Comparative Effectiveness of Carvedilol Versus Other Nonselective β-Blockers in Cirrhosis

Background: In cirrhosis, nonselective β-blockers (NSBBs; carvedilol, nadolol, and propranolol) reduce hepatic portal pressure and have demonstrated benefit versus placebo for preventing decompensation. Although carvedilol has emerged as the preferred NSBB, direct evidence remains limited about its effectiveness for preventing decompensation and death versus other NSBBs. Objective: To compare the effectiveness of carvedilol versus nadolol versus propranolol in cirrhosis. Design: Database cohort study. Setting: A U.S. administrative claims database, Optum Clinformatics Data Mart (2013 to 2025). Participants: Adults with cirrhosis initiating carvedilol, nadolol, or propranolol. Measurements: The primary outcome was a composite of hospitalization for major decompensation (ascites, spontaneous bacterial peritonitis [SBP], hepatorenal syndrome [HRS], hepatic encephalopathy, or variceal hemorrhage). Absolute risk differences (RDs) and risk ratios (RRs) at 6 months of follow-up were estimated using inverse probability of treatment weighting accounting for 129 preexposure covariates. Results: Carvedilol initiators had meaningfully lower 6-month risk for major decompensation events compared with nadolol (RD, −3.69 percentage points [95% CI, −5.33 to −2.09 percentage points]; RR, 0.80 [CI, 0.72 to 0.88]) or propranolol (RD, −2.88 percentage points [CI, −4.29 to −1.49 percentage points]; RR, 0.83 [CI, 0.76 to 0.90]). This included substantially lower 6-month risk for specific decompensation events with carvedilol compared with nadolol or propranolol, including reduced risk for variceal hemorrhage (RDs, −3.51 percentage points [CI, −4.79 to −2.20 percentage points] and −1.65 percentage points [CI, −2.71 to −0.59 percentage points], respectively) and ascites, SBP, or HRS (RDs, −3.05 percentage points [CI, −4.52 to −1.75 percentage points] and −1.58 percentage points [CI, −2.77 to −0.44 percentage points], respectively). Limitation: Nonrandomized treatment selection. Conclusion: Among U.S. patients with cirrhosis, carvedilol initiation—as opposed to nadolol or propranolol—was associated with meaningfully lower rates of major decompensation events. Primary Funding Source: National Institutes of Health.

Summary for Patients: Fluvoxamine and Metformin for Fatigue in Patients With Long COVID

The Effect of Fluvoxamine and Metformin for Fatigue in Patients With Long COVID: An Adaptive Randomized Trial: Annals of Internal Medicine: Vol 179, No 5

Background: Postacute sequelae of SARS-CoV-2, or long COVID, presents a major therapeutic challenge, with fatigue being a prevalent and debilitating symptom. Objective: To assess the efficacy of fluvoxamine and metformin for long COVID fatigue. Design: Randomized, placebo-controlled, adaptive trial. (ClinicalTrials.gov: NCT06128967) Setting: Outpatient sites in Brazil. Participants: 399 adults with fatigue persisting 90 or more days after confirmed SARS-CoV-2 infection. Intervention: Participants were randomly assigned to fluvoxamine (100 mg twice daily), metformin (750 mg twice daily), or matching placebo for 60 days. Measurements: The primary outcome was change in Fatigue Severity Scale (FSS) score. Results: Fluvoxamine showed a significant reduction in fatigue compared with placebo at day 60 (mean difference, −0.43 [95% credible interval {CrI}, −0.80 to −0.07]), with a sustained effect at day 90 (mean difference, −0.58 [CrI, −0.98 to −0.16]). Fluvoxamine also improved quality-of-life scores with high posterior probability. Metformin showed no significant benefit. Adverse events were less frequent with fluvoxamine (20.0%) than with metformin (28.8%) or placebo (29.7%). Grade 3 and higher adverse events were rare across all groups. Limitations: The 90-day follow-up period limits conclusions about the durability of treatment effects, and the exclusive focus on fatigue as the primary outcome does not address other prevalent long COVID symptoms, leaving fluvoxamine's broader therapeutic utility uncertain. Conclusion: Fluvoxamine, but not metformin, may be an effective treatment for reducing fatigue and improving quality of life in patients with long COVID. Primary Funding Source: The Latona Foundation.

Summary for Patients: Multisite External Validation of a Clinical Screening Tool for Interpersonal Firearm Violence Risk

Multisite External Validation of a Clinical Screening Tool for Interpersonal Firearm Violence Risk

Background: Screening tools for interpersonal firearm violence (FV) are needed to facilitate prevention. Objective: To validate the 4-item, 10-point SaFETy (Serious fighting, Friend weapon carrying, community Environment, and firearm Threats) score. Design: Prospective longitudinal study. Setting: 4 level 1 emergency departments (EDs) in 3 cities. Participants: Adults aged 18 to 24 years seen in an ED for any reason. Measurements: FV (shooting someone or being shot) 12 months after baseline from self-report and medical record review, SaFETy score, and self-reported baseline covariates (demographic characteristics; baseline assault injury; violence-related ED use in the past 6 months; drug misuse; anxiety, depression, and posttraumatic stress screening; and FV in the past 6 months). Results: Among 1506 participants (61.4% female; mean age, 21.3 years; 3.8% with assault injury at baseline), 12-month FV could be ascertained in 1122 (74.5%); of those, 73 (6.5%) had 12-month FV. For baseline SaFETy scores of 0, 1 to 5, and 6 or greater, 12-month FV rates were 1.8% (12 of 654), 12.1% (49 of 406), and 25.0% (10 of 40), respectively. The area under the receiver-operating characteristic (ROC) curve (AUC) for the score was 0.78 (95% CI, 0.72 to 0.83). The optimal ROC cut point was a SaFETy score greater than 0, with a sensitivity of 83.1% and specificity of 62.4%; a SaFETy score greater than 4 optimized positive predictive value (31.6%). Logistic regression of 12-month FV, including the full covariate set, examined estimated risks for patients grouped by SaFETy score and found that model-based predictions underestimated risk among those with SaFETy scores of 0 and overestimated risk among those with SaFETy scores of 1 to 5 or 6 or greater. Adding the SaFETy score to the full covariate set improved the predictions’ AUC (0.84 vs. 0.81; P = 0.025). The added contribution of the SaFETy score to predictions based only on variables typically available at triage (demographic data, ED visit reason, and recent ED use) was larger. Limitation: Outcomes were primarily self-reported, and the highest-risk subsamples were more likely to have missing data. Conclusion: The SaFETy score predicts FV risk in general samples of young adults in the ED. A comprehensive covariate set, involving factors that are difficult or intrusive to measure, did not reproduce the SaFETy score’s risk gradient or explain its discriminatory power, suggesting that the score provides distinct predictive information. Primary Funding Source: Centers for Disease Control and Prevention.

Stable Supportive Footwear for Self-managing Hip Osteoarthritis Pain: A Randomized Clinical Trial: Annals of Internal Medicine: Vol 179, No 4

Background: Few effective nonsurgical treatments exist for hip osteoarthritis. Footwear influences hip forces and may be a promising novel approach. Objective: To evaluate whether stable supportive shoes are more effective than flat flexible shoes for hip pain. Design: 2-group, pragmatic, comparative effectiveness, superiority randomized trial. (Australian New Zealand Clinical Trials Registry: ACTRN12621001532897) Setting: Community. Participants: 120 people with hip osteoarthritis pain. Intervention: Off-the-shelf stable supportive (n = 60) or flat flexible (n = 60) shoes that met prespecified criteria. Participants chose from options in their randomly assigned shoe group and were instructed to wear selected shoes at least 6 hours per day for 6 months. Measurements: The primary outcome was 6-month change in average hip pain on walking in the previous week (11-point scale; range, 0 to 10, with higher scores indicating worse pain). Secondary outcomes included other measures of pain, symptoms, function in daily living, function in sport and recreation, quality of life, physical activity, global improvement, and adverse events. Results: A total of 120 participants were randomly assigned, and 116 (97%) completed 6-month primary outcomes. Stable supportive shoes did not differ from flat flexible shoes in improving hip pain (mean difference [MD], −0.5 point [95% CI, −1.3 to 0.2 point]; P = 0.163). Few secondary outcomes differed by shoe type, but flat flexible shoes showed greater improvement in the Hip Disability and Osteoarthritis Outcome Score symptom subscale (MD, 6.6 points [CI, 1.4 to 11.7 points]) and quality-of-life subscale (MD, 7.8 points [CI, 1.1 to 14.4 points]), whereas stable supportive shoes showed more improvement in contralateral foot or ankle pain (MD, 0.8 point [CI, 0.0 to 1.5 points]). There were fewer adverse events in the stable supportive shoe group (n = 7 [12%]) than the flat flexible shoe group (n = 18 [31%]; relative risk, 0.39 [CI, 0.18 to 0.86]). Limitation: Unblinded participants. Conclusion: Stable supportive shoes were not superior to flat flexible shoes for improving hip osteoarthritis pain while walking. Primary Funding Source: National Health and Medical Research Council.

Chronic Coronary Artery Disease

Chronic coronary artery disease (CCAD) is a leading cause of death in the United States and many other countries. The defining pathobiology is an imbalance between the metabolic demands of the myocardium and oxygen supply, which most often results from coronary artery atherosclerosis. The classic presenting symptom of CCAD is angina, but clinical presentation varies greatly among patients. Since the last In the Clinic on CCAD (previously termed “stable ischemic heart disease”) in 2019, several new medications have been approved to reduce ischemic complications.

Expression of Concern: Medical Masks Versus N95 Respirators for Preventing COVID-19 Among Health Care Workers

Cannabis-Based Products for Chronic Pain: An Updated Systematic Review: Annals of Internal Medicine: Vol 179, No 2

Background: Benefits and harms of cannabinoids for chronic pain are uncertain. Purpose: To update an evidence synthesis on cannabinoids for chronic pain. Data Sources: Ovid MEDLINE, PsycINFO, Embase, the Cochrane Library, and Scopus to 28 July 2025. Study Selection: Randomized placebo-controlled trials. Data Extraction: Data extraction, risk of bias, and strength of evidence were dually reviewed. Cannabinoids were categorized by tetrahydrocannabinol (THC)-to-cannabidiol (CBD) ratio (high, comparable, or low), source (synthetic, purified, extracted), and administration method. Data Synthesis: 25 short-term (1 to 6 months) randomized controlled trials (n = 2303; 64% neuropathic pain) assessed cannabinoids. Oral synthetic/purified high THC-to-CBD (THC only) may slightly reduce and oromucosal, extracted, comparable THC-to-CBD ratio products probably slightly reduce pain severity (pooled differences, −0.78 and −0.54 points, respectively, [0 to 10 scale]), with moderate or large increased dizziness, sedation, and nausea. Among THC-only products, nabilone moderately reduced pain severity but dronabinol did not (pooled differences, −1.59 and −0.23 points, respectively). Low THC-to-CBD interventions may not improve outcomes. Although low THC-to-CBD mixed THC/CBD products may increase dizziness, sedation, and nausea, CBD alone may not increase harms. Limitation: Variability within categories; lack of product details; unclear U.S. availability of studied products; restricted to English-language studies. Conclusion: Comparable and high THC-to-CBD ratio cannabinoid products may result in small improvements in pain and increased common adverse events during short-term treatment of primarily neuropathic pain; among high-ratio THC-only products, nabilone (but not dronabinol) reduced pain. Low THC-to-CBD products may not improve outcomes. Studies are needed on long-term outcomes and other cannabis product types. Primary Funding Source: Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services (PROSPERO: CRD42021229579).

Immigration Enforcement Tactics and Systemic Health Harms: The Ethical Imperative for Medical Advocacy