Continuing Medical Education Questions: August 2023.

Article Title: Impact of Cold Snare v Cold Forceps Resection of Diminutive Adenomas on Segmental Incomplete Resection Rate.

Systematic Review of Safety of Selective Androgen Receptor Modulators in Healthy Adults: Implications for Recreational Users.

Selective Androgen Receptor Modulators (SARMs) are not FDA approved, and obtaining SARMs for personal use is illegal. Nevertheless, SARM use is increasingly popular amongst recreational athletes. Recent case reports of drug-induced liver injury (DILI) and tendon rupture raise serious concerns for the safety of recreational SARM users. On 10 November 2022 PubMed, Scopus, Web of Science, and ClinicalTrials.gov were searched for studies that reported safety data of SARMs. A multi-tiered screening approach was utilized, and any study or case report of generally healthy individuals exposed to any SARM was included. Thirty-three studies were included in the review with 15 case reports or case series and 18 clinical trials (total patients N = 2136 patients, exposed to SARM N = 1447). There were case reports of drug-induced liver injury (DILI) (N = 15), Achilles tendon rupture (N = 1), rhabdomyolysis (N = 1), and mild reversible liver enzyme elevation (N = 1). Elevated alanine aminotransferase (ALT) was commonly reported in clinical trials in patients exposed to SARM (mean 7.1% across trials). Two individuals exposed to GSK2881078 in a clinical trial were reported to have rhabdomyolysis. Recreational SARM use should be strongly discouraged, and the risks of DILI, rhabdomyolysis, and tendon rupture should be emphasized. However, despite warnings, if a patient refuses to discontinue SARM use, ALT monitoring or dose reduction may improve early detection and prevention of DILI.

Synthesis and In vitro Efficacy of Tetracyclic Benzothiazepines Against Blood-Stage Plasmodium falciparum and Liver-Stage P. berghei.

OBJECTIVE: A series of novel, substituted tetracyclic benzothiazepines were designed and prepared in an effort to optimize the potency of this chemical class against drug-resistant strains of the malaria parasite. METHODS: Tetracyclic benzothiazepines bearing structural modification at seven distinct positions within the structure were synthesized in Knoevenagel condensation reactions followed by sequential intermolecular thio-Michael and then intramolecular imine formation reactions. Following purification and chemical characterization, the novel compounds were tested for in vitro efficacy against blood-stage P. falciparum and liver-stage P. berghei and also for in vivo efficacy against P. berghei. RESULTS: Benzothiazepines bearing structural modification at the sulfur atom and at the three carbocycles within the molecule were successfully synthesized. The majority of analogs inhibited bloodstage P. falciparum with submicromolar IC50 values. The potency of an 8-methoxy-substituted analog 12 exceeded that of chloroquine in all three P. falciparum strains tested. The parent benzothiazepine 1 possessed liver-stage activity, inhibiting P. berghei sporozoites infecting HepG2 cells with an IC50 of 106.4 nM and an IC90 of 408.9 nM, but failed to enhance the longevity of P. berghei infected mice compared to the controls. Compounds displayed modest toxicity toward HepG2 cells and were tolerated by mice at the highest dose tested, 640 mg/kg/dose once daily for three days. CONCLUSION: The tetracyclic benzothiazepine described, which inhibits P. berghei infected hepatic cells with an IC50 of 106.4 nM, would appear to warrant further investigation. Optimization of ADME properties may be required since the most active analogs are probably excessively lipophilic.

Care of the Hepatology Patient in the COVID-19 Era.

Background and Purpose of Review: The COVID-19 pandemic has resulted in over 800,000 deaths worldwide and resulted in fundamental changes in practice in nearly every aspect of medicine. The majority of symptomatic patients experience liver-associated enzyme (LAE) elevations which appear to be correlated to disease severity. Furthermore, there are unique considerations of COVID-19 on chronic liver disease. Background, including epidemiology, pathophysiologic mechanisms and therapeutics, as well as the impact of COVID-19 on specific chronic liver disease, is discussed. Findings: Studies suggest that degree of LAE elevation correlates with illness severity, although it is unclear whether this represents true liver injury. Numerous proposed treatments for COVID-19 have been linked with drug induced liver injury and may have clinically significant drug-drug interactions. Others may have unintended consequences on chronic liver disease treatment including reactivation of hepatitis B. The risk of severe COVID-19 in patients with chronic liver disease is largely unknown; metabolic dysfunction-associated fatty liver disease may be linked to higher risk for severe illness. Implications for cirrhosis of other etiologies, autoimmune hepatitis, and viral hepatitis are less well defined. The treatment of chronic liver disease has been severely impacted by the pandemic. The societal factors created by the pandemic have led to decreased in person visits, evolving access to invasive screening modalities, food and financial insecurity, and likely increased alcohol use. Conclusions: The impacts of COVID-19 on the liver range from a potential increased risk of severe infection in chronic liver disease patients, to hepatotoxic effects of proposed treatments, to second and third order impacts on the care of patients with chronic liver disease.

Use of Lactulose to Treat Hyperammonemia in ICU Patients Without Chronic Liver Disease or Significant Hepatocellular Injury.

OBJECTIVES: To review ICU patients with elevated ammonia without a clear hepatic etiology, to compare outcomes between those who received lactulose and those who did not. DESIGN: Retrospective observational study. SETTING: Medical, surgical, and subspecialty intensive care units at Wake Forest Baptist Medical Center, Winston-Salem, North Carolina between December 2012 and August 2016. PATIENTS: Adults with ammonia levels above 50 µmol/L, excluding those with known chronic liver disease, inborn error of metabolism, active use of valproic acid, total bilirubin ≥ 2 µmol/L, or alanine aminotransferase ≥ 100 units/L. INTERVENTIONS: Comparison in ICU length of stay (LOS), hospital LOS, in-hospital mortality, and mortality at 30 and 90 days. MEASUREMENTS AND MAIN RESULTS: Criteria for inclusion were met in 103 cases. Mean ammonia level was 75 µmol/L, with undetermined etiology in the majority of subjects. Lactulose was given in 48 cases (46.6%), with a median of 9.5 doses given. There were no significant differences in outcomes between the lactulose and non-lactulose groups. Among subjects with multiple data points, lactulose did not have a dose-dependent effect on ammonia level, and was not associated with faster ammonia normalization compared to non-lactulose. When analyzed separately, patients with moderate hyperammonemia (60-99 µmol/L) who received lactulose had longer hospital and ICU length of stay compared to non-lactulose (417.8 hours vs. 208.4 hours, P = 0.003, and 229.2 hours vs. 104.7 hours, P = 0.025; respectively), though confounders were present. CONCLUSIONS: Routine use of lactulose to treat mild to moderate hyperammonemia in this patient population was not associated with improved outcomes.

Systems-based Strategies Improve Positive Screening Fecal Immunochemical Testing Follow-up and Reduce Time to Diagnostic Colonoscopy.

INTRODUCTION: Fecal immunochemical testing (FIT) is the most commonly used colorectal cancer (CRC) screening tool worldwide and accounts for 10% of all CRC screening in the United States. Potential vulnerabilities for patients enrolled to facilities within the military health system have recently come to light requiring reassessment of best practices. We studied the impact of a process improvement initiative designed to improve the safety and quality of care for patients after a positive screening FIT given previously published reports of poor organization performance. METHODS: During a time of increased utilization of nonendoscopic means of screening, we assessed rates of colonoscopy completion and time to colonoscopy after positive FIT after a multi-faceted process improvement initiative was implemented, compared against an institutional control period. The interventions included mandatory indication labeling at the time of order entry, as well as utilization of subspecialty nurse navigators to facilitate rapid follow-up even the absence of a referral from primary care. RESULTS: Preintervention, 34.8% of patients did not have appropriate follow-up of a positive FIT. Those that did had a variable and prolonged wait time of 140.1 ± 115.9 days. Postintervention, a standardized order mandating test indication labeling allowed for proactive gastroenterology involvement. Colonoscopy follow-up rate increased to 91.9% with an average interval of 21.9 ± 12.3 days. CONCLUSION: The addition of indication labels and patient navigation after positive screening FIT was associated with 57.1% absolute increase in timely diagnostic colonoscopy. Similar highly reliable systems-based solutions should be adopted for CRC screening, and further implementation for other preventative screening interventions should be pursued.

Continuing Medical Education Questions: June 2021.

Article Title: Exploratory comparative effectiveness trial of green kiwifruit, psyllium, or prunes in US patients with chronic constipation.

Perforated Hemocholecyst: An Unintended Consequence of Endoscopic Variceal Ligation?

Ectopic varices are a rare sequelae of portal hypertension and present in unique ways, which may not always prompt consideration. Furthermore, endoscopic interventions on venous collaterals in the setting of portal hypertension affect the portal system hemodynamics, which may further complicate the clinical picture. We report a man with decompensated hepatitis C cirrhosis who developed hemocholecyst complicated by perforation with hemoperitoneum soon after endoscopic variceal ligation of the esophageal varices in the setting of retrospectively discovered gallbladder varices.

Emphysematous Gastritis in a Patient with Untreated Cyclic Vomiting Syndrome.

Emphysematous gastritis (EG) is an uncommon and potentially fatal disease characterized by gastric pneumatosis in the setting of infection. While this disease has been described in the literature, it has not previously been identified as a potential complication of cyclic vomiting syndrome. We describe a patient with a history of cyclic vomiting syndrome who presented acutely ill and was found to have radiographic, endoscopic, and histologic evidence of EG. This case illustrates how an untreated functional bowel disorder can lead to severe and potentially fatal complications.

Nighthawk: Making Night Float Education and Patient Safety Soar.

BACKGROUND: Some residency programs responded to duty hour restrictions by implementing night rotations. Night supervision models can vary, resulting in potential patient safety issues and educational voids for residents. OBJECTIVE: We evaluated the impact of multiple evidence-based interventions on resident satisfaction with supervision, perception of the education value of night rotations, and residents' use of online educational materials. METHODS: The night team was augmented with an intern to assist with admissions and a senior resident (the "nighthawk") to supervise inpatient care and deliver a night medicine curriculum. We instituted a "must-call" list, with specific clinical events requiring mandatory attending notification, and reduced conflict in the role of the night float team. We studied patient contact, online curriculum use, residents' perceptions of nighthawk involvement, exposure to educational materials, and satisfaction with supervision. RESULTS: During the first half of academic year 2016-2017, 51% (64 of 126) of trainees were on the night medicine rotation. The nighthawk reviewed 1007 intern plans (15 per night; range, 6-36) and supervised 215 hands-on evaluations, including codes and rapid responses (3 per night; range, 0-12). The number of users of the online education materials increased by 85% (13 to 24), and instances of use increased 35% (85 to 115). The majority of residents (79%, 27 of 34) favored the new system. CONCLUSIONS: A nighthawk rotation, a must-call list, and reducing conflict in night team members' roles improved resident satisfaction with supervision and the night medicine rotation, resulting in increased communication.

High-Value, Cost-Conscious Care: Iterative Systems-Based Interventions to Reduce Unnecessary Laboratory Testing.

BACKGROUND: Inappropriate testing contributes to soaring healthcare costs within the United States, and teaching hospitals are vulnerable to providing care largely for academic development. Via its "Choosing Wisely" campaign, the American Board of Internal Medicine recommends avoiding repetitive testing for stable inpatients. We designed systems-based interventions to reduce laboratory orders for patients admitted to the wards at an academic facility. METHODS: We identified the computer-based order entry system as an appropriate target for sustainable intervention. The admission order set had allowed multiple routine tests to be ordered repetitively each day. Our iterative study included interventions on the automated order set and cost displays at order entry. The primary outcome was number of routine tests controlled for inpatient days compared with the preceding year. Secondary outcomes included cost savings, delays in care, and adverse events. RESULTS: Data were collected over a 2-month period following interventions in sequential years and compared with the year prior. The first intervention led to 0.97 fewer laboratory tests per inpatient day (19.4%). The second intervention led to sustained reduction, although by less of a margin than order set modifications alone (15.3%). When extrapolating the results utilizing fees from the Centers for Medicare and Medicaid Services, there was a cost savings of $290,000 over 2 years. Qualitative survey data did not suggest an increase in care delays or near-miss events. CONCLUSIONS: This series of interventions targeting unnecessary testing demonstrated a sustained reduction in the number of routine tests ordered, without adverse effects on clinical care.