found hyperkalemia of 6.7 mEq/L (3.5-5.1 mEq/L), elevated blood urea nitrogen of 34 mg/dl (8-25 mg/dl) with normal creatinine of 0.6 mg/dl (0.6-1.3 mg/dl), and severely elevated total bilirubin of 10.8 mg/dL (0.1-1.4 mg/dL). Blood culture collected from two different sites revealed no growth. Direct Coombs test was positive, and direct Coombs C3D test was also found to be positive during this admission. Testing from prior admissions had determined a cold agglutinin titer of 1:512. Other relevant testing included negative findings on hepatitis B virus IgM core antibodies, hepatitis B virus surface antigen, and hepatitis C virus antibody. To treat the symptomatic anemia, the patient was transfused with two units of crossmatch least incompatible warmed blood on day one and one unit of the same on day two of admission. The SARS-CoV-2 pneumonia was treated with oral remdesivir for five days and intravenous dexamethasone 6 mg for seven days. The patient was also given intravenous 40 mg furosemide for pulmonary congestion, and empiric ceftriaxone and azithromycin for pneumonia for three days. Post-transfusions, the patient’s day-three hemoglobin was 10.2 g/dL, which dropped in the next few days but stabilized at her baseline of 7-8 g/dL by discharge on day 10. By day three, the patient’s hyperkalemia had improved without intervention; the furosemide was discontinued since the patient was euvolemic on examination, and the azithromycin and ceftriaxone were stopped due to low concern for concomitant bacterial pneumonia. The patient remained in stable condition in the designated isolation room through the rest of her hospital stay, and after 10 days since her initial positive coronavirus 2019 (COVID-19) test, the isolation protocol was lifted. She reported feeling like she was “regaining her strength”. Yet, her oxygen levels persisted to desaturate with exertion and an ambulatory pulse oximetry examination revealed that she required 3 L of oxygen on discharge. The patient was recommended to be discharged to a sub-acute rehabilitation center. Two days post-discharge, the patient had another drop in her hemoglobin to 6.3 g/dL and required admission to a cancer institute where she was hospitalized for eight days, requiring five units of packed red blood cells and 60 mg of methylprednisolone IV daily. She had no signs and symptoms of bleeding during her admission. Her hemoglobin level improved to 9.2 g/dl and remained stable prior to discharge. On evaluation by an oncologist, weekly treatment with rituximab was recommended post-discharge for four weeks. On discharge, she was also prescribed prednisone 40 mg for seven days followed by a taper to 20 mg for another seven days and a follow-up appointment with oncology.

pmc-8656134-1

A 32-year-old male patient with no significant past medical history other than COVID-19 infection, months prior to admission, presented to ED complaining of dysphagia. Symptoms began about 1 week prior to presentation with difficulty swallowing liquids that progressed to involve solids as well. Dysphagia was described by the patient as a choking sensation and that he feels the food getting stuck in his chest. Dysphagia is partially relieved with belching. The patient also reported pyrosis and occasional vomiting. Denied nausea, abdominal pain or any change in bowel habits. On review of systems, the patient endorsed subacute cough for 3-4 weeks duration. The cough was mainly nonproductive and has been worsening since onset. It was associated with shortness of breath. Shortness of breath occurred mainly with exertion and while talking. The patient denied hemoptysis, fevers, chills, night sweats, weight loss, myalgia and arthralgia. On presentation, the patient was afebrile, HR: 94, RR: 19, O2sat: 100% RA and BP: 129/81. Examination revealed mild wheezes over lung bases bilaterally and no palpable lymphadenopathy. The remainder of the physical examination was unremarkable. Complete blood count and comprehensive metabolic panel were within normal range. Angiotensin-converting enzyme level was elevated at 81 U/L (Normal range 9 - 67 U/L). HIV Ag/Ab screening test was negative as well as COVID-19 PCR test. CT-chest with contrast (Figure ) showed prominent mediastinal and bilateral hilar adenopathy, multiple pulmonary nodules, mild interlobular septal thickening, suggesting interstitial pulmonary edema and peripheral left lower lobe ground-glass opacities, which could be pulmonary edema or infection. Esophagram (Figure ) showed findings compatible with extrinsic mass effect involving the middle esophagus, in keeping with bulky mediastinal lymphadenopathy noted on CT chest. On the third day of admission, the patient underwent Endobronchial Ultrasound Bronchoscopy (EBUS) with transbronchial needle aspiration. Samples were sent for cytology, pathology and flow cytometry. Flow cytometry was negative for monoclonal B-cells and immuno-phenotypically abnormal T-cells. The pathology report showed abundant non-necrotizing granulomas, mature lymphocytes and endobronchial cells in all biopsied samples. Grocott methenamine silver (GMS) and AFB stains were negative for microorganisms. Fungus and AFB cultures were negative as well. The patient was tolerating PO intake and was discharged from the hospital. The patient followed up with the pulmonology clinic one week after discharge for biopsy results and was started on oral prednisone 40 mg qDay. The patient respiratory symptoms did improve after three months of steroid therapy. Nonetheless, dysphagia persisted. Due to the persistence of dysphagia and as evidence of esophageal compression does not rule out infiltrative involvement. The patient underwent EGD with dilation followed by manometry studies a few months after discharge. The mucosa was grossly and histologically normal. Manometry studies were also unremarkable. The patient reported partial improvement of dysphagia after dilation. The patient is still following up with pulmonology and gastroenterology clinics for further evaluation and management.

pmc-8656291-1

A two-year-old female, previously healthy and normally developing, presented with a six-week history of macrocephaly and truncal and peripheral ataxia. An eye examination showed a lack of papilledema but was suspicious for mild peripheral loss of vision. Her past medical history was unremarkable. She did not have diencephalic syndrome at presentation. An urgent brain MRI demonstrated the presence of a large lobulated multicompartmental supra-sellar mass centered within the hypothalamus/optic chiasm (5.4cm x 3.4cm x 5cm) (Figure ), with extension into the surrounding structures and mass effect on the midbrain and third ventricle causing obstructive hydrocephalus. She initially underwent an endoscopic biopsy and septostomy, along with a right-sided ventriculoperitoneal (VP) shunt to manage her hydrocephalus. The pathology of the lesion confirmed the diagnosis of a low-grade glioma (LGG) that was BRAF-V600E negative on immunohistochemistry but positive on next-generation sequencing (Figure ). She was started on chemotherapy with vincristine and carboplatin, but unfortunately she had rapid tumor progression with worsening hydrocephalus six weeks into chemotherapy. This progression caused the patient to develop further complications, including progressive right-sided hemiparesis, bitemporal hemianopia, central hypothyroidism, and feeding difficulties requiring a gastrostomy tube and placement of a second VP shunt. After extensive discussions and mutual expert consensus, her chemotherapy was stopped, and she was started on the novel targeted agent dabrafenib (5.25mg/kg/day). By three months of starting dabrafenib, the size of her tumor decreased by more than 70% (2.5cm x 3.5cm x 2.7cm), with continued decline until plateauing after two years of therapy (Figure ). Prior to dabrafenib, the patient had marked motor and speech impairments but is now able to perform all age-appropriate developmental skills independently. She no longer requires tube feeding and has been growing well. Her bitemporal hemianopia has improved markedly. Her visual acuity is the only symptom that has not shown significant recovery, as she continues to have low but stable visual acuity bilaterally. Our patient is currently five years old, has been on dabrafenib for 30 months, and, to date, she has not experienced any side effects while on targeted therapy. Our plan is to continue on dabrafenib as long as the patient is tolerating the therapy well with no recurrence or progression of the tumor. Consent was obtained from the parents for sharing of the clinical information and participation in the ORCYD (Oncology Repository for Children and Young Adults) biomarker study. Samples (both blood and CSF) were collected every three months after starting targeted therapy with dabrafenib. Cell-free DNA (cfDNA) from CSF and plasma isolated from blood collected in DNA BCT tubes (Streck, La Vista, NE) were extracted using the QIAamp® Circulating Nucleic Acid kit (Qiagen, Hilden, Germany). Samples were quantified with Qubit™ and the 1X dsDNA high sensitivity (HS) kit (ThermoFisher, Waltham, MA); 1-ul aliquots were loaded on HS DNA chips and run on a Bioanalyzer (Agilent, Santa Clara, CA) to check for cfDNA profile. Samples were pre-amplified with the SsoAdvance™ PreAmp Supermix (Bio-Rad, Hercules, CA) for 10 cycles (annealing temperature = 58°C) following manufacturer's instructions. Diluted pre-amplified samples were mixed with 2X droplet digital polymerase chain reaction (ddPCR) probe mix then used to generate droplets on a QX200 DG (Bio-Rad). Droplets were then submitted to PCR amplification: 95°C for 10 minutes, 94°C for 30 seconds, 56°C for 1 minute (45 cycles), and 98°C for 10 minutes. Droplets were then read on a QX200 Droplet Reader, and data were analyzed using QuantaSoft™ version 1.7 software (Bio-Rad). The primers/probes sequences used for pre-amplification and ddPCR steps are given below: 5’-TCTTCATGAAGACCTCACAGTAA-3’ (BRAF_Fw76pb) 5’-ATGGGACCCACTCCATC-3’ (BRAF_R-long/short) Wild-type probe: /5HEX/AGATTT+C+A+CTG+T+AGC/3IABkFQ/ Mutant probe: /56-FAM/AGATTT+C+A+CTG+T+AGC/3IABkFQ/ Three months after starting dabrafenib, the patient was enrolled in the ORCYD biomarker study to test her plasma and CSF for the presence of the BRAF-V600E mutation and to correlate the assay results with the MRI changes observed while on dabrafenib therapy. Samples were collected from the patient (peripheral blood and CSF obtained by lumbar puncture) while sedated for follow-up MRIs over the course of a year. However, the BRAF-V600E mutation was not detected in any of the samples from either plasma or CSF (Figure ).

pmc-8657278-1

A 75-year-old male presented to our hospital with worsening mental status. Gait instability and expressive aphasia were noted on the physical examination. He was otherwise hemodynamically stable, with unremarkable laboratory studies and a negative urine drug screen. Computed tomography (CT) of the head without contrast showed a large right frontoparietal lesion crossing midline with surrounding vasogenic edema (Figure ). Further characterization with magnetic resonance imaging (MRI) showed a 5.5-cm intra-axial mass within the deep white matter of the right frontal lobe, with gadolinium enhancement and prominent FLAIR (fluid-attenuated inversion recovery) signal concerning malignancy. Later, the patient was started on dexamethasone, and a frontal stereotactic brain biopsy was performed. The initial pathology report showed a B-cell lymphoma with cells positive for CD20 immunostain (Figures -). However, due to its complexity, the sample was sent to an outside institution for a second opinion, which found the sample to be positive for the MYD88L265P mutation. Due to the strong association between this mutation and WM, quantitative serum immunoglobulins were measured, which showed an elevated IgM monoclonal paraprotein, confirming the diagnosis of WM. The patient was started on treatment with rituximab, methylprednisolone, carfilzomib, and ibrutinib. The patient showed a good response by MRI at three months, and he was transitioned to oral ibrutinib only. Surveillance MRI at one year post-diagnosis showed patchy right frontal lobe enhancement indicating disease progression, although the patient had no clinical symptoms; he was then restarted on the initial chemo-immunotherapy protocol. However, ibrutinib was later held due to thrombocytopenia. Soon after, the patient presented to the hospital again with cognitive dysfunction, leg weakness, and falls, with MRI showing significant disease progression. At this point, his treatment was changed to palliative chemotherapy with high-dose methotrexate and rituximab. His disease responded avidly to this regimen, and he is currently completing a one-year course of treatment, with no radiologic or clinical evidence of recurrence (Figure ).

pmc-8658045-1

A 79-year-old male with a past medical history of chronic infection of a left knee prosthesis, hypertension, and chronic kidney disease stage 3A presented to the wound care clinic after two days of subjective fever that partially improved with acetaminophen. He denied any associated symptoms. The patient had recently undergone multiple left knee revisions and received several antibiotics in an attempt to treat the draining chronic left knee infection (Table ). He developed severe allergic reactions (urticarial rashes and angioedema) to cephalexin and ciprofloxacin trimethoprim/sulfamethoxazole. Subsequently, 11 days prior to presentation, he was started on ertapenem and daptomycin. Moreover, before intravenous daptomycin and ertapenem were started, he had not received additional antibiotics for over a month. The patient had no previous history of pulmonary diseases and he denied any exposure to pulmonary irritants. Upon admission, the patient had a Hickman catheter for long-term antibiotic use without signs of acute inflammation. He had wheezing throughout the bilateral lung fields but no crackles. A draining tract with serosanguinous fluid drainage was observed on his left knee. His physical exam was otherwise unremarkable. The initial laboratory work demonstrated moderate anemia, normal white blood cells but with bandemia, and an elevated erythrocyte sedimentation rate and C-reactive protein (Table ). A chest x-ray showed new diffuse interstitial opacities (Figure ). A single anteroposterior portable chest X-ray was obtained on admission. Compared to a chest X-ray nine months prior, there were new diffuse branching interstitial opacities extending outward from hila associated with additional circular interstitial opacities. These were likely representing peribronchovascular interstitial thickening. There may be a trace of left pleural effusion without right pleural effusion. Additionally, the aorta was atherosclerotic and a right internal jugular central venous catheter terminating at the cavoatrial junction was seen in situ. On the second day of admission, the patient started having worsening shortness of breath, desaturation, tachycardia, and persistent fever. Examination of the lungs revealed bilateral crackles while the lower limbs and the trunk showed a new reticulopapular, non-pruritic rash. Repeat complete blood count (CBC) revealed new-onset eosinophilia. A computed tomography (CT) scan of the chest showed diffuse reticulonodular opacities in the lungs with peripheral predominance, areas of ground-glass opacities, and nodularities. Daptomycin AEP was suspected and the antibiotic was promptly discontinued and meropenem was started. Methylprednisolone and inhaled breathing treatments were ordered and the patient’s symptoms significantly improved thereafter. A repeat chest x-ray one month later showed resolution of the interstitial markings (Figure ). One month after the initial presentation, a repeat chest x-ray was obtained. The lungs appeared clear without apparent pleural effusion. No active disease in the chest was identified.

pmc-8671579-1

An 88-year-old woman (height, 150 cm; weight, 41 kg) with no history of drug allergy or general anesthesia was scheduled for transfemoral TAVI because of severe aortic stenosis (AS). The surgery was performed under general anesthesia to facilitate the use of transesophageal echocardiography and to manage any intraoperative complications. She was taking 0.625 mg/day bisoprolol, a selective β-1 blocker, for hypertension and chronic atrial fibrillation. Additionally, she was taking amlodipine for hypertension. Preoperative transthoracic echocardiography showed severe AS (aortic valve peak flow velocity: 4.73 m/s; mean aortic valve pressure gradient: 47 mmHg; aortic valve area: 0.41 cm2) and myocardial hypertrophy (left ventricular posterior wall thickness and interventricular septum thickness: 14 mm). Pre-anesthetic medication for sedation was not administered. She received bisoprolol and amlodipine 3 h before entering the operating room. Figure shows the anesthesia record. General anesthesia was induced using midazolam and remifentanil; additionally, rocuronium was administered to facilitate tracheal intubation. She received total intravenous anesthesia: continuous infusions of propofol and remifentanil. Noradrenaline and dopamine were infused continuously through the central venous catheter to maintain blood pressure. AS disappeared after valve implantation. During the surgery, complete atrioventricular block occurred, and ventricular pacing (VVI mode: 60 ppm) was initiated. No other complications were associated with the surgical procedure. Postoperatively, she received 100 mg sugammadex through the central venous catheter, but 2 min later, her systolic arterial blood pressure (ABP) decreased unexpectedly to less than 40 mmHg. Simultaneously, ventilator monitoring revealed elevated peak and plateau airway pressures (60 and 40 cmH2O, respectively). No skin rash was observed on the body surface. Transthoracic echocardiography showed underfilling of the left ventricle without right ventricular dilatation or pericardial effusion. No abnormalities were observed in left ventricular wall motion. The patient developed distributive shock, which was clinically diagnosed as anaphylactic shock caused by sugammadex because of the rapid onset of severe hypotension and bronchospasm. First, two boluses of 0.05 mg adrenaline were administered through the central venous catheter, followed by rapid volume resuscitation using crystalloid (1 L infusion within 30 min). The dose of noradrenaline was increased to 0.3 μg/kg/min. Consequently, the airway pressures returned to the original level, but the hypotension persisted. Thereafter, adrenaline was administered via bolus (0.1 mg twice) and continuous infusion (0.1 μg/kg/min); however, the increase in her ABP was minimal. Therefore, 1 mg glucagon was administered intravenously, and her systolic ABP immediately rose to 130 mmHg. An erythematous rash also appeared on her neck with the increase in ABP. Her general condition was stable after the therapeutic interventions. Ventricular pacing was continued because bradycardia with complete atrioventricular block was persistent during the interventions. She was admitted to the intensive care unit under tracheal intubation. Subsequently, the continuous infusion of adrenaline was discontinued, and the continuous infusion of noradrenaline was reduced. We also administered 125 mg methylprednisolone for 3 days. She was extubated 9 h after the onset of anaphylaxis, and circulatory agonists were discontinued the following day. She was discharged without complications on postoperative day 9. Blood tests revealed a total serum tryptase level of 7.3 ng/mL and 1.2 ng/mL at 1 h and 24 h after onset, respectively. We advised the patient to undergo allergy tests, such as skin prick tests or intradermal tests, to identify the cause of anaphylaxis. However, the patient refused these tests because she was elderly and unlikely to undergo surgery under general anesthesia in the future. Written informed consent was obtained from the patient for the publication of this case report. This report was approved by the Institutional Review Board of Nagasaki University Hospital (Approval number: 21041932).

pmc-8671581-1

A 62-year-old man, affected dysphagia, was endoscopically diagnosed with lower esophageal cancer confirmed squamous cell carcinoma on biopsy, and was reffered to our hospital (Fig. ). He had no medical history. His lifestyle has included 1500 ml beer consumption per day and 40 cigarettes per day for the past 40 years. Computed tomography (CT) showed thickening of the wall in the lower esophagus as the primary lesion was demonstrated and the tumor formed a mass with the solitary metastatic abdominal lymph node, and invaded pancreas body and gastric body (Fig. ). No other distant metastasis was detected on CT. He was diagnosed with lower esophageal cancer cT4 N1 M0, with pancreatic invasion, cStage IIIC according to 7th edition of the Union for International Cancer Control system []. At first, we considered definitive chemoradiotherapy. However, radiation oncologists evaluated that the tumor was less candidate for chemoradiotherapy because of the risk of gastric mucosal damage. For the purpose of definitive therapy, radical esophagectomy with distal pancreatectomy was planned. As neoadjuvant chemotherapy, CF therapy (cisplatin and 5-fluorouracil therapy; cisplatin was dripped 80 mg/m2 plus 5-fluorouracil was infused 800 mg/m2 on day 1 through 4 continuously) was started according to standard therapy of localized advanced esophageal cancer []. However, after once administration, he could not continue chemotherapy for the exacerbation of dysphagia, and underwent radical surgery. Preoperative evaluation of tumor was similar to initial findings on endoscopy and CT. In findings on laparotomy, abdominal lymph node was infiltrated directly to pancreas body. As the radical surgery, Ivor Lewis esophagectomy with distal pancreatectomy and splenectomy, followed by reconstruction of gastric conduit. Two fields lymphadenectomy was performed according to the treatment strategy of the abdominal esophageal cancer. Reconstruction of gastric conduit was possible although the lymph node was adherent to lesser side of gastric body, which was resected when reconstruction of gastric conduit. In addition, partial resection of lung was performed simultaneously owing to involvement of bilateral pulmonary ligaments to the primary tumor (Fig. ). The operative time was 528 min. The estimated blood loss was 2850 ml, and the patient was transfused 4 units of red blood cell concentrates. The patient had an uneventful postoperative course and was able to take orally. He was discharged 16 days after operation with tube-free. After discharge, he underwent two courses of CF therapy as adjuvant chemotherapy. At present, he is still alive and has no recurrence for 7 years after surgery. In the resected specimen, the primary lesion was observed from lower esophagus to esophagogastric junction, and metastatic lymph node was fixed to stomach and pancreas body (Fig. ). Pathological examination revealed that primary lesion was not infiltrated to lung (Fig. a, b). Massive metastatic lymph node (over 5cm) was observed in the lesser curvature of stomach, and infiltrated to pancreas and gastric wall with extranodal extension (Fig. c, d). The tumor was diagnosed with squamous cell carcinoma, moderately differentiated type. The vascular and lymphatic invasion was confirmed. The surgical margin was negative. The pathological stage was ypT4 N1 (1/61) M0 (metastatic lymph node invasion into pancreas), ypStage IIIC. The histopathological response of chemotherapy was grade 1a, which was equivalent that proliferable cells were 2/3 or more, in 7th edition of the Union for International Cancer Control system [].

pmc-8672569-1

A 48-year-old Japanese woman with high myopia presented with decreased visual acuity. Axial length was 29.0 mm in the right and 28.7 mm in the left eyes, respectively; refractive errors were −11.5 and −10.5 diopter; best-corrected visual acuity (BCVA) was 20/28 and 20/16, respectively. The BCVA was described by converting the decimal visual acuity into fractional visual acuity. Mild cataract was observed in both eyes. Fundoscopy and optical coherence tomography (OCT) images showed epiretinal membrane (ERM) in the left eye (Fig. ). Three years later, she developed blurred vision and BCVA in the left eye decreased to 20/33; OCT revealed thickening of the ERM. The patient opted for vitrectomy after thorough discussion and considering recent reports showing good treatment outcome for ERM with good visual acuity []. The patient subsequently underwent uncomplicated 25-gauge pars plana vitrectomy with ERM and internal limiting membrane (ILM) peeling in the left eye. After 6 months, BCVA was 20/28. CRA was noted in the parafovea, and OCT revealed irregularities in the RPE with increased transmission signal from the sclera, suggesting atrophy of the RPE (Fig. ). After another 3 weeks, BCVA in the left eye decreased suddenly from 20/28 to 20/100. OCT demonstrated disruption of the interdigitation and ellipsoid zones and elevation of the RPE. Choroidal thickness at this site increased from 134 µm to 151 µm (Fig. a, b). Fluorescein angiography (FA) revealed hyperfluorescence (Fig. a), which coincided with the site where changes were observed in RPE and choroid on OCT (Fig. b). Hyperfluorescence was observed from an early stage, but no leak thereafter. Typical choroidal neovascularization (CNV) or lacquer crack were not shown on FA. Indocyanine green angiography (ICGA) did not detect abnormal blood vessels suggesting CNV (Fig. b). Although fluorescein and indocyanine green angiography did not show typical CNV or lacquer crack, myopic CNV could not be ruled out. Therefore, intravitreal ranibizumab injection was recommended. However, 2 days after the injection, the patient presented with a further decline in vision to 20/222 in her left eye. Despite no obvious change on fundus examination, OCT revealed a nodule-like outer retinal lesion with disruption of the RPE, suggesting PIC. Choroidal thickness had decreased slightly to 142 μm (Fig. c). Careful observation was recommended after thorough discussion with the patient concerning possible treatment options, including steroid therapy. One month after the injection, BCVA improved to 20/100 and the nodule-like lesion regressed, leaving an expanded RPE defect with a decrease in choroidal thickness to 84 μm. The lesion was judged to be inactive, and further observation was recommended. However, the area of CRA increased gradually to 0.38, 0.90, and 1.59 mm2 and choroidal thickness decreased to 52, 40, and 16 μm by 14, 30, and 40 months post-injection, respectively (Fig. ). CRA progressed at a rate of 0.45 mm2/year. The CRA was measured on color photographs of the fundus using ImageJ software (freely available at ). Three years after the injection, BCVA was 20/70 in the left eye and two new atrophic lesions were noted in the parafovea (Fig. c).

pmc-8672589-1

An 82-year-old male patient with angina on anticoagulant medication and without viral infection was referred to our department for the surgical treatment of HCC. His personal and family medical history was otherwise unremarkable. Abdominal computed tomography (CT) showed a huge HCC mass in segment 4 and PVTT invasion from the nearby portal vein to the left portal trunk, main portal trunk, through to the contralateral right portal trunk. The tip of the PVTT progressed over to the bifurcation of the anterior and posterior branches of the portal trunk. The anterior branch was filled with PVTT, while the posterior branch was filled with PVTT or blood thrombus (Fig. ). No apparent intra- and extra-hepatic metastases were detected other than the main tumor. Laboratory data showed a serum albumin level of 3.8 g/dL, total bilirubin level of 0.5 mg/dL, platelet count of 13.9 × 104/uL, and a Child-Pugh score of 6. Serum levels of alfa-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist II were 90,770 ng/mL and 2847 mAU/mL, respectively. An antithrombotic drug was administered for the PVTT. Due to the overwhelming PVTT extensions, poor performance status, and old age, the patient was deemed not to have a surgical indication. Therefore, a combination treatment using atezolizumab plus bevacizumab with radiotherapy for PVTT was selected. During preparation for radiotherapy, one-time atezolizumab (1200 mg) and bevacizumab (15 mg/kg) were administered. He developed anal pain and persistent fever 9 days after administration, and CT showed perianal abscess due to anal fistula. Although he recovered soon after percutaneous abscess drainage, this adverse event interrupted atezolizumab plus bevacizumab treatment, and radiotherapy could not be introduced. Abdominal CT, conducted 3 weeks after the first administration, showed size reduction of the main tumor and PVTT, with a reduction in tumor enhancement on contrast-enhanced CT. Serum AFP decreased from 90,700 ng/mL before treatment to 18,371 ng/mL and 6301 ng/mL 3 and 5 weeks after atezolizumab plus bevacizumab treatment, respectively. Considering the excellent response to atezolizumab plus bevacizumab treatment (one-time administration), we decided to continue with this treatment after creating colostomy. Colostomy was performed 47 days after the first administration of atezolizumab plus bevacizumab. Subsequently, beginning from the 83rd day after the first administration of atezolizumab plus bevacizumab, atezolizumab monotherapy was initiated. The reason for choosing atezolizumab monotherapy was that the bleeding from the colostomy persists from the collateral blood circulation due to the liver cirrhosis. The serum AFP decreased to 89 ng/mL just before the next atezolizumab monotherapy, and abdominal CT showed continued partial response (Fig. ); serum AFP levels kept decreasing toward the normal range (Fig. ). He received a one-time atezolizumab plus bevacizumab treatment and continued with atezolizumab monotherapy afterward (9 regimens administered until now); there is no apparent sign of residual tumors at 9 months after the introduction of atezolizumab plus bevacizumab treatment.

pmc-8672608-1

A 54-year-old man with a history of excessive intake of alcohol (100 g/day × 30 years) and locally grown tobacco use (500g/month × 30 years) was admitted to our hospital because of chronic persistent swallowing dysfunction for six months. White light endoscopy (WLE) revealed a 22 mm flat lesion in the middle esophagus.The lesion was covered with scattered leukoplakia, and normal vascular network could not be seen in the lesion (Fig. a). Narrow-band imaging (NBI) under endoscopy revealed the lesion with an indistinct brownish area, local white penniform area, and white tiny papillary surface structure (Fig. b). Further low and high magnifying endoscopy with NBI (ME-NBI) showed tiny irregular papillary microsurface structure with various shapes and sizes, and non-typical type B1 pattern of intraepithelial papillary capillary loops (IPCL) confined to the papillary microsurface structure (Fig. c, low magnification, and Fig. d, high magnification) according to the classification of Japan Esophagus Society (JES classification) []. Iodine staining endoscopy revealed a less-stained lesion (Fig. e) and showed more distinct white tiny papillary surface structure (Fig. f) than conventional WLE. Biopsy showed a low grade intraepithelial neoplasia. Chest and abdominal CT scan revealed no abnormal lesions. According to the endoscopic manifestations under WLE, ME-NBI, and iodine staining endoscopy, combining with pathology, we considered the lesion to be early esophageal cancer. Therefore we chose endoscopic therapy. The lesion was completely resected with endoscopic submucosal dissection. Histopathology showed that the layer of neoplastic spinous cells was significantly thickened (Fig. a) with local keratosis presenting the appearance of the so-called church spire (Fig. b). The lamina propria papilla was elongated upward to the surface layer (Fig. c), and the nuclei in the basal region had double or more nucleoli. Tumor cell displayed expanding growth, and partial tumor cells broke through the basement barrier and invaded into superficial lamina propria (Fig. d). The IPCL were observed in lamina propria papilla with elongating upward to the surface layer growing underneath the layer of neoplastic spinous cells, which corresponds to the IPCL observed by ME-NBI (Fig. e). The lesion was histopathologically confirmed as early VCCE which was limited within the mucosal lamina propria (m2) and completely resected. There were no lymphovascular and neural invasions of cancer cells, and no cancer cells to be seen in the lateral and vertical margin of the resected specimen (the distance of the lesion to the closest margin of the resected specimen was 3.012mm) (Fig. ).

pmc-8672614-1

A previously healthy 25-year-old White man presented with a 1-year history of blurred vision in the right eye, headache, and weight loss of about 30 kg. On physical examination, he had a body mass index of 28 kg/m2 and visual field defects in the right eye. Initial MRI showed a lightly spotted heterogeneous 19 × 16 × 19 mm tumor located suprasellarly, close to the pituitary gland with no ingrowth or association with the pituitary gland (Fig. A). Endocrine evaluation revealed secondary hypogonadism with low follicle-stimulating hormone, luteinizing hormone, and testosterone but intact thyrotroph and lactotroph axes. An ACTH test was performed with a subnormal cortisol response (30-minute cortisol 248 nmol/L, reference > 420 nmol/L) and low plasma ACTH concentration, indicating secondary adrenal insufficiency, and the patient started treatment with hydrocortisone. The somatotroph axis was not evaluated. Visual field measured by perimetry revealed visual field defects in the right eye. The tumor was initially diagnosed based on MRI as a craniopharyngioma for which reason the patient was referred to craniotomy as standard treatment. At surgery, the tumor appeared gray and reddish, and was capsulated and fragile with easy bleeding, unlike craniopharyngiomas with sharp, irregular borders, which have a tendency to adhere to vital neurovascular structures and often consist of cystic and/or solid parts []. The pituitary tumor was partially resected, and a small amount of capsule remnant underneath the optic chiasm could not be surgically removed. Perioperative frozen section histological examination described the tumor as a possible malignant lymphoma due to lymphocytic infiltration. The patient was transferred to the Department of Endocrinology at Odense University Hospital for further diagnostic workup and management of pituitary hormone deficiencies. Postoperatively, the patient was still affected by headache and visual deficits on ophthalmologic assessment. MRI showed regression of the pituitary mass (9 × 6 × 8 mm), but remnant pituitary tissue was located just below the optic chiasm (Fig. B). Pituitary hormone insufficiency of all anterior axes and diabetes insipidus was diagnosed, and treatment with hydrocortisone, levothyroxine, testosterone, growth hormone, and desmopressin was implemented. Endocrine evaluation did not support a hormone-producing adenoma. Sellar lymphoma is a very rare disease often related to immunodeficiency, for example HIV-related, or seen in immunocompetent patients who are over 60 years old []. Metastasis was not suspected; the patient did not suffer from cancer in another location. Workup for infectious and rheumatologic etiologies was not indicative of secondary hypophysitis, nor was drug-related infiltration of the pituitary gland a possible differential diagnosis. Final histological diagnosis showed lymphoid reaction with predominant CD20 positive B-cell infiltration and no sign of significant IgG4 involvement. The patient was diagnosed with autoimmune hypophysitis. Ten months postoperatively, the patient reported impaired vision. MRI showed that the remnant tissue lifted and exerted pressure at the optic chiasm. Perimetry confirmed progression of visual field defects in the right eye and now involvement of the left eye. Because of progression of visual field defects, treatment with glucocorticoid pulse therapy was initiated: methylprednisolone 500 mg infusion for 3 days, followed by reduced prednisolone doses, that is, 37.5 mg per day. Follow-up MRI after 1 month of glucocorticoid treatment (11 months postoperatively) demonstrated significant reduction of the pituitary mass and decreased pressure at the optic chiasm. Perimetry was unchanged. Treatment with prednisolone continued for 3 months. The patient had intolerable adverse effects to glucocorticoid treatment with excessive weight gain of about 50 kg and cushingoid features. The need for long-term treatment led to initiation of steroid-sparing treatment with 150 mg azathioprine per day under gradual tapering of prednisolone (13 months postoperatively). Visual field defects improved, and repeated MRI showed additional regression of the remnant pituitary mass. Perimetry revealed stable conditions. Due to stable condition over 26.5 months, treatment with azathioprine was reduced. Control MRI after one and a half month showed recurrence with increasing mass in sella turcica causing mass effect on the optic chiasm. Treatment was resumed: azathioprine 100 mg per day in combination with prednisolone 37.5 mg per day. Despite additional 11 months treatment with azathioprine and prednisolone treatment (52 months postoperatively), control MRI showed further progression with increasing pituitary mass size (11 × 6 × 7 mm) reaching the optic chiasm (Fig. C). Treatment with rituximab was initiated: 1000 mg infusions 14 days apart, repeated every 12 months. This resulted in almost complete regression of pituitary mass (3 × 2 × 7 mm) evaluated by MRI (Fig. D). Rituximab treatment was discontinued after 25 months (77 months postoperatively) because of stable disease. To date, the patient has been followed up for ten and a half years postoperatively. According to control MRI 4 years after end of treatment with rituximab, he is in sustained remission with unchanged pituitary mass size and no affection of the optic chiasm.

pmc-8672627-1

In November 2016, a Caucasian 75-year-old woman, a former smoker (7.5 pack-years), was hospitalized for breathlessness. Her past medical history included atrial fibrillation treated with warfarin, arterial hypertension treated with betaloxol, and gastroesophageal reflux. She ran a bar–tobacco shop with significant long-term exposure to passive smoking. She was not exposed to asbestos. Clinical examination on admission revealed good performance status, stage 1 modified Medical Research Council (mMRC) dyspnea, crackles at lung bases, and no digital clubbing or extrathoracic signs. Chest computed tomography (CT) scan showed interstitial lung disease (ILD) with subpleural reticulations without evidence of honeycombing or enlarged lymph node (Fig. ). Standard biology, serological testing, bronchoscopy, and bronchoalveolar lavage were normal. Pulmonary function tests demonstrated bronchial obstruction [forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio, 0.66; FEV1, 97% of predicted values (% pred.)], preserved volumes [FVC, 121% pred.; total lung capacity (TLC), 111% pred.], and alteration of gas diffusion (TLCO, 62% pred.). ILD multidisciplinary discussion (MDD) reached a CT pattern of possible usual interstitial pneumonia (UIP), which led to the proposal of performing surgical lung biopsy. Wedge resection of the right upper and lower lobes was performed by video-assisted thoracoscopic surgery in July 2017. Both resected lung specimens showed a similar pattern of UIP: fibroblastic foci and honeycombing. In addition, the right lower lobe specimen displayed numerous disseminated foci of well-differentiated focally invasive SCC without invasion of visceral pleura (Fig. ). Complete resection was obtained without SCC-positive surgical margins. A PET–CT scan performed in September 2017 showed mild hypermetabolism of ILD [maximum standardized uptake value (SUVmax), 3.5], without hypermetabolic lung nodule, mass, or enlarged lymph node. Cerebral magnetic resonance imaging (MRI) was normal. There was no indication for adjuvant antineoplastic treatment based on pathological findings. After ILD MDD in October 2017, it was decided to introduce an antifibrotic treatment owing to pathological confirmation of UIP. Nintedanib was chosen as this molecule is also known for its antitumor properties. At the last follow-up in October 2019, that is, 2 years after initiation of nintedanib, clinical, functional (FVC, 130% pred.; TLCO, 61% pred.), and CT scan evaluations were stable (Fig. ). There was no evidence of squamous cell carcinoma progression.

pmc-8674090-1

The patient was a 48-year-old male who had been undergoing regular dilatations for the last 8 years for sustaining relief from his urethral stricture. He had a history of having undergone open suprapubic cystostomy (SPC) 8 years ago for acute urinary retention secondary to recurrent urinary tract infection (UTI). He developed surgical site infection (SSI) postoperatively which was managed conservatively. The stricture had been managed with internal optic urethrotomy (IOU) and serial dilatations, following which the patient started doing well with 6 monthly dilatations. Since last 2 years, he developed a swelling in the right inguinoscrotal region associated with repeated thinning of urinary stream and recurrent episodes of burning micturition. The swelling became static and persistent in the last 2 months. On examination, there was a 5-cm long vertical midline scar in the suprapubic region. An irreducible soft swelling of 8 cm × 6 cm was present in the right inguinal region which extended up to the base of scrotum. Cough impulse was present, and we could not get above the swelling. The defect could not be localized. There was also a gradual growing difficulty in negotiating urethral dilators due to the path distortion by the contents of the hernia. Cystoscopy revealed narrowing in bulbar urethra with deviations in the proximal anterior urethra and the scope needed to be negotiated to reach the urinary bladder. Ultrasound showed findings consistent with right inguinal omentocele and a scarred suprapubic region. Defect could not be localized. The patient had been coaxed for surgery multiple times but he did not agree due to poor past surgical experience. He eventually landed with difficulty in micturition and inability to get dilators passed. A preoperative diagnosis of right sided, complete, irreducible, inguinal omentocele with urethral stricture was made, and the patient was planned for right open hernioplasty with cystourethroscopy along with IOU. Intraoperatively, a right indirect hernial sac with omentum as content was found; the sac was opened, omentum resected, and sac was transfixed at its neck followed by posterior wall strengthening. Another hernial sac with omentum as content was found in midline beneath the scar of old SPC which was densely adherent to the surrounding fibrotic tissue ( ). This sac was dissected out, opened, content resected, and sac was closed. For the right inguinal hernia, a mesh hernioplasty was done. After the closure of the external oblique aponeurosis, anatomical repair of midline defect was achieved and strengthening was done with overlay mesh covering the midline defect. On cystourethroscopy, a stricture was present from posterior part of penile urethra to bulbar urethra. IOU was done and 18-Fr Foley's catheter left in situ. A postoperative diagnosis of right-sided, complete, irreducible, indirect inguinal hernia, and incisional hernia with omentum as contents with urethral stricture was made. The patient developed SSI on post operative day (POD)-2 which was managed by wound irrigation and oral antibiotics. At follow-up after 1 month, a repeat cystourethroscopy was performed which showed fibrosis and narrowing at the site of IOU. A repeat IOU was done. The anterior urethra had straightened out and dilatation was simple and smooth. The patient now has a good urinary stream, no complaint of restriction in passage and dilatations have become a smooth affair. The patient has been on 4 monthly dilatation for the past year which have all been smooth and has now been called after 6 months for next follow-up.

pmc-8674092-1

A 35-year-old man presented with the complaints of low back ache for 12 years, radiating to right leg for 4 months and numbness extending to lateral side of the sole of right foot. On examination, there was a 30% sensory loss in right S1 dermatome as compared with contralateral limb, with no bladder bowel involvement. Patient had no motor deficit. Magnetic resonance imaging (MRI) of the lumbosacral spine was suggestive of IM cystic lesion at L2-3 hypointense on T1-weighted images and hyperintense on T2-weighted images. MRI brain did not reveal any abnormality. Lumbar puncture and serologic studies were not performed. With the differential diagnosis of neoplastic lesion, the patient was taken up for posterior laminectomy. L2-3 laminectomy was done. A dural bulge was identified. On durotomy, the cord was found to be enlarged. Under microscopic guidance, posterior longitudinal myelotomy was done, the cysts were approached, and subtotal resection of cysts was done. Intraoperatively, three grayish white cysts were identified. Cysts were found to be adherent to the nerve roots causing their inflammation. As a result, one of the cysts could not be excised and was only decompressed. The remaining two cysts were completely excised. Histopathology revealed it to be NCC. The patient improved postoperatively. Back pain was relieved, and there was significant reduction in radiating pain. He was started on albendazole (15 mg/kg body weight) for 4 weeks and steroids for 2 weeks. The patient was discharged on the 4th post-operative day. He was followed-up biweekly for the first month. Thereafter, monthly follow-up was done for the next 2 months. MRI done at 6 months confirmed resolution of the cystic lesion. Thereafter, 6 monthly follow-up was done. Patient is symptom free and not on any medication at 2 years of follow-up.

pmc-8674093-1

A 65-year-old gentleman with no comorbidities presented with progressive jaundice, anorexia, and weight loss since 4 to 5 weeks. He had no similar complaints in past. His clinical examination apart from icterus was normal. Investigations revealed a direct hyperbilirubinemia of 3.3 mg/dL. Ultrasound revealed a hypoechoic lesion in head of pancreas 3 cm × 3 cm in size with dilated common bile duct and intrahepatic biliary radical dilatation. A pancreatic protocol contrast-enhanced computed tomography (CECT) scan was performed which confirmed the ultrasound findings as shown in . In addition to this, it showed a replaced right hepatic artery arising from superior mesenteric artery (SMA) as shown in , and a reversal of relationship of superior mesenteric vein (SMV) and SMA, that is, the artery to the right of vein was seen as shown in . The complete vascular anatomy is schematically shown in . The duodenojejunal flexure was in midline. There was no significant lymphadenopathy, no liver lesions, and no free fluid. These findings were suggestive of pancreatic head adenocarcinoma with incomplete intestinal rotation and an rRHA arising from SMA. Carbohydrate antigen 19–9 (CA 19–9) was elevated at 196 U/mL (normal: < 37 U/mL) and Carcinoembryonic antigen was normal. A pylorus-preserving pancreaticoduodenectomy was planned for the patient. During surgery, the small bowel loops were found clumped in right upper abdomen and a Kocher's maneuver was carefully performed after interbowel adhesiolysis to free all the loops till the third part of duodenum. SMA and SMV were then identified and looped at the lower border of pancreas. Hepatoduodenal ligament dissection was then performed to identify the replaced right hepatic artery and the main portal vein. The retropancreatic tunnel was created in a plane above the portal vein superiorly and the SMA inferiorly, and then the plane was widened till the area above SMV ( ). Uncinate dissection, duodenojejunal flexure mobilization, and standard lymphadenectomy were then performed, followed by division of jejunum, first part of duodenum common bile duct and pancreas. The vascular relations can be seen after resection completion in . Reconstruction was performed as the modified Blumgart technique of duct to mucosa pancreatico-jejunostomy with 5–0 polypropylene, single layer interrupted hepatico jejunostomy using 4–0 polypropylene and antecolic stapled posterior gastrojejunostomy. The patient recovered uneventfully and was discharged on the postoperative day 8. Histopathological examination showed moderately differentiated adenocarcinoma confined to pancreas with all margins free and single peripancreatic node out of 18 was positive. The patient is doing well at 4-month follow up on adjuvant 5-fluorouracil based chemotherapy.

pmc-8674093-2

A 56-year-old gentleman with no comorbidities presented with progressive jaundice, anorexia, and weight loss of 6 to 8 weeks of duration. He had no similar complaints in past. His clinical examination apart from icterus was unremarkable. Investigations revealed direct hyperbilirubinemia of 10.3 mg/dL. Ultrasound abdomen revealed a hypoechoic lesion in head of pancreas 4 cm × 3 cm in size with dilated common bile duct and intrahepatic biliary radical dilatation. A pancreatic protocol CECT scan was performed which confirmed the ultrasound findings. In addition to this, there was intestinal nonrotation with entire small bowel on right of abdomen and large bowel on left side. Cecum and hepatic flexure was in midline. SMA was seen coursing between the jejunal and ileal branch of SMV and to right of SMV as shown in . There was no significant lymphadenopathy, liver lesions, or free fluid. These findings were suggestive of pancreatic head adenocarcinoma with intestinal nonrotation. CA 19–9 was elevated at 237 U/mL (normal: < 37 U/mL) and Carcinoembryonic antigen was normal. A pancreaticoduodenectomy was planned for the patient. During surgery, the small bowel loops were clumped in right upper abdomen and the duodenum was vertically linear instead of the usual C loop configuration, with duodenojejunal flexure on the right side. Kocher's maneuver was performed ( ). The infracolic SMA first approach helps to identify the vascular structures, as well as the replaced hepatic artery from SMA early in surgery, thereby reducing bleeding and it was our approach in this case. SMA and both ileal and jejunal branches of SMV were identified and looped at the lower border of pancreas. Inferior pancreaticodeuodenal vessels were identified to its origin and then divided. Hepatoduodenal ligament dissection was then performed. The retropancreatic tunnel was created in a plane above the portal vein superiorly and the SMV inferiorly, and then the plane was widened till the area above SMA and then above ileal branch of SMV, as we kept dissecting from left to right ( ). Uncinate dissection, duodenojejunal flexure mobilization, and standard lymphadenectomy were then performed followed by division of jejunum at a slightly longer distance from the duodenojejunal flexure to gain mobility of mesentery to allow length for anastomosis, division of first part of duodenum, common bile duct, and pancreas. The vascular relations can be seen after the resection in . Reconstruction was performed by bringing the jejunal loop up from the right paracolic side and not in the conventional retrocolic fashion. The modified Blumgart technique of duct to mucosa pancreaticojejunostomy was performed with 5–0 polypropylene, single layer interrupted hepatico jejunostomy was done using 4–0 polypropylene and stapled posterior gastrojejunostomy was done. The patient had a postoperative chyle leak and superficial surgical site infection which was managed conservatively and he was discharged on the postoperative day 25. Histopathological examination showed tumor confined to pancreas with all margins free and no node out of 16 was positive. The patient is doing well at 3-year follow-up with no adjuvant therapy.

pmc-8674386-1

A 70-year-old man was referred to our institution by his family doctor for the examination of repeated upper abdominal pain. Preoperative computed tomography (CT) suggested resectable pancreatic cancer of the pancreatic body (Fig. A) concomitant with stricture of the CA root (Fig. B), which may have been caused by median arcuate ligament (MAL). Pancreaticoduodenectomy with division of the MAL was scheduled. Unexpected bleeding around the CA was observed during surgery, which may have been caused by the injury incurred when the MAL was cut to release CA compression (Fig. A, B). As bleeding could be controlled by simple compression only, hemostasis by suturing was attempted first. Contrary to our expectations, the bleeding intensified, making it difficult to confirm the bleeding point. Therefore, we attempted supraceliac aortic cross-clamping (SAC) to manage bleeding. To expose the aorta, the crus of the diaphragm was divided, and the aorta was clamped upstream of the CA by a Fogarty vascular-clamp forceps. After performing SAC, the bleeding intensity significantly decreased and a defect of the adventitia measuring 7 mm in diameter on the CA was confirmed (Fig. C). The defect was repaired using a 4-0 Prolene continuous suture (Johnson & Johnson K.K, NJ, USA). The procedure time for SAC was 2 min and 51 s, and the intraoperative blood loss was 480 ml. The maximum blood pressure increased from 120 to 150 mmHg when SAC was performed and then decrease to 120 mmHg after releasing the clamp. The operative policy was changed to underdo distal pancreatectomy to decrease the risk of hepatic infarction. The patient was discharged uneventfully on postoperative day 19. A surgical procedure of SAC is shown in Additional file .

pmc-8674393-1

A 56-year-old woman, a mother of 3 children, presented to the surgical department with a history of multiple neck lumps of 4 months duration. She also had generalised vague abdominal pain, loss of appetite and lower back pain. She had no significant medical, family or psychosocial history. Clinical examination revealed multiple, bilateral enlarged cervical lymph nodes which were firm to hard in consistency. Thyroid examination revealed a 2 × 2 cm firm lump on the lower pole of the left thyroid lobe. Examination of other lymph node groups revealed enlarged right inguinal lymph nodes. Abdominal examination and rectal examination were normal. Vaginal examination revealed a hard, unhealthy uterine cervix. Breast and axillary examination were unremarkable. She had spinal tenderness, but the neurological examination of the lower limbs was normal. Her basic blood investigations, liver profile and renal functions were within the normal limits. Ultrasound scan of the abdomen revealed no abnormalities. Ultrasound scan of the neck revealed multiple nodules in the thyroid, with increased vascularity, and multiple enlarged cervical lymph nodes with obliterated fatty hila suggestive of malignant deposits. Contrast enhanced computed tomography of the neck, chest, abdomen and pelvis showed a mass in the uterine cervix (Fig. ) with multiple enlarged lymph nodes in the inguinal, iliac, para-aortic, anterior mediastinal and bilateral deep cervical groups (Fig. ). There were multiple low-density nodules in the thyroid gland (Fig. ). A mixed density mass lesion was also noted in the lower pole of the left thyroid lobe (Fig. ). Furthermore, an anterior wedge fracture of the L2 vertebra was seen, probably secondary to bone metastases. Biopsies from the uterine cervix and endometrial curettage revealed moderately differentiated squamous cell carcinoma, signifying local extension of the cervical carcinoma into the endometrium (Fig. ). Excision biopsy of a left cervical lymph node revealed metastatic deposits of moderately differentiated squamous cell carcinoma similar to that of the uterine cervix (Fig. ). Ultrasound-guided fine needle aspiration cytology of intra-thyroid nodules revealed malignant squamous cells (Fig. ). This was followed by a panendoscopy of the upper aerodigestive tract which yielded negative results. A multidisciplinary meeting with the oncologists, surgeon, gynaecologists, pathologists and radiologists was conducted. Considering the histopathological and imaging findings with negative panendoscopy, a diagnosis of squamous cell carcinoma of the uterine cervix metastasising to the cervical lymph nodes and thyroid gland was made. A decision was made to commence palliative chemoradiotherapy. After 6 months, the patient developed generalised body oedema. She was transferred to a specialised cancer treatment centre for further palliative management, where she passed away a short while later, due to acute renal failure secondary to ureteric obstruction.

pmc-8675093-1

This was a 43-year-old woman with cervical carcinoma who received pelvic exenteration. Continuous intravenous infusion of oxycodone at 30 mg/day was started to relieve postoperative pain. The dose was increased in a stepwise way to 288 mg/day (MED 576 mg/day). The pain gradually subsided, and the oxycodone dose was reduced (). Continuous intravenous infusion was discontinued at 18 mg/day (6.25% of the maximum administered dose). However, six hours after discontinuation, she developed restlessness and an itching sensation in her legs. Therefore, continuous intravenous infusion of oxycodone at a dose of 18 mg/day was resumed the same day, and symptoms disappeared. The oxycodone dose was further reduced and discontinued gradually over 10 days. Subsequently, no withdrawal symptoms occurred.

pmc-8675093-2

This was a 43-year-old man with hepatocellular carcinoma who had undergone liver transplantation from a living donor. A year later, he developed severe acute pancreatitis with severe abdominal pain. On admission to the hospital, continuous intravenous infusion of fentanyl at 1200 μg/day was started to control abdominal pain. The fentanyl dose was increased according to pain intensity, reaching 2400 μg/day (MED 240 mg/day) after 10 days in the hospital. Administration of a pancreatic enzyme inhibitor, antibiotic, and fluid alleviated the pancreatitis and abdominal pain. shows that continuous fentanyl infusion was discontinued after reaching 240 μg/day (10% of the maximum dose). He subsequently developed nausea/vomiting, elevated blood pressure, and restlessness 12 hours after discontinuation. Continuous intravenous fentanyl infusion of 240 μg/day was resumed, and these symptoms disappeared. However, restlessness occurred each time the dose was reduced. Therefore, a transdermal fentanyl patch was initiated to taper the opioid more slowly. Pancreatitis with abdominal pain recurred transiently one month later. Therefore, continuous intravenous fentanyl infusion was resumed, titrated to 600 μg/day. The dose was gradually decreased daily (600, 300, 240, 180, 120, and 60 μg/day). Once the pancreatitis had improved, the fentanyl could be discontinued without causing withdrawal symptoms. The discontinuation was finally completed 64 days after the onset of withdrawal symptoms.

pmc-8675093-3

This was a 49-year-old woman with vulvar sarcoma who was irradiated with proton beam radiotherapy. Unfortunately, a very painful ulcer formed within the irradiation field one month after completion of treatment. Sustained-release oxycodone administration was started at 40 mg/day. The oxycodone dose was increased according to pain intensity, reaching 160 mg/day (MED 240 mg/day). The ulcer was treated with skin grafting and relieved the pain. The oxycodone dose was decreased every two days (). Mild restlessness occurred at 20 mg/day (12.5% of the maximum dose). Since the symptom was mild, the same dose was administered continuously and the restlessness disappeared after a few days. However, oxycodone 20 mg/day was continued for another two months before being reduced to 10 mg/day for 14 days and then discontinued. Six hours after discontinuing oxycodone, she developed cold sweats, malaise, and leg pain. Sustained-release oxycodone (10 mg/day) was restarted, and symptoms were relieved. This lasted for about five months because she was afraid of developing withdrawal symptoms. Final oxycodone discontinuation was achieved 323 days after the first onset of withdrawal symptoms.

pmc-8675273-1

As home care doctors and general practitioners, we encountered a 37-year-old woman with ASD who lived with her parents in Japan. Her mother had end-stage breast cancer. We visited her house regularly to care for her mother. The woman with ASD was the main caregiver and a key person for her mother because her father was visually impaired. There were some obstacles we need to overcome together, but in the end, she was able to fulfill the role of the main caregiver for her mother. When we started home care for the mother, we did not have any knowledge that the daughter was a person with ASD. However, we occasionally heard about her from home visit nurses and home care staff because they worried about whether the mother could continue to stay at home due to the lack of care provided by family members. According to home care staff members, the woman with ASD was usually not present when the home care staff visited the home for her mother's care. They could not contact her or talk with her about her mother's condition. She focused on dishwashing and did not appear concerned about how her mother's medications or clothes were organized or whether the room was clean or not. She could not communicate well with home care staff even when she talked with them. Thus, we did not initially recognize that she was a person with ASD or another developmental disorder. We were wondering why she was having trouble managing the home care schedule and chores even though she worked as an engineer. The home care staff's distrust of the daughter caused irritation and stress in the daughter and the home care staff. After a few home care visits, with the daughter's consent, the mother's care manager informed us that she had been diagnosed with ASD in adulthood. Her parents had not been informed of the diagnosis. The daughter did not want to let her parents know about the diagnosis. The home care staff started to feel strongly that it was too difficult for the daughter to continue home care for the mother. The woman with ASD also felt difficulties in communicating with staff and understanding how her mother felt or how it feels to be severely ill. Therefore, we initiated consultation and social skill training in our outpatient clinic for the daughter. We discussed the traits of ASD as well as solutions or strategies to manage ASD traits in the home care setting. When we gave her instructions, we tried to make them more specific and provided examples so that she could understand them easily. For example, we suggested that she needed to come into her mother's room to share her mother's condition when the home care staff made a visit. After several consultations, she gradually obtained life skills in communication, scheduling, and managing things related to home care, such as expectations during home care staff visits or what she should do for her mother. Her psychological stress and caregiving burden decreased day by day. We also shared the fact that she was diagnosed with ASD with home care staff as well as appropriate attitudes, support, and communication styles. We shared her behavioral characteristics with staff, such as lower interest in sharing emotions with others or having difficulties in understanding social cues such as eye contact, facial expressions, and metaphors. Five months after the start of home-based care, her mother's condition worsened temporarily. The woman with ASD could not understand her mother's discomfort or pain and her father's sadness and serious feelings about the poor prognosis of his wife. She could not understand why her father was at a loss for words upon hearing the doctor's explanation of her mother's severe condition. Therefore, she asked him “Didn't you hear, Dad?” in a loud voice. These types of reactions by the daughter interfered with her father's acceptance of her mother's condition and he was unable to continue to listen the explanation. After this event, we explained why her father become silent while during the explanation of her mother's condition. We made a rule that we will tell her beforehand what we would say and how she should act when we share bad news. For example, we told her beforehand that we were going to tell her father about her mother's poor condition and prognosis and asked her to listen until we finished. We also told her how her father would react and our guess of the reasons for his reaction. Inappropriate behavior that is not suitable for the situation decreased afterward. She also felt relieved that she knew what she should do and could support her father as much as possible. Seven months after the start of home-based care, the mother passed away at home as her mother and she herself hoped. When her mother needed to use oral opioids and subcutaneous injection of opioids, the woman with ASD was able to communicate with homecare staff and ask for help to offer better care for her mother. Her mother died peacefully without any severe pain or discomfort. The woman with ASD did not become confused and was able to accept her mother's death peacefully with her father.

pmc-8677559-1

A 57-year-old man with NASH without cirrhosis presented to a satellite hospital with acute onset of painless hematochezia for 1 day. He had unprovoked deep venous thrombosis with a negative hypercoagulable workup and portal-vein thrombosis on Apixaban diagnosed 18 months prior to presentation. He was tachycardic and mildly hypotensive. There was no evidence of chronic liver disease on exam. The hemoglobin level was 130 g/L and subsequently decreased to 80 g/L, while the platelet count was 160 × 109/L. Laboratory tests revealed the following values: INR, 1.13; lactate, 1 mmol/L; albumin, 3.7 g/dl; and liver enzymes were within normal limits. Anticoagulation was discontinued and he was resuscitated using intravenous (IV) crystalloids. Esophagogastroduodenoscopy (EGD) revealed small non-bleeding esophageal varices. Colonoscopy revealed a complex ascending colonic varix with active bleeding (). He was treated with IV octreotide at the satellite hospital at which he presented and then transferred to our tertiary institution for escalation of care. Liver-protocol computed tomography (CT) was performed for TIPS evaluation and revealed a steatotic liver and collateralized chronically thrombosed SMV with patent portal vein. He was deemed not to be a candidate for either TIPS or BRTO in the setting of chronic SMV thrombosis. Colonic resection was not recommended, since it was unlikely to prevent future bleeding with significant collaterals. He continued to have hematochezia with Hgb nadir of 78 g/L. A trans-hepatic portogram performed by interventional radiology revealed an elevated absolute portal pressure of 18 mmHg. Digital subtraction images confirmed the site of the SMV occlusion at the confluence of two large SMV branches, in addition to retrograde flow through the large right CV. The occluded SMV was cannulated through a left patent branch using a 4-French angled glide catheter and a stiff Glidewire. A Cobra 2 catheter and a stiff Glidewire were used to cannulate the right SMV branch at the confluence. Recanalization of the occluded SMV () was achieved by using 5 × 40 mm balloon angioplasty to 5 mm, then two overlapping 10 × 40 mm self-expanding stents were successfully deployed into the origin of the right SMV branch, extending proximally into the portal splenic confluence. The stents were then post-dilated using balloon angioplasty to 8 and 10 mm. Follow-up venography showed antegrade flow in the right SMV branch into the SMV stent with a marked reduction in filling of the right CV (). The procedure was terminated after restoration of the SMV flow and the portal pressure was not measured post-procedurally. Liver biopsy showed steatohepatitis with stage 2/4 fibrosis. Apixaban and low-dose aspirin were started. Two months after discharge, the patient had no recurrent bleeding and CT showed patent SMV stents (). A plan for surveillance was determined using cross-sectional imaging every 6 months for 2 years.

pmc-8677941-1

A 63-year-old male presented on November 16, 2018, with complaints of persistent left epistaxis and a history of swelling in the left orbit and maxillary sinus for 3 months. Examination revealed multiple enlarged, indurated, and painless lymph nodes in the cervical and left submandibular areas, the largest of which was 4 mm × 3 mm. Blood tests at diagnosis showed anemia (Hb 122 g/L) and thrombocytopenia (90 × 109/L). Syphilis and HIV screenings were negative. Initial enhancement MRI scanning on November 27, 2018, revealed heterogeneous enhancement shadow filling in the left maxillary sinus along with adjacent bone absorption (). The patient underwent a subsequent biopsy by nasal endoscopy on November 29, 2018. Histology highlighted a diffuse infiltrate of large atypical cells with lymphocytic or plasmacytoid morphology (). Neoplastic cells expressed a high proliferative index (Ki-67, 95%) (). Immunohistochemical profiling showed positive results in neoplastic cells for MUM1, CD38, CD138, c-myc, and EBV-EBER, the ratio of kappa chain (+) neoplastic cells to lambda chain (+) neoplastic cells is greater than 64:1 (), and they were negative for CD30, CD19, CD79a, PAX-5, CD20, CD21, bcl-6, CD10, bcl-2, CD15, HMB45, S-100, MelanA, CK, and EMA ().18F-FDG PET/CT was performed for further assessment of the mass lesion metabolic activity and the general conditions at diagnosis on December 6, 2018. Transverse PET/CT scan revealed a 3.7 cm × 3.9 cm × 4.3 cm solid mass, partial bone destruction, and swelling of soft tissues. A markedly FDG-avid space-occupying lesion was observed at the left maxillary sinus, and it invaded the left nasal cavity, left orbital apex, and left alar mandibular space (SUVmax, 7.8; SUVmean, 6.3) (). Bone marrow aspirate and trephine biopsy were negative for lymphoma involvement. The screening investigations specific for multiple myeloma or plasmacytoma results showed that this patient was negative for serum protein electrophoresis, immunofixation, and free light chain assay. The final diagnosis was confirmed to be consistent with stage II PBL. With curative intent, bortezomib was initiated (2.3 mg d1, 4, 8, 11) in combination with CDOP (cyclophosphamide 1.3 g d2, epirubicin 40 mg d2, vindesine 4 mg d21, prednisolone 65 mg d2–6) chemotherapy regimen on a 21-day cycle. After two cycles of V-CDOP, enhanced MRI scanning on February 11, 2019, revealed an excellent initial response, with a substantial decrease in the size and intensity of nasopharyngeal lesions (). After three cycles of the V-CDOP regimen, re-evaluation of the 18F-FDG PET/CT in the transverse dimension on May 21, 2019, showed a diminished range of lesions to 3.8 cm × 2.9 cm × 3.8 cm and reduced 18F-FDG uptake in the left maxillary sinus (SUVmax, 7.0; SUVmean, 4.5) and other regions (SUVmax, 4.0; SUVmean, 3.6) (). The patient achieved a partial response (PR) after five cycles of V-CDOP chemotherapy treatment. This planned treatment was followed by mobilization and collection of autologous peripheral blood stem cells on May 24, 2019. After one cycle of V-CDOP, enhanced MRI scanning revealed no significant change on June 27, 2019 (). On regular follow-up, he received local radiotherapy (RT) to nasopharyngeal regions (30 Gy in 15 fractions over 3 weeks). After RT, he was switched to two cycles of V-CDOP regimens supplemented with lenalidomide (25 mg d1–21) on August 9 and September 10, 2019. The main toxic side effect was grade 2 myelosuppression and improved after symptomatic treatment. Subsequent enhancement MRI scanning revealed a reduction in the size of nasopharyngeal lesions on September 14, 2019 (). The therapeutic assessment by FDG PET/CT on September 29, 2019, showed a complete metabolic response (cMR), a diminished range of lesions to 1.0 cm × 1.3 cm, significantly reduced 18F-FDG uptake in the left maxillary sinus (SUVmax, 3.5; SUVmean, 2.5), and a lack of metabolic activity in other regions (). The patient received conditioning BEAM (BCNU, etoposide, cytarabine, and melphalan) high-dose chemotherapy with consolidative autologous hematopoietic stem cell transplantation (ASCT) in October 25, 2019. A total of 8.6 × 108/kg mononuclear cells (MNCs) and 2.1 × 106/kg CD34+ peripheral blood mononuclear cells (PBSCs) were reinfused, and complete engraftment was observed by day + 11. During autologous transplantation, he experienced grade 4 myelosuppression, requiring G-CSF. To consolidate the response, the patient received lenalidomide-based maintenance therapy after the transplant. A repeated enhancement MRI scanning showed increased abnormal signal shadows in the maxillary sinus, which was considered as an inflammatory reaction on May 6, 2020 (). He developed herpes zoster during maintenance treatment on October 2020. Follow-up PET-CT on March 10, 2021 showed continued cMR 16 months after ASCT (). Currently, the patient was monitored with serial MRI scanning and presented 32 months OS and 22 months PFS.

pmc-8678037-1

A 19-year-old man presented to our institute with right hand and foot dyskinesia. He had a significant family history of PKD. His uncle, grandfather, and grandfather's brother had involuntary movements triggered by voluntary movements. Proline-rich transmembrane protein 2 (PRRT2) on chromosome 16, which is associated with movement disorders including PKD (PRRT2-PxMD), was confirmed in his uncle and grandfather through genetic testing (c.649delC/pArg217-Glufs). All of them underwent stereotactic ablative surgery (Vo thalamotomy). The patient's grandfather and grandfather's brother experienced complete remission of involuntary movement attacks after the surgery. His uncle experienced a significant reduction in the frequency of daily attacks without medication. The patient first experienced paroxysmal involuntary left hand and toe flexion with left forearm pronation triggered by sudden voluntary movements at the age of 14. The frequency of attacks was 20–30 per day. Carbamazepine (100 mg/day) was prescribed, which led to a significant reduction in the frequency of attacks. However, drowsiness was significant after the intake of carbamazepine and significantly interfered with his daily life, especially school life. He underwent right-sided Vo thalamotomy at the age of 15, which resulted in complete resolution of PKD attacks immediately after the surgery. The detailed clinical course of right-sided Vo thalamotomy has been reported previously (). Four months after the thalamotomy, the patient developed right elbow, hand, and toe flexion (). The frequency of attacks was 10–20 per day. The duration of the attacks ranged from 10 to 20 seconds. Carbamazepine (100 mg/day) was prescribed again, and the PKD attacks reduced to 5–10 times per day. However, the drowsiness induced by carbamazepine severely interfered with his daily and school lives. He underwent left-sided Vo thalamotomy at the age of 19. The target coordinate of the left Vo nucleus was set the same as in the previous surgery (15-mm lateral, 2-mm posterior, and 1-mm superior to the midpoint of the anterior commissure-posterior commissure). A total of six lesions were created on the left Vo nucleus in the same manner as in the previous surgery. Immediately after surgery, the PKD attacks resolved completely. However, mild dysarthria developed, which spontaneously resolved within three months. Left-sided PKD attacks never developed six years after the right Vo thalamotomy, and right-sided PKD attacks never developed two years after the left Vo thalamotomy without medication. The locations of the coagulated lesions were confirmed using Brainlab Elements. Bilateral lesions covered the Vo and ventral intermediate (Vim) nuclei (). The Vo nucleus is located just anterior to the Vim nucleus of the thalamus. We included both anterior and posterior coagulated lesions in order to cover the entire Vo nucleus. Based on our experience, insufficient lesions to cover the Vo nucleus are likely to develop symptomatic recurrence. The time course of PKD onset and intervention is shown in . The data for this study were retrospectively collected and analyzed. Considering the observational nature of the study, the ethics committee of our institution approved this study, and patient consent was waived.

pmc-8678078-1

Case 1: a 46-year-old female with refractory pain in the cervical spine, the head, and the upper arm at the left side for two years with rising intensity. She had a high need for pain medication. The clinical examination revealed a reduced range of motion of the cervical spine and a sensible radicular syndrome corresponding to the nerve roots C4-C6. The laboratory tests showed no hint for tumor or infection. Radiographs, CT scan, and MRI revealed a tumor at the left side C3-C4 in the cervical spine () without further pathologies in the complete tumor workup (PET-CT, laboratory tests). The biopsy and additional reference pathology yielded the result of an aggressive osteoblastoma (Enneking Type III). Hence, in the interdisciplinary tumor board, the decision for complete wide resection was made. Radiation was considered in dependence on the final pathology after tumor resection. An unremarkable occlusion test of the left vertebral artery was performed in order to simulate a potentially necessary ligation.

pmc-8678079-1

The first patient was a 44-year-old man with Ebstein's anomaly resulting in severe right atrial and right ventricular dilatation with right moderate ventricular dysfunction and severe tricuspid regurgitation. The patient also suffered from HIV immunodeficiency with previous cerebral infection and Kaposi's Sarcoma. In the post-operative period he suffered from severe right ventricular dysfunction with low cardiac output syndrome (LCOS), which required ECMO support.

pmc-8678079-2

The second patient died was a 39-year-old female with univentricular heart (tricuspid atresia), who had had previously two cardiac surgeries (the last was atrio-pulmonary Fontan, 33 years earlier). The patient suffered from a serious right atriomegaly with frequent episodes of atrial tachycardia, so she was a candidate for Fontan conversion surgery. Pre-operative ventricular function was mildly reduced (50%). In the post-operative, the patient suffered from severe single ventricle dysfunction resulting in LCOS and the need for ECMO implantation. Both patients could not be weaned from ECMO due to multi-organ failure. Seven patients required pace-maker implantation due to post-operative sinus node dysfunction or atrioventricular conduction abnormalities. All patients were discharged on oral antiarrhythmic for 3–6 months and anticoagulants for 6 months. At discharge, 15 patients were in sinus rhythm, 5 had a stable pacemaker rhythm, 2 had atrial fibrillation, and 1 atrial flutter. One patient discharged in sinus rhythm had a pacemaker implant 5 months after the operation due to the presence of sinus node dysfunction. During a median follow-up of 14 months (IQR 7–27), there was no late mortality and 17/23 patients had an improvement of NYHA functional class. Five patients in NYHA III progressed to class II and 4 to class I; eight patients progressed from class II to class I. At follow up electrocardiogram, 16 patients were in sinus rhythm, 6 with stable pacemaker rhythm, and 1 with permanent atrial fibrillation. Recurrence of arrhythmia occurred in 2/23 (8.6%) patients, more than 3 months after surgery. These patients presented at surgical ablation with history of atrial fibrillation lasting 4 and 19 years, respectively, and both had atrial fibrillation, which was treated with right-sided Maze rather than Cox maze III due to technical issues. Sixteen (69%) patients are in stable sinus rhythm, 12 without any anti-arrhythmic therapy. At median follow up of 14 months (IQR 7–27), freedom from recurrence of arrhythmia was 90.9% and cumulative risk of recurrence was 9.6% ().

pmc-8678082-1

On July 2008, a 59-year-old man, ex-smoker (45 packs/year), underwent upper right lung lobectomy and regional lymph adenectomy with the diagnosis of stage I (pT2, pN0) lung adenocarcinoma, solid pattern. On July 2020, the chest CT scan revealed the presence of an upper left lung lobe and two lower left lung lobe lesions. On August 2020, the patient underwent a wedge resection of the upper and the lower lung lobes lesions with N1 and N2 nodal sampling. Gross examination of the surgical specimens of the first atypical pulmonary resection of left inferior lobe revealed an Intraparenchymal, peripheral, solid, yellow-white lesion measuring 1.4 cm in greatest dimension. Histological assessment identified a well-circumscribed lesion composed of two different morphological components, tightly adhered but not intermingled each other. The first component represented about 60% of the whole neoplasm and was characterized by a solid and trabecular proliferation of polygonal-shaped uniform tumor cells, with nuclei with finely granular chromatin and inconspicuocus nucleoli, consistent with carcinoid. Four mitosis/2 mm2 were identified, without tumoral necrosis. The second component, which represented about 40% of whole neoplasm, showed a main lepidic, non-mucinous pattern with secondary papillary architecture, corresponding to a lepidic-papillary pattern PA. Immunoreactivity for chromogranin A, synaptophysin, TTF-1, and pan-cytokeratins AE1–3 was documented in carcinoid component, while adenocarcinomatous component was positive only for TTF-1 and cytokeratins (). CK7 immunoreactivity was selectively documented in the adenocarcinomatous component. A final diagnosis of “combined pulmonary adenocarcinoma with atypical carcinoid” was made. No immunoreactivity for ALK and ROS1 was documented in both components. TPS for PD-L1 was <1% in both components. Both two other lesions on atypical pulmonary resections of the upper left lobe and inferior left lobe showed intraparenchymal neoplasm of 1.8 and 1.5 cm, respectively, corresponding both to PA with a main solid pattern and lepidic, non-mucinous second pattern. A positivity ROS1 score of 2+ with gene rearrangement on FISH was documented in the upper pulmonary lobe neoplasia. No immunoreactivity for ALK and a PD-L1 TPS of 1%–49% were observed. No immunoreactivity for ALK and ROS1 with PD-L1 TPS of >50% were documented in the lower lobe neoplasia. No pleural invasion was observed. No lymph nodes metastases were found. The final UICC 2017 stage pT4 (m-3) (PL0) pN0 was assigned. Targeted NGS analysis on Ion Torrent NGS platform using the Ocav3 panel was performed on DNA and RNA extracted from each microdissected histological components of the primary mixed neoplasm (I1/I2) and in the other two adenocarcinomas located in the inferior (I3) and superior (S1) left pulmonary lobes. Summary of genetic results are shown in . Among a total of 161 investigated genes included in the NGS panel, both common and private somatic genes mutations were identified in each entity (). The adenocarcinoma I1 and carcinoid I2 components of the mixed neoplasm shared the same mutations in BRAF (p.Gly466Ala), NF1 (p.Pro1359LeufsTer19 and p.Glu1928Ter), STK11 (p.Gly188AlafsTer99), and AKT2 (p.Leu52Ter) genes. Four additional somatic mutations were detected in the DDR2 (p.Arg806Ter), CDK6 (p.Thr107Ser), and SMARCA4 gene (p.Arg1135Gln) were identified in the adenocarcinoma component, whereas no specific mutations were identified in the carcinoid component. A different genetic profile emerged from the molecular analysis of the two additional adenocarcinoma nodules I3 and S1, lacking those somatic mutations identified in the mixed nodules, but shared two somatic missense mutations in the KRAS (p.Gly12Asp) and NOTCH1 (p.Pro498Arg). In addition, the I3 adenocarcinoma showed a specific, somatic mutations in ATM (p.Gln1117Ter), TP53 (p.Gly245Asp), and CDK12 (p.Arg44Trp) genes, whereas the S1 adenocarcinoma showed a specific, somatic, missense mutations in IDH2 gene (p.Arg172Ser). Since November 2020, considering the ROS1 positivity, the patient started crizotinib, which is still ongoing, reporting a stable disease.

pmc-8678082-2

On October 2016, a 66-year-old woman, never smoker, underwent upper left lung lobectomy and regional lymph adenectomy, for a pulmonary mass discovered on radiological examination for shoulder pain present for a long time. The gross examination of the surgical specimens showed an intraparenchymal, subpleural, whitish mass, measuring 8.5 cm in greatest dimension. Histologically, a well-circumscribed neoplasia composed of two different morphological components, which were separated in some areas and intermingled in others, was documented. The first component represented about 70% of the tumor burden and consisted of an organoid proliferation of polygonal, shaped uniform tumor cells with nuclei with finely granular chromatin and inconspicuous nucleoli, consistent with carcinoid. Four mitosis/2 mm2 and diffuse, punctate necrosis were identified. The second component, representing about 30% of the tumor burden, showed a glandular architecture corresponding to acinar pattern of PA. Neoplastic infiltration of parietal pleura was documented (PL3). Immunoreactivity for chromogranin A, synaptophysin, TTF-1, and pan-cytokeratins (AE1-3 clone) was observed in carcinoid component, while glandular component was positive only for TTF-1 and cytokeratins; cytokeratin 7 was selectively expressed in the adenocarcinomatous component (). Metastatis constituted by both neuroendocrine and non-neuroendocrine component was found in four out of six hilar lymph nodes, showing the same immunoreactivity in different neoplastic areas such as primitive lesion (). Immunoreactivity for ALK and ROS1 resulted negative in both component, in primitive tumor and in lymph nodal metastasis. TPS for PD-L1 was <1% in both component, in primitive tumor and in lymph nodal metastasis. A final diagnosis of “combined pulmonary adenocarcinoma with atypical carcinoid” was made with stage pT3 (PL3) pN2 sec UICC 2017. Each neoplastic component in both primitive and metastatic lesions was individually microdissected from unstained FFPE slides for DNA and RNA extraction. Targeted NGS analysis on Ion Torrent NGS platform was performed using the Ocav3 panel. Among the 161 investigated genes, both common and private genes mutations were identified in each investigated entity of primary and metastatic sites (). No shared point mutations, CNVs, or gene fusions were identified in both adenocarcinoma and carcinoid components from any sites (S1/S2 and mL1/mL2). By contrast, one somatic mutation in the PTEN gene (p.Thr319Ter) was detected specifically in the adenocarcinoma components of both primary and metastatic sites (S2 and mL2), whereas the carcinoid component of both sites shared one somatic mutation in the NF1 gene (p.Arg1325Thr). Primary carcinoid S1 showed one private somatic mutation in the CDK12 gene (p.Arg44Leu), whereas the adenocarcinoma component of metastatic site showed a private mutation in the NOTCH1 gene (p.Pro498Arg). On December 2016, she progressed due to the onset of osteoblastic bone lesions detected by TAC with a negative octreoscan performed on January 2017. In February 2017, cisplatin plus pemetrexed regimen started for six cycles, reporting a partial response after four cycles. In November 2017, due to a massive bone metastasis with bone marrow infiltration, the patient died.

pmc-8682870-1

We report a case of a 58-year-old African American male with a long history of scaly itchy feet. The patient presented to the clinic on February 8th, 2018 with an apparent inflammatory reaction on the plantar surface of both feet ( and ). An initial specimen collection from the patient’s plantar surface revealed hyphae indicative of a fungal infection under KOH preparation. This supported the diagnosis of a tinea pedis infection. The patient was treated with ketoconazole topical cream and 20% Urea creams to be applied daily. Follow-up approximately 6 weeks later revealed resolution of underlying fungal infection with minimal remaining inflammation ( and ). With consideration to the subject’s initial presentation of a possible exaggerated immune reaction caused by Trichophyton, we suspected an underlying allergic response (delayed-type hypersensitivity reaction) to the fungus, instead of a cutaneous fungal infection alone. In order to test this hypothesis, we subjected the patient to intradermal skin testing with intradermal Candida and Trichophyton allergens. On March 21, 2018, the patient underwent application of Candida, normal saline, and Trichophyton allergens on the left volar forearm ( and ).

pmc-8683160-1

A 70-year-old female with multiple medical comorbidities, including hypertension, end-stage renal disease (ESRD), and multiple prosthetic joints including a left total knee arthroplasty (TKA), presented to the emergency room with one-week history of left knee pain, erythema, and swelling. Prior to developing the symptoms in her knee, she suffered from loose stools and abdominal pain that had resolved by the time the patient developed pain in her knee. The patient denied any recent trauma, any rashes, or recent travel. Physical examination was pertinent for tachycardia with a heart rate of 147 beats per minute, respiratory rate of 25 breaths per minute, temperature of 100.5 F, and oxygen saturation of 100% on room air. Blood pressure was 101/59 mmHg. The left knee was red, hot, and swollen. The range of motion of the left knee was restricted. The rest of her physical examination was unremarkable. On laboratory work up, hemoglobin was 15.2 g/dL (13.5–17.5 g/dL); white blood cell (WBC) count, 14,900 cells/uL (4.5–11 k/uL), total bilirubin, 0.8 mg/dL (0.3–1.0 mg/dL); aspartate aminotransferase, 35 U/L (13–39 U/L); alanine aminotransferase, 33 U/L (4–33 U/L); alkaline phosphatase, 124 U/L (34–104 U/L); s. creatinine, 2.3 mg/dl; and sodium and potassium, within normal limits. Lateral and anterior-posterior view X-rays of the left knee joint showed prior total knee replacement but no other significant findings (Figures and ). The initial differentials included septic arthritis of her prosthetic knee joint and reactive arthritis after her recent diarrhea. Gout and other rheumatologic conditions were less likely. A preliminary diagnosis of sepsis due to septic arthritis was made, and supportive management with intravenous (IV) fluids, empiric antibiotics (vancomycin and zosyn), and antipyretics was initiated. Arthrocentesis was performed, and purulent fluid was drained. This was sent for Gram staining and cultures. Gram staining was significant for numerous WBCs and Gram-negative coccobacilli. The culture came back the next day growing Gram-positive coccobacilli that were subsequently identified as Yersinia enterocolitis. This was sensitive to all the antibiotics it was tested against. The blood cultures came back positive for Yersinia enterocolitica too. Yersinia enterocolitica was identified as the cause of the septic arthritis, which was likely the cause of her diarrhea prior to presenting. The patient was seen by orthopedic surgery in consultation and underwent resection of her left TKA and placement of a biodegradable implant without any complications. The patient was also seen by infectious disease in consultation, and based on their recommendations, the patient was discharged home to complete 6 weeks of outpatient IV antibiotics in the form of 2 g of ceftriaxone daily considering her sepsis and prosthetic material in her knee joint. The patient completed this without any complications. The patient was seen on follow-up, and her infection resolved completely. She has not had a recurrence or reinfection of her knee after over a year of follow-up.

pmc-8683162-1

A 73-year-old male with a past medical history of chronic obstructive pulmonary disease, hypertension, and cerebrovascular accident with a right-sided deficit and speech deficit presented in a somnolent state to the emergency room. The patient reportedly had generalized body aches, dyspnea, and cough, which had been progressively worsening over the past two to three days. The patient tested positive for SARS-CoV-2. The patient experienced a prolonged hospital course, remaining in the hospital for approximately three months. A brief overview of the first month of hospitalization is given as follows: the patient was started on dexamethasone, azithromycin, and ceftriaxone at admission. His condition was complicated by a gastrointestinal bleed requiring multiple blood transfusions and a pulmonary embolism. The pulmonary embolism could not be adequately treated with anticoagulation due to his gastrointestinal bleed. His respiratory status declined, due to COVID-19, necessitating intubation which the patient required for most of his hospital stay. Broad-spectrum antibiotics were continued for the majority of his hospital course, switching to vancomycin, piperacillin-tazobactam, and levofloxacin to cover for ventilator-associated pneumonia. The patient required two courses of triple antibiotic therapy to cover for ventilator-associated pneumonia due to persistent leukocytosis and a chest X-ray significant for signs of infiltrates which remained following his initial treatment course for ventilator-associated pneumonia. During the second month of his hospital stay, after his initial antibiotics courses had been completed, due to worsening respiratory status, sputum cultures were performed on hospital day (HD) # 26 which revealed Stenotrophomonas maltophilia and Citrobacter koseri, which were treated with trimethoprim-sulfamethoxazole (). Due to his gastrointestinal bleed, the patient underwent an esophagoduodenoscopy and a colonoscopy. Esophagoduodenoscopy revealed mild antral gastritis with a deformed duodenal bulb as well as some mild diverticulosis. Colonoscopy revealed a large ascending-colon mass. Two biopsy samples were taken of this colon mass, which returned consistent with tubular adenoma without cytologic atypia. However, it was suggested by the pathologist that if this biopsy material was part of a larger lesion, a more advanced malignant lesion could not be excluded. The patient was too unstable during his hospitalization to undergo resection of the mass. On HD # 38, the patient received a tracheostomy which he tolerated well without complications. On HD # 49, the patient experienced a febrile episode (maximum temperature of 101.2 °F). At this time, the patient had both a Foley catheter and an internal jugular central line in place (he required both of these for the majority of his hospital course). Urinalysis, urine cultures, blood cultures, and a chest X-ray were ordered on the same day (). Urinalysis revealed 38 red blood cells per High Powered Field (HPF), 13 white blood cells/HPF, 2+ bacteria, many budding yeast, and 3+ hyaline casts (). Due to the bacteria and yeast in his urine, the Foley catheter was replaced the same day. Leukocytosis was only mild (10.6 cells per cubic millimeter of blood), but continued to increase to 15 cells per cubic millimeter of blood over the ensuing four days (). The urine culture that resulted on HD # 53 revealed T. asahii. Isolates of T. asahii were obtained by performing a culture on a TSA blood agar plate with 5% sheep blood. The isolates were incubated at 35°C in an incubator at an ambient atmosphere for 24 hours. Isolates were identified using the VITEK 2 system (bioMérieux, Inc., Hazelwood, MO). Although the urinalysis had shown 2+ bacteria, no bacterial growth was seen in the urine culture. Blood culture revealed no growth after five days. Serum beta-D glucan was negative. The urine culture was sent to an outside laboratory (Quest Diagnostics Nichols Institute, Chantilly, VA) to determine sensitivities. At Quest Diagnostics, the isolates were reincubated on Sabouraud Dextrose Agar (SDA) overnight. The inoculum was prepared in sterile demineralized water and standardized to a 0.5 McFarland. Twenty microliters of the suspension was added to a tube with 11 mL of Sensititre YeastOne Inoculum Broth and then prepared by inoculating 100 uL per well. In vitro advanced fungal susceptibility testing was performed using anidulafungin, micafungin, caspofungin, 5-flucytosine, posaconazole, voriconazole, itraconazole, fluconazole, and amphotericin B. Trichosporon organisms were tested with these agents using broth microdilution according to the Clinical and Laboratory Standards Institute (CLSI). The stock solutions purchased by Quest Diagnostics are prediluted (information regarding dilution preparation is not available). Isolates were identified using the Sensititre Trek YeastOne panel (Trek Diagnostic Systems, Cat. No. YO-9), which is a broth microdilution panel. The manufacturer's instructions were followed for setting up, reading, and analyzing the assay. Plates were incubated at 33–35°C for 24 hours minimum. The Sensititre system monitors for colorimetric change. MIC values were determined by demonstrating the lowest concentration of drug that does not demonstrate a color change. CLSI document M27 was used for the interpretation of results. Pending sensitivity results, a repeat urine culture was ordered (HD # 53). On HD # 58, the patient again experienced a febrile episode, with a maximum temperature of 103.0°F accompanied by a leukocyte increase from 10 to 15 cells per cubic millimeter of blood (). On HD # 58, the repeat urine culture results confirmed the presence of T. asahii. Again, no bacterial growth was seen in the urine culture. Antifungal medication had not been started initially as there was concern that the initial urine culture obtained on HD # 49 had revealed a contaminant or was reflective of asymptomatic colonization. However, with the repeat urine culture revealing T. asahii, the febrile episode, and leukocyte increase despite broad-spectrum antibiotics, antifungal coverage was deemed necessary. The patient was started on empiric fluconazole on HD # 58, and his Foley catheter was again replaced that same day (). A tracheal aspirate culture was ordered which returned results on HD # 63 revealing Stenotrophomonas maltophilia. Treatment with trimethoprim-sulfamethoxazole was again started (). On HD# 65, the sensitivities for the urine culture (sent to an outside laboratory on HD # 52) returned which revealed nonsusceptibility to fluconazole (MIC 2 mcg/mL), resistance to caspofungin and micafungin (MIC > 8 mcg/mL), and sensitivity to voriconazole (MIC 0.03 mcg/mL). Based on the advanced fungal testing, voriconazole was started on HD # 65 (following seven days of fluconazole) per infectious disease recommendations and continued for seven days (). The patient had remained afebrile with improved leukocytosis since starting fluconazole (white blood cell count decreased from 15 cells per cubic millimeter of blood to 9 cells per cubic millimeter of blood). With the initiation of the voriconazole, the leukocyte count continued to drop to normal levels (4.40 cells per cubic millimeter of blood). A percutaneous endoscopic gastrostomy tube was placed on HD # 78, and the patient tolerated the procedure well without complication. Urine cultures were obtained on HD # 78 and revealed 10,000 CFU/mL of usual skin flora. T. asahii was no longer present in urine (). At this point, the patient was accepted and transferred to a long-term care facility on HD # 80. At this long-term care facility, multiple attempts failed to fit the patient with an aerosolized tracheostomy collar. A decision was made to initiate palliative care. On HD # 44 at the long-term care facility, he was found without spontaneous respirations or palpable pulse.

pmc-8683165-1

A 33-year-old male presented to our center with chief complaints of profuse per rectal bleed mixed with stool for three days that was associated with easy fatigability for one week prior to the initial presentation. He also had one episode of black tarry stool. However, he had no complaints of blood in vomit, purpuric rashes, or petechiae. He also had no hematuria, weight loss, night sweats, evening rise of temperature or loss of appetite, cough, chest pain, dyspnea, palpitation, limb edema, loose stools, jaundice, and abdominal distension. Bleeding was absent from other orifices. He had no history of diabetes mellitus, hypertension, cardiac diseases, and pulmonary tuberculosis in the past. He consumed 80 grams of alcohol per day for 15 years, but he did not smoke. On examination, he was ill looking, conscious, and was well oriented to time place and person. He had pallor and was dehydrated. However, he had no icterus, clubbing, cyanosis, or edema. His pulse rate was 110 beats/minute, blood pressure was 80/60 mm of Hg, body temperature was 98°F (36.6°C), respiratory rate was 19 breaths/minute, and oxygen saturation was 95% in room air. The digital rectal examination showed fresh blood over the examining finger and otherwise normal findings. Abdominal and cardiac examination was normal. Laboratory investigations showed hemoglobin 10.8 g/dl and hematocrit 31.6%. The total leukocyte count was 11510/mm3, neutrophils were 78%, and platelet count was 291000/mm3. The prothrombin time was 14 seconds, and the International normalized ratio was 1.08. The albumin level in the blood was 2.4 gm/dl, and total protein was 6.1 gm/dl, total and direct bilirubin were 0.7 and 0.1 mg/dl in the blood. Alanine aminotransferase and aspartate aminotransferase level was 97 U/L and 114 U/L, respectively. HbA1C level in the blood was 7.2. The level of urea (33 mg/dl), creatinine (1.1 mg/dl), sodium (132 mEq/l), and potassium (3.6 mEq/l) were within normal range. Traces of sugar and albumin (++) were present in the urine examination. The fecal occult blood was found in the stool. Mycobacterium tuberculosis was not detected in sputum in the acid-fast bacilli (AFB) stain. The chest X-ray was normal. Ultrasonography (USG) of the abdomen and pelvis and upper gastrointestinal endoscopy showed normal findings. A Computed Tomography (CT) scan of chest and abdomen showed asymmetric circumferential thickening in the ileocaecal region with lobulated thickened caecum, soft-tissue stranding and necrotic mesenteric lymphadenopathy, and indeterminate lobule in the lung (). Colonoscopy showed multiple transverse ulcers with overlying exudates in terminal ileum and ascending and transverse colon. Histopathological examination of the ileum and colon showed patchy ulcers with exudates, granulation tissue, fibrosis, deep lymphoplasmocytic inflammation, and crypt regenerative changes with fibrinoid changes in scattered capillaries and venules and was inconclusive. However, gene XPERT was positive for Mycobacterium tuberculosis. He was diagnosed with ileocaecal tuberculosis. The hemoglobin level dropped to 6.1 g/dl after two days of admission, and he had an episode of weakness associated with profuse sweating and rigor. Fluid resuscitation followed by two pints of whole blood transfusion was performed. After that, his hemoglobin was increased to 10.2 mg/dl. He was managed with four antitubercular drugs and showed significant improvement. Following this, he was discharged on oral antitubercular medications (isoniazid, rifampicin, pyrazinamide, ethambutol, and pyridoxine) after 10 days of admission. On follow-up after two weeks, he was responding well to antitubercular medications with improved symptoms, i.e., no per rectal bleeding, and his liver function test was within the normal range.

pmc-8683194-1

We present the case of a 46 year-old-female, never smoker, with a history of ulcerative colitis who initially presented as an outpatient for the evaluation of persistent cough, wheezing, and chest tightness for 6 months. Her review of systems was otherwise negative and her only medication included mesalamine for ulcerative colitis. She had no history of environmental or occupational exposures and denied any allergies. She denied any personal or family history of lung disease. Her vital signs were within normal limits. This patient was evaluated by pulmonology and was diagnosed with cough variant asthma and was started on montelukast and albuterol as needed. A northeast allergy panel was unremarkable. She subsequently presented to the emergency room with an episode of wheezing and chest tightness and Computed Tomography Angiogram (CTA) revealed multiple lung nodules with mosaic attenuation. The nodules were seen bilaterally in clusters, with the largest measuring up to 1.8 cm in the right middle lobe. Multiple serologic markers were ordered to screen for autoimmune disease including ANA, ANCA, anti-dsDNA, hypersensitivity pneumonitis panel, Sjogren's antibodies, angiotensin converting enzyme, and rheumatoid factor. These were unremarkable other than a positive ANA with titer 1 : 640 homogenous pattern. Due to uncontrolled symptoms, her inhaler regime was escalated to Flovent twice daily with as needed albuterol. A repeat CT chest 3 months later indicated no change in diffuse mosaicism and multiple pulmonary nodules, similar in size, with the largest 1.8 cm in the right middle lobe (Figures –). She then underwent robotic-assisted navigational bronchoscopy with fine needle aspiration, brushing, and transbronchial biopsy of the right middle lobe nodule (Figures and). Pathology from the nodule was positive for groups of bland appearing small blue cells, consistent with low-grade neuroendocrine tumor (carcinoid). Pathology was positive for chromogranin and synaptophysin, neuroendocrine markers, and low Ki-67 positivity, indicating low rate of proliferation (Figures –). Endobronchial ultrasound was also performed and Level 7 lymph node was negative for malignancy. The patient was presented at multidisciplinary chest tumor conference and it was recommended that she undergo PET CT scan and surgical resection of the biopsy-proven typical carcinoid tumor in the right middle lobe.

pmc-8683236-1

A 35-year-old female presented to the Emergency Department (ED) for evaluation of 3 months of worsening exertional dyspnea and bilateral lower extremity edema. The patient initially noted mild dyspnea on exertion, which gradually progressed to the point of being unable to climb a single flight of stairs without stopping to rest. The patient endorsed a nonproductive cough, pleuritic chest pain, occasional orthopnea, and an unintentional 20-pound (9.1 kg) weight loss over a one-month period. She denied any associated fevers, chills, or night sweats; had no nausea or vomiting; and had no easy bruising or bleeding. The patient denied any other recent illness and also denied any significant exposures or risk factors for tuberculosis. She had no significant past medical history including any previous cardiac pathology, thromboembolic disease, structural heart disease, indwelling catheters, or asthma. She denied any current or prior intravenous drug use (IVDU). Family and surgical history was also noncontributory. Physical exam demonstrated a nontoxic appearing patient sitting comfortably in bed. Vital signs included a temperature of 98.1°F (36.7°C) with mild tachycardia at 109 beats per minute, blood pressure of 107/64 mmHg, and respiratory rate of 20 breaths per minute. Pulmonary examination revealed lungs clear to auscultation bilaterally without adventitious sounds or retractions; however, the patient was only able to speak in 4–5-word sentences with effortless tachypnea and no accessory muscle use. Cardiac examination demonstrated mild tachycardia without murmurs, rubs, or gallops; no jugular venous distention; and no carotid bruits. Extremity examination was notable for symmetric 2+ pitting edema to the midshin of both lower extremities. Skin exam revealed no purpura, Osler nodes, Janeway lesions, splinter hemorrhages, or track marks. Abdominal exam was nontender, and neurological examination was nonfocal. Multiple laboratory studies including 2 sets of blood cultures were obtained () and remarkable only for mild hyponatremia with a sodium of 127 mEq/L, a chloride of 90 mEq/L, and mild anemia with a hemoglobin of 8.5 g/dL. There was no leukocytosis, troponin was undetectable, and brain-natriuretic peptide was within the normal range. These laboratory findings were not suggestive of any particular pathological processes. The finding of anemia was noted, but the lack of any corresponding elevation in bilirubin made acute hemolysis less likely. The hyponatremia was felt to be consistent with the patient's hypervolemic clinical picture. The lack of leukocytosis was noted, though limited inferences can be made from this value in isolation. Overall, the laboratory results made acute decompensated congestive heart failure and bacterial pneumonia lower on the differential. A 12-lead electrocardiogram revealed sinus tachycardia with normal axis and intervals, with no acute injury pattern and no evidence of right-heart strain. A chest radiograph was obtained () and was interpreted by the radiologist as demonstrating “bilateral patchy atelectasis”—however, the emergency physicians felt it demonstrated a pleural-based wedge-like consolidation in the right inferior lobe consistent with Hampton's Hump. The initial differential considered by the providers included pulmonary embolus, pneumonia, congestive heart failure, pulmonary hypertension, cardiomyopathy, and infectious endocarditis. At this time, a third set of blood cultures were added to the patient's workup. A limited bedside transthoracic echocardiogram (Figures and ) in the ED revealed findings concerning for tricuspid valve vegetations as well as a slightly enlarged right ventricle without any D-sign (i.e., a D-shaped left ventricle on parasternal short-axis view, consistent with right ventricular strain causing shift of the ventricular septum). Cardiology was consulted for concern for potential IE. A CT-angiogram (CTA) of the chest was ordered to assess for pulmonary embolism and further characterize the pulmonary lesions seen on radiography, and the patient received intravenous (IV) ceftriaxone and azithromycin to cover possible community-acquired pneumonia while the CTA was pending. The CTA revealed findings consistent with multiple septic emboli and mycotic aneurysms (Figures and ), as well as multiple segmental pulmonary arterial occlusions with associated infarcts or hemorrhage. A stat formal echocardiogram was obtained and interpreted at bedside by the cardiology fellow, confirming the presence of tricuspid vegetations as well as moderate tricuspid regurgitation, with no evidence of right ventricular strain. The patient was treated with IV vancomycin, gentamycin, and ciprofloxacin to provide coverage for possible MRSA endocarditis, due to the concern for possible undisclosed IVDU, and was admitted with consultation of Cardiothoracic Surgery and Infectious Disease (ID). The patient was maintained on IV gentamycin and vancomycin and underwent a transesophageal echocardiogram (TEE) on hospital day 2 which revealed a large 2.0 × 2.1 cm posterior leaflet tricuspid valve vegetation with severe tricuspid regurgitation. On hospital day 5, the patient admitted to a history of heroin IVDU but was not forthcoming about the date of her most recent use, and a urine toxicologic screen was negative. The patient underwent a tricuspid valve annuloplasty and reconstruction using autologous pericardial tissue by Cardiothoracic Surgery on hospital day 8. The patient's blood cultures remained negative on hospital day 9, at which time ID recommended the patient receive ceftriaxone 2 g IV daily for 6 weeks. Pathology of the valve leaflets resulted on hospital day 10 and indicated granulation tissue with focal areas of bacterial colonization without bacterial identification. The remainder of the patient's postoperative course was uncomplicated, and on hospital day 15, she was transferred in good condition to a skilled nursing facility to complete her 6-week course of IV ceftriaxone. The blood cultures remained negative, and the causative pathogen was not identified.

pmc-8683245-1

We present a 5-year-old female child who was symptomatic since the early neonatal period with skin lesions, intermittent painless vaginal bleeding, and breast enlargement. For these complaints, the parents took the child to the nearby health facility, but they were reassured. Compared to her peers, her growth in length was fast since her early childhood, but she had poor weight gain. At the age of 3 ½ years, she presented to an orthopedic clinic with bowlegs for which she was seen and sent home without any intervention. But after one week, she had a trivial fall down accident, and she sustained pathological fractures on both upper and lower extremities. Plaster of Paris (POP) cast was applied for the lower left arm, and open fixation with plate was done for the left femur. During the procedure, tachycardia was detected, for which she was investigated and diagnosed to have hyperthyroidism. She was initially put on propylthiouracil (PTU) and propranolol. After eight months of the procedure, there was displacement of the plate. The orthopedic surgeon decided to revise the operation, but the thyroid function was not controlled for which she was referred to a paediatric endocrinology clinic for better management of hyperthyroidism. On physical examination at the paediatric endocrinology clinic, she was emaciated. Her weight was 16 kg (between 10th and 25th percentiles) and her height was 115 cm (on the 95th percentiles). Weight for height was far less than 5th percentile (underweight), based on CDC growth charts. Her pulse rate was 123 bpm, and she had protruded eyes. CAL spots were noticed on her face, neck, and trunk (). There was a 5 cm by 3 cm anterior neck mass with an irregular surface (). There was also breast enlargement. She had a grade III early systolic murmur best heard at the left upper sternal border. There was swelling and tenderness at the right midshaft of the humerus and short POP on the left lower arm. She had a wide gait. Based on her clinical findings, she was diagnosed to have MAS.

pmc-7451506-1

A 45-year-old obese man (height, 178.7 cm; weight, 97 Kg; body mass index, 30.8 kg/m2) complained of general fatigue and drowsiness at work. A blood examination revealed severe diabetes mellitus (HbA1c 10.6%), and he was accordingly referred to our university. Treatment for diabetes mellitus was started and extensive evaluations for sleep apnea syndrome were performed. Although treatment using a continuous positive airway pressure mask was initiated, general fatigue continued. Concurrently, SITSH was diagnosed based on the following findings: serum TSH, 6.890 µIU/mL; free T3, 4.9 pg/mL; and free T4, 2.29 ng/dL. Magnetic resonance imaging of the pituitary gland revealed a poorly enhanced mass measuring 5 × 6 × 8 mm ( and ). The TRH loading test showed a low and delayed TSH response (pre-TSH, 6.89 µIU/mL; max TSH, 10.8 µIU/mL; 60 minutes after TRH loading). However, there were no abnormal responses for both GH and PRL on several other loading tests. The absence of a family history of SITSH or TRβ gene mutations prompted the diagnosis of thyrotroph adenoma. Initial treatment with the somatostatin analog (SSA) did not yield any response. Further, the free T4 levels remained over 2 ng/dL after 3 courses of lanreotide autogel (90 mg). Since his diabetes mellitus was already under control, we decided to remove the tumor surgically. The surgery was performed using the standard endoscopic endonasal transsphenoidal approach. The pituitary gland appeared normal on the surface. However, a midline split revealed a well-circumscribed whitish tumor inside the pituitary gland (). Complete tumor resection was achieved (), and tumor tissues were collected wherever possible. As the intraoperative pathological diagnosis ruled out a pituitary adenoma, tissue samples for electron microscopy were obtained. His serum TSH levels decreased drastically to 0.320 µIU/mL on postoperative day 1. However, the patient developed transient diabetes insipidus that was treated with oral desmopressin acetate tablets. Three days after the operation, he was diagnosed with influenza type A, followed by hyponatremia with a minimum serum Na level of 118 mEq/L. Electrolyte levels were closely monitored during the treatment for influenza, and he was discharged 18 days after the operation without any electrolyte management. Oral administration of hydrocortisone and levothyroxine was started after the operation, which was tapered and ceased completely after 3 months. The patient’s complaint of fatigue improved, and his cardiac heart rate was reduced by 10 bpm. Blood examination 6 months after the operation revealed an improvement in endocrinological parameters, including serum TSH (0.808 µIU/mL), free T3 (2.9 pg/mL), and free T4 (1.35 ng/dL). The TRH loading test showed a normal TSH response (pre-TSH, 0.589 µIU/mL; max TSH, 7.830 µIU/mL) 30 minutes after TRH loading. The patient has remained healthy for 2 years without tumor recurrence. Postoperative MRI revealed complete tumor resection. Hematoxylin and eosin staining showed that the tumor was composed of small- to large-sized neuronal or ganglionic cells containing abundant acidophilic cytoplasm and nuclei with a prominent nucleolus against a background of fine, fibrillar, neuropil-like matrix ( and ), which were diffusely immunoreactive to synaptophysin, chromogranin A, neurofilament, and NCAM (CD56), and partially immunoreactive to NeuN (). Interjacent small cells were considered to be reactive lymphocytes and not adenomatous cells based on their immunoreactivity to CD3. The cytoplasm of the tumor cells with peripheral displacement of the nucleus was immunoreactive for low-molecular-weight keratins, CAM 5.2, and patchy reactive for CK7 ( and ), but not for CK5/6, CK 8, CK 20, and CK 34βE12, supporting the exclusion of paragangliomas. Further, the absence of immunoreactivity to glial fibrillary acidic protein confirmed the exclusion of ganglioglioma (). Although Ki-67 staining revealed a labeling index of 2.6%, no other atypical features were detected. Only 0.4% of the entire tumor showed P53 immunopositivity. Based on these findings, a final pathological diagnosis of isolated GC was made. With respect to the pituitary and hypothalamic hormones, the cytoplasm of the tumor cells showed diffuse but strong immunoreactivity for TSH () and equivocal faint positivity for gonadotropin; however, it was negative for GH, PRL, and ACTH. Meanwhile, it also showed diffuse but strong immunoreactivity to TRH (). Transcription factors such as the acidophilic cell lineage transcription factor Pit-1, SF-1, Tpit, ER, and GATA-2 are important to pituitary cytodifferentiation from the Rathke pouch stem cell. Further immunohistochemical studies for these transcription factors revealed diffuse and strong nuclear immunoreactivity for Pit-1 and GATA-2 ( and ), but not for SF-1, Tpit, and ER, confirming thyrotropic cell differentiation of tumor cells. Thyroid transcription factor-1 (TTF-1) is a tissue-specific transcription factor that regulates the expression of selected genes in the thyroid, lung, and diencephalon for embryonic development and differentiation; it is well known that it aids in nuclear expression, specifically that of posterior pituitary, thyroid, and lung tumors (, ). All tumor cells stained negatively for TTF-1. Somatostatin receptor (SSTR) status may predict treatment response to first- and second-generation SSAs. With respect to SSTR membranous immunopositivity proposed by Volante et al (), more than 50% of tumor cells stained positively for SSTR2 (Score 3 ()); however, none of the cells stained positively for SSTR5 (Score 0). Based on these immunohistochemical findings, this tumor was considered to be differentiated into an entirely neuronal lineage rather than mixed or interjacent with 2 components. Electron microscopy revealed the tumor cell has a light nucleus with a prominent nucleolus, which is surrounded by many secretary granules, synaptic vesicles, and some lysosomes in the cytoplasm. Typical neuronal processes contained both dense core vesicles and clear vesicles ().

pmc-7947878-1

A 28-year-old nonbinary individual presumed female at birth has recently commenced full masculinizing hormone therapy with transdermal testosterone gel. You receive a referral from their primary care physician concerned about polycythemia. Their hemoglobin is 168 g/L with hematocrit 0.49, which has been flagged in the laboratory report as high (reported with female reference range of 115-155g/L and 0.33-0.45 relative to the male reference interval of 120-170g/L and 0.36-0.50). Androgens are known to stimulate erythropoiesis while the impact of estrogens are not as well understood. In trans people who have been on established and full-dose feminizing hormone therapy (estradiol and anti-androgen) for at least 6 months, there is a significant decrease in hemoglobin, hematocrit, and red blood cell count to the female reference range (, ). Conversely after 6 months of masculinizing testosterone therapy, trans people demonstrate an increase in hemoglobin, hematocrit, and red blood cell count to the male reference range (, , , ). Serum hematocrit in the range of the affirmed gender is evident from 3 months after commencing gender-affirming hormone therapy (). Of note, there are association studies suggesting higher hematocrit is associated with a higher risk of cardiovascular disease (, ). This is probably a consideration for people using masculinizing hormone therapy, more so than those using feminizing hormone therapy. As smoking may additionally increase hematocrit, smoking cessation should be emphasized in those with elevated hematocrit. While the long-term cardiovascular implications of using a different reference range for hemoglobin or hematocrit are unclear in general, reference ranges of the affirmed gender should be used. Female reference ranges should be used for someone taking gender-affirming feminizing hormone therapy and male reference ranges should be used for people using masculinizing hormone therapy. In trans women, there is a small statistically significant but clinically insignificant rise in platelet count (which remains within the normal reference range) shown in several cohort studies after 6 to 12 months of feminizing hormone treatment (, ), while white blood cells do not change significantly. No apparent changes are observed in either platelet count or white blood cells with masculinizing hormone therapy (, ). Case 1 outlines a nonbinary individual presumed female at birth receiving full-dose masculinizing hormone therapy. In this case, the male reference range for hemoglobin and hematocrit would be most appropriate and this should be shared with the nonbinary individual so they are aware and can expect to be misgendered when reviewing their own results. As such, their hemoglobin of 168 g/L and hematocrit of 0.49 would fall within the expected reference range and no change in management needs to occur. Reference ranges for serum ferritin, a common indicator of body iron status, vary depending on age and sex (). Ferritin reference ranges are typically lowest in premenopausal people presumed female at birth, followed by postmenopausal people and are highest in people presumed male at birth, with lower limits of the female reference range approximately 10 to 20 ug/L below that of the male reference range (30 ug/L) (). This may be partially attributed to increased iron utilization in menstruating individuals resulting in lower ferritin, as well as a multitude of factors that have been shown to impact upon adult serum ferritin levels including age, body mass index, waist to hip ratio, and liver function (, ). Animal studies suggest that iron is distributed differently in males and females associated with differences in hepatic hepcidin expression rather than sex-steroid concentrations (, ). No studies have evaluated whether ferritin or other iron indicators change with gender-affirming hormone therapy. From a practical perspective, the main reason to evaluate for iron deficiency is anemia. In individuals who have a ferritin below the “male” reference range, we suggest interpreting the iron studies in the context of red cell indices such as mean corpuscular volume and mean corpuscular hemoglobin concentration to guide management rather than on the use of gender-affirming hormone therapy. If the trans individual is menstruating or pregnant, it would be most practical to use the premenopausal female reference range for interpretation of iron studies. For evaluation of possible iron overload, in situations of borderline results which fall between the female and male reference ranges, relying on the absolute ferritin level or transferrin saturation will be difficult. It is pertinent to assess for concurrent inflammatory disease, liver disease, or iron overload states, such as hemochromatosis, which may further guide clinical management.

pmc-7947878-2

A cardiologist calls as they are planning a coronary angiogram for a 68-year-old trans woman and are concerned because the estimated glomerular filtration rate (eGFR) is unknown. They are uncertain how to risk stratify her for potential contrast-induced nephropathy. She has a history of longstanding hypertension and hypercholesterolemia, vaginoplasty, and has been on various formulations of estradiol therapy for over 20 years. On review of her investigations, her serum creatinine is 109 umol/L (1.23 mg/dL) but her eGFR has not been reported for the last 18 months. Laboratory providers cannot report eGFR if a male or female marker is not provided on the request form, as this is required along with age to estimate eGFR. Using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, if classified as female, the eGFR would be 45 mL/min/1.73m classed as Stage 3 chronic kidney disease and would meet the guidelines for intravenous hydration prior to procedure. However, if classified male, the patient would have an eGFR of 60 mL/min/1.73m which would be classed as Stage 2 chronic kidney disease and would not require prehydration. Which is the most appropriate eGFR to use? Accurately assessing renal function is essential for not only assessment of renal diseases, but also clinical situations that may potentially affect renal function (such as diabetes or radioiodine contrast administration) as well as considerations for medication dosing of renally cleared drugs. The most commonly used marker of renal function in clinical pathology laboratories is eGFR, which is calculated based upon an individual’s serum creatinine level, age, and sex (). Typically, people presumed male at birth have a higher eGFR than people presumed female at birth at the same level of serum creatinine because the formula assumes a higher muscle mass in men contributing to the serum creatinine independent of renal function. The difference between these groups (given the same age and weight) is more marked at higher levels (with a difference of approximately 30 when eGFR >90 mL/min/1.73m2), becoming much more similar as eGFR declines (difference of approximately 4 when eGFR <30 mL/min/1.73m2). In clinical situations where accurate assessment of renal function is necessary, such as in the transplant setting, it may be more appropriate to use 24-hour urine creatinine clearance, urinary inulin clearance (), or serum cystatin c levels, which are less affected by sex and not affected by muscle mass in contrast to serum creatinine (). Inulin clearance and cystatin c are more expensive and less readily available. Creatinine clearance can be calculated on paired 24-hour urine and serum creatinine concentration and is independent of muscle mass and sex steroids. This can provide a baseline estimation for renal function and cumulative serum creatinine results can then be used to monitor decline in renal function with aging. From a practical perspective, laboratory reports will need to make an assessment on how to report the eGFR for trans individuals. For individuals receiving masculinizing or feminizing hormone therapy, changes in body composition appear to be maximal in the early period after commencement, evident within the first 3 months of treatment (, ). For those receiving masculinizing hormone therapy with testosterone, given higher muscle mass and lower fat mass compared to females, the male CKD-EPI formula would be more appropriate. Conversely if a person has been on feminizing hormone therapy, which typically induces gain in fat and decrease in muscle mass from 3 months of use, then the female equations should be used. It would be a challenging task to expect pathology laboratories to provide the “right” eGFR given limited access to clinical information. We recommend that the treating clinician specify the sex-specific reference interval desired for reporting on the laboratory request (ie, female for a trans person using feminizing hormone therapy). Using current laboratory information systems, the gender marker can be used as a field to specify the reference range desired for reporting. While the binary female or male gender may not necessarily reflect the individual’s gender, this will allow for the appropriate reference range to be reported and the trans patient informed so they can prepare to be misgendered. For laboratory providers, if the gender marker is unknown, then treating clinicians should be contacted to specify the sex-specific reference interval desired. For the trans woman described in Case 2 who was on longstanding feminizing hormone therapy with female body composition, the female reference range for renal function would be most appropriate triggering appropriate renoprotection prior to administration of radioiodine contrast for her angiogram. From a harm reduction approach, given the absence of data in the field, if either the male or female calculated eGFR suggests renoprotective strategies, then this can be implemented. A 24-hour urine creatinine clearance can also be performed to more accurately assess renal function.

pmc-7947878-3

A 70-year-old trans woman who had been on feminizing hormone therapy for 6 months had a PSA performed as part of a routine health check. She was taking transdermal estradiol 100mcg/24hr patches twice weekly and cyproterone acetate 12.5mg daily. Her total testosterone was 1.5 nmol/L (43 ng/dl) and PSA was 2 ng/mL. She had mild lower urinary tract symptoms with reduced urinary flow over a number of years but had no family history of prostate cancer. How should she be managed? There are no studies examining the effect of feminizing hormone therapy on PSA. It is known that androgen deprivation as part of feminizing hormone therapy is associated with a substantially lower risk for prostate cancer than the general male population (). All published case reports of prostate cancer in trans people using feminizing hormone therapy have had histology showing high risk adenocarcinoma with PSA concentrations at diagnosis ranging from 5 to 1722 ng/mL (ng/mL equivalent to ug/L) (, ). Physiologically, in the setting of androgen deprivation in people with a prostate gland, it would be expected that PSA should be lower than the age-specific reference interval. There is insufficient data to recommend a specific cutoff for trans people using feminizing hormone therapy. Individualized decisions based upon clinical history and examination should inform need for serial monitoring for PSA velocity or imaging. Case 3 had a digital rectal examination which showed a smooth but mildly enlarged prostate gland. She had an ultrasound of her prostate which showed a mildly enlarged prostate volume of 35 mL. Repeat PSA monitoring revealed progressive lowering of her PSA concentration with ongoing feminizing hormone therapy and an improvement in her urinary flow.

pmc-7947878-4

A 49-year-old trans man who had been on testosterone therapy for 10 years presented to the emergency department with central chest pain. His high-sensitivity cardiac troponin was 24 ng/L (female reference range <16 ng/L, male reference range <26 ng/L). How should he be managed? Cardiac troponin is released from damaged cardiomyocytes and is one of the most common biomarkers used in the prediction of myocardial infarction. There is considerable debate regarding the use of sex-specific reference ranges for high-sensitivity cardiac troponin (hs-cTn), as there is uncertainty whether the use of sex-specific reference limits impact upon clinical management or outcome prediction (). However, as upper reference limits based on sex-specific 99th percentiles for hs-cTn are subtly higher for people recorded as males than those recorded females in population studies (), use of sex-specific cutoffs for hs-cTn assays have been endorsed by the International Federation of Clinical Chemistry and Laboratory Medicine (). The difference has been attributed to people presumed male at birth having a larger cardiac mass as well as subclinical coronary artery disease (). No studies have been performed to examine cardiac mass changes that may occur with masculinizing hormone therapy in people presumed female at birth. There are however data in polycystic ovary syndrome in which high testosterone concentrations are a clinical feature (albeit far lower than testosterone concentrations seen in transgender men). Polycystic ovary syndrome has been associated with higher left ventricular mass index and larger left atrial diameter over 5 years of follow-up, even after adjustment for blood pressure, body mass index, glucose, and lipids (). Large population-based studies have also shown that left ventricular mass correlates with body weight, lean body mass, and fat mass (). There is currently insufficient data to draw an inference regarding the appropriate reference range in people using gender-affirming hormone therapy, and emphasis must be placed on clinical history, electrocardiogram (ECG) changes, and serial trajectory of hs-cTn levels if the hs-cTn falls in between the male and female-specific reference ranges. Despite the fact that Case 4 had been on established testosterone therapy for 10 years with resultant male body composition, there is insufficient data to suggest that cardiac remodeling or change in cardiac size occurs with high (or low) testosterone concentrations. Despite the risk of being oversensitive, in order to minimize the risk of missing an acute coronary event, we suggest that the reference range of the sex presumed at birth (female) should be used to interpret hs-cTn, provided the patient is informed of this rationale in addition to monitoring with serial troponin to ensure there is no rise. Case 3’s subsequent hs-cTn was elevated above the male reference range and his ECG revealed anterior ST-segment depression consistent with acute coronary syndrome.

pmc-8650745-1

A 42-year-old gentleman with no prior medical illness admitted with complaints of generalized muscle pain, dry skin, and mild facial puffiness of eight days duration, associated with choking sensation in his throat. The review of systems was negative for fever, hoarse voice, cold intolerance, hair loss, dysphagia, constipation, weight gain, focal limb weakness, or changes in memory. He denied doing strenuous exercise recently, alcohol consumption, trauma, or recent medication use. There was no family history of autoimmune thyroid diseases. His vital signs were as following: pulse rate, 65/min (regular); blood pressure, 120/85 mmHg; respiratory rate, 19/min; and oral temperature, 37.1°C. Physical examination revealed mild facial puffiness, dry skin, and minimal non-pitting lower limb edema. A small goiter without tenderness or nodule was found on neck examination. The musculoskeletal examination did not show muscle wasting, hypertrophy, or weakness. Other system examinations were unremarkable. Laboratory investigations were suggestive of severe hypothyroidism: thyroid-stimulating hormone (TSH), >100 mIU/ml (normal range <4.35 mIU/L); free T4, <0.5 ng/dl (normal range 11 – 23.3 pmol/L); anti-thyroid peroxidase antibody titer, >600 IU/ml (normal range <34 IU/ml); and anti-thyroglobulin antibody (TgAb) titer, 1831 IU/ml (normal range <115). Elevated levels of anti-thyroid peroxidase antibody and anti-thyroglobulin antibody titers were suggestive of Hashimoto's thyroiditis. Serum creatine kinase (21,644 U/L, normal range 39–308 U/L) and myoglobin (2,208 ng/ml, normal range 28–72 ng/ml) levels were also raised (Table ). This was associated with acute kidney injury with mild elevation of serum creatinine (1.44 mg/dl). Urine examination was negative for myoglobinuria or hematuria. The daily urine output was normal (250–300 ml/h). Electrocardiogram (ECG) and chest X-ray were normal. Transthoracic echocardiography (TTE) showed minimal circumferential pericardial effusion without regional wall-motion abnormalities and with a left ventricular ejection fraction (EF) of 58%. Fiber-optic (flexible) laryngoscopy was normal. A probable diagnosis of hypothyroidism due to Hashimoto's thyroiditis with rhabdomyolysis was made based on the clinical and laboratory parameters. He was treated with intravenous fluids and was started on oral levothyroxine. His symptoms improved with the treatment, and the levels of CK and myoglobin showed a decreasing trend. He was discharged on Day 4, and on further follow-up, the muscle enzymes showed a further decreasing trend (Figures and ) and normalization of renal parameters. Since there was complete resolution of symptoms with the patient returning to his regular day-to-day activities, further workup to exclude muscle diseases was not carried out.

pmc-8650747-1

A 33-year-old woman, with severe postburn mentosternal contracture and cicatricial carcinoma, presented for skin grafting surgery in our hospital. The burn occurred when she was 4-year-old. She underwent two reconstructive procedures at 7 and 14 years in local medical centers. Due to the pain caused by the occurrence of cicatricial carcinoma, affecting eating and speaking, she had tried several medical centers for treatment in the past year, but failed for unsuccessful ATI. In preoperative physical examination, severe scar contractures and large tumor of approximately 15 × 12 cm were observed on the lower lip, neck, and anterior chest (Figure ); the chin, chest, and bilateral armpits fused together; the cervicomental and mentosternal angles completely obliterated; the anterior neck structures, including the larynx, the trachea, and the carotid arteries, were unidentifiable or impalpable. Mouth opening was limited (15 mm) and Mallampati test could not be performed. The left nostril was obstructive for stenosis, but the right nostril breathing was smooth. Preoperative X-rays and a computed tomography scan (data not shown) revealed distortion of the upper airway and no stenosis of the trachea. It was difficult to perform face mask ventilation because of the nearly fixed neck and regressed mandible. According to the guidelines on the management of difficult airway, awake flexible bronchoscopic intubation with topicalization is preferred in such patients, but the patient rejected ATI for discomfort and nociceptive recall before. Meanwhile, other awake strategies, including lightwand, GlideScopeⓇ Video laryngoscope, laryngeal mask airway, oral or nasal blind intubation, retrograde intubation, surgical tracheostomy, seem impossible. Therefore, a flexible bronchoscopic intubation protocol under precise sedation, topicalization, and spontaneous respiration preservation seems a promising strategy, but the airway should be secured for there was no definite backup plan. A written informed consent was taken with explanation focused on the risks of difficult airway. Atropine 0.5 mg was intramuscular injected to reduce secretion 30 min before transferring to the operating room. The patient was monitored by respiration rate, ventilation volume, pulse oximetry, electrocardiogram, blood pressure and bispectral index (BIS), and preoxygenated once she arrived in the operation room. Vital signs were stable. A pillow and some folded sheets were stuffed between the patient back and the operating bed to make her feel comfortable. Intravenous midazolam 2 mg and sufentanil 5 μg were given. Nasal passage was anesthetized by pledgets with 2% lidocaine and 0.25% phenylephrine. Sevoflurane 2% with a flow rate of 4 L/min with 100% O2 was administered via an endoscopic mask connected to the ventilator circuit. The concentration of sevoflurane was gradually increased to 4% and stopped when the BIS reached 55–60 within 3 min, then airway reassessment and precise topicalization were achieved by a modified SAYGO technique., , An epidural catheter (Figure ), with an outer diameter of 3.8 mm, was fixed and 1.5 cm longer was applied at the end of the fiberscope (MDH A10; Zhuhai Mindhao Medical Technology Co., Ltd., ShenZhen, China). Topicalization was achieved by spraying 2% lidocaine (7 ml) via the catheter onto the posterior nasal canal, pharyngeal cavity, epiglottis, glottis, and tracheal (Figure ). Meanwhile, supplemental oxygen 10 L/min was delivered by a hose (Figure ) through the mouth to avoid hypoxemia. When lidocaine worked, about 5 minutes later, sevoflurane was inhaled again until the BIS reached 55–60. Then, a Parker Flex-Tip® tube with an inner diameter of 6.0 mm (Lead Medical Instrument Co., Ltd., Guangzhou, China), which was heated by 40 ℃ and lubricated in advance, was successfully and smoothly inserted into the trachea from the direction of flexible bronchoscopy (Figure ). No stress reactions, including cough, hypertension, tachycardia, arrhythmia, hypoxia, and bronchospasm, and no intubation related complications, such as airway trauma, airway obstruction, and bleeding, were occurred during intubation. Finally, the patient was very satisfied with this experience after emergence.

pmc-8650748-1

The patient was a 28-year-old woman, Gravida 2 Parity 1 Live Birth 1, who presented at 38 weeks of gestation with epigastric pain radiating to her back with a history of recent travel and symptoms of subjective fevers with a new sense of smell and taste disorders for 1 week. The patient had received regular prenatal care, and her past obstetric history was uncomplicated, with one full-term vaginal delivery. She was overweight (body mass index = 25.7) and had no significant past medical history and drug history.

pmc-8650807-1

A patient in her late seventies was incidentally found to have a large infrarenal abdominal aortic aneurysm in 2013 for which she had undergone an uneventful percutaneous endovascular aortic repair with left chimney. She lived alone, remained independent in her activities of daily living, and was community ambulant without aid. She was electively admitted in September 2019 for embolization of a type 2 endoleak by the interventional radiologist. Super selective cannulation of the distal aspect of the iliolumbar branch supplying the nidus with a micro catheter was performed. Embolization was carried out using Onyx® until complete exclusion of the nidus. This was followed by repeat aortogram, which showed complete exclusion of the nidus from right-sided branches. However, there was continued filling of the nidus from the left lumbar branches. It was therefore decided to embolize the left side. After embolization, angiogram showed complete exclusion of the endoleak and the left-sided branches supplying the endo leak. Five hours after the procedure the patient complained of bilateral lower limb weakness and numbness, right more than left. Physical examination revealed lower motor neurone pattern of weakness over bilateral lower limbs, right worse than left (Table ). Sensation testing revealed normal sensation over left, impaired sensation for right L2 to S1. Proprioception at bilateral big toes was intact. Reflexes were absent in bilateral lower limbs. Lumbar spinal drain was inserted to decompress the spinal cord to allow more arterial flow as there was concern with spinal cord ischemia. The patient was started on fluid replacement to maintain the mean arterial pressure above 80 mm Hg. Urgent CT aortogram followed by MRI thoracolumbar spine was performed. Aortogram showed postinterval embolization of bilateral feeding arteries. Onyx material was seen within a branch of the embolized right iliolumbar artery, which extends into the spinal canal at the level of L3 and appears to exit at the level of L2. It ran external to the thecal sac. MRI thoracolumbosacral spine showed no abnormal cord signal or restricted diffusion. She was subsequently admitted for inpatient multidisciplinary rehabilitation. On initial functional assessment, she required moderate assistance for bed mobility and transfer with poor dynamic sitting and standing balance. She did not complain of pain. After 1 month of inpatient rehabilitation, she made some neurological recovery with functional improvement. She had good dynamic sitting balance and was able to transfer under supervision. She can self-propel wheelchair within the ward. However, she had poor standing balance and was still unable to ambulate. She was discharged to a subacute rehabilitation facility before being discharged home. Please see her functional improvement over time using the Functional Independence Measure (FIM) instrument illustrated in Table . Electrophysiology study was performed 12 weeks later showed electrophysiological evidence of an acute right lumbar plexopathy involving the right obturator and femoral nerves, with no evidence of axonal continuity. She was reviewed in the outpatient clinic 14 weeks later. Neurologically remained largely unchanged for right lower limb; however, left lower limb power had further improved to about 4 on manual motor testing. Functionally, she had also made slight progression, and she was able to walk 25 meters using walking frame with 1 person providing standby assist. However, she was still dependent on wheelchair for longer distance ambulation.

pmc-8652042-1

A 4-year-old girl was referred to our tertiary hospital for the specialist evaluation of a non-specific cough, which was present for 6 weeks, associated with a right pulmonary mass. The physical examination was normal; on auscultation, diminished breath sounds were present on the right side of the lung. The medical history and growth were unremarkable. Chest radiograph revealed a mass located in the right upper lobe and the middle lobe of the right lung, with a central area of calcification (Figure ). Chest computed tomography (CT) scan confirmed the chest radiograph findings; a solid, well-contoured, heterogeneous, mass was noted in the right upper lobe and middle lobe of the lung with an area of central calcification (Figure ). No lymphadenopathy was detected. Microscopy, culture and cytology of the sputum were unremarkable. The erythrocyte sedimentation rate was 10, haemoglobin was 11.6 g/dl and the leucocyte count was 8.8 × 109/L. The other serum haematological and biochemical results were normal. The serology of Echinococcus and Mantoux test were negative. The patient did not respond to antibiotics; therefore, surgical removal of the mass was performed. Thoracotomy performed on the right side showed a lesion in the lung parenchyma, extended to the upper and middle lobes. The differential diagnosis of congenital lesions of the lung was made. As there was no success with fine-needle aspiration in several cases, we decided to perform surgical resection. The lesion was resected and lobectomy of both upper lobe and middle lobe was also performed. No associated lymphadenopathy was noted. Macroscopically, a well-circumscribed mass measuring 5.5 × 5.5 × 4 cm was present. The excised tumour had an osseous centre measuring 2 × 1 × 1 cm. From the histological point of view, the mass consisted of disorganization of the normal bronchoalveolar parenchyma, myofibroblastic cells and inflammatory cell infiltrates, such as lymphocytes, neutrophils, eosinophils and histiocytes. In the centre of the lesion, a large ossification was found. Immunohistochemistry revealed calponin antigens, SMA, desmin, P53, bcL2, CK, HMW, and, in several myofibroblastic cells, expression of ALK-1. It was negative for beta-catenin, cyclin D1, Myo-D1, S100p, CD34, CD99 and CD117. The histological and immunohistochemistry characteristics were compatible with an inflammatory myofibroblastic pseudotumor. The post-operative course was uneventful, and the patient was discharged home after 2 weeks of surgery. The patient re-presented to the hospital 1 year after surgery. The child had normal daily activities, normal chest x-ray and no recurrences.

pmc-8652043-1

A 35-year-old gentleman came to our institution in February 2021 for evaluation of persistent fever and non-resolving pneumonia. He had a polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection in October 2020, with classical radiological findings. He was managed conservatively under home quarantine. Two weeks later (November 2020), he had a recurrence of high spiking fever. Imaging revealed a left-sided lung consolidation. He was treated for probable pneumonia with oral amoxicillin-clavulanate. At 1-month follow-up (December 2020), there was an inadequate clinical improvement with an increase in the size of the consolidation (Figure ). Bronchoscopy was done, and bronchoalveolar lavage grew Streptococcus pneumoniae. He received another course of linezolid antibiotic. In 2017, he had probable vaccine-related/autoimmune optic neuritis for which he received 13 doses of rituximab between January 2017 and May 2019 (600 mg per dose). He had developed rituximab-induced hypogammaglobulinaemia in 2019. Since then, he has had persistent B-cell depletion and low immunoglobulin levels (Table ). The absolute B-cell count was zero. During our evaluation, SARS-CoV-2 real-time reverse transcription PCR (RT-PCR) was negative (February 2021 and March 2021). Antibodies to SARS-CoV-2 nucleoprotein (N) and spike receptor-binding domain (S-RBD) tested on the Roche Elecsys platform were undetectable in February 2021. We considered the following differentials: tuberculosis (TB), organizing pneumonia, lymphoma, Antineutrophil Cytoplasmic Antibodies (ANCA) associated vasculitis and lung malignancy. Sputum Xpert-TB-PCR was negative. Multiple blood cultures, bone marrow biopsy and culture reports for routine bacteria, Mycobacterium and fungal organisms were negative. A bronchoscopic transbronchial lung biopsy was done. Histopathology was suggestive of organizing pneumonia. Past COVID-19 infection was considered as the likely cause for organizing pneumonia. He was started on high-dose steroids, with which he improved. He was readmitted in April 2021 with a persistent fever. Since the patient was on high-dose steroids, the fever was attributed to a probable secondary infection or organizing pneumonia itself. Sputum culture grew Pseudomonas aeruginosa, and an antibiotic, piperacillin, was commenced. Computed tomography thorax showed resolution of the previously seen left lower lobe consolidation but had new-onset bilateral ground-glass opacities (GGOs) (Figure ). Nasal swab for SARS-CoV-2 RT-PCR was positive (Cepheid assay, April 2021), with a Ct value of Envelope gene (E gene) 23.2 and nucleoprotein gene (N) 24.1. A diagnosis of COVID-19 re-infection was made. He received remdesivir injection and other symptomatic medications. He became afebrile within 2 days and was discharged from the hospital. During routine follow-up in June 2021, he was asymptomatic and was now positive for antibodies to SARS-CoV-2 (anti-N: 9.6 and anti-S-RBD: 41.4) (Table ).

pmc-8654626-1

A 34 year old woman from the east of Morocco, married and mother of two children, was admitted to the emergency room with intense periumbilical and pelvic abdominal pain associated with acute vomiting without any notion of metrorrhagia. The clinical examination revealed a conscious patient with an irreducible and impulsive painful mass at the umbilical level reminiscent of a strangulated inguinal hernia (). We performed an abdominal ultrasound scan which showed an evolving mono-fetal pregnancy; with an estimated weight of 1 kg, and a normal amount of amniotic fluid; strangulated through an umbilical orifice (). Faced with this exceptional diagnosis, the case was quickly discussed in a multidisciplinary team and the decision was made to perform an MRI. It was done without injection because of the teratogenic nature of the scan (, ). Our radiological examination showed a strangulation of a pregnant uterus through an orifice of 6 cm, which resulted in a strangulated hernia of a pregnant uterus at the umbilical level with the right ovary. There was however no intestinal loop. After discussion with the patient, a multidisciplinary discussion was quickly made in front of this exceptional presentation and opting for a ceolioscopic exploration. It was made by the head of visceral surgery under general anesthesia was performed. It reduced the gravid uterus and the right ovary by a carefully dissection of the hernia sac and external manual assistance. Prior to the placement of the intraperitoneal plate, an obstetrical ultrasound scan had shown an evolving pregnancy (, , ). The procedure went well, and it was tolerated by the patient without any adverse event allowing a good postoperative evolution The patient was discharged two days later and a cesarean section was scheduled at the end of the pregnancy, giving birth to a 2.5 kg male infant with good psychomotor development. Our patient had opted for tubal ligation, and the two-year follow-up did not show any recurrence.

pmc-8654778-1

A 57-year-old retired male presented in 2019 to Al-Bairouni Hospital complaining of a mass in his left breast. He is a non-smoker, with a history of grade (I) LP in the right thigh root 14 years ago which was treated surgically along with radiotherapy of the right thigh, with no signs of recurrence. He also had well-controlled diabetes. The physical examination showed a left breast mass with a suspicious abnormality on Ultrasound that measured 32 mm. The computed tomography scan (CT) showed left breast infiltration with no signs of metastases. The patient underwent an excisional biopsy which revealed a poorly differentiated grade III invasive ductal carcinoma (). Then he underwent a mastectomy in 2019 with axillary node resection. The final diagnosis based on the histological findings was invasive ductal carcinoma stage IIA [T:2, N:0, M:0]. Hormonal receptors tests showed the following: positive Estrogen Receptor (ER+), negative Progesterone Receptor (PR-), and negative Human Epidermal Receptor (HER-) (). He received eight cycles of chemotherapy with Docetaxel and 16 sessions of radiation to the chest wall; The last one was on the fourth of October 2020. A positron emission tomography (PET) scan six months after the surgery showed no signs of recurrence ().

pmc-8654780-1

A pregnant female, 34 years old, fourth gestation primiparity with current pregnancy estimated at 25 weeks of amenorrhea (WA) + 5 days, diabetic for 1 year, initially on oral antidiabetic drugs and then insulin therapy, hypertensive for 2 years on alpha methyldopa with a history of 3 miscarriages secondary to hypertensive peaks. During the 4th pregnancy, the patient was hospitalized at 20 WA in the endocrinology department for an etiological assessment of a hypertensive crisis at 180/110 mmHg associated with headaches, palpitations and hot flashes, without proteinuria or edema. In front of these symptoms the diagnosis of a secretory neuroendocrine tumor is suspected, and a biological assessment including urinary and plasma catecholamines (metanephrine and normetanephrine) came back positive after eliminating other causes of secondary hypertension (nephropathy, renal artery stenosis or hyperaldosteronism), by renal evaluation, renal artery Doppler ultrasound and renin-angiotensin-aldosterone system exploration. Urinary dosages showed Metanephrines at 0.87 μmol/24 h (normal: 0.20–1), high Normetanephrine 24.14 μmol/24 h (normal: 0.4–2.10), While plasma dosages showed a Metanephrine level of 0.10 nmol/l (normal: < 0.33 nmol/l), a high level of Normetanephrine of 14.02 nmol (normal: <1.07 nmol/l). A thyroid workup was performed to rule out multiple endocrine neoplasia (MEN) returning normal: TSH 1.821 (normal: 0.340–5.330), anti-thyroperoxidase Ac < 0.8 IU/ml (normal <0.8). Abdominal-pelvic magnetic resonance imaging (MRI) showing an abdominal latero-aortic mass measuring 36 * 33 mm, corresponding to paraganglioma without any other obvious location []. For evaluation of maternal and fetal impact of the tumor: Clinical examination including cardiovascular examination was normal. With an ECG that did not show rhythm or repolarization disorders or left ventricular hypertrophy. A standard biological workup (blood cell count, platelet count, hemostasis, blood ionogram, blood sugar-HBA1c, renal and hepatic function) was unremarkable. On the obstetrical level, the clinical examination and the obstetrical ultrasound showed a monofetal pregnancy with no uterine or fetal abnormalities. After placing the patient on medical treatment and scheduling her for surgery, she was declared discharged with an ambulatory follow-up. At 25 weeks of amenorrhea; the patient was admitted to the operating room for laparoscopic removal of her paraganglioma. In the operating room, considering the risk of perioperative morbidity related to severe per and postoperative hemodynamic instability (hypertensive crisis with sometimes rhythm disorder, coronary ischemia, left ventricular failure and hypotension secondary to a sudden release of catecholamines: to stress, painful stimulation due to intubation and incision, insufflation and manipulation of the tumor, abrupt and profound hypotension by sudden decrease of catecholamines at the fall of the part and venous clamping) and in front of the obligation to maintain a uterine perfusion and a good oxygenation of the fetus while avoiding maternal hypoxemia, the anesthetic management was as follows:Monitoring: Hemodynamic: heart rate (HR), blood pressure (BP) Respiratory: respiratory rate, pulse oxygenometry (SpO2), capnography. ECG and ST segment monitoring. Cardiac output monitoring by pulse wave contour analysis.Left jugular venous line (for central venous pressure monitoring and vasoactive drugs perfusion) A right femoral arterial line with invasive arterial pressure monitoring Heating of the patient to prevent hypothermia After installation of the patient in left lateral decubitus proclive 30°, a pre-oxygenation was started, and an anesthetic induction was done by: 150mg Propofol 150μg Fentanyl, 50 mg Atracurium 50mg; intubation by tube No. 6.5 cm; maintenance of anesthesia was provided by: Propofol IVOC system with concentration of: 2ug/ml. Maintenance of etCO2 32–35 mmHG with insufflation pressures not exceeding 12 mmHG (8–10 mmHG) and close monitoring of blood glucose due to the risk of blood glucose imbalance. During tumor manipulation 3 episodes of arterial hypertension peaks were observed) (180/110–195/120-200/130 mmHg controlled by reinforcement of analgesia by reinjections of fentanyl 50 μg, deepening of anesthesia (Propofol concentrations 3.5 μg/ml), and administration of Nicardipine at 1–3 mg/h. Glycemia: varied between (0.98–1.21 g/l) The tumor removal was followed by episodes of arterial hypotension (75 -45 mmHg), the conduct was to lighten the anesthesia, a volemic expansion with administration of norepinephrine at 2mg/h. For paraganglioma extraction, the procedure lasted 2 hours [, ]., with an intraoperative diuresis of 500 ml and bleeding estimated at 80 cc.Norepinephrine infusion was gradually decreased and stopped just before extubation. The patient was subsequently extubated with the following parameters BP: 140/75 mm hg HR: 90bpm, SaO2 100% and then sent to the intensive care unit for clinical and biological monitoring. Postoperative analgesia was started with paracetamol, nefopam and morphine. The antihypertensive treatment was resumed in front of the reappearance of hypertensive peaks. An obstetrical evaluation with a foeto-placental ultrasound immediately and 6 hours after the operation returned normal with the presence of fetal heart activity []. 2 days after the postoperative hospitalization in the intensive care unit, the patient was weaned from all drugs with good evolution and was transferred to the visceral surgery department for further management. This cases report follows SCARE guidelines 2020 [].

pmc-8666159-1

Patient XY, a 44-year-old female presented to the ED with vomiting following consumption of locally foraged mushrooms. An experienced forager, the patient had collected and prepared the mushrooms for dinner. Between six to eight hours later, the patient noted abdominal pain and associated vomiting. The vomitus was bilious in nature with multiple episodes occurring over the next two to three hours. With persistent vomiting, she called an ambulance that brought her to her local hospital. Admission and investigation found a deranged liver profile, and the diagnosis of acute liver failure secondary to the fungi consumption was made. Ms. XY was transferred to the National Liver Unit where she underwent orthotopic liver transplant. Following a tumultuous post-operative course including an ICU admission, and Hepatic, Renal, Plastics, Rheumatology and Dermatology input, an incidental finding on CT of the abdomen/pelvis foreshadowed the orthopaedic trajectory of our patient. Following discharge from the ICU, the patient began recovery on the ward. At this point, her primary concern was painful discolouration at the pulps of her fingers and toes. Painful lesions were also noted in the right flank region. Dermatology input resulted in a diagnosis of skin necrosis post-transplant with microvascular thrombosis of the hands and feet. Skin graft to the right flank region was performed by the Plastics team. The post-operative period was once again complicated by sepsis and treated with antibiotics. She remained on a prolonged course of steroids for up to six months post-operatively. As XY continued to improve clinically, her recovery was aided by our multi-disciplinary team input. Throughout this period, the patient noted a new onset of groin pain resulting in regression in her mobility. In the proceeding four weeks, Ms. XY continued to suffer from pain, impeding her progress with physiotherapy. A physical exam now revealed a swollen and erythematous knee, with a reduced range of motion. An X-ray excluded knee pathology including joint effusion and fracture and confirmed normal alignment, as shown in Figure and Figure . The Pain team now became involved and recommended increased medication doses and frequency. XY’s pain continued to increase over the subsequent six weeks and she was unable to engage fully in physiotherapy for six months. XY described the pain as sharp, without radiation and aggravated by movement. A physical exam revealed an oedematous swollen joint surrounding the cruciate ligament. An MRI was conducted as suggested by the pain team to investigate the integrity of the surrounding soft tissues. The cruciate ligaments, the menisci and both the quadriceips and patellar tendons were found to be intact. The associated musculature was atrophic. Several serpiginous lines within the subchondral marrow of the medial and lateral femoral condyles and in the patella with alternating hyper- and hypointensity were noted. Heterogenous surrounding marrow was also visualized, all of which was depicting AVN and a reactive sclerosis. Orthopaedic intervention was not advised. Evidence is provided in Figure and Figure . XY was in bed almost 24 hours a day and was experiencing bilateral hip pain. Normal X-Ray is shown in Figure . However, pelvis MRI now revealed marked bilateral femoral head oedema, with bilateral sepiginous low-signal circumscribed areas also noted in both femoral heads, with advanced loss of joint space and articular cartilage bilaterally (Figure ). A subchondral collapse in the superolateral aspect of the left femoral head was noted (Figure ). Complex effusions were described bilaterally, thus showing a secondary synovial osteochondromatosis. Muscular oedema was noted throughout; the right rectus muscle was severely atrophic. Avascular necrosis was confirmed. Orthopaedic input One week later, the patient underwent bilateral total hip replacements. Left femoral neck osteotomy was performed from the posterior approach and Multihole Pinnacle size 50 was inserted. A 48-mm cup was inserted on the right side from the posterior approach. The surgery was conducted under a general anaesthetic and then a spinal anaesthetic. Jubilee dressings were applied bilaterally, and continued for up to three weeks post-operatively. Serous ooze was noted particularly on the left side. She was treated with a course of intra-venous antibiotics and the ooze resolved. All clips had been removed by day 21 post-operatively and there were no complications noted. The patient restarted her physiotherapy program, using a wheelchair. Figure shows the bilateral prostheses in situ. The patient was mobilising up to 20 metres with the assistance of a frame, denied any pain and was increasing muscle strength and mobility daily. Objectives for discharge included the patient being able to mobilise independently at home and use a wheelchair outside. The patient was satisfied with this result and continued with physiotherapy and rehabilitation. Over 18 months later, the patient is mobilizing independently at home and using crutches while outside. Despite complications post-transplant, she maintains good mobility and range of movement in her lower limbs.

pmc-8666202-1

A 73-year-old male presented to the emergency department with persistent hiccups over the past five days. The patient is a known diabetic and hypertensive for 15 years and has rate-controlled atrial fibrillation, managed with beta-blockers and warfarin. Two weeks ago, he suffered a subacute ischemic infarct of the right medial occipital lobe, which was confirmed on a computed tomography (CT) scan of the brain. The patient had both a preserved gag and swallow reflex. The family reported one bout of post-prandial emesis while upright five days earlier, after which the hiccups began eight hours later. The patient had no other symptoms, and the family denies him experiencing fever, chills, dyspnea, cough, malaise, and confusion. On clinical examination, there were decreased breath sounds and crackles noted in the basal segments of the right lower lobe. The patient had a low-grade fever (temperature 37.8 C) whilst other vital signs were stable (blood pressure 134/92mmHg, heart rate 92 beats per minute, respiratory rate 22 breaths per minute, oxygen saturations 97%). Chest radiograph confirmed the presence of bilateral lower lobe pulmonary infiltrates (Figure ). Blood investigations revealed a leukocytosis, neutrophilia, and an elevated C-reactive protein (CRP) (Table ). Blood cultures were negative and arterial blood gases were normal. Additionally, a coronavirus disease 2019 (COVID-19) polymerase chain reaction (PCR) test was negative. A tentative diagnosis of persistent hiccups secondary to aspiration pneumonia was made. The patient was immediately started on an intravenous antibiotic regime consisting of amoxicillin/clavulanic acid 1g at 12-hour intervals and metronidazole 400mg dosed at eight-hour intervals. Additionally, the patient was placed on a low-dose chlorpromazine infusion (25mg chlorpromazine diluted in 1000ml 0.9% saline infused over four hours), and his blood pressure was closely monitored. The patient experienced a near-complete resolution of his hiccups within 36 hours of treatment and a complete resolution prior to discharge four days later. Laboratory investigations were repeated prior to discharge and a decrease was noted in both CRP and leukocytes (Table ). The patient was transitioned to a 10-day course of oral amoxicillin/clavulanic acid and metronidazole. At outpatient follow-up 14 days later, the patient is well and had no recurrence of the hiccups.

pmc-8666563-1

A 53-year-old man presented with a gradually increasing mass located in the soft tissue of the oral cavity. The lesion was biopsied, and the pathology report showed increased infiltration of the buccal mucosa with monoclonal plasma cells. Immunochemistry demonstrated positivity for CD138, CIgA, and negativity for CD56, Cyclin D1 and CD20. Therefore, the diagnosis of soft tissue plasmacytoma was confirmed, for which he received localized radiotherapy with a total dose of 40 Gy, due to the absence of systemic disease as the bone marrow biopsy revealed the absence of neoplastic infiltration and serum and urine immunofixation were all negative. After five years, the patient noticed a painless swelling in his right testis. An ultrasound of the scrotum was performed that showed a hypoechoic mass in the right testicle with increased vascularization, and a normal-appearing left testis (Figure ). The patient subsequently underwent a right radical orchiectomy and the histopathology report showed testicular infiltration by a plasma cell neoplasm with identical immunophenotype (CD138+, CIgA+, CD56-, CD20-, Cyclin D1-) to the primary site in the oral cavity. Subsequently, the patient underwent a bone marrow biopsy that showed the absence of monoclonal plasma cell infiltration, and a PET/CT scan that was negative for reactive lesions suspicious of malignancy. In addition, serum and urine protein electrophoresis, as well as serum-free light chain assay were all within normal range, thus, excluding the presence of systemic disease, while complete blood count and full biochemical profile were normal. However, after one year, the patient presented again with painless swelling of his left testis that was attributed to disease relapse based on the imaging findings (Figure ). He refused to undergo left orchiectomy, thus he proceeded with systemic treatment based on lenalidomide, bortezomib and dexamethasone. Following 4 cycles of treatment, the patient underwent high dose melphalan with autologous stem cell transplantation. The blood tests of the patient revealed an increase in serum creatinine (1.3 mg/dl with 1mg/dl baseline level), normal calcium levels and normal complete blood count. Complete response was achieved with negative PET/CT scan and negative marrow minimal residual disease assessment. The patient continued on lenalidomide maintenance; however, six months later he was diagnosed with disease relapse in his left testicle (Figure ). A PET/CT scan was then performed, and showed a reactive lesion with an increased SUV max of 7 in the left testis, with no other loci suspicious of disease relapse. The blood analysis of the patient revealed no abnormal values. Since the patient refused surgery, he was initiated with next-line therapy, with bortezomib, cyclophosphamide and dexamethasone, he responded partially and still remains in remission (Figure ), while serum protein electrophoresis, immunofixation and serum-free light chain assay, all remain within normal levels.

pmc-8667962-1

Our patient was a 12-year-old Bahraini male who was seen initially in the A&E with a history of a fall from a height of around 2 meters on an outstretched hand. He had an obvious deformity of his elbow joint with an intact soft tissue envelope and no distal neurovascular deficits. Plain radiographs revealed a closed fracture-dislocation involving the olecranon process, a Salter-Harris type I fracture of the radial neck, and posterior dislocation of the elbow joint (Figure ). Open reduction and internal fixation of the fracture were undertaken the following day, under general anesthesia and in the lateral position; the elbow was approached posteriorly. The radial head was indirectly reduced and held using a 1.6-mm K-wire; the olecranon was reduced under direct vision and held with a tension band using two 1.6-mm K-wires (Figure ). Postoperatively, the elbow was protected using an above-elbow slab for three weeks, after which both active and passive elbow range of motion (ROM) was initiated. The fracture healed uneventfully, and the patient had a complete ROM of 30-130 degrees at the elbow joint within six weeks of fixation. The implant was removed after six months. The patient was completely asymptomatic with a full range of flexion, extension, supination, and pronation along with the evidence of bony union (Figure ).

pmc-8668042-1

A 38-year-old Caucasian woman, 35 weeks into her first pregnancy, presented to the emergency department for acute right-sided hip pain which precluded weight-bearing. Her right leg was shortened and externally rotated - there was no bruising or evidence of trauma. The patient’s history was significant for hereditary thrombophilia (Factor V Leiden) and secondary anemia. Hip radiography revealed an unstable, displaced, right-sided femoral neck fracture with no evidence of osteonecrosis (Figure ). The decision to administer radiography, in this case, was based on the American College of Radiology guidelines, which cite an absence of in-utero deterministic effects of ionizing radiation effects after 27 weeks of gestation. Unfortunately, it was not possible to evaluate the symptoms of the patient with MRI at this time due to the coronavirus disease pandemic-induced stress on the healthcare system of our country. The patient denied falls or trauma during the pregnancy, nor was there any history of smoking, alcohol abuse, use of glucocorticoids, or presence of rheumatologic/oncologic disease. Additionally, the patient was not malnourished, she underwent routine antenatal care, and took multivitamins. Serologic tests for inflammatory markers, as lab tests for serum calcium, phosphate, alkaline phosphatase, parathyroid hormone, vitamin D, and D-dimer returned normal. During multidisciplinary rounds, it was decided that delaying surgery was the best course of action out of fear of causing either mechanical or fluoroscopy-induced damage to the fetus during total hip arthroplasty. Five days later the patient experienced premature rupture of membranes, which was managed with emergency cesarean section (C-section) - no complications were encountered and a healthy 2300 g female was successfully delivered. Three days later the patient was transferred to our orthopedic surgery department for the treatment of the fracture. The significant degree of displacement (grade IV) of the fracture lasting over one week precluded open reduction with internal fixation due to fears of femoral head necrosis. During our literature review, we encountered a similar case of femoral neck fracture with grade IV displacement that was treated with open reduction internal fixation - despite restoration of blood flow to the femoral head within 15 hours, the authors still encountered femoral head necrosis with collapse six months later []. Given the considerable delay between symptom presentation and treatment, we decided the case warrants total hip arthroplasty instead of native hip salvage. Hemiarthroplasty was considered but was ultimately discarded as the conversion rate to total hip arthroplasty in young patients remain relatively high and the fracture was subsequently treated with a total uncemented prosthesis (Figure ), consisting of a 50 mm cup with 32 mm ultra-high-molecular-weight polyethylene insert and a 32 mm head with a 4 mm ceramic insert (Link Inc., Hamburg, Germany). Postoperative radiography confirmed prosthesis placement (Figure ); antibiotic and anticoagulant prophylaxis was initiated with ampicillin/sulbactam and enoxaparin sodium, respectively. Three days after the intervention the patient developed moderate abdominal pain without fever and accelerated intestinal transit, which both worsened over the next four days. Given the clinical presentation, there was a high index of suspicion for infection with Clostridium difficile (C. diff), although the diagnosis was ambiguous as the enzyme immunoassay (EIA) for the C. diff-specific antigen glutamate dehydrogenase was positive, while EIA for exotoxin A and B were negative. Due to exacerbation of symptoms and development of moderate hypokalemia (2.9 mEq/L), empiric treatment with metronidazole was began and marked rapid improvement. The patient was discharged five days later.

pmc-8668043-1

A 54-year-old Japanese woman was transferred to Hamanomachi Hospital, Fukuoka, Japan, for persistent fever with chest imaging abnormalities. She had a smoking history of 30 pack years. She had been diagnosed with oropharyngeal cancer and had been treated with chemoradiotherapy five years earlier. Two years prior to this clinical presentation, the patient had an established diagnosis of HTLV-1-associated myelopathy (HAM), with neurological findings of neurogenic bladder, orthostatic hypotension, bilateral lower limb spasticity, increased deep tendon reflexes, and positive bilateral Babinski reflexes, as well as positive serum and cerebrospinal fluid tests for anti-HTLV-1 antibodies. Post diagnosis of HAM, the patient experienced recurrent episodes of aspiration pneumonia and had a gastrostomy placed a year and a half earlier. A year earlier, she developed acute progressive HTLV-1-related myelopathy of bilateral lower limbs and was treated with methylprednisolone 1000mg pulse therapy, followed by 5mg of prednisone maintenance therapy at Fukuoka Central Hospital, Fukuoka, Japan. In the outpatient clinic at Fukuoka Central Hospital, she presented a fever with mild sputum. Her chest computed tomography (CT) showed infiltration in the upper right lobe and she was diagnosed with pneumonia. Despite treatment with levofloxacin for five days, a high fever persisted, and she was admitted to Fukuoka Central Hospital. At Fukuoka Central Hospital, she was placed on total parenteral nutrition, suspected of aspiration pneumonia, and was treated with tazobactam/piperacillin (TAZ/PIPC), followed by meropenem (MEPM) and vancomycin (VCM). She was also suspected to have vasculitis from the findings of purpura on her both lower limbs, and the corticosteroid dose was temporarily increased. Despite this effort of examinations and treatment for one month, her fever, high levels of serum C-reactive protein (CRP), and chest imaging abnormalities persisted. She was then transferred to Hamanomachi Hospital for further investigation and treatment on hospital day 28 (Figure ). On admission to Hamanomachi Hospital, she was sarcopenic with a body mass index of 13.5. She had muscle weakness of manual muscle testing (MMT) of 2-3/5, mainly in her lower limbs, which were the same levels of her baseline. Her respiratory condition was normal, with a respiratory rate of 15/min and SpO2 98% on room air. Crackles were not detected in her chest. Persistent, increased levels of CRP (7.7 mg/dL) and a white blood cell count of 6400 /μL were noted (Figure ). Chest x-ray imaging showed a giant air-space in the right upper lung field one year earlier (Figure , panel A). Consolidation was found in the right upper lung field on admission to Hamanomachi Hospital (Figure , panel B). Chest CT imaging showed dense consolidation with an air bronchogram and a giant bulla with fluid retention in the right upper lobe, as well as an emphysematous change in the bilateral lungs (Figure , panel A). Given the clinical course at Fukuoka Central Hospital and examination results on admission to Hamanomachi Hospital, a refractory lung abscess and an infected bulla were suspected. Suspected pathogens were Pseudomonas aeruginosa and Methicillin-resistant Staphylococcus aureus (MRSA), which were detected by sputum culture at Fukuoka Central Hospital. The differential diagnoses were opportunistic infections such as aspergillosis, mycobacteriosis, vasculitis, HTLV-1-associated bronchioalveolitis, and adult T-cell leukemia infiltration. To confirm the diagnosis, a bronchoscopy was performed on hospital day 30 (Figure ). Transbronchial lung biopsies (TBLB), bronchial brushing, and bronchial washing were conducted from the right B2 bronchus. Bacterial culture from bronchial washing was positive for Pseudomonas aeruginosa and MRSA, consistent with the sputum culture at Fukuoka Central Hospital and on admission to Hamanomachi Hospital. Neither Aspergillus species nor Mycobacterium species was detected. Hematoxylin and eosin staining of TBLB showed bronchial tissues with mild to moderate chronic inflammation and lymphocyte-predominant infiltration (Figure , panels A-C). Infiltrating lymphocytes were small and showed no morphological abnormalities. A small number of neutrophils and plasma cells were also seen. No findings suggestive of malignancy or adult T-cell lymphoma were noted. Infiltrating lymphocytes were a mixture of cluster of differentiation (CD)20-positive B lymphocytes and CD3-positive T lymphocytes (Figure , panel D), with a slight predominance of B lymphocytes. CD8-positive T lymphocytes were predominant among T lymphocytes (Figure , panels E and F). The pathological meaning is explained in the Discussion section. Based on these results, the patient was initiated with antibiotics (MEPM and VCM, followed by ceftazidime and linezolid). She was also treated with 5 g/day of intravenous immunoglobulin for three days, considering her immunosuppressive condition. However, she remained febrile with the upward trend of CRP. Considering the refractory state of the infected lung bulla, we performed percutaneous ultrasound-guided drainage of the bulla on day 38, following daily washing using sterile saline (Figure , panel C and Figure , panel B). The fluid from the drain was reddish-brown and cloudy, and Aspergillus species were detected in the drainage culture (Figure ). Given the pulmonary aspergillosis in addition to Pseudomonas aeruginosa and MRSA infection, voriconazole was initiated on day 49, although beta-D-glucan (14.3 pg/mL) and galactomannan (0.1 index) were negative. During treatment, we had to change antibiotics several times because of the drug resistance of Pseudomonas aeruginosa (carbapenem and quinolone resistance with moderate cephem resistance) and the side effects of the antibiotics. Amikacin was used for the combination treatment of drug-resistant Pseudomonas aeruginosa from day 60. Complications arising from anti-MRSA drugs included serum AST/ALT elevation caused by VCM, pancytopenia triggered by linezolid, and serum creatine kinase (CK) elevation (>1000 U/L) in response to daptomycin (Figure ). Prednisolone was gradually reduced and discontinued in consideration of its adverse effect on refractory infections. On approximately day 70, she gradually developed polyarthritis in her knees, right shoulder, and both wrist joints. Serological examination revealed elevation of rheumatoid factor (59.7 IU/L), but no elevation of anti-CCP antibodies (0.8 U/mL). Joint ultrasound showed active synovitis in both hand joints. The differential diagnosis of her poly-arthritis was antibiotic use-related arthritis, sepsis-related arthritis, pseudogout crystal arthropathy, rheumatoid arthritis, and HTLV-1-associated arthritis. She was treated with non-steroidal anti-inflammatory drugs (NSAIDs). Corticosteroids or other immunomodulating drugs could not be used until the infected bulla and lung abscess were completely healed. Her poly-arthritis persisted several months after the transfer to Fukuoka Central Hospital. From these results and clinical course, she was considered to have rheumatoid arthritis or HTLV-1-associated arthritis, which had been suppressed by the corticosteroid treatment. Thereafter, the fever gradually resolved, and the inflammatory response trended downwards. Chest imaging showed improvement of infiltration and reduction of the size of the infected bulla (Figure , panel D and Figure , panel C). We removed the drain tube on day 87. Her general condition improved, and she was transferred to Fukuoka Central Hospital on day 94. She was discharged to her home on day 150. No relapse of the infection has been observed since the discontinuation of antibiotics.

pmc-8668047-1

A 21-year-old male patient came to the hospital with complaints of fever, vomiting, pain in the abdomen, headache, and myalgia for three days. The patient was apparently alright three days ago when he started complaining of fever that was sudden in onset, intermittent, without diurnal variation, and not associated with chills or rigors. The fever was temporarily relived with antipyretics. He also had generalized weakness and joint pain associated with fever. The patient also complained of pain in the abdomen for three days. The pain was diffuse, present in the epigastrium and umbilical region, and aggravated after consumption of food. It was associated with nausea and vomiting. The patient had around four to five episodes of vomiting after food every day. Vomitus contained food particles. There was no hematemesis. The patient was nonalcoholic. On examination, his pulse rate was 88 beats per minute, blood pressure was 110/80 mmHg in the right arm in the supine position, and oxygen saturation was 98% on room air. On abdominal examination, there was tenderness in the umbilical area. Heart sounds were normal, no murmur was heard, normal breath sounds were heard, and there was no focal neurological deficit. On investigation, the patient tested positive for nonstructural antigen 1 for dengue fever. Platelets on admission were 53000/mm3, which gradually decreased until the fifth day after admission and then progressively increased (Table ). The patient’s serum amylase and lipase were found to be raised. Ultrasonography of the abdomen showed a bulky pancreas without ascites. Following this, contrast-enhanced computed tomography of the abdomen was done, which revealed bulging of the uncinate process of the pancreas and peripancreatic fluid collection along with minimal ascites (Figure ). These features were suggestive of acute pancreatitis with a score of 2/10 (mild) as per the revised Atlanta classification of acute pancreatitis []. The patient was kept nil by mouth and was treated with intravenous fluids, antibiotics (ceftriaxone and doxycycline), antipyretics, opioids, and proton pump inhibitors. During the course of the hospital stay, the patient improved gradually along with an increase in platelet count. The patient did not require any platelet transfusion. Along with the improvement in hematological parameters, there was a decrease in amylase and lipase levels. He was discharged in stable condition eight days after admission in stable condition and is presently doing well on follow-up.

pmc-8668048-1

A 59-year-old female patient presented to a plastic surgery clinic with a lump on her right medial thigh. She noticed the lump eight months ago and it was gradually increasing in size. It was painless initially; however, the lump gradually became tender. The patient was otherwise fit and well with no co-existing morbidities. Closer examination of the right thigh revealed a high consistency mass, with reduced mobility. There was no right inguinal lymphadenopathy or lymph nodes enlargement. Laboratory blood tests were unremarkable. An MRI scan was requested to further assess the mass, which was irregular but well-defined in the medial compartment of the thigh, measuring 8.2 x 6.6 x 4.3 cm in size. The mass showed an intermediate signal on both T1 and T2-weighted imaging, appearing hyperintense compared to the adjacent muscular tissue, which also persisted on fat-suppressed imaging. The mass invaded the intramuscular fat planes and caused compression and displacement of the adductor muscles. There was no evidence of intra-muscular invasion. Normal cortical outline and medullary signal intensity of the femur were seen in the right thigh. There was no evidence of bone contusion, marrow oedema, fracture line, or cortical discontinuity. Other muscles of the thigh had a normal outline and signal intensity with no evidence of focal or diffuse oedema. Neurovascular structures were unremarkable. Overall, MRI findings were suggestive of soft tissue neoplasm, with a possibility of a neurogenic tumour. A wide excisional biopsy was then performed to further assess the tissue histologically by the pathologist and confirm the diagnosis. The removed mass measuring 8.5 x 6.5 x 5.4 cm and is shown in Figure . The mass had a smooth outer surface and a soft consistency. The cut surface showed a homogenous tan-white appearance with some slit-like spaces and occasional haemorrhagic spots. Multiple sections were processed for histopathological examination from different planes. Histopathology of the mass revealed a tumour arranged in sheets and fascicles composed of round to oval cells along with variably sized adipocytes (Figure ). Numerous interspersed lipoblasts with indented nuclei were also seen. Moreover, severe nuclear atypia was noted including bizarre cells (Figure and Figure ). An area of necrosis was seen with a few areas, which showed malignant and fibrous histiocytoma-like features. Furthermore, a few thin-walled dilated and congested blood vessels were also noted. Also, brisk mitosis was noted (35-38 per 10 HPF) (Figure ). Immunohistochemical staining (IHC) was also performed and the tumour cells were diffusely positive for vimentin and focally positive for S-100; while negative for creatine kinase (CK), smooth muscle antigen (SMA), desmin, CD34 and MyoD1. Overall, the pathological findings are all suggestive features of a high-grade sarcoma, favouring the epithelioid variant of PLS. The patient was also referred to the Department of Nuclear Medicine & Molecular Imaging for post-surgical restaging and assessment for possible metastases using 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) scan. The abdominopelvic section showed the liver measuring within normal limits; however, the scan revealed an ill-defined hypermetabolic hypodense lesion seen involving segment VI measuring approximately 2.8 x 1.8 cm suggestive of hepatic metastases with concurrent fatty liver. The scan was also remarkable for the musculoskeletal system, revealing multiple hypermetabolic osseous lesions involving the skull base, right iliac bone, and few vertebrae (predominantly T7-L1); which was suggestive of skeletal metastases. A non-hypermetabolic pulmonary nodule in the right lung field was also detected; it was considered to be likely benign, but interval scanning is suggested to monitor further progress. Finally, there was also evidence of diffuse subtle hypermetabolism at the site of surgery which is suggestive of postsurgical inflammatory sequelae; however, microscopic residual disease cannot be completely ruled out. These multi-organ lesions were due to be biopsied to examine their immunohistochemical findings to confirm metastatic lesions of primary pleiomorphic liposarcoma. However, the patient did not attend the follow-up appointments.

pmc-8668049-1

A 22-year-old healthy woman presented to the emergency department complaining of a five-day history of several red and painful areas that were associated with swelling of the lower extremities. Her complaint started one day after receiving the first dose of the Pfizer vaccine. She had received all vaccinations during childhood without any complications. There is no history of preceding infections including COVID-19 infection, sore throat, or diarrhea. In addition, she never complained of prior skin lesions or systemic diseases. She did not use any topical or systemic medication. All the laboratory investigations were normal. She stated that there is no history of contact with the sick patients and no family history of tuberculosis. Skin examination revealed multiple, tender, and erythematous nodules were present on her both legs. Based on the patient history, examination, and laboratory investigation all pointed to the vaccine-related erythema nodosum; however, we considered the Arthus-like phenomenon which can mimic the erythema nodosum lesions. She received oral ibuprofen 600 mg four times daily to relieve symptoms. Three days after receiving the treatment, she improved and the nodules started to flatten (Figure ). Two weeks later, on the follow-up examination, her symptoms had completely resolved.

pmc-8668144-1

A 71-year-old man initially presented to clinic with right hip and low back pain with radiation to his posterior right thigh. He denied numbness, tingling, and weakness of his bilateral lower extremities. He had reproducible pain in the right SI joint region after SI joint provocative testing. A radiographic spine survey was unrevealing for a structural source of low back pain or radiculopathy. Preoperative imaging, including MRI, did reveal lumbarization of the S1 vertebra, mammillary bodies in the alar region, and a residual S1-S2 disc (Figure , ). After obtaining adequate pain relief from two separate right-sided SI joint injections, the patient decided to pursue surgical intervention in the form of SI joint fusion using the iFuse implant System® (SI-Bone, Inc., Santa Clara, California). In the operating room, the patient underwent general anesthesia and was positioned prone on the Jackson table. He was then prepped and draped in the usual sterile fashion. Fluoroscopy was used to mark the borders of the sacrum on the patient’s skin. Next, a 3 cm incision was made parallel to the sacrum beginning over the center of the S2 vertebral body as approximated with lateral fluoroscopy. The incision was carried down through the gluteal fascia. The first implant was placed within the S2 body caudal to the level of the residual S1-S2 disc on the lateral radiograph. The mid-S2 body was chosen as the site for the first implant in an effort to avoid iatrogenic L5 nerve root damage from starting more cranial due to the known sacral dysmorphism seen on preoperative imaging. The next pin was placed caudal to the first using a double-barrel guide. After the path for the second implant was broached, there was an immediate flow of bright red blood from the wound. The second implant was quickly inserted, and the bleeding stopped. Therefore, we decided to proceed with the third implant (Figure ). The third implant was then placed, and the wound was irrigated and closed without evidence of continued bleeding. The patient was discharged home the same day in stable condition. On postoperative day 19, the patient presented to the emergency room with a three-day history of pain in the right gluteal and posterior thigh regions. He also complained of dizziness and occasional syncope when ambulating. Physical exam revealed a well-healed surgical incision with a large bruise extending from his right hip down the right leg (Figure ). CT of the pelvis showed a large gluteal hematoma with extension into the posterior compartment of the thigh (Figure ). CT angiogram (CTA) of the right lower extremity showed disruption of the blood flow through the superior gluteal artery at the level of the inferior two implants as the vessel exited the greater sciatic notch (Figure ). Interventional radiology was consulted for possible embolization, but they determined there was no visible active extravasation and recommended observation and serial hemoglobin draws. The patient’s hemoglobin on the day of presentation was 9.8 g/dL, and on hospital day one it was 8.5 g/dL. Due to this drop in hemoglobin over 24 hours and the patient’s increasing pain level, the decision was made to take the patient to the operating room for exploration and removal of hematoma. The patient was placed in a left lateral decubitus position, and a curved incision was made over the right posterolateral hip for a Kocher-Langenbach approach. Electrocautery dissection was taken down to the level of gluteus maximus muscle fascia. The fascia was carefully incised, and the hematoma was progressively evacuated from under the gluteus maximus and gluteus medius planes. After evacuation, the greater trochanter became palpable. Once the surgical bed was cleared of hematoma, the SGA was identified. A branch of the SGA was noted to have been lacerated with active bleeding (Figure ). The vessel was clamped and ligated using 3-0 silk sutures. A 15-French subfascial Jackson Pratt drain was placed at the end of the procedure. On postoperative day three, he was discharged in improved condition. His surgical drain was removed at the three-week postoperative visit. At his two-month follow-up visit, the patient’s right-sided SI joint pain was gone. At four months, the patient was walking unassisted and was not requiring pain medicines.

pmc-8668145-1

A 67-year-old female with a past medical history of iatrogenic hypothyroidism secondary to thyroidectomy stopped taking her levothyroxine over a year ago. Three months prior to her presentation, she had been experiencing progressively worsening confusion and respiratory distress. According to her family, she became bed-bound approximately a week before admission, when she was brought in by ambulance after being found unresponsive by family members. On admission, her vital signs were unremarkable with a heart rate of 70 beats per minute. Her physical examination was significant for lethargy, facial swelling, macroglossia, and bibasilar crackles of the lung fields. Laboratory findings were pertinent for thyroid-stimulating hormone (TSH) at 58.5 ng/dL and free thyroxine (T4) of 0.19 ng/dL. Electrocardiogram (EKG) showed normal sinus rhythm with low voltage QRS complexes with electrical alternans (Figure ). The enlarged cardiac silhouette was noted on chest radiography (CXR) along with congested lung fields (Figure ). Following consultation with the endocrinology service, the patient was started on intravenous levothyroxine and hydrocortisone and admitted to medicine telemetry service for further management. On the following day, a transthoracic echocardiogram (TTE) showed a large pericardial effusion with the swinging of the heart in the pericardial sac with the diastolic collapse of both atria and the right ventricle (Figure , Figure , Figure ). The patient was upgraded to Cardiac ICU and underwent urgent pericardiocentesis with 1300 mL serous straw-colored fluid drained. Analysis of pericardial fluid was negative for malignant cells. Acid-fast bacilli stain and culture were negative. The patient was discharged on levothyroxine. Serial TSH and T4 measurements over the subsequent two months showed normalization of both values. On six months follow-up, repeat TTE showed diminishing pericardial effusion without echocardiographic evidence of cardiac tamponade.

pmc-8668146-1

A 95-year-old lady with a past medical history of heart failure with reduced ejection fraction (HFrEF) and biventricular implantable cardioverter-defibrillator (ICD), hypertension, and asthma presented to the emergency department for evaluation of nausea, vomiting, and a two-month history of intermittent diarrhea, which had been worsening for a few days prior to admission. Diarrhea was associated with severe, diffuse, waxing, and waning abdominal cramps, which were noted to improve after emesis. No correlation was noted with eating habits and no history of recent antibiotic use was reported. On examination, the abdomen was soft but tender on deep palpation, with audible bowel sounds. No organomegaly or costovertebral angle (CVA) tenderness was appreciated. Initial laboratory results revealed hypokalemia (3.3 mEq/L), lipase within normal limits (32 U/L), and normal transaminases (aspartate aminotransferase [AST]: 19 U/L; alanine aminotransferase [ALT]: 10 U/L) and bilirubin (total bilirubin: 0.7 mg/dl; direct bilirubin: 0.1 mb/dl). Stool studies were unremarkable and coronavirus disease 2019 (COVID-19) reverse transcription-polymerase chain reaction (RT-PCR) was negative. CT abdomen revealed a long segment of the colon with a loop within loop appearance from the proximal transverse colon to the distal descending colon, consistent with intussusception (Figures , ). The underlying lesion for the lead point was not well identified. The patient was taken to the operating room the next day where local exploration using laparoscopy revealed complete telescoping and intussusception of terminal ileum into the distended ascending and transverse colon. At that time, it was decided to proceed with an open procedure and right hemicolectomy extending from the terminal ileum to about one-third of proximal transverse attachment of the mid transverse colon was performed and side-side anastomosis was created between terminal ileum and transverse colon at the anti-mesenteric border. The patient tolerated the procedure well with no immediate complications. Surgical pathology revealed a tubulovillous adenoma with high-grade dysplasia as the lead point of the intussusceptum. It was negative for in-situ or invasive carcinoma. The postoperative course was significant for acute kidney injury (Cr 1.3 mg/dl with oliguria) on postoperative day two, which resolved after administration of IV fluids. The patient was discharged home with home care services on postoperative day six.

pmc-8668149-1

A 31-year-old Caucasian male presented to the ED with a 10-day history of progressively worsening symptoms that started with a sore throat and dysphagia. Five days after the development of initial symptoms, productive cough with orange-colored sputum began. His condition worsened four days before presentation, with the development of fever, chills, night sweats, significant diarrhea, emesis, and pleuritic chest pain. On initial presentation, the patient appeared ill and anxious. He was febrile with a temperature of 102° Fahrenheit, tachycardic with a heart rate of 118 beats per minute, and hypotensive with a blood pressure of 109/54 mmHg. On physical exam, he had a respiratory rate of 18 breaths per minute and oxygen saturation of 95% on room air. His neck was supple with absent lymphadenopathy and both lungs were clear to auscultation. Laboratory work on admission was remarkable for a leukocyte count of 23.2 x 10^9/Liter, a neutrophil count of 85.6% with 16% bands, serum sodium of 132 mmol/Liter, and a D-Dimer of 4.29 mg/L FEU. Initially, one gram of ceftriaxone and 500 mg of azithromycin were administered intravenously in the ED. Tests were then ordered including a monospot and rapid Streptococcus A antigen via pharyngeal swab, as well as (1,3)-beta-D-glucan and HIV-1 RNA via serum, and Legionella pneumophila urine antigen; all without remarkable findings. A complete viral respiratory panel was negative, and PCR did not detect Mycoplasma pneumoniae, SARS-CoV-2, or Chlamydia pneumoniae. A portable chest X-Ray performed in the ED demonstrated right upper lobe pneumonia (Figure 1). A CT angiogram of the chest ordered to rule out pulmonary embolus (Figures -) demonstrated no signs of acute pulmonary emboli. However, findings displayed a large consolidation in the right lower lobe and a 4 cm cavitation in the left lower lobe. Transthoracic ECG was then performed, demonstrating no vegetations or valvular abnormalities. Trans-esophageal ECG was recommended to the patient, but he declined. Next, a CT scan of the neck was ordered, showing no evidence of abnormalities. Without significant improvement in WBC count for three days and persistent fevers >100° Fahrenheit, his antibiotic regimen was escalated to three grams of ampicillin-sulbactam administered intravenously every six hours. This resulted in an improved WBC to 16.1 x 10^9/Liter the following day. The patient had no further fevers and reported improvement in pleuritic chest pain and dysphagia. On day five of hospitalization, the initial blood culture grew a single anaerobic gram-negative bacterium, F. necrophorum. The patient continued to show improvement without signs of fever, nausea, or vomiting. A repeat negative blood culture and final WBC count of 14.5 x 10^9/Liter was reported on day eight of hospitalization before the patient was discharged later that afternoon. He was discharged home in a stable condition with 500 mg of amoxicillin-clavulanic acid given orally every twelve hours for seven days and was instructed to follow up with his primary care physician in three weeks for a repeat CT scan of his chest to monitor the resolution of pulmonary lesions.

pmc-8668258-1

A 48-year-old African American man with a medical history of COVID-19 pneumonia and obesity presented to the emergency department with left foot pain for the past three days. Initial workup returned a diagnosis of gout but also uncovered an incidental finding of a platelet count of 7x103/mL. All other labs including white blood cell count and hemoglobin were normal. The patient stated he had been hospitalized for COVID-19 pneumonia five weeks prior but denied any lingering symptoms, had not noticed any bleeding and denied any home medications. Additionally, the patient denied any relevant family or social history. Vital signs were stable. The physical exam did not reveal any petechiae, purpura, palpable lymphadenopathy, or visceromegaly. Chart review showed that the patient's platelet count was 325x103/ml when he was discharged from the hospital five weeks prior. Upon further workup for thrombocytopenia, a repeat complete blood count confirmed the initial finding, and microscopy did not reveal any clumping or abnormal platelet morphology. Coagulation studies were non-contributory. A viral panel, including HIV, hepatitis C virus (HCV), and Epstein-Barr Virus (EBV), was non-reactive and folate and B12 levels were within normal limits. Ultrasound of the spleen was unremarkable. Having ruled out other causes of thrombocytopenia, we made a diagnosis of secondary immune thrombocytopenia due to COVID-19. The patient was admitted for observation and transfusion. The patient was given two units of platelets. The patient was also started on prednisone 40mg daily. He was discharged home on day two with a platelet count of 47x103/ml. During follow-up as an outpatient two weeks later, complete blood count (CBC) revealed his thrombocyte count was 120x103/ml.

pmc-8675448-1

A 21-year-old Danish man diagnosed with attention deficit hyperactivity disorder (ADHD) in adolescence, which was currently untreated, was involuntarily admitted to a psychiatric ward by the police in an agitated and aggressive state after a violent conflict with his parents. Clinically, the patient’s state was compatible with acute intoxication, and the patient confirmed “drug intake,” but quantification could not be specified at admission. Eight months prior, the patient had spent 2 weeks in deep propofol sedation at an intensive care unit (ICU) with acute organic delirium due to GHB withdrawal. At the psychiatric ward, the patient’s threatening and aggressive behavior intensified. To avoid violent incidents, the patient was subjected to physical restraint (abdominal belt) and tablet lorazepam 4 mg was administered twice. The patient was disorientated, started expressing paranoid ideas, and developed diaphoresis, tachycardia (heart rate 130 beats per min), and hyperthermia (37.8 °C, tympanic). Because he started biting the metal locks on his abdominal belt, his hands and feet were also restrained. On the second day, the patient was diagnosed with acute organic delirium caused by GHB withdrawal and treatment was initiated. In accordance with ICD-102, the diagnosis was based upon the clinical presentation in combination with a history of GHB substance abuse. The patient was treated with a cumulative dose of 300 mg diazepam (40 mg as oral administration and 260 mg intravenously), without induction of sleep. To obtain sedation the restrained patient was transferred to the ICU, where he was intubated and sedated with intravenous infusions of propofol (up to 16 mg/kg/hour) and sufentanil (up to 100 μg/hour). On days 3–6, the patient remained deeply sedated and on mechanical ventilation. To counteract potential withdrawal symptoms, clonidine 225 μg was administered every 6 hours via a nasogastric tube (NG tube), intravenous diazepam 20 mg every 5 hours, and continuous midazolam infusions (up to 1 mg/kg/hour). To prevent Wernicke encephalopathy, intravenous thiamine 200 mg and vitamin B 2 ml solution were given. Due to elevated C-reactive protein (64 mg/L) and white blood cell count (leukocytes 12.2 × 109/L; neutrophils 9.1 × 109/L), empiric treatment with piperacillin/tazobactam 4 g every 6 hours was initiated. On day 6, a first wake-up call was attempted. However, upon awakening the patient was disoriented and severely agitated, and he was readily reintubated and resedated. The psychopharmacological treatment was intensified with olanzapine 20 mg/day (via NG-tube), intravenous diazepam 40 mg every 5 hours, clonidine 225 μg every 6 hours (via NG-tube), and continuous midazolam infusions (up to 1 mg/kg/hour). On days 7–9, the intravenous diazepam was increased to 60 mg every 5 hours, and to supplement the propofol sedation, methadone 10 mg twice a day (via NG-tube) was initiated. On day 10, a second wake-up was attempted. Again, the patient was disoriented, reported of ants crawling in the room, and presented with severe agitation. Physical restraints were reinstated and intravenous haloperidol 30 mg/day was added. On day 11, the psychiatrists decided to initiate bilateral frontotemporal ECT as “en bloc” treatment, that is ECT on three consecutive days. Medication status during the three en bloc ECTs was: olanzapine 20 mg twice a day (BID, via NG-tube), methadone 10 mg BID (via NG-tube), intravenous phenobarbital 100 mg every 4 hours, pregabalin 150 mg BID (via NG-tube), haloperidol 5 mg as needed (PRN), up to 50 mg a day, clonidine 225 mg every 6 hours (via NG-tube), and continuous infusions of midazolam (up to 1 mg/kg/hour). Because treatment with high doses of benzodiazepines with long half-lives could compromise seizure induction, the starting ECT dose was set at the maximal energy of 200% (1008 mC) along with intravenous flumazenil 0.4 mg. The ECT series are shown in Fig. . On day 12, the first ECT was administered (ECT #1A). Due to an administrative error, flumazenil was not administered, and restimulation with concurrent flumazenil was performed (ECT #1B). After ECT, the patient remained awake although clinically unchanged. On day 13, the second ECT was administered (ECT #2). Subsequently, the patient’s level of agitation decreased, he briefly responded adequately to verbal communication and sleep improved. On day 14, the third ECT (ECT #3A) was administered. Due to seizure at threshold level, restimulation after hyperventilation was performed (ECT #3B). The patient was less agitated and engaged in brief conversations. Haloperidol was increased to 20 mg every 6 hours. On day 15, 50 mg hydroxyzine once a day (QD) was added. On day 16, agitation had completely subsided, restraints were removed, and the patient cooperated with the remaining treatment. On day 17, the fourth ECT was administered (ECT #4). On day 18, the patient displayed no neurological or psychiatric symptoms, all sedatives and psychopharmacological treatment were discontinued, and he was transferred to a general internal medicine ward. On day 19, the patient was still in complete remission, and he insisted on discharge. Upon discharge the patient confirmed daily use of GHB and cocaine prior to hospitalization, and he provided oral and written consent to report his case in the medical literature. Since this is a case report, ethical approval was waived according to Danish regulations.

pmc-8675449-1

A 56-year-old woman of North African origin, with no medical and surgical history, was admitted to the Department of Internal Medicine for investigation of a Raynaud phenomenon evolving for 3 months, associated with inflammatory arthralgias involving the wrists, elbows, and ankles; the patient also reported pain and progressive proximal muscle weakness in her lower limbs when climbing stairs, which extended to the upper limbs. There was no rash. Neuromuscular examination revealed proximal tetraparesis, mild neck flexion, and extension weakness. Strength at the neck was 4/5; at the shoulder 3/5; at the wrist 4/5; at the hips 2/5; and at the ankle 4/5; dorsiflexion/plantar flexion was normal. Tendon reflexes were normal. A few days after her hospitalization, the patient developed slight dysphonia and dysphagia; then this symptomatology was accentuated over time. Nail fold capillary microscopy was normal. Blood tests showed significant levels of muscle enzymes [creatinine kinase (CK) 40,000 IU/L]. Autoimmune screening for myositis-specific and myositis-associated autoantibodies was negative. Electromyography (EMG) showed a decrement in compound muscle action potential on repetitive stimulation and clear signs of myopathy. The diagnosis of inflammatory myopathy was confirmed by muscle biopsy, which showed myositis (Fig. ). The patient was treated with prednisone 60 mg daily; we observed a slight improvement in muscle weakness and a significant decrease in CK serum level. A month later, she developed intermittent diplopia, ptosis, and mild dysarthria during the conversation. Serum acetylcholine receptor (AChR) antibodies were positive (5.59 nmol/L), and muscle-specific kinase antibodies were negative. A broader workup performed with computed tomography (CT) of the chest revealed a large anterior mediastinal mass (114 × 57 × 100 mm) (Fig. ), which a subsequent biopsy revealed as B1-type thymoma (Fig. ). Inflammatory myositis associated with myasthenia gravis was diagnosed. Pyridostigmine in combination with steroids was started, with significant improvements in generalized weakness, ptosis, and dysarthria. The patient underwent thymectomy as part of the additional treatment. Currently, she is on a low dose of steroids and pyridostigmine and is asymptomatic. The features of myositis have not relapsed.

pmc-8677888-1

A 70-year-old man with a high carbohydrate antigen 19-9 level was diagnosed with resectable pancreatic cancer. Enhanced CT revealed a 15-mm mass in the pancreatic body and dilatation of the peripheral main pancreatic duct (Fig. A). The patient underwent DP with lymph node dissection. DP was performed by transecting the pancreas at the right border of the PV with a powered linear stapler. Additional pancreatic tissue was observed on the dorsal aspect of the PV (Fig. B), and the patient was diagnosed with PAP (type II). After the diagnosis, additional pancreatic resection was conducted using a powered linear stapler. The total operative time was 527 minutes, and the estimated blood loss was 730 mL. Based on the Union for International Cancer Control TNM staging, the pathological diagnosis was T3N0M0, stage IIA. In addition, the pathological margin was negative. The patient had no complications and was discharged on postoperative day 23. PAP was detected on preoperative CT images during a retrospective review (Fig. A).

pmc-8677888-2

A 46-year-old woman with a history of familial adenomatous polyposis and rectal cancer underwent PD with lymph node dissection for a newly diagnosed duodenal papillary carcinoma. Pancreatectomy was performed by transecting the pancreas superior to the PV. The pancreatic parenchyma was subsequently identified on the dorsal side of the PV (Fig. A) and transected, resulting in the exposure of a section (2 mm in length) of the main pancreatic duct. The remaining pancreas was mobilized caudally. An additional section was made in the pancreatic body caudal to the cricoid pancreatic junction so that the pancreatic cross-section was oriented in 1 plane. The diagnosis was PAP (type II). The total operative time was 439 minutes, and the estimated blood loss was 250 mL. Based on the Union for International Cancer Control TNM staging, the pathological diagnosis was pT1aN0M0, stage IA. In addition, the pathological margin was negative. Although the patient had a grade-B pancreatic fistula (International Study Group of Pancreatic Fistula Classification) that was diagnosed on postoperative day 3, the patient recovered after conservative treatment, which is continuous drainage until 2 days before discharge, and was discharged on postoperative day 18. We retrospectively reviewed the patients’ preoperative CT images and identified the PAP (Fig. B).

pmc-8677895-1

A 28-year-old woman presented to the emergency department with severe lower abdominal pain that was associated with nausea. Two weeks prior to admission, she had symptoms of abdominal pain and bloody diarrhea which was later diagnosed to be amebiasis. The patient was diagnosed with tuberous sclerosis at the age of 6 months when she developed arrhythmia related to a cardiac rhabdomyoma. The rest of the medical history included adenoma sebaceum, Ash leaf spots, bilateral renal angiomyolipomas, left-sided retinal hamartoma, and allergic rhinitis. She was previously operated 3 times for the removal of multiple renal angiomyolipomas and underwent partial cystectomy due to invasion of the tumor. Physical examination was normal. The laboratory work-up was unremarkable except for anemia (hemoglobin 9.6 g/dL) and an elevated C-reactive protein value of 125 mg/dL. The computerized tomography (CT) scan revealed extralumination of the rectal contrast material at the rectosigmoid region, indicating bowel perforation. The patient underwent proctosigmoidectomy and formation of an end colostomy together with the closure of the anorectal stump (Hartmann operation). Two weeks after the operation, the patient developed a new onset abdominal pain. The CT scan revealed contrast extralumination in the distal ileum and the patient underwent ileocecal resection due to a new onset bowel perforation and severe adhesions. Several days after the second operation she developed fever and was diagnosed with SARS-CoV-2 infection for which she took treatment. Both of the rectosigmoid resection specimen and the ileocecal resection specimen were reported as leiomyomatosis-like lymphangioleiomyomatosis (Fig. ). After 8 months of follow-up, the patient's rectoscopic examination together with a control CT scan was normal. At the first year of follow-up, the patient had an ileostomy closure surgery. Grossly, the rectosigmoid specimen (16 cm in length, 7 cm in width, 1 cm in thickness) consisted of full-thickness hemorrhage extending 7 cm proximally from the surgical margin. Macroscopically, there was a 3 cm perforation area in the central part of this hemorrhagic region. Pseudopolypoid lesions ranging from 0.1 to 0.3 cm in diameter were observed in the surrounding mucosa. The ileocecal resection material (ileum 4 cm and colon 16 cm in length) consisted of a 5 cm, pale-colored, nodular lesion in the cecum. Numerous pale nodular lesions, ranging from 0.3 to 5 cm in diameter extending from the mucosa to the subserosa were observed in the cecum. In all resected specimens, the intestinal wall was diffusely thickened and nodular. Infiltration into the subserosal adipose tissue was observed. Histological examination revealed nodular lesions with an extensive growth pattern, extending from the submucosa to the mesorectal adipose tissue in some areas, without affecting the mucosa. Microscopically, the nodules consisted of spindle cell bundles with prominent elongated nuclei organized into branching short fascicles (Fig. ). Necrosis, pleomorphism, and mitotic activity were not observed. Among the spindle cells, clusters of epithelioid cells were observed around dilated vascular structures lined with endothelium in some areas (Fig. ). It was noted that these epithelioid cell assemblages in the vessel walls tended to merge with the surrounding lymphatics. Mature adipose tissue was not observed. In the surrounding intestine where the tumor was absent, severe active colitis findings were observed. Immunohistochemically, the spindle and epithelioid cells in both of the resected specimens stained positive for desmin, SMA, and HMB45 and negative for CD34, DOG-1, c-KIT, S100, ER, and PR (Fig. ). The Ki-67 proliferation index was found to be 3%. There was no evidence of lymphatic or vascular invasion.

pmc-8677896-1

A 27-year-old G1P0 pregnant woman, whose results of non-invasive prenatal gene detection at 21+2 weeks of gestation, suggested that the risk of trisomy 18 (– 6.6) was high, while the risk of trisomy 21 (0.681) and trisomy 13 (2.363) was low. Ultrasound examination at 23+2 weeks of gestation revealed a single live fetus with a gestational age of 23+2 weeks in utero, whereas the umbilical cord was wrapped around the neck of the fetus for 1 week. The measurement indexes of fetal development are as follows: biparietal diameter = 6.0 cm, head circumference = 20.9 cm, abdominal circumference = 17.4 cm, femur long = 4.0 cm, amniotic fluid index = 16.7 cm, and the 3 values of umbilical artery S/D were 4.6, 3.2, and 2.7 respectively. It is suggested that amniocentesis, chromosome karyotype analysis, and CNVs should be recommended to further confirm the condition of the fetal chromosome. Chromosome karyotype analysis after amniocentesis showed that the fetal chromosome karyotype was 46, XY, del (18) (q22.3; q23) (Fig. A). CNV detection results showed that this sample detected chromosome aneuploidy or CNVs of more than 100 kb, which was regarded as the definite pathogenic genomic: 18q22.3q23 (68900001-76560000), and the size of the deleted fragment was 7.66 Mb (Fig. B, C).

pmc-8677896-2

A 35-year-old G4P1 pregnant woman who had 1 natural birth and 2 induced abortions. The results of non-invasive prenatal gene detection at 19+2 weeks of gestation suggested that the risk of trisomy 21 (–1.249), trisomy 18 (–1.534), and trisomy 13 (–1.904) were all at low levels. Ultrasound examination at 21+2 weeks of gestation revealed that there is a single live fetus with a gestational age of 21+2 weeks in utero, whereas it is difficult to determine whether the fetus has only 1 umbilical artery to supply blood. The measurement indexes of fetal development are as follows: biparietal diameter = 4.9 cm, femur long = 3.6 cm, and the deepest amniotic fluid was 5.7 cm. The couple requested amniocentesis, chromosome karyotype analysis, and CNVs to further confirm the diagnosis. Chromosome karyotype analysis after amniocentesis showed that the fetal chromosome karyotype was 46, XY, del (18) (q22.2; q23) (Fig. A). CNV detection results showed that this sample detected chromosome aneuploidy or CNVs of more than 100 kb, which was regarded as the definite pathogenic genomic: seq [hg19] del (18) (q22.1q23), chr18: g.6602000178020000del (Fig. B, C). After half a year, the personnel of the prenatal diagnosis center followed up the 2 couples and learned that both couples voluntarily terminated their pregnancy after knowing the results of amniocentesis.

pmc-8677899-1

In January 2018, a 78-year-old man presented with complaints of numbness in the soles of both feet. There was no motor weakness on neurologic examination. Severe L4-5 central stenosis and root redundancy were diagnosed on lumbar MRI (Fig. ). On February 28, 2018, we performed L4-5 OLIF, followed by bilateral L4 laminotomy and L4-5 percutaneous posterior screw fixation (PPSF). To perform OLIF first, after administering general anesthesia, we ensured that the hip joint was not flexed in the standard right posture. The axilla and hip were fixed using a wide cloth and tape. The external oblique, internal oblique, and transverse abdominal muscles were incised and approached through the retroperitoneum to gently retract the abdominal organs and psoas to expose the intervertebral space. There was no direct blood vessel injury or nerve injury during this process. After determining the height and length of the cage using the C-arm, we vertically inserted a cage (Clydesdale DLIF Cage, 6°∗14∗50 mm; Sofamor, Memphis) combined with a demineralized bone matrix into the intervertebral space. After turning the patient to the prone position, bilateral laminotomy was performed, with minimal damage to the posterior tension band, and severe ligamentum flavum hypertrophy was confirmed and removed. Thereafter, L4-5 PPSF was performed. Intraoperatively, an increase in the disc height and foramen height was confirmed using the C-arm, and sagittal alignment was maintained well. There was no motor weakness postoperatively. Two days later, the patient was allowed to walk while wearing an orthosis, and the radiating pain improved; he was then discharged from the hospital. At 6 weeks after surgery, he complained of pain and swelling below both ankles at the outpatient clinic. Lumbar CT and radiographic examination showed that the fusion was maintained without subsidence of the surgical site, the height of the intervertebral disc space and foramen increased, and there was no abnormality in the alignment between the lumbar vertebrae (Fig. ). In addition, a prominently protruding osteophyte, which was considered insignificant before the first surgery, was again observed. In particular, the osteophytes on the foraminal side were severely protruding (Fig. ). In the 10th week after surgery, he visited the outpatient clinic with a cane, complaining of persistent pain below both ankles and motor weakness of the right ankle. A marked decrease in dorsiflexion of the right ankle was observed. The Medical Research Council (MRC) muscle strength grade of the right ankle was 2. We confirmed the resolution of the previous central stenosis and root redundancy on lumbar MRI and found no other specific findings (Fig. ). We thought that it was necessary to explore the L4 nerve roots again, focusing on the right side. On May 21, 2018, we performed right L4/5 facetectomy and foraminotomy to release the right L4 nerve root. During surgery, the tissues compressing the L4 nerve root and the osteophyte protruding severely and trapping the nerve root were identified and removed. Within 1 week of hospitalization after surgery, the radiating pain in both feet disappeared, and dorsiflexion of the right ankle was restored to MRC grade 4. After the second surgery, follow-up CT of the lumbar spine confirmed clear decompression of the right foramen (Fig. ). To date, he has no radiating pain in both feet, and motor performance of the right ankle has been restored and maintained.

pmc-8677945-1

An 80-year-old female patient presented to the emergency department of our institution with a 5-day history of headaches. A week ago, she had presented with a minor head trauma that was caused by a fall. She had a history of hypertension and dyslipidemia and had experienced focal cerebral infarction 10 years earlier. The patient had no neurologic abnormalities, except for headache. An initial non-contrast brain computed tomography (CT) scan showed a scanty subarachnoid hemorrhage (SAH) on the left ambient cistern with an enlarged ventricle (Fig. A). Subsequent brain CT angiography (CTA) showed no vascular abnormalities. Based on the CT findings and the patient's history of trauma, she was admitted to the neurosurgery department as a suspected case of traumatic SAH, following which her symptoms improved gradually. On the 10th day of hospitalization, the patient showed sudden stuporous mental deterioration. Brain CT performed at that time revealed SAH on all the cisterns, with intraventricular hemorrhage (Fig. B). A CTA performed immediately after the procedure revealed no definitive cerebral aneurysm on 3-dimensional reconstruction images, but a suspicious aneurysmal lesion was seen in the distal PICA in the thin axial CTA image (Fig. C). Subsequent digital subtraction angiography (DSA) revealed a bilobulated distal PICA aneurysm, and an endovascular treatment was planned (Fig. A). Coil embolization was performed under general anesthesia. After a right femoral artery puncture, the left vertebral artery (VA) was not visible on left subclavian angiography; therefore, a 6-Fr soft, torqueable catheter optimized for intracranial access (SOFIA; MicroVention Terumo, Tustin, CA) was advanced into the V4 segment of the right VA under roadmap guidance. Subsequently, we attempted to reach the Headway 17 microcatheter (MicroVention Terumo, Tustin, CA) into the aneurysmal sac, but it failed due to the acute angle of the vertebra–PICA junction. Therefore, after deploying the coil in the VA just before the PICA origin, we planned to position the microcatheter in the PICA with the support of the coil mass (Fig. B). However, some of the coil masses deployed to the VA migrated upward of the PICA origin unintentionally during the navigation process using a microwire and microcatheter (Fig. C). Therefore, we additionally deployed a coil to the VA and finished the procedure after confirming PICA occlusion (Fig. D). Fortunately, with supportive care in an intensive care unit after the procedure, the patient recovered fully, and follow-up magnetic resonance imaging showed no definitive acute cerebral infarction in the PICA territory. One year after embolization, a follow-up angiography was performed, which revealed recanalization of the right PICA with normal arterial configuration, and no aneurysmal sacs were observed in the distal PICA. The recanalized VA was located medial to the deployed coil mass (Fig. E).

pmc-8677960-1

An 8-year-old Chinese boy with no specific family or psychosocial history was admitted to our hospital with an emergency occurrence of purpura, severe hematemesis, large bloody stools, and sharp abdominal pain. His symptoms had begun 2 weeks prior to admission, with abdominal pain and an erythematous pinpoint rash on his arms. The rash developed from his upper limbs (opisthenar and arms) to his lower limbs. Laboratory examination in the outpatient clinic revealed no abnormalities in indicators such as white blood cell count, platelet count, and hemoglobin. After oral medication (specific unknown), his abdominal symptoms began to reduce, as did the purpura. Ten days prior, the rash progressed mostly on the legs, and he experienced deeper abdominal pain in the form of persistent pain with abdominal gassiness and emesis. He was admitted to another hospital with a diagnosis of HSP. Seven days prior, he had melena. After fasting and fluid replacement, there was no obvious improvement in the symptoms. Half a day prior, his face and lips appeared pale, and he had increased abdominal pain, accompanied by numerous bloody stools and hematemesis. He was immediately treated with methylprednisolone, posterior pituitary injection, somatostatin, and hemocoagulase, together with the infusion of large blood products (Table ). At this stage, the patient still produced large amounts of blood in the vomit and stool. His vital signs were extremely unstable, and he was transferred to the pediatric intensive care unit of our hospital. The patient had purpura with lower limb predominance and abdominal pain (consistent with one of the following 4 criteria: abdominal pain, histopathology, arthritis or arthralgia, and renal involvement), and was diagnosed with HSP.[ On admission, he had severe anemia, with a blood pressure of 76/44 mm Hg, pulse of 135 beats/min, and respiratory rate of 25 breaths/min. There was also a palpable purpura rash on both legs, tenderness in the abdomen, and absence of bowel sounds. Routine blood examination revealed a hemoglobin level of 70 g/L, white blood cell count of 11.48 × 109/L, and platelet count of 13 × 109/L. The liver function test showed albumin 10 g/L. The serum electrolytes showed sodium 140 mmol/L, potassium 2.92 mmol/L, chloride 112.1 mmol/L, and bicarbonate 15.9 mmol/L (Table ) with coagulopathy. Therefore, HSP complicated with an alimentary tract hemorrhage was diagnosed. He was immediately treated with intravenous methylprednisolone (2 mg/kg per day), infusion of blood products, and somatostatin but after 2 days after treatment (day 3), he still had massive gastrointestinal hemorrhage, poor circulation, a reduced level of consciousness, and unstable vital signs. Abdominal ultrasonography and plain abdominal radiography revealed no enterobrosis. The patient was also evaluated by pediatric surgeons, and the continuation of medical treatment was suggested. However, his condition deteriorated, and he needed to rely on a life-supporting blood transfusion. He developed signs of peritonitis with abdominal distension. Gastrointestinal tract perforation was suspected. A contrast-enhanced computed tomography (CT) scan of the whole abdomen revealed curved liquid samples and gas shadows on the left and front of the stomach, supporting the possibility of gastrointestinal tract perforation (Fig. ). On day 4, an emergency laparotomy was performed. The surgery revealed that the anterior wall of the descending duodenum was thinner with a 1 cm × 1 cm diameter perforation, and the posterior wall had a 3 cm × 1 cm ulcer, which had penetrated into the peritoneum of the pancreas and experienced active bleeding from the broken end of the vessel. The intraoperative hemorrhage volume was approximately 3000 mL, including intragastric bleeding and intestinal blood clots. Pathological examination indicated chronic inflammation of the intestinal wall mucosa in the descending part of the stomach and duodenum, with hemorrhage, ulceration, interstitial congestion, and edema. Immunofluorescence microscopy of paraffin sections showed granular and lumpy IgA focal deposition in the blood vessel walls (Fig. ). Postoperatively, he was administered nasal continuous positive airway pressure-assisted ventilation, anti-infection treatment, albumin transfusion, platelet transfusion, abdominal drainage, methylprednisolone, fluconazole antifungal treatment, and wound dressing. The general symptoms gradually improved, vital signs were stable, and abdominal pain was relieved. The drainage tube was assessed after discharge, the abdominal CT was repeated after 1 month and the duodenostomy tube was removed 50 days after surgery. There was no evidence of rebleeding during the 2-month follow-up assessment.

pmc-8677961-1

A 42-year-old man was admitted to emergency service after a ski injury. He was unable to weight-bear. Effusion of the knee, severe posterior knee pain, and tenderness of the posterior structures of the knee were determined in the initial physical examination. The pain was getting worse when the knee was extended. The range of motion (ROM) was very limited, and the motion itself was causing the patient a lot of pain. The patient did not allow the tests Lachmann, McMurray, or posterior drawer to be performed due to pain and spasm. There were no findings of neurovascular damage. Two avulsed fragments were revealed in the plain radiographs (Fig. A&B). MRI showed the fragments belonged to PCL and lateral meniscus, and concomitant avulsion fractures of the medial meniscus and PCL were diagnosed (Fig. ). ACL, lateral meniscus and medial/lateral collateral ligaments were intact. Based on these radiological and clinical findings, and due to the instability and locking risk that simultaneous PCL and medial meniscus avulsion fracture would create in the knee, the patient was recommended to operate. The operation was performed the day after the injury. Under general anesthesia, physical examination was performed again, and the posterior drawer test was positive with a soft endpoint. Lachmann test was negative, and valgus stress test when the knee flexed 30° was positive as grade I laxity (opening of the medial joint <5 mm). Varus/valgus stress radiographs were performed under fluoroscopy, and medial space opening was checked and confirmed. Then the patient was placed in the prone position, and a tourniquet was applied and inflated. An L-shaped incision was made over the fossa poplitea. Dissection was performed, and the interval between the semimembranosus and medial head of the gastrocnemius was used, as described by Burks and Schaffer.[ At that point, a varicose vein that enlarged and curved, that we thought it was caused by trauma, was detected over the capsule; a cardiovascular surgeon was attended to the surgery and ligated the veins (Fig. A). And then gastrocnemius muscle was retracted laterally, and the posterior capsule was exposed. The avulsed bone fragments were palpated over the capsule, and a vertical capsular incision between these fragments was made (Fig. B). After removing the bone clots and soft tissues around the avulsed fragments, bone beds were prepared. Firstly, the medial meniscus's avulsion fracture was reducted and fixed with two Kirschner wires temporarily, and then PCL avulsion fracture was reducted in the same way under fluoroscopy control. Later, permanent fixation of the avulsion fracture of the medial meniscus was done with two headless 3.0 mm compression screws after drilling and measurement (Fig. C). Then, the PCL avulsion fracture was fixed with a 4.0 mm partially threaded, cannulated, cancellous screw with a washer (Fig. D). The fixation of the fragments was confirmed under fluoroscopy again, and the posterior drawer test was performed gently to check stability. After the irrigation of the wound, the capsule, subcutaneous layers, and skin was closed. A hinged, long leg brace was applied and locked in 0° knee extension. The knee was kept in full extension with the hinged brace for two weeks and instructed for leg raises only in the brace several times daily. On the third week, isometric and passive ROM exercises with continuous passive motion device were applied and gradually increased as tolerated. Weight-bearing was not allowed for six weeks. At postoperative controls, knee X-rays were taken, and fracture healing was followed (Fig. C&D). No complications were encountered in the follow-up of the patient. Full weight-bearing and ROM without pain were achieved in the third month after the operation. The visual analog scale score was 8 before surgery and 2 in the third month after the surgery. Lysholm score was 14 before surgery and 85 in the sixth month after the surgery.

pmc-8677974-1

A 71-year-old woman visited our hospital in January 2018 with vision loss affecting her left eye. The best-corrected visual acuity (BCVA) in the left eye was 13/20. Ultra-wide-field pseudo-color (UWPC) and optical coherence tomography (OCT) images showed inferior temporal BRVO and secondary macular edema (ME) in her left eye. (Fig. A, B) Her left eye received 3 doses of intravitreal aflibercept (IVA), which resolved her ME. (Fig. C, D) Her BCVA was 20/20. No recurrence was found at the time of follow-up. This patient had not previously been infected with SARS-CoV-2. She received a second dose of the SARS-CoV-2 mRNA vaccine BNT162b2 (Pfizer-BioNTech) in July 2021. The following day, the patient noticed vision loss in her left eye. Her BCVA decreased to 20/30, and her UWPC and OCT images showed superior temporal BRVO and secondary ME in her left eye. (Fig. E, F) No avascular area was found on OCT angiography. The left eye received an additional one-time dose of IVA. The ME resolved (Fig. G, H), and the BCVA improved to 20/20.

pmc-8677974-2

A 74 year-old man visited our clinic in February 2020 with a complaint of vision loss affecting the right eye. His BCVA in the right eye was 20/20. His posterior pole fundus photographs and OCT images showed temporal superior BRVO without ME. (Fig. A, B) He was followed without treatment. He did not have a prior SARS-CoV-2 infection. He received his first dose of the SARS-CoV-2 mRNA vaccine BNT162b2 (Pfizer-BioNTech) in July 2021. On the following day, the patient noticed vision loss in his right eye. The patient was referred to our hospital. His UWPC and OCT images showed recurrence of temporal superior BRVO and secondary ME. (Fig. C, D) His BCVA was 20/25. No avascular area was found on the Optical coherence tomography angiography images. His right eye received 2 doses of intravitreal ranibizumab, which resolved the ME. His BCVA was 20/25. (Fig. E, F) The patient received his second vaccination dose 3 weeks after his first. He did not have any symptoms, nor did he have any changes in the examination of his right eye after receiving this second dose.

pmc-8677981-1

A 65-year-old woman presented with metamorphopsia and blurred vision in her left eye and was referred to Akita City Hospital for further examination. She had hypertension and dyslipidemia, which were treated with oral medication. At the initial visit, her best-corrected visual acuity (BCVA) was 20/20 in both eyes. Spherical equivalent refraction was –10.5 diopters and –14.0 diopters in the right and left eyes, respectively. The intraocular pressure was 18 and 16 mm Hg in the right and left eyes, respectively. Slit-lamp examination showed a slight nuclear cataract of grade 1 in both eyes, based on Emery-Little classification. Fundus examination revealed tigroid fundus in both eyes, and a white, well-defined, and patchy lesion at the superonasal to the fovea in the left eye (Fig. A). Autofluorescence showed hypofluorescence area in the macula. This is consistent with the aforementioned lesion in the left eye (Fig. B). Upon applying OCT to the vertical section through the fovea, the sclera curved posteriorly at the location superonasal to the fovea, and the choroid was thickened in the area (Fig. C). Additionally, the ellipsoid zone (EZ) was disrupted in the area between the fovea and the curved sclera. Horizontal volume scans of the OCT through the patchy lesion also showed posterior curvature of the sclera, thinning of the outer retina, and disappearance of the RPE–Bruch's membrane complex, resulting in a pseudo-fovea appearance (Fig. D). Another horizontal volume scan of the OCT demonstrated a connection of blood vessels running from the sclera to the choroid (Fig. E). There was no obvious connection between the vitreous cavity and the superior choroidal cavity with OCT; taken together, we diagnosed this case as PCA with macular ICC. During a 4-year follow up, the white patchy lesion in the fundus and the hypofluorescence region determined by autofluorescence gradually expanded, especially toward the optic disc (Fig. A and B). The BCVA in the left eye decreased with the expansion of the lesion and was 20/100 at the final visit. OCT through the fovea showed that the disrupted EZ expanded toward the ICC and the sensory retina of the fovea became thinner with time (Fig. C). Moreover, RPE–Bruch's membrane complex was not observed 3 years after the initial visit. During the follow-up period, the sensory retina was prominently displaced posteriorly to the ICC, though no obvious change was observed in the structure of the sclera.

pmc-8677983-1

A 51-year-old male patient was admitted to our center because of cough, fatigue, and shortness of breath for 2 weeks. He had previously been treated with antibiotics (cephalosporin and azithromycin) over 10 days. However, the symptoms continued. A detailed medical history revealed that he had an episode of pulmonary cryptococcosis 5 years ago (Fig. A). He recovered without any treatment and became asymptomatic. He has chronic HBV infection and is undergoing long-term treatment with entecavir. In addition, exposure to bird droppings was reported. Computed tomography (CT) performed at admission revealed multiple areas of consolidations and ground-glass shadows of bilateral lung fields (Fig. B). Chest auscultation demonstrated crude lung respiratory sounds and no evidence of dry and moist rales. His temperature was 36.6°C, respiratory rate was 22 breaths/min, pulse rate was 70 beats/min, and blood pressure was 118/70 mm Hg. Laboratory examinations were notable for C-reactive protein (CRP) of 27.1 mg/L and erythrocyte sedimentation rate (ESR) of 44 mm/h. Other findings such as complete blood cell count, flow cytometry analysis, procalcitonin, Mycoplasma pneumoniae (serological assay), HIV, and sputum culture were normal. Blood gas results were as follows: pH 7.426, pO2 67.4 mm Hg, pCO2 39.7 mm Hg, and SpO2 93.4%. Pulmonary infection was first considered, and piperacillin sodium/tazobactam sodium was given empirically for 1 week. Contrast-enhanced CT was then performed and the results showed multiple consolidations and ground-glass shadows with rough margins and a maximum CT density of 77 HU, with scattering under the pleural surface (Fig. C and D). No obvious changes were observed compared with the previous CT scan. For rapid identification of the etiology, bronchoscopic examinations (such as BALF culture and mNGS) were performed. However, no additional information was available. Further examinations were performed; the lab findings included T-SPOT.TB (−), PPD (−), tumor markers (−), p- and c-ANCA (−), (1 → 3)-β-D-glucans (−), and GM assay (−). Notably, cryptococcal antigen testing was positive (55.85 ng/mL; reference value, <8.0 ng/mL). Therefore, a clinical diagnosis of pulmonary cryptococcosis was made. The patient was orally treated with fluconazole (200 mg/day) and bicyclol (50 mg/day). After 3 weeks of antifungal therapy, his symptoms disappeared and the abnormality on CT scanning had improved (Fig. E). During the follow-up of 3 and 6 months, his conditions improved again, and he recovered fully (Fig. F and G). Cryptococcal antigen level was 12.57 ng/mL. During the 2-year follow-up, no recurrence occurred.

pmc-8677986-1

A 45-year-old man (occupation: medical doctor) visited a university hospital with a chief complaint of fainting 1 day back. He had no history of medical problems and was not taking any medications. He had hiked 4 to 5 times a week for 2 years. Syncope occurred while hiking on a cold winter night (temperature: −8°C). He fainted while resting for a while in a standing position after hiking at a fast speed for an hour. The witness reported that he lost consciousness for about 1 minutes, and no head strike or seizure-like activity was observed. Upon awakening from syncope, the patient had no syncope recollection. After syncope, the patient did not have any illnesses or symptoms, such as headache, cognitive deficits, or somnolence. He had no prior episodes of syncope or fainting. At the time of examination (the day after the syncope), his blood pressure was 122/77 mm Hg, and his resting heart rate was 75 beats per minute. Electrocardiogram, 24 hours ambulatory electrocardiogram monitoring, echocardiogram, tilt table test, and exercise tolerance test showed no abnormal findings. In addition, in conventional brain and chest computed tomography and brain MRI, no abnormalities were observed. All blood test results, such as electrolyte level, hemoglobin level, erythrocyte sedimentation rate, and C-reactive protein level, were normal. In the physical examination, he did not show any neurological symptoms, including motor, sensory, or cognitive deficits (Mini-Mental State Exam: full marks, no patient's subjective symptoms). The deep tendon reflex was normoactive in all the extremities. Based on the patient's history and examination results, the cardiologist diagnosed the patient with transient loss of consciousness due to syncope. In addition, considering that syncope occurred during excessive physical activity at cold temperatures, the possibility of vasovagal syncope was thought to be high. DCE scans were acquired using a 3T system (Skyra, Siemens Healthcare, Erlangen, Germany). In addition to the patient, a DCE scan was obtained from a healthy control participant (42-year-old man) who volunteered for the study. Seven pre-contrast sets of DCE-MRI (echo time= 1.92 ms, repetition time= 5.46 ms, the field of view = 230 × 135 mm2, matrix size of 256 × 150, and slice thickness of 3 mm), followed by an additional 114 sets under the intravenous injection of contrast agent were imaged in axial view. The permeability (Ktrans) of the mid-slice was calculated using the Patlak model.[ Here, t indicates the time step, τ indicates the variable of integration, Vp indicates the volume of plasma, and Ct (t) and Cp (t) indicate the temporal variation of the concentration of the contrast agent in the tissue and plasma, respectively. A circular region of interest (ROI) with an inner diameter of 1 to 2 cm was located at the superior sagittal sinus, which has higher consistency and plausibility compared to the internal carotid artery or the arterial vessel closest to the lesion.[ In the axial image where the body and crus of the fornix were presented, 10 round random ROIs of 2 cm diameter (dotted circles in Fig. ) were selected (5 in each hemisphere) to quantify the overall averaged Ktrans of the brain. ROIs were depicted, including sulci in which the bright blue colored lines (BBB disruption) are presented. For the quantitative analysis, in each ROI of the healthy control participants and the patients, the T2 and Ktrans values were measured. The differences in the measured values between the healthy controls and patients were compared using an independent t-test. Statistical significance was set at P < .05. In the conventional MRIs of the healthy control and the patient, no lesions were observed (Fig. A, 1B). In addition, in the Ktrans map of DCE MRI of healthy control participants, no specific abnormal findings were observed (Fig. C). However, in the patient, bright blue-colored lines were observed within the sulci throughout the cerebral cortex (Fig. D). These findings indicate disruption of the BBB of vessels in the overall cerebral sulci. In the quantitative analysis, the averaged T2 intensity (within 10 randomly selected ROIs) of healthy control and patient was 403.95 ± 24.91 (AU) and 404.50 ± 24.21 (AU), which was not statistically different (P = .9625). Here, the average Ktrans of healthy controls within 10 randomly selected ROIs was 0.000156 ± 0.000099 (minutes−1) and 0.001067 ± 0.000806 (minutes−1) for the patient. The average Ktrans of the patient was 6.86 times higher than that of the healthy controls, and the difference was statistically significant (P = .003409).

pmc-8677990-1

The patient, a 53-year-old female, was admitted to the hospital on April 05, 2019 in a car accident resulting in a fracture of the distal left tibiofibula, and was given routine heel traction and symptomatic treatment to reduce swelling after admission. On April 18, 2019, we performed “tibiofibular fracture incision and internal fixation + bone grafting,” after which we were given symptomatic treatment for swelling and pain relief. He was discharged from the hospital on May 16, 2019, and at the time of discharge there was still about 3 cm of poorly healed skin and localized redness and swelling in the lower and middle sections of the left ankle incision, and then continued to have the left ankle dressing changed at the local community hospital, and the wound never healed. One year after the operation, he was readmitted to the hospital for rehabilitation. A follow-up X-ray showed that the metal internal fixation of the left inferior tibiofibular fracture was in place, no loosening was seen, the alignment of the severed end was acceptable, and the left inferior tibial segment was mildly osseointegrated (Fig. ). On examination: the left ankle incision was interrupted for about 3 cm with poor healing, a small amount of muscle necrosis, fat liquefaction, a large amount of yellow purulent secretion overflow and necrotic material was seen in the local wound. The wound did not improve after routine dressing changes. PRF gel preparation and application the preparation process was strictly aseptic: - A disposable screw-in 20 mL syringe with an 18G needle was used to draw 20 mL of autologous blood under strict aseptic conditions, and the screw-in syringe was tightened with a disposable plug, and the posterior projection and tail were cut off. Weigh, level, and centrifuge at 3000 r/min for 10 minutes. After resting, the blood sample was divided into 3 layers, the upper layer of yellowish clarified liquid was platelet plasma, the lower layer of red loose jelly-like material was red cell debris, and the middle layer of yellowish gel was PRF gel, and the PRF gel was obtained by removing the PRF gel using a three-way connecting tube, and then it was rested in a dry sterilized container for 10 minutes to obtain the PRF gel (Fig. ). Admission to the hospital to improve blood routine, blood sedimentation, C-reactive protein and other tests to exclude contraindications. Necrotic tissue was scraped out of the wound with a sterile blade (see extensive muscle necrosis, fat liquefaction, and large amounts of purulent secretions overflowing as in Fig. A) until the wound oozed blood. Then, after rinsing with saline, PRF was injected into the wound and the submerged area, so that the autologous platelet-rich fibrin mixed with the preparation could fully contact with the wound and close the wound, and then covered with oil gauze to keep the wound moist and promote the growth of granulation. The wound was covered locally with PRF on April 17, 2020, bandaged and covered with PRF again after 1-week interval.