Controversies in Colorectal Cancer Screening

Comparative Effectiveness and Safety of Apixaban, Rivaroxaban, and Warfarin in Patients With Cirrhosis and Atrial Fibrillation: A Nationwide Cohort Study: Annals of Internal Medicine: Vol 177, No 8

Background: Apixaban, rivaroxaban, and warfarin have shown benefit for preventing major ischemic events, albeit with increased bleeding risk, among patients in the general population with atrial fibrillation (AF). However, data are scarce in patients with cirrhosis and AF. Objective: To compare the effectiveness and safety of apixaban versus rivaroxaban and versus warfarin in patients with cirrhosis and AF. Design: Population-based cohort study. Setting: Two U.S. claims data sets (Medicare and Optum’s de-identified Clinformatics Data Mart Database [2013 to 2022]). Participants: 1:1 propensity score (PS)–matched patients with cirrhosis and nonvalvular AF initiating use of apixaban, rivaroxaban, or warfarin. Measurements: Primary outcomes included ischemic stroke or systemic embolism and major hemorrhage (intracranial hemorrhage or major gastrointestinal bleeding). Database-specific and pooled PS-matched rate differences (RDs) per 1000 person-years (PY) and Cox proportional hazard ratios (HRs) with 95% CIs were estimated, controlling for 104 preexposure covariates. Results: Rivaroxaban initiators had significantly higher rates of major hemorrhagic events than apixaban initiators (RD, 33.1 per 1000 PY [95% CI, 12.9 to 53.2 per 1000 PY]; HR, 1.47 [CI, 1.11 to 1.94]) but no significant differences in rates of ischemic events or death. Consistently higher rates of major hemorrhage were found with rivaroxaban across subgroup and sensitivity analyses. Warfarin initiators also had significantly higher rates of major hemorrhage than apixaban initiators (RD, 26.1 per 1000 PY [CI, 6.8 to 45.3 per 1000 PY]; HR, 1.38 [CI, 1.03 to 1.84]), particularly hemorrhagic stroke (RD, 9.7 per 1000 PY [CI, 2.2 to 17.2 per 1000 PY]; HR, 2.85 [CI, 1.24 to 6.59]). Limitation: Nonrandomized treatment selection. Conclusion: Among patients with cirrhosis and nonvalvular AF, initiators of rivaroxaban versus apixaban had significantly higher rates of major hemorrhage and similar rates of ischemic events and death. Initiation of warfarin versus apixaban also contributed to significantly higher rates of major hemorrhagic events, including hemorrhagic stroke. Primary Funding Source: National Institutes of Health.

The Impact of Health Care Algorithms on Racial and Ethnic Disparities: A Systematic Review: Annals of Internal Medicine: Vol 177, No 4

Background: There is increasing concern for the potential impact of health care algorithms on racial and ethnic disparities. Purpose: To examine the evidence on how health care algorithms and associated mitigation strategies affect racial and ethnic disparities. Data Sources: Several databases were searched for relevant studies published from 1 January 2011 to 30 September 2023. Study Selection: Using predefined criteria and dual review, studies were screened and selected to determine: 1) the effect of algorithms on racial and ethnic disparities in health and health care outcomes and 2) the effect of strategies or approaches to mitigate racial and ethnic bias in the development, validation, dissemination, and implementation of algorithms. Data Extraction: Outcomes of interest (that is, access to health care, quality of care, and health outcomes) were extracted with risk-of-bias assessment using the ROBINS-I (Risk Of Bias In Non-randomised Studies – of Interventions) tool and adapted CARE-CPM (Critical Appraisal for Racial and Ethnic Equity in Clinical Prediction Models) equity extension. Data Synthesis: Sixty-three studies (51 modeling, 4 retrospective, 2 prospective, 5 prepost studies, and 1 randomized controlled trial) were included. Heterogenous evidence on algorithms was found to: a) reduce disparities (for example, the revised kidney allocation system), b) perpetuate or exacerbate disparities (for example, severity-of-illness scores applied to critical care resource allocation), and/or c) have no statistically significant effect on select outcomes (for example, the HEART Pathway [history, electrocardiogram, age, risk factors, and troponin]). To mitigate disparities, 7 strategies were identified: removing an input variable, replacing a variable, adding race, adding a non–race-based variable, changing the racial and ethnic composition of the population used in model development, creating separate thresholds for subpopulations, and modifying algorithmic analytic techniques. Limitation: Results are mostly based on modeling studies and may be highly context-specific. Conclusion: Algorithms can mitigate, perpetuate, and exacerbate racial and ethnic disparities, regardless of the explicit use of race and ethnicity, but evidence is heterogeneous. Intentionality and implementation of the algorithm can impact the effect on disparities, and there may be tradeoffs in outcomes. Primary Funding Source: Agency for Healthcare Quality and Research.

Computer-Aided Diagnosis for Leaving Colorectal Polyps In Situ: A Systematic Review and Meta-analysis: Annals of Internal Medicine: Vol 177, No 7

Background: Computer-aided diagnosis (CADx) allows prediction of polyp histology during colonoscopy, which may reduce unnecessary removal of nonneoplastic polyps. However, the potential benefits and harms of CADx are still unclear. Purpose: To quantify the benefit and harm of using CADx in colonoscopy for the optical diagnosis of small (≤5-mm) rectosigmoid polyps. Data Sources: Medline, Embase, and Scopus were searched for articles published before 22 December 2023. Study Selection: Histologically verified diagnostic accuracy studies that evaluated the real-time performance of physicians in predicting neoplastic change of small rectosigmoid polyps without or with CADx assistance during colonoscopy. Data Extraction: The clinical benefit and harm were estimated on the basis of accuracy values of the endoscopist before and after CADx assistance. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The outcome measure for benefit was the proportion of polyps predicted to be nonneoplastic that would avoid removal with the use of CADx. The outcome measure for harm was the proportion of neoplastic polyps that would be not resected and left in situ due to an incorrect diagnosis with the use of CADx. Histology served as the reference standard for both outcomes. Data Synthesis: Ten studies, including 3620 patients with 4103 small rectosigmoid polyps, were analyzed. The studies that assessed the performance of CADx alone (9 studies; 3237 polyps) showed a sensitivity of 87.3% (95% CI, 79.2% to 92.5%) and specificity of 88.9% (CI, 81.7% to 93.5%) in predicting neoplastic change. In the studies that compared histology prediction performance before versus after CADx assistance (4 studies; 2503 polyps), there was no difference in the proportion of polyps predicted to be nonneoplastic that would avoid removal (55.4% vs. 58.4%; risk ratio [RR], 1.06 [CI, 0.96 to 1.17]; moderate-certainty evidence) or in the proportion of neoplastic polyps that would be erroneously left in situ (8.2% vs. 7.5%; RR, 0.95 [CI, 0.69 to 1.33]; moderate-certainty evidence). Limitation: The application of optical diagnosis was only simulated, potentially altering the decision-making process of the operator. Conclusion: Computer-aided diagnosis provided no incremental benefit or harm in the management of small rectosigmoid polyps during colonoscopy. Primary Funding Source: European Commission. (PROSPERO: CRD42023402197)

Association of Semaglutide With Tobacco Use Disorder in Patients With Type 2 Diabetes: Target Trial Emulation Using Real-World Data: Annals of Internal Medicine: Vol 177, No 8

Background: Reports of reduced desire to smoke in patients treated with semaglutide, a glucagon-like peptide receptor agonist (GLP-1RA) medication for type 2 diabetes mellitus (T2DM) and obesity, have raised interest about its potential benefit for tobacco use disorders (TUDs). Objective: To examine the association of semaglutide with TUD-related health care measures in patients with comorbid T2DM and TUD. Design: Emulation target trial based on a nationwide population-based database of patient electronic health records. Setting: United States, 1 December 2017 to 31 March 2023. Participants: Seven target trials were emulated among eligible patients with comorbid T2DM and TUD by comparing the new use of semaglutide versus 7 other antidiabetes medications (insulins, metformin, dipeptidyl-peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, sulfonylureas, thiazolidinediones, and other GLP-1RAs). Measurements: The TUD-related health care measures (medical encounter for diagnosis of TUD, smoking cessation medication prescriptions, and smoking cessation counseling) that occurred within a 12-month follow-up were examined using Cox proportional hazards and Kaplan–Meier survival analyses. Results: The study compared 222 942 new users of antidiabetes medications including 5967 of semaglutide. Semaglutide was associated with a significantly lower risk for medical encounters for TUD diagnosis compared with other antidiabetes medications, and was strongest compared with insulins (hazard ratio [HR], 0.68 [95% CI, 0.63 to 0.74]) and weakest but statistically significant compared with other GLP-1RAs (HR, 0.88 [CI, 0.81 to 0.96]). Semaglutide was associated with reduced smoking cessation medication prescriptions and counseling. Similar findings were observed in patients with and without a diagnosis of obesity. For most of the group comparisons, the differences occurred within 30 days of prescription initiation. Limitation: Documentation bias, residual confounding, missing data on current smoking behavior, body mass index, and medication adherence. Conclusion: Semaglutide was associated with lower risks for TUD-related health care measures in patients with comorbid T2DM and TUD compared with other antidiabetes medications including other GLP-1Ras, primarily within 30 days of prescription. These findings suggest the need for clinical trials to evaluate semaglutide’s potential for TUD treatment. Primary Funding Source: National Institutes of Health.

Submitting Your Work to Annals: Author-Friendly Features

Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2022 Clinical Practice Guideline

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2022 clinical practice guideline on prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease (CKD) is an update of the 2018 guideline from KDIGO. Methods: The KDIGO Work Group (WG) updated the guideline, which included reviewing and grading new evidence that was identified and summarized. As in the previous guideline, the WG used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to appraise evidence and rate the strength of recommendations and used expert judgment to develop recommendations. New evidence led to updating of recommendations in the chapters on treatment of hepatitis C virus (HCV) infection in patients with CKD (Chapter 2), management of HCV infection before and after kidney transplant (Chapter 4), and diagnosis and management of kidney disease associated with HCV infection (Chapter 5). Recommendations in chapters on detection and evaluation of hepatitis C in CKD (Chapter 1) and prevention of HCV transmission in hemodialysis units (Chapter 3) were not updated because of an absence of significant new evidence. Recommendations: The 2022 updated guideline includes 43 graded recommendations and 20 ungraded recommendations, 7 of which are new or modified on the basis of the most recent evidence and consensus among the WG members. The updated guidelines recommend expanding treatment of hepatitis C with sofosbuvir-based regimens to patients with CKD glomerular filtration rate categories G4 and G5, including those receiving dialysis; expanding the donor pool for kidney transplant recipients by accepting HCV-positive kidneys regardless of the recipient’s HCV status; and initiating direct-acting antiviral treatment of HCV-infected patients with clinical evidence of glomerulonephritis without requiring kidney biopsy. The update also addresses the use of immunosuppressive regimens in such patients.

Evening Chronotype, Circadian Misalignment, and Metabolic Health: Implications for Diabetes Prevention and Beyond

From Tool to Team Member: A Second Set of Eyes for Polyp Detection

Effectiveness of Nirmatrelvir–Ritonavir Against the Development of Post–COVID-19 Conditions Among U.S. Veterans: A Target Trial Emulation: Annals of Internal Medicine: Vol 176, No 11

Background: COVID-19 has been linked to the development of many post–COVID-19 conditions (PCCs) after acute infection. Limited information is available on the effectiveness of oral antivirals used to treat acute COVID-19 in preventing the development of PCCs. Objective: To measure the effectiveness of outpatient treatment of COVID-19 with nirmatrelvir–ritonavir in preventing PCCs. Design: Retrospective target trial emulation study comparing matched cohorts receiving nirmatrelvir–ritonavir versus no treatment. Setting: Veterans Health Administration (VHA). Participants: Nonhospitalized veterans in VHA care who were at risk for severe COVID-19 and tested positive for SARS-CoV-2 during January through July 2022. Intervention: Nirmatrelvir–ritonavir treatment for acute COVID-19. Measurements: Cumulative incidence of 31 potential PCCs at 31 to 180 days after treatment or a matched index date, including cardiac, pulmonary, renal, thromboembolic, gastrointestinal, neurologic, mental health, musculoskeletal, endocrine, and general conditions and symptoms. Results: Eighty-six percent of the participants were male, with a median age of 66 years, and 17.5% were unvaccinated. Baseline characteristics were well balanced between participants treated with nirmatrelvir–ritonavir and matched untreated comparators. No differences were observed between participants treated with nirmatrelvir–ritonavir (n = 9593) and their matched untreated comparators in the incidence of most PCCs examined individually or grouped by organ system, except for lower combined risk for venous thromboembolism and pulmonary embolism (subhazard ratio, 0.65 [95% CI, 0.44 to 0.97]; cumulative incidence difference, −0.29 percentage points [CI, −0.52 to −0.05 percentage points]). Limitations: Ascertainment of PCCs using International Classification of Diseases, 10th Revision, codes may be inaccurate. Evaluation of many outcomes could have resulted in spurious associations with combined thromboembolic events by chance. Conclusion: Out of 31 potential PCCs, only combined thromboembolic events seemed to be reduced by nirmatrelvir–ritonavir. Primary Funding Source: U.S. Department of Veterans Affairs.

EBV Acalculous Cholecystitis Secondary to Cystic Duct Node Lymphadenitis With Positive EBER in Situ Hybridization | Annals of Internal Medicine: Clinical Cases

Primary Epstein-Barr virus (EBV) infections are commonly subclinical and seen in adolescents. Although infectious mononucleosis is the most common manifestation, EBV has diverse manifestations within the gastrointestinal system. We describe a rare case of a 27-year-old woman with acute EBV acalculous cholecystitis and hepatitis secondary to cystic duct node lymphadenitis causing compression. EBV-encoded RNA in situ hybridization stained positive within sinusoids of liver and cystic duct lymphoid tissue but negative in gallbladder tissue. Work-up for a cause of hepatitis was negative except for serology confirming primary EBV infection. She underwent laparoscopic cholecystectomy, with a resolution of symptoms.

α-Gal Syndrome: Busting Paradigms in Food Allergy | Annals of Internal Medicine: Clinical Cases

α-Gal syndrome, also known as red or mammalian meat allergy, results from immunoglobulin E–mediated hypersensitivity responses to the carbohydrate galactose-α-1,3-galactose (α-gal). Patients with α-gal syndrome experience immediate onset of allergic symptoms following the injection of pharmaceutical products containing α-gal. However, it typically takes 2 hours or more after dietary α-gal ingestion before patients with α-gal syndrome experience immunoglobulin E–mediated hypersensitivity responses. The case report by Heffes-Doon and colleagues highlights the lack of official guidelines on when and how to reintroduce mammalian meat products into the diet when there is clear laboratory evidence of declining α-gal immunoglobulin E levels.

Hyperlipasemia Due to Duodenal Obstruction Secondary to Gastrostomy Tube Migration | Annals of Internal Medicine: Clinical Cases

A nonverbal woman with cerebral palsy and a chronic gastrostomy tube presented with nonbilious vomiting of tube feeds and abdominal pain. Initial work-up showed elevated lipase; however, computed tomography imaging revealed duodenal obstruction from gastrostomy tube migration as the cause of her symptoms. This case represents alternative causes to hyperlipasemia, such as bowel obstruction.

Pouchitis After Immune Checkpoint Inhibitors | Annals of Internal Medicine: Clinical Cases

Immune checkpoint inhibitors (ICIs) are becoming increasingly used for various cancers, but their association with immune-related adverse events often leads to significant morbidity and mortality. Here we report 2 unusual cases of pouchitis after ICI therapy—treated with steroids and biologics. To our knowledge, this is the first example to be reported in literature. One patient achieved short-term remission, while the other achieved long-term remission without further flares.

Linagliptin-Induced Pancreatitis | Annals of Internal Medicine: Clinical Cases

Incretin-based medications are well-established agents used for glycemic control in patients with type 2 diabetes mellitus. Of these medications, glucagon-like peptide 1 agonists have a well-known association with pancreatitis. However, controversy still exists about a similar association with dipeptidyl peptidase 4 inhibitors. Linagliptin, in particular, has not been studied thoroughly. Therefore, to the best of our knowledge, we report linagliptin-induced pancreatitis, the fourth case reported in the medical literature, that resolved after stopping the medication and did not recur with the resumption of all of the other patient's medications.

Severe Azithromycin-Induced Liver Injury With Vanishing Bile Duct Syndrome Necessitating Liver Transplantation | Annals of Internal Medicine: Clinical Cases

Drug-induced liver injury is a common cause of liver damage, with antimicrobial use as the leading cause. Although most patients recover after discontinuing the offending agent, severe cases may result in progressive disease or death, requiring liver transplantation. Azithromycin is a rare cause of idiosyncratic drug-induced liver injury, usually resolving within 4 to 8 weeks of discontinuation. Vanishing bile duct syndrome may occur in severe cases, marked by progressive ductopenia and cholestasis. We describe a rare case of azithromycin-induced liver injury with acute vanishing bile duct syndrome necessitating liver transplantation.

Endoscopic Troubleshooting for Acute Cholecystitis With a Stone Impacted in the Cystic Duct | Annals of Internal Medicine: Clinical Cases

Endoscopic transpapillary gallbladder drainage is considered an alternative procedure in patients with acute cholecystitis who are not surgical candidates; however, it remains challenging, especially in cases with a stone impacted into the cystic duct (CD). In cases in which a stone is impacted at the CD orifice, a cholangioscope and forceps may be used to release the stone. In cases in which the stone is impacted in the middle of the CD, contrast pressure from above the injection retrieval balloon may be used to push the stone toward the gallbladder. We believe this is the first report of such cases in the literature.

A Case of Turmeric-Induced Liver Injury | Annals of Internal Medicine: Clinical Cases

Turmeric spice and its active ingredient, curcumin, are becoming more commonly used, despite a simultaneous increase in reports of turmeric-induced hepatotoxicity. Our report demonstrates an additional case of turmeric-induced liver injury with concurrent ingestion of bioavailability-increasing substances. Despite known underreporting, a significant proportion of documented drug-induced liver injuries are secondary to herbal and dietary supplements. There are also high variabilities in supplement dosage and delivery, as well as lack of regulation in the supplements industry. Our case highlights the importance of discussing supplement-specific medical histories and educating patient on the risks for unregulated supplement use.

Infectious Proctitis From Cytomegalovirus in an Immunocompetent Patient | Annals of Internal Medicine: Clinical Cases

Cytomegalovirus colitis typically causes immunocompromised patients to present with hematochezia, abdominal pain, fever, or diarrhea and rarely as perforation. Here we report an 83-year-old woman with no other traditional immunocompromising risk factors who presented with cytomegalovirus proctitis. Providers should be aware of the potential for this severity of presentation even in immunocompetent patients.

Vitamin C Deficiency as a Mimicker of Vasculitis: A Case | Annals of Internal Medicine: Clinical Cases

Scurvy causes poor wound healing, hemarthrosis, petechiae, perifollicular hemorrhages, and nonspecific myalgia. Although studies report that scurvy can mimic vasculitis on physical examination, the disease lacks the laboratory evidence for vasculitis. We introduce a patient with scurvy whose clinical presentation and laboratory findings mimicked vasculitis, which led to a delayed diagnosis and high resource expenditure. This case highlights the importance of early dietary history in patients with concern for vasculitis. Early dietary history and involvement of the nutrition team can significantly decrease invasive and costly testing procedures and improve diagnosis and patient outcomes.