Uncontrolled Acromegaly Resulting in the Need for LVAD as Bridge to Heart Transplant

Introduction: Acromegaly is an uncommon pituitary disorder with an incidence of six per million persons. While hypertension is often encountered in these patients, heart failure rarely is seen with an incidence rate under 10%. We describe a case of an individual who was diagnosed with acromegaly after an acute exacerbation of heart failure with subsequent management requiring an LVAD to perform Transsphenoidal Surgery (TSS). Case Description: 37-year-old male otherwise healthy initially presented to an emergency room and was found to be in acute heart failure exacerbation. Concerning acromegaly features included macrognathia, enlarged hands and feet, swollen phalanges, widened spacing of teeth, and frontal bossing. IGF-1 level was found 455 ng/mL. MRI showed a 10mm macroadenoma. A right heart catheterization showed elevated filling pressures. Cardiac MRI showed no defects or enhancement. Endomyocardial biopsy showed no inflammatory infiltrates or evidence of infiltrative diseases. Patient had an ejection fraction of 15% corroborated by cardiac MRI along with the presence of aortic root dilatation and mitral regurgitation. The patient started on 0.5mg of Cabergoline twice weekly and 120mg weekly Lanreotide injections. Patient stabilized with plans for further close monitoring and outpatient neurosurgical evaluation. The COVID-19 pandemic and insurance gaps led the patient to spend two years off his medicines and he was unable to be seen by his medical team. Patient was seen by our system after recurrent hospitalizations for heart failure at our sister hospital, AICD was unable to be placed due to the patient's anatomy, he was placed on wearable cardiac defibrillator and required milrinone infusion for progression to end-stage heart failure with cardiac cachexia. At our institution, the patient was evaluated for Orthotopic Heart Transplant (OHT) but due to active GH secreting macroadenoma there was concern for OHT failure without TSS. Decision was made to utilize LVAD as Bridge-to-Transplant for OHT so the patient could be stabilized and safely undergo TSS. The patient tolerated surgeries well and is currently on the active transplant list. Discussion(s): Heart failure is an uncommon presentation of severe acromegaly requiring multidisciplinary management. We describe a case of a patient who initially presented with heart failure too unstable for surgery. Due to the COVID-19 pandemic the patient's disease progressed resulting in end-stage heart failure requiring LVAD placement for further treatment. We would like to draw attention to the use of LVAD placement in acromegalic patients who develop severe cardiovascular disease who are not candidates for OHT.Copyright © 2023

Relationship between sarcopenia and cachexia with prognostic markers of middle-aged and older inpatients with COVID-19: a case-control study.

PURPOSE: SARS-CoV-2 infection can lead to various manifestations beyond an inflammatory response, such as anorexia, hyposmia, and other symptoms that may increase the risk of nutritional disorders. Sarcopenia and cachexia are conditions that appear to influence COVID-19 evolution. Thus, this study aimed to evaluate sarcopenia and cachexia in hospitalized patients with COVID-19, verifying their clinical impacts and relationship with prognostic markers. METHODS: This is a case-control study involving inpatients with and without a COVID-19 diagnosis. The occurrence of sarcopenia was evaluated according to European Working Group on Sarcopenia 2 criteria. Cachexia was evaluated according to (Evans et al. in Clin Nutr 27:793-799, 2008) criteria. Inflammatory markers and the 4C Mortality Score were evaluated. RESULTS: Our study included 96 individuals, divided into two groups: COVID-19 (n = 32) and control (n = 64). The mean age of the COVID-19 group was 63.3 ± 11.8 years, and the control group had a mean age of 64.3 ± 5.5 years. No significant differences in mean age were found between the groups. The prevalence of sarcopenia and cachexia in patients with COVID-19 was 21.9% and 28.1%, respectively, while in the control group, it was 29.7% and 26.6%, respectively. Sarcopenic patients with COVID-19 had a higher risk of death (4C Mortality Score) (p = 0.038). The occurrence of sarcopenia or cachexia within the COVID-19 group was not associated with inflammatory biomarkers or a higher number of COVID-19 symptoms (p > 0.05). CONCLUSION: The presence of sarcopenia among COVID-19 patients increased the risk of mortality.

The atypical ß-blocker S-oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model.

BACKGROUND: Beta-blockers and selected stereoisomers of beta-blockers, like bisoprolol and S-pindolol (ACM-001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia-the Yoshida AH-130 rat model and the Lewis lung carcinoma (LLC) mouse model. METHODS AND RESULTS: In the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S-oxprenolol (HR: 0.49, 95% CI: 0.28-0.85, P = 0.012) was superior to 50 mg/kg/d R-oxprenolol (HR: 0.83, 95% CI 0.38-1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S-oxprenolol groups vs the same combination of the R-oxprenolol groups lead to a significantly improved survival of S-oxprenolol vs R-oxprenolol (HR: 1.61, 95% CI: 1.08-2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S-oxprenolol-treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R-oxprenolol. A dose-dependent attenuation of weight and lean mass loss by S-oxprenolol was seen in the Yoshida rat model, whereas R-oxprenolol had only had a significant effect on fat mass. S-oxprenolol also non-significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 ± 25 and 539 ± 37 g/100 g body weight for placebo and S-oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S-oxprenolol: 11.9 ± 2.5 g vs placebo: 4.9 ± 0.8 g, P = 0.013 and also vs 25 mg/kg/d R-oxprenolol: 7.5 ± 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF-1 receptor, Akt) and catabolic signalling is inhibited (FXBO-10, TRAF-6) by S-pindolol, but not he R-enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK. CONCLUSIONS: S-oxprenolol is superior to R-oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.

Analysis of methods to improve engagement of under-represented and socioeconomically deprived patients in clinical research

The current under-representation of racial and ethnic minorities and socio-economically disadvantaged participants in clinical trials represents an important problem, because it reduces generalizability of trial results and should urgently be addressed in all diseases. Decentralized trials may improve engagement of under-represented populations with long-standing health disparities and may be relevant to patients with pancreatic cancer who would benefit from at home trial participation. We completed a fully decentralized randomized double-blind phase II clinical trial in New York State for participants with mild-to-moderate COVID-19. Electronic data were collected for 28 days (5 vital readings and 1 survey with 20 questions per day) from 55 non-hospitalized participants. Home monitoring devices, HIPAA compliant data submission technology, and internet access were provided free-of-charge. We enrolled 40% White, 33% Black or African American and 27% Other/Mixed/Unknown participants. Of these, 25% self-identified as Hispanic or Latino. This exceeded national and New York state averages of minority populations, in contrast with the current clinical trial landscape. We found that the local area within a 30-minute return car journey from our main research hospital disproportionately over-represented socio-economically advantaged white inhabitants. We found that decentralization enabled the inclusion of participants living up to a 2-hour journey from this hospital in socio-economically deprived geographies with higher minority race representation. We excluded selection bias, by demonstrating that our trial population represented the differences of social deprivation observed between races at the national and state level (p = 0.003). In addition to trial enrollment, completeness of trial data has an important impact on the veracity of trial results. Half our participants were assigned a dedicated team member to make telephone call reminders if participants had not submitted data by mid-day despite of a pre-ceding automated notification to the supplied electronic device. Daily telephone follow-up significantly reduced missing electronic data in participants living above the median deprivation index (submitted data per day 4 out of 6 vs 6 out of 6: p = 0.03), thereby aiding equitable data collection from traditionally under-represented participant groups. Our findings require further validation and refinement from multiple centers and expansion to patients with reduced mobility and cachexia due to progressing pancreatic cancer. Also, other factors such as language assistance and recruitment methods, need to be addressed in clinical trials to mitigate against their negative impact on equitable recruitment. Nevertheless, for now we identify decentralization combined with engagement telephone calls as readily actionable methods to improve inclusion of under-represented participants in clinical trials.

Partial Nephrogenic Diabetes Insipidus Secondary to Lithium Use

Introduction: Nephrogenic diabetes insipidus (NDI) is caused by reduced renal response to vasopressin. NDI affects up to 40% of patients on lithium. We present a case of partial NDI secondary to lithium use. Case Description: A 66 year old male with bipolar disorder on lithium presented with shortness of breath, chest tightness and cough. On exam he was cachectic, lethargic, tremulous with decreased skin turgor and dry mucous membranes found to have COVID-19 with initial unremarkable blood work. Received treatment for COVID and subsequently developed worsening encephalopathy, follow up blood work revealed elevated serum sodium of 168 mg/dl, with urine osmolality of 382 and lithium level was elevated at 1.6 mEq/L. He received adequate IV fluid hydration with hypotonic fluids and free water. Serum sodium remained elevated with polyuria. Follow up labs showed urine osmolality decrease to 94 mosml/L therefore nephrogenic diabetes insipidus was suspected. A desmopressin stimulation test was performed and hourly urine osmolality was obtained [Table 1] confirming the diagnosis of nephrogenic diabetes insipidus with a partial response to desmopressin compatible with lithium-induced partial diabetes insipidus. Treatment was started initially with chlorthalidone with inappropriate response, then dose increased to 100mg daily with further addition of amiloride 10mg twice daily with subsequent response and decrease of sodium level from 167 to 147 mEq/L. Discussion(s): Lithium-induced NDI is explained by downregulation of aquaporin 2 channel expression in the principal cells due to accumulation of toxic concentrations of lithium and reduction of the kidneys' ability to preserve water in response to vasopressin. NDI usually presents with polyuria, polydipsia, severe dehydration, and electrolyte imbalance. A less than 50% increase in urine osmolality following desmopressin administration proves NDI. Treatment options include high doses of desmopressin, low sodium diet, thiazide diuretics, amiloride, and NSAIDs. (Table Presented).

A UNIQUE CASE OF SEVERE PULMONARY NOCARDIOSIS PRESENTING WITH ARDS AND CARDIOGENIC SHOCK

SESSION TITLE: Shock and Sepsis in the ICU Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Nocardiosis is a rare bacterial infection, which frequently affects immunocompromised patients. It can present as an acute, subacute, or chronic pulmonary infection with non-specific symptoms, such as fever, cough, dyspnea, weight loss, and hemoptysis. CASE PRESENTATION: A 34-year-old female with a history of chronic granulomatous disease and hidradenitis suppurativa on adalimumab presented to the ED with fever, shortness of breath, and productive cough of 2 days. Her vitals were T 101F, BP 66/48, HR 148, RR 42, and SPO2 94% on room air. On exam, she was cachectic, with bilateral crackles and rales in the right lung base. Extremities were cold, with trace pitting edema was present on bilateral lower extremities. COVID-19 PCR was negative. Despite fluid resuscitation, she remained hypotensive and was started on norepinephrine. Blood cultures were collected, and broad-spectrum antibiotics and an antifungal agent were initiated. Chest CT demonstrated bilateral multifocal consolidation with surrounding ground-glass opacities and complete consolidation of the right lower lobe. Due to worsening respiratory distress and tachypnea, and lack of improvement with non-invasive ventilation, she was intubated, placed on mechanical ventilation, and admitted to the Medical ICU. On hospital day 1, due to the patient's immunosuppression, unresolving shock, and radiographic findings, a bronchoscopy with bronchoalveolar lavage (BAL) was performed. On hospital day 2, a transthoracic echocardiogram showed LV ejection fraction of 20-25% with severe global hypokinesis of the LV. ACS workup had been unremarkable, with mildly elevated troponin and no ischemic changes on EKG. She was initiated on cardiac inotropes. On hospital day 3, BAL culture revealed Nocardia cyriacigeorgica. TMP-SMX and ceftriaxone were started for severe pulmonary nocardiosis. On hospital day 11, she was liberated from mechanical ventilation, and by hospital day 14, she was weaned off all pressors and inotropes. Approximately 4 weeks after admission, repeat TTE showed recovery of LV ejection fraction (55-60%) and she was discharged with a prolonged course of TMP-SMX and IV ceftriaxone, with duration to be determined at outpatient infectious disease follow-up. DISCUSSION: We discuss a unique case of severe pulmonary nocardiosis, presenting with ARDS and cardiogenic shock. To the best of our knowledge, this is the first case of a patient with pulmonary nocardiosis presenting with stress cardiomyopathy reported in the literature. While the pathophysiology is not well understood, theorized mechanisms include catecholamine excess, coronary artery spasm, microvascular dysfunction. CONCLUSIONS: This case highlights the need for a broad differential diagnosis in patients presenting with ARDS and cardiogenic shock and illustrates the value of clinical bronchoscopy in patients with unique presenting features. Reference #1: Lerner PI. Nocardiosis. Clin Infect Dis. 1996 Jun;22(6):891-903;quiz 904-5. doi: 10.1093/clinids/22.6.891. PMID: 8783685. Reference #2: Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, Wu KC, Rade JJ, Bivalacqua TJ, Champion HC. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005 Feb 10;352(6):539-48. doi: 10.1056/NEJMoa043046. PMID: 15703419. Reference #3: Park JH, Kang SJ, Song JK, Kim HK, Lim CM, Kang DH, Koh Y. Left ventricular apical ballooning due to severe physical stress in patients admitted to the medical ICU. Chest. 2005 Jul;128(1):296-302. doi: 10.1378/chest.128.1.296. PMID: 16002949. DISCLOSURES: no disclosure on file for D. Clark Files;No relevant relationships by Nisha Patel No relevant relationships by Meehir Shah

An evaluation of nutritional status and specific nutritional issues during a rehabilitation period post COVID-19 infection

Patients recovering from COVID-19 infection are at a high risk of malnutrition, reduced nutritional intake and decline in muscle mass and strength.1 The aim of this service evaluation is to describe baseline characteristics, quantify risk of malnutrition, provide an overview of nutritional status and nutritional related outcomes for patients recovering post COVID-19 infection on rehabilitation wards. Data collection occurred between the 1st of February and the 1st of July 2021. This cohort included all patients who were recovering from COVID-19, who were referred to dietetic service and transferred to a rehabilitation ward. Demographic data and nutritional parameters were gathered from electronic records, and dietetic assessments. A total of 54 patients were included: 59% male, 41% female. Ages ranged from 46 to 95 years with average age of 79.9 years and average length of hospital stay of 92 days. One fifth of those included had an ICU stay. Where data was available on sarcopenia risk, 50% were identified as at risk of sarcopenia. Of those where serum 25-hydroxyvitamin D was checked, 45% had insufficient vitamin D levels. A nutrition focused physical exam was completed for 18 patients (one third of the cohort). Using this exam, 61% were diagnosed with moderate or severe malnutrition. At least 15% of patients experienced significant weight loss between their admission to the hospital compared to their weight on admission to post COVID-19 rehabilitation ward. Of those where Malnutrition Screening Tool was completed on admission to COVID-19 rehabilitation ward, 33% were identified as at risk of malnutrition. On discharge from the dietetic caseload, the proportion of those identified at risk of malnutrition using this tool decreased to 18%. During the period from admission to COVID-19 rehabilitation ward and discharge from dietetic service, 42% gained weight, 54% maintained their weight, 4% lost weight. Of those with data available regarding nutritional intake on admission to COVID-19 rehabilitation ward, 28% met energy requirements and 44% met protein requirements. On discharge from dietetic service these proportions increased to 66% meeting energy requirements and 74% meeting protein requirements. The average kcal intake on admission to COVID-19 rehabilitation increased from 1531kcal to 1778kcal on discharge and the average protein intake increased from 67g on admission to post COVID-19 rehabilitation to 75g on discharge. These results demonstrate the high prevalence of malnutrition and high risk of sarcopenia in patients admitted for rehabilitation post COVID-19 infection. With dietetic input, improvements were observed in patient’s nutritional intake, and nutritional outcomes such as weight and malnutrition risk. These results illustrate the need for early dietetic input in those recovering post COVID-19 infection to optimise nutritional status and nutritional outcomes. References: 1. Anker M. S., Landmesser U., von Haehling S et al. Weight loss, malnutrition, and cachexia in COVID-19: facts and numbers. Journal of Cachexia, Sarcopenia and Muscle, 12, 9– 13.

Atypical Presentation of Cocaine-Induced Thrombotic Microangiopathy

Cocaine is one of the most used illicit drugs. Cocaine induced toxicity can result in hepatotoxicity, pulmonary toxicity, and renal dysfunction. Acute kidney injury (AKI) is an emergent complication in cocaine abusers. Rhabdomyolysis and vasoconstrictions mechanism are well known cause of AKI, cocaine induce thrombotic microangiopathy (TMA) is rarely reported. Cocaine is widely used in the United States, we report a case of Cocaine induced TMA in a cocaine abuser. We chronicle a case of a 42-Year-old male cocaine abuser, who presented to ED with complaints of Dyspnea, cough, anorexia and chest tightness for two days. He attributed to inhaling ammonia from cat urine along with cocaine abuse. No prior history of kidney disease or any other chronic illness. On examination, the patient appeared malnourished and cachectic. He was normotensive, lethargic and oriented. There were crackles at the lung bases. Blood tests revealed serum creatinine 18.0 mg/dL, blood urea nitrogen 150 mg/dL, hemoglobin 8.2 g/dL, platelets 173000/mm3, Retics count 8 %, LDH 1120 (84–246 IU/L) and haptoglobin < 8 (30–200mg/dL). A blood film revealed occasional schistocytes. Urinalysis showed proteinuria and microscopic hematuria. Urine toxicology revealed cocaine. Routine blood and urine cultures showed no growth. Serologic tests showed reduced complement C3 level of 40 (82-185 mg/dL) and normal C4 level of 32 (10–53mg/dL). There were no antibodies against HIV 1/2 and Covid 19. His ADAMTS-13 results showed 0.61 and 0.63 (0.68 to 1.63). Renal Ultrasound was unremarkable. Patient was intubated and ventilated in ICU;he was initiated on hemodialysis. He was provided four sessions of plasma exchanges till his ADAMTS-13 result came back near normal that was indicative of Cocaine induce TMA. Cocaine abuse is a global issue with increasing number of cases in the USA. It can cause AKI due to well-known etiologies like Rhabdomyolysis, Vasculitis, Acute interstitial Nephritis and Renal Infarction. However, Clinicians and nephrologists should also consider rare causes like TMA as a possible differential cause of AKI in the setting of cocaine abuse.

SPONTANEOUS PNEUMOTHORAX IN AN HIV/AIDS PATIENT WITH CONCURRENT COVID-19 AND PNEUMOCYSTIS PNEUMONITIS

CASE: A 25-year-old homeless male with nonadherent HIV presented with dyspnea on exertion for 4 days, productive cough for 1 week, fevers, chills and night sweats. He arrived hypoxic to 74% requiring 2L O2 and was cachectic on exam. WBC, lactate and procalcitonin were normal. C-reactive protein was 26.7 mg/L, LDH was 686 units/L and COVID-19 was positive. An arterial blood gas showed a primary respiratory alkalosis with a secondary metabolic alkalosis. Computed tomography of the chest, abdomen and pelvis with contrast showed multifocal large thin-walled cavitary lesions throughout the bilateral lungs with subpleural large cystic disease. Dexamethasone, remdesivir and empiric antibiotics were initiated. Absolute CD4 count was 7 cells/uL with HIV-1 RNA load of 139,000 copies/mL. Sputum was positive for Pneumocystis jirovecii (PCP) by DFA and PCR, but no evidence of mycobacterium. Trimethoprim-sulfamethoxazole (TMP-SMX) was added. On hospital day 13, he developed severe right-sided chest pain, dyspnea and required up to 15L O2. A chest x-ray revealed a large right-sided pneumothorax (PTX) and a chest tube was placed. Cardiothoracic Surgery was consulted for consideration of bullectomy with pleurodesis;this was not recommended as the cystic lesions were extensive with some intraparenchymal. His oxygen requirements improved and his chest tube was removed in 6 days. He was discharged on hospital day 21 to begin prophylactic dosing of TMP-SMX until his CD4 count was over 200 cells/uL and to attend his first appointment at an outpatient HIV clinic the following day. IMPACT/DISCUSSION: Secondary spontaneous pneumothorax (SSP) can be a complication of necrotizing pneumonia due to PCP. In one study, in a cohort of 599 patients with HIV infection, only 1.2% developed a PTX. Bilateral PTX is more common with PCP, unlike in our patient. In HIV, the degree of immunosuppression can influence the cause of PTX. Our patient had a PTX with a CD4 count under 200, which is more common with PCP. In addition, SSP as a complication of SARS-CoV-2 is more rare. There are case series that describe COVID-19 patients who develop PTX in the absence of barotrauma secondary to mechanical ventilation. However, this is uncommon as one retrospective study reports PTX occurring in 1% of patients with COVID-19 requiring hospital admission. In this case, it is unclear to what extent the patient's concomitant COVID-19 contributed to the development of a PTX. Our patient was ineligible for definitive intervention to prevent recurrence, thus underwent tube thoracostomy placement which is consistent with the majority of treated patients. While the prognosis of PTX secondary to COVID-19 is generally good, prognosis of cominant co-infection with PCP is an area of further research as the overall mortality of PCP-induced PTX alone can be 23%. CONCLUSION: This case represents a rare occurrence of spontaneous pneumothorax secondary to both PCP and COVID-19. We suggest the incidence to increase as the pandemic continues.

A 51-YEAR-OLD MAN WITH WEIGHT LOSS AND CARDIOGENIC SHOCK

CASE: A 51-year-old man without significant past medical history presented to our hospital with dyspnea on exertion. SARS-CoV-2 was detected on routine occupational screening 2 months prior to admission. He subsequently reported a 100lb weight loss, during which time he experienced dysgeusia and ate primarily cereal, sandwiches, and potatoes and consumed nearly no fruits or vegetables. Three weeks prior to admission he developed postprandial nausea and vomiting and anorexia. A week later he developed progressive epigastric pain, lower extremity edema, and dyspnea while walking around the college campus where he worked as a security guard, and sought medical attention. He did not have fever, chills, night sweats, cough, orthopnea, paroxysmal nocturnal dyspnea, rash, or diarrhea. He had not seen a doctor in 20 years and took no medications. He did not drink alcohol, smoke cigarettes, or use illicit substances. Vital signs were T 36.6°F HR 104 BP 149/111 RR 20 and SpO2 97%. Physical examination revealed a cachectic man with bitemporal wasting, sunken orbits, poor dentition, and severe periodontal disease. JVP was 14cm of H2O at 45°. An S3 was present. The abdomen was tender to palpation in the mid epigastrium. The extremities were cool with 3+ pitting edema. Pancreatitis was diagnosed after discovery of markedly elevated lipase levels and peripancreatic fat stranding on abdominal CT. TTE showed biventricular systolic dysfunction with LVEF 15%. He developed cardiogenic shock complicated by oliguric renal failure, congestive hepatopathy and obtundation, requiring ICU transfer for diuresis and inotropic support. Further workup revealed deficiencies of thiamine, zinc, and vitamins A, C, and D. A regadenoson myocardial perfusion PET/CT showed no flow-limiting coronary artery disease, and workup for inflammatory, infectious, and toxic-metabolic causes of heart failure was unrevealing. While COVID myocarditis and multisystem inflammatory syndrome in adults (MIS-A) were considered, ultimately, a diagnosis of wet beriberi was made. After 5 months of aggressive nutritional supplementation via percutaneous gastrostomy tube and initiation of guideline-directed medical therapy, LVEF improved to 53% and weight increased by 35lbs. IMPACT/DISCUSSION: Wet beriberi is a potentially underrecognized cause of dilated cardiomyopathy in resource-rich areas. Within 3 months, thiamine deficiency can cause high-output heart failure due to impaired myocardial energy metabolism and dysautonomia. Risk factors include alcohol use disorder, prolonged vomiting, and history of bariatric surgery. CONCLUSION: The laboratory evaluation of non-ischemic dilated cardiomyopathy should include measurement of serum thiamine, carnitine, and selenium levels in select patients, alongside iron studies, ANA, screening for HIV, Chagas disease, and viral myocarditis, and genetic testing in patients with a suggestive family history. Empiric thiamine repletion should be considered in all critically ill patients with evidence of malnutrition.

The Functional Role of Long Non-Coding RNA in Myogenesis and Skeletal Muscle Atrophy.

Skeletal muscle is a pivotal organ in humans that maintains locomotion and homeostasis. Muscle atrophy caused by sarcopenia and cachexia, which results in reduced muscle mass and impaired skeletal muscle function, is a serious health condition that decreases life longevity in humans. Recent studies have revealed the molecular mechanisms by which long non-coding RNAs (lncRNAs) regulate skeletal muscle mass and function through transcriptional regulation, fiber-type switching, and skeletal muscle cell proliferation. In addition, lncRNAs function as natural inhibitors of microRNAs and induce muscle hypertrophy or atrophy. Intriguingly, muscle atrophy modifies the expression of thousands of lncRNAs. Therefore, although their exact functions have not yet been fully elucidated, various novel lncRNAs associated with muscle atrophy have been identified. Here, we comprehensively review recent knowledge on the regulatory roles of lncRNAs in skeletal muscle atrophy. In addition, we discuss the issues and possibilities of targeting lncRNAs as a treatment for skeletal muscle atrophy and muscle wasting disorders in humans.

AN UNUSUAL CASE OF DISSEMINATED TUBERCULOSIS FOLLOWINGANTIPSYCHOTIC THERAPY: AN AUTOPSY-BASED CASE REPORT

Tuberculosis (TB) is a communicable bacterial infection caused by Mycobacterium tuberculosis. It is the second leading fatal infectious disease after COVID-19. Tuberculosis also stands at 13th position, with respect to the leading cause of death. In 2020, around 86% of new tuberculosis cases were reported in 30 countries, of which two-thirds of cases were recorded in eight countries alone, with India leading the chart. Tuberculosis in a mentally ill patient is a common entity because of its common comorbidities, but prolonged antipsychotic drug therapy is rare. Here we discuss a case of a 36 years old female who was brought dead to casualty. She was apparently alright 10 days back and then developed symptoms like fever, breathlessness, and cough. She had severe anorexia and cachexia for the past few months. She has been under antipsychotic medication for schizophrenia. On autopsy, there were multiple whitish nodules present all over the intestine and various abdominal organs. We identified disseminated tuberculosis, and we analyzed histopathology and microbiology of tissues. We reported Ziehl-Neelsen staining negative for TB. Culture reported positive for Mycobacterium tuberculosis. Histopathology study tissues showed caseous necrotizing granulomas. As seen in some literature, tuberculosis can be seen in mentally ill patients, whereas literature showing the association between tuberculosis and antipsychotic drugs is less. This article highlights the association between such occurrence of tuberculosis while undertaking antipsychotic drug therapy.

Primary analysis of MOUNTAINEER: A phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC

Background: Despite the occurrence of HER2 amplification/overexpression (HER2+) in ~3% to 5% of all patients with metastatic colorectal cancer (mCRC) and up to ~10% of patients with RAS/BRAF wild-type mCRC, there are currently no FDA- or EMA-approved HER2-directed therapies for HER2+ mCRC. Patients with mCRC who progress on early lines of chemotherapy regimens receive limited clinical benefit from current standard-of-care treatments. Tucatinib is a highly selective, HER2-directed, tyrosine kinase inhibitor. The MOUNTAINEER trial (NCT03043313) was initiated to evaluate the efficacy and safety of the investigational combination of tucatinib with trastuzumab in patients with HER2+ mCRC. Here we present results from the primary analysis of MOUNTAINEER. Methods: MOUNTAINEER is a multi-center, open-label, randomised, phase 2 trial conducted in the US and Europe. Eligible patients had HER2+ (one or more local tests: 3+ immunohistochemistry, 2+ immunohistochemistry with amplification by in situ hybridization, or amplification by next‑generation sequencing of tumor tissue) and RAS wild-type mCRC with progression on or intolerance to fluoropyrimidine, oxaliplatin, irinotecan, and an anti-VEGF antibody. Measurable disease and an ECOG performance status of 0–2 were required. Previous HER2-directed therapies were not permitted. The trial initially consisted of a single cohort (Cohort A) to be treated with tucatinib (300 mg PO BID) and trastuzumab (8 mg/kg IV then 6 mg/kg IV every 3 weeks). The trial was expanded to include patients randomised 4:3 to receive tucatinib + trastuzumab (Cohort B) or tucatinib monotherapy (Cohort C). The primary endpoint is confirmed objective response rate (ORR) per RECIST 1.1 by blinded independent central review (BICR) in Cohorts A+B. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety and tolerability. Results: MOUNTAINEER enrolled 117 patients between 08Aug2017 and 22Sept2021. Data cutoff was 28Mar2022. The median age was 56.0 years (range, 24, 77), and baseline characteristics were balanced across cohorts. Eighty-six patients received at least 1 dose of study treatment in Cohorts A+B, and 30 patients received tucatinib monotherapy in Cohort C (total, 116). The overall median duration of follow-up was 16.3 months (IQR, 10.8, 28.2). In Cohorts A+B, the confirmed ORR by BICR was 38.1% (95% CI, 27.7, 49.3). The median DOR was 12.4 months (95% CI, 8.5, 20.5). The median PFS was 8.2 months (95% CI, 4.2, 10.3), and the median OS was 24.1 months (95% CI, 20.3, 36.7). The most common adverse events (AEs) in Cohorts A+B were diarrhoea (64.0%), fatigue (44.2%), nausea (34.9%), and infusion-related reaction (20.9%);the most common AE of grade ≥3 was hypertension (7.0%). Adverse events leading to tucatinib discontinuation in Cohorts A+B occurred in 5.8% of patients and included alanine amino transferase increase (2.3%), COVID-19 pneumonia (1.2%), cholangitis (1.2%), and fatigue (1.2%). No deaths resulted from AEs. Conclusions: In patients with chemotherapy-refractory HER2+ mCRC, tucatinib in combination with trastuzumab was well tolerated with clinically meaningful antitumor activity including durable responses and a median overall survival of 2 years. Tucatinib in combination with trastuzumab has the potential to become a new standard of care for patients with HER2+ mCRC. Clinical trial identification: NCT03043313. Editorial acknowledgement: The authors thank Joseph Giaconia of MMS Holdings, Michigan, USA for providing medical writing support/editorial support, which was funded by Seagen Inc., Bothell, WA, USA in accordance with Good Publication Practice (GPP3) guidelines. Legal entity responsible for the study: Seagen Inc. Funding: Seagen Inc. Disclosures: J. Strickler: Advisory / Consultancy: Seagen, Bayer, Pfizer;Research grant / Funding (institution): Amgen, Roche/Genentech, Seagen. A. Cercek: Advisory / Consultancy: Bayer, Merck, Seagen;Research grant / Funding (institution): Seagen, GSK, Rgenix. T. André: Honoraria (self : Amgen, Astra-Zeneca, Bristol-Myers Squibb, Gritstone Oncology, GlaxoSmithKline, Haliodx, Kaleido Biosciences, Merck & Co., Inc., Pierre Fabre, Sanofi, Servier, Merck & Co., Inc, Servier;Advisory / Consultancy: Astellas Pharma, BMS, Gritstone Oncology, Transgène, Roche/Ventana, Seagen, Merck & Co., Inc, Servier;Research grant / Funding (institution): BMS, Seagen, GSK;Travel / Accommodation / Expenses: BMS, Merck & Co., Inc. K. Ng: Advisory / Consultancy: Seattle Genetics, Bicara Therapeutics, GlaxoSmithKline;Research grant / Funding (institution): Pharmavite, Evergrande Group, Janssen. E. Van Cutsem: Advisory / Consultancy: AbbVie, Array, Astellas, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Daiichi, Halozyme, GSK, Helsinn, Incyte, Ipsen, Janssen Research, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Pierre Fabre, Roche, Seattle Genetics, Servier, Sirtex, Terumo, Taiho, TRIGR, Zymeworks;Research grant / Funding (institution): Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. C. Wu: Research grant / Funding (institution): Seagen. A. Paulson: Research grant / Funding (institution): Seattle Genetics. J. Hubbard: Research grant / Funding (institution): Seattle Genetics. H. Lenz: Honoraria (self): BMS, Bayer, Roche;Advisory / Consultancy: Bayer, Merck, Roche;Travel / Accommodation / Expenses: BMS, Bayer, Merck KG;Shareholder / Stockholder / Stock options: Fulgent. M. Stecher: Full / Part-time employment: SeaGen. W. Feng: Full / Part-time employment: Seagen. T. Bekaii-Saab: Honoraria (self): Royalties: Uptodate;Advisory / Consultancy: Consulting (to institution): Ipsen, Arcus, Pfizer, Seattle Genetics, Bayer, Genentech, Incyte, Eisai and Merck., Consulting (to self): Stemline, AbbVie, Boehringer Ingelheim, Janssen, Daichii Sankyo, Natera, TreosBio, Celularity, Exact Science, Sobi, Beigene, Kanaph, Astra Zeneca, Deciphera, MJH Life Sciences, Aptitude Health, Illumina and Foundation Medicine, IDMC/DSMB: Fibrogen, Suzhou Kintor, Astra Zeneca, Exelixis, Merck/Eisai, PanCan and 1Globe;Research grant / Funding (institution): Agios, Arys, Arcus, Atreca, Boston Biomedical, Bayer, Eisai, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Genentech, Novartis, Mirati, Merus, Abgenomics, Incyte, Pfizer, BMS.;Licensing / Royalties: WO/2018/183488: HUMAN PD1 PEPTIDE VACCINES AND USES THEREOF – Licensed to Imugene, WO/2019/055687: METHODS AND COMPOSITIONS FOR THE TREATMENT OF CANCER CACHEXIA – Licensed to Recursion. All other authors have declared no conflicts of interest.

A Case of Hydroxyurea-Induced Interstitial Pneumonitis

Introduction: First synthesized in 1869, Hydroxyurea is known for its efficacy in treating myeloproliferative disorders, cervical cancer, and sickle cell disease. Usually well-tolerated, Hydroxyurea has numerous documented adverse effects, including bone marrow suppression, fevers, gastrointestinal upset, anorexia, and maculopapular rash. In addition, one rare side effect is interstitial pneumonitis, a potentially devastating complication if overlooked. We present one such case of Hydroxyurea-induced interstitial pneumonitis. Case Description: A 65-year-old man with a six-month diagnosis of Chronic Granulocytic Leukemia (CGL) on Hydroxyurea developed acute hypoxemic respiratory failure saturating 80% on room air with HR 102, RR 24, and increasing oxygen requirements (10 Lpm) after being admitted with complaints of worsening dyspnea, fatigue, and productive cough with yellow/green sputum. Physical examination was notable for cachexia, ill appearance, generalized weakness, hoarse voice, tachycardia, tachypnea, diffusely diminished breath sounds, and scattered rales on auscultation of lung fields. Initial imaging was notable for bilateral airspace disease and pulmonary opacities on chest radiography and bilateral pneumonia (concerning for COVID-19 pneumonia), mediastinal adenopathy, and splenomegaly on chest computed tomography. Initial laboratory results were notable for leukocytosis 62.5 th/uL, lactic acidosis 2.5 mmol/L, procalcitonin level 4.95 ng/mL, and negative COVID-19 PCR test. Prompt initiation of Vancomycin/Cefepime therapy ensued upon collection of blood cultures in light of possible sepsis. Flagyl, Valacyclovir, and Posaconazole were added to antimicrobial coverage, along with steroid therapy, due to minimal clinical improvement. Tachycardia with significant oxygen requirements alternating between BiPAP and heated high flow nasal cannula with FiO2 ranging from 70-85% persisted. Daily imaging also showed worsening airspace disease. Negative viral, bacterial, and fungal cultures led to subsequent discontinuation of Hydroxyurea therapy due to suspicion of medicationinduced pneumonitis. Three days after cessation of Hydroxyurea, the patient's oxygen requirements began to decrease and imaging revealed interval resolution of pneumonitic changes in the absence of antimicrobial therapy. The patient was later transitioned to Ruxolitinib for his underlying CGL prior to his discharge home without the need for home oxygen therapy. Discussion: Thought to be caused by hypersensitivity pneumonitis, pulmonary toxicity from Hydroxyurea can easily be misdiagnosed. Unfortunately, while much is known about the pancytopenic, gastrointestinal, and cutaneous side effects of Hydroxyurea, few cases in the literature highlight the potentially fatal interstitial pneumopathy caused by Hydroxyurea, first reported in 1999. Thus, this case serves as an additional contribution to the minutiae of literature detailing Hydroxyurea's adverse pulmonary side effect profile. (Figure Presented).

“I want to get myself as fit as I can and not die just yet” – Perceptions of exercise in people with advanced cancer and cachexia: a qualitative study

Cachexia is a prevalent muscle wasting syndrome among people with advanced cancer that profoundly impacts patient quality of life (QoL) and physical function. Exercise can improve QoL, physical function, and overall health in people with cancer and may be an important addition to treatment approaches for cancer cachexia. Greater understanding of patients’ perception of exercise can help elucidate the feasibility of implementing exercise interventions for cancer cachexia and facilitate the design of patient-centered interventions. We aimed to describe the perception of exercise in patients with advanced cancer and cachexia, and capture exercise motivators, barriers, and preferences, to inform the feasibility of exercise interventions. Individual interviews (n = 20) with patients with locally advanced or metastatic cancer with cachexia were conducted and analyzed using reflexive thematic analysis. Main themes from interviews were: 1) Life is disrupted by cancer and cachexia;2) Exercise offers hope;3) Exercise barriers are multifaceted;and 4) Exercise access and support are important. Participants reported that their cancer and cachexia had intensely altered their lives, including ability to exercise. Exercise was perceived as important and participants described a hope for exercise to improve their health and wellbeing. Yet, several complex exercise barriers, such as burdensome cancer symptoms and the overwhelming impact of the COVID-19 pandemic, hindered exercise participation and prevented participants from fully realizing the perceived benefits of exercise. Factors believed to improve exercise engagement and overcome exercise barriers included increased exercise support (e.g., professional supervision) and accessibility (e.g., convenient locations). Patient-reported exercise barriers and preferences can inform the design of exercise interventions, particularly within future research studies aiming to establish exercise feasibility and efficacy in people with advanced cancer and cachexia.

"I want to get myself as fit as I can and not die just yet" - Perceptions of exercise in people with advanced cancer and cachexia: a qualitative study.

Cachexia is a prevalent muscle wasting syndrome among people with advanced cancer that profoundly impacts patient quality of life (QoL) and physical function. Exercise can improve QoL, physical function, and overall health in people with cancer and may be an important addition to treatment approaches for cancer cachexia. Greater understanding of patients' perception of exercise can help elucidate the feasibility of implementing exercise interventions for cancer cachexia and facilitate the design of patient-centered interventions. We aimed to describe the perception of exercise in patients with advanced cancer and cachexia, and capture exercise motivators, barriers, and preferences, to inform the feasibility of exercise interventions. Individual interviews (n = 20) with patients with locally advanced or metastatic cancer with cachexia were conducted and analyzed using reflexive thematic analysis. Main themes from interviews were: 1) Life is disrupted by cancer and cachexia; 2) Exercise offers hope; 3) Exercise barriers are multifaceted; and 4) Exercise access and support are important. Participants reported that their cancer and cachexia had intensely altered their lives, including ability to exercise. Exercise was perceived as important and participants described a hope for exercise to improve their health and wellbeing. Yet, several complex exercise barriers, such as burdensome cancer symptoms and the overwhelming impact of the COVID-19 pandemic, hindered exercise participation and prevented participants from fully realizing the perceived benefits of exercise. Factors believed to improve exercise engagement and overcome exercise barriers included increased exercise support (e.g., professional supervision) and accessibility (e.g., convenient locations). Patient-reported exercise barriers and preferences can inform the design of exercise interventions, particularly within future research studies aiming to establish exercise feasibility and efficacy in people with advanced cancer and cachexia.

Megestrol Acetate in the Treatment of Post COVID-19 Fatigue in a Patient of Advanced Cancer: A Case Report and Mini Review of Literature

Megestrol acetate is one of the pharmacological agents used for cancer-associated fatigue. To date, there are no studies on its use in the treatment of post-COVID-19 (coronavirus disease 2019) fatigue. So, we report a case of metastatic carcinoma lung with a partial response with three cycles of palliative chemotherapy. He was contracted with mild COVID-19 infection post three cycles of his chemotherapy. Post this episode, fatigue was his main and most troublesome symptom. After a thorough clinical history, physical examination, and investigations, type 2 post-COVID-19 syndrome was diagnosed. After explaining the risks and benefits, we started the patient on low-dose megestrol acetate (160 mg/d per oral) with low to moderate benefits. However, upon increasing the dose to 480 mg/d, the benefit on the subjective quality of life was significant. Studies with a larger sample and randomized controlled trials have to be conducted to substantiate the hypothesis and actual effect of megestrol acetate in the treatment of post-COVID-19 fatigue.

Treatment-emergent COVID-19 infections in ozanimod ulcerative colitis and multiple sclerosis clinical trials

Background: Ozanimod, a sphingosine 1-phosphate (S1P) receptor S1P1 and S1P5 modulator, is approved in the United States for moderately to severely active ulcerative colitis (UC) and in multiple countries for relapsing multiple sclerosis (MS). We describe COVID-19 outcomes in ozanimod-treated UC or MS patients (pts) in active phase 3 openlabel extension (OLE) studies. Methods: A database search identified COVID-19 infection reports in ozanimod-treated pts with UC in the True North OLE and MS in the DAYBREAK OLE. The analysis period was November 1, 2019 to either August 31, 2021 (UC) or May 10, 2021 (MS). The last COVID-19 event from all pts with ≥1 event was analyzed. Results: Among 2792 ozanimod-treated pts with UC or MS, 258 developed COVID-19 (confirmed: 215);thus, the incidence in these clinical trial settings was 9.2% during the analysis periods. Most pts with confirmed cases (193/215 [89.8%]) had nonserious infections not requiring hospitalization or meeting other International Conference on Harmonisation criteria for a serious event. Of 611 ozanimod-treated pts with UC, 68 (11.1%) developed COVID-19 (confirmed: 55;Fig 1). A majority of UC pts with confirmed cases (45/55 [81.8%]) had nonserious COVID-19;most (54/55 [98.2%]) recovered (2 with sequalae) and 1 was recovering at data cutoff. One UC pt with confirmed COVID-19 discontinued ozanimod (1.8%), 23 temporarily interrupted it (41.8%), and 31 had no change to treatment (56.4%). No COVID-19-related deaths were reported in UC pts. Of 2181 ozanimod-treated pts with MS, 190 (8.7%) developed COVID-19 (confirmed: 160;Fig 2). Most MS pts with confirmed COVID-19 (148/160 [92.5%]) had nonserious cases;most (158/160 [98.8%]) recovered (5 with sequelae) (Fig 1). No MS pts with confirmed cases discontinued ozanimod, 61 temporarily interrupted it (38.1%), and 99 had no change to treatment (61.9%). Outcomes in 13 additional UC pts (Fig 1) and 30 additional MS pts (Fig 2) with suspected COVID-19 were similar to those with confirmed cases. There were 3 COVID-19-related deaths in the MS program. One pt died from a presumed pulmonary embolism;this pt had received high-dose corticosteroids for MS relapse immediately before COVID-19 symptom onset. Another pt died from suspected COVID-19-related respiratory failure. One tetraplegic, cachectic pt died from a lung abscess following COVID-19 infection. Conclusion: In the UC and MS OLE studies, most pts with confirmed COVID-19 had nonserious infections, recovered, and did not require ozanimod discontinuation. There were 3 deaths in MS patients (casefatality rate 1.6% in MS, 1.2% overall).