Current Issue Highlights

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    Does This Child Have a Concussion?

    May 05, 2026: 335(17):1515-1524

    Importance

    Concussion is a mild traumatic brain injury with associated abnormalities in brain function, rather than structural injury. An estimated 1.1 million to 1.9 million pediatric concussions occur annually in the US.

    Objective

    To determine the accuracy of clinical history and physical examination findings for identifying concussion in children and adolescents who have had a plausible mechanism of injury.

    Data Sources and Study Selection

    PubMed, Embase, ClinicalTrials.gov, Cochrane Library, CINAHL, Web of Science, and Google Scholar were searched from January 2002 through December 2025 without language restrictions. Observational studies including patients aged 2 to 18 years evaluated for concussion in outpatient, emergency, or inpatient settings were included.

    Data Extraction and Synthesis

    Four reviewers independently extracted study characteristics and diagnostic accuracy data and assessed study quality with the Rational Clinical Examination levels of evidence.

    Main Outcomes and Measures

    Sensitivity, specificity, and likelihood ratios (LRs) for symptoms and physical signs associated with concussion were calculated using random-effects meta-analysis when summary measures were appropriate.

    Results

    Of 7110 screened abstracts, 23 studies (level 4 evidence; case-control design) met inclusion criteria. The presence of mental fog (LR, 11.8-12.0; specificity, 0.96), noise sensitivity (LR, 6.9; 95% CI, 3.6-13.1; specificity, 0.94), nausea (LR, 6.7; 95% CI, 3.1-14.6; specificity, 0.93), and light sensitivity (LR, 6.4; 95% CI, 2.1-19.7; specificity, 0.93) were most useful for increasing the likelihood of a concussion diagnosis. The absence of headache was the most useful symptom for decreasing the likelihood of concussion (LR, 0.20; 95% CI, 0.10-0.39; sensitivity, 0.74). Signs that increased the likelihood of concussion were abnormal near-point convergence, which is the inability to maintain ocular convergence on a near target (LR, 7.0; 95% CI, 2.0-24.9; specificity, 0.97); abnormal smooth pursuits, which are jerky, irregular eye movements when tracking a target (LR, 6.5; 95% CI, 2.4-17.5; specificity, 0.96); and saccades, which are inaccurate or slow eye movements with overshooting or undershooting when looking between 2 or more targets (LR, 4.8; 95% CI, 1.8-13.1; specificity, 0.92); however, none of these findings had a sensitivity of more than 0.40. A consensus statement by the International Conference on Concussion in Sport recommends the Sport Concussion Assessment Tool to systematize the comprehensive evaluation of patients with symptoms concerning for concussion.

    Conclusions and Relevance

    While no single finding was sufficient to confirm or exclude concussion, the presence of mental fog, noise and light sensitivity, nausea, or ocular abnormalities were most useful to identify patients more likely to have had a concussion, while absence of a headache made a concussion less likely. These symptoms and signs are integrated into structured clinical assessments to support the clinical diagnosis and management of pediatric concussion.

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    Colorectal Cancer and Mortality Risk Among Older Adults With vs Without Adenoma on Prior Colonoscopy

    May 05, 2026: 335(17):1499-1506

    Importance

    Colorectal cancer (CRC) risk among older adults with prior adenoma is uncertain.

    Objective

    To estimate cumulative CRC risks, non-CRC mortality, and all-cause mortality among adults 75 years of age or older with vs without adenoma at prior colonoscopy (in the latter of whom, guidelines recommend against repeat colonoscopy screening).

    Design, Setting, and Participants

    Retrospective cohort study of older adults who underwent colonoscopy between January 1, 2006, and December 31, 2019, and prior to 75 years of age within the US Department of Veterans Affairs.

    Exposures

    Colonoscopy with vs without adenoma prior to 75 years of age.

    Main Outcomes and Measures

    Estimated cumulative incidence of CRC, CRC death, non-CRC death, and all-cause mortality for individuals with vs without adenoma at prior colonoscopy (incidence of CRC and CRC death were compared using the Gray test). For those with adenoma, incidence of CRC and non-CRC death were stratified based on 5 Veterans Affairs Frailty Index categories of increasing all-cause mortality risk (nonfrail, ≤0.10; prefrail, 0.11-0.20; mild frailty, 0.21-0.30; moderate frailty, 0.31-0.40; and severe frailty, >0.40).

    Results

    Of 91 952 individuals (median age, 71 [IQR, 69-73] years at last colonoscopy; 98% male) who had undergone colonoscopy prior to 75 years of age, there were 25 538 (27.8%) with adenoma vs 66 414 (72.2%) without adenoma. At 10-year follow-up, the cumulative incidence of CRC was 1.1% (95% CI, 0.8%-1.3%) in those with adenoma vs 0.7% (95% CI, 0.5%-0.8%) in those without adenoma (Gray test P < .001). At 10-year follow-up, the cumulative incidence of CRC death was 0.5% (95% CI, 0.3%-0.7%) in those with adenoma vs 0.4% (95% CI, 0.3%-0.5%) in those without adenoma (Gray test P = .005). The cumulative incidence of non-CRC death ranged from 46.9% to 48.4% at 10 years. For those with adenoma, incidence of CRC was substantially exceeded by the cumulative incidence of non-CRC death at 10-year follow-up across all frailty levels (ranged from 34.2% among nonfrail individuals to 82.0% among severely frail individuals).

    Conclusions and Relevance

    Adults 75 years of age or older with adenoma at prior colonoscopy were more likely to experience subsequent CRC and CRC death compared with those without adenoma, but cumulative risks were low and were far exceeded by competing risks for non-CRC death. Older adults may consider deprioritizing surveillance colonoscopy relative to other health concerns.

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    Cost-Effectiveness of ApoB, Non–HDL-C, and LDL-C Goals for Primary Prevention Lipid-Lowering Therapy

    May 05, 2026: 335(17):1507-1514

    Importance

    Apolipoprotein B (apoB) is a superior marker of residual atherosclerotic cardiovascular disease risk in patients treated with lipid-lowering therapy (LLT) compared with low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non–HDL-C). The cost-effectiveness of LDL-C, non–HDL-C, and apoB goals has not been established.

    Objective

    To determine the relative cost-effectiveness of intensifying LLT for primary prevention based on LDL-C, non–HDL-C, and apoB goals.

    Design, Setting, and Participants

    This economic evaluation used a computer simulation model to evaluate the cost-effectiveness of intensifying LLT with high-intensity statins or ezetimibe according to LDL-C, non–HDL-C, or apoB goals. A cohort of 250 000 statin-eligible and atherosclerotic cardiovascular disease–free US adults was constructed from 2005 to 2016 National Health and Nutrition Examination Survey participants (N = 4149). Individuals commenced the simulation after lipid screening and received statin therapy based on 2018 American Heart Association/American College of Cardiology guidelines. Model inputs were derived from national survey data, pooled longitudinal cohort studies, and published literature. Uncertainty was explored with traditional and probabilistic sensitivity analysis.

    Exposures

    Lipid-lowering therapy was intensified if individuals did not achieve treated LDL-C level less than 100 mg/dL, non–HDL-C level less than 118 mg/dL, or apoB level less than 78.7 mg/dL.

    Main Outcomes and Measures

    Lifetime quality-adjusted life-years (QALYs) and costs (in 2025 US dollars), discounted 3.0% annually. The primary outcome was the incremental cost-effectiveness ratio. Strategies were considered cost-effective if they cost less than $120 000 per QALY gained.

    Results

    Compared with an LDL-C goal, 965 QALYs (95% uncertainty interval [UI], −3551 to 5341 QALYs) would be gained with a non–HDL-C goal, alongside a $2.1 million (95% UI, −$94.2 million to $92.0 million) reduction in costs. Compared with a non–HDL-C goal, 1324 QALYs (95% UI, −2602 to 5669 QALYs) would be gained with an apoB goal, alongside a $40.2 million (95% UI, −$43.6 million to $134 million) increase in costs, yielding an incremental cost-effectiveness ratio of $30 300 per QALY gained. At a willingness-to-pay threshold of $120 000 per QALY gained, an apoB goal was optimal in 65% of probabilistic analyses and a non–HDL-C goal was optimal in 25%. The cost of apoB testing was marginal; higher costs reflected longer life expectancy and prolonged preventive treatment.

    Conclusions and Relevance

    The results of this computer simulation study suggest that apoB can be used as a cost-effective marker to guide primary prevention LLT and improve population health.

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    Discontinuation of Levothyroxine in Adults Aged 60 Years or Older

    May 05, 2026: 335(17):1491-1498

    Importance

    Many adults aged 60 years or older take the thyroid hormone levothyroxine, which is generally continued for life. However, it is uncertain whether long-term continuation is always necessary.

    Objective

    To determine the percentage of adults aged 60 years or older who can successfully discontinue levothyroxine treatment.

    Design, Setting, and Participants

    This single-group, prospective study included community-dwelling adults aged 60 years or older who were taking levothyroxine at a stable dosage (≤150 µg/d) for at least 1 year and had a thyrotropin (TSH) level of less than 10 mIU/L. The study was conducted at 58 general practices in the Netherlands. Participants were enrolled between January 2020 and July 2022 and final follow-up occurred on December 12, 2023.

    Interventions

    Open-label, protocol-driven, stepwise dose reduction with thyroid function testing performed at least 6 weeks after each reduction in levothyroxine dose.

    Main Outcomes and Measures

    The primary outcome was the proportion of participants who discontinued levothyroxine and had both a thyrotropin level of less than 10 mIU/L and a free thyroxine level within the reference range at 1 year after the start of discontinuation. The secondary outcomes included factors associated with successful discontinuation (demographics, thyroid function, dose) and thyroid-related quality of life.

    Results

    Of the 370 participants who started the levothyroxine discontinuation phase (median age, 70 [range, 60-89] years; 80% female; median thyrotropin level, 2.2 [range, 0.02-9.69] mIU/L; mean free thyroxine level, 1.21 [SD, 0.18] ng/dL), 366 completed final follow-up at 1 year. Of the 370 participants (median levothyroxine dose at baseline, 50 [range, 12.5-150] µg/d), 95 (25.7% [95% CI, 21.5%-30.4%]) successfully stopped taking levothyroxine and had a median thyrotropin level of 5.03 mIU/L (range, 1.56-9.40 mIU/L) and a mean free thyroxine level of 1.01 ng/dL (range, 0.80-1.43 ng/dL) at 1 year. Of the 95 participants who successfully discontinued levothyroxine, 46 (48.4% [95% CI, 38.6%-58.3%]) had a thyrotropin level of less than 4.8 mIU/L. Among the 88 participants taking a levothyroxine dose of 50 µg/d or lower, 56 (63.6%) successfully discontinued this treatment. Thyroid-related quality of life showed no clinically relevant changes overall from baseline to 1 year and stratified by successful levothyroxine discontinuation vs unsuccessful discontinuation.

    Conclusions and Relevance

    In this open-label, single-group prospective study, 25.7% of adults aged 60 years or older discontinued levothyroxine treatment while maintaining adequate thyroid function at 1 year. Evaluation of the need to continue levothyroxine should be considered in adults aged 60 years or older, particularly in those taking a dose of 50 µg/d or lower.

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    Diagnosis and Management of Resistant Hypertension

    April 28, 2026: 335(16):1428-1439

    Importance

    Hypertension, defined as office systolic blood pressure (SBP) 130 mm Hg or greater and/or diastolic blood pressure 80 mm Hg or greater, affects 43.9% of women and 49.5% of men in the US. Approximately 19.7% of patients treated for hypertension have apparent resistant hypertension (blood pressure ≥130/80 mm Hg) despite using 3 or more antihypertensive medications, preferably a renin-angiotensin system blocker, a calcium channel blocker, and a thiazide-type diuretic, at maximally tolerated doses.

    Observations

    Approximately 10% of patients treated for hypertension have true resistant hypertension confirmed with home or 24-hour ambulatory blood pressure monitoring to exclude white-coat hypertension (approximately 37.5% of apparent resistant hypertension) and after excluding medication nonadherence (approximately 50%) and secondary hypertension such as primary aldosteronism (approximately 5%-25%). Conditions associated with resistant hypertension include obesity, diabetes, chronic kidney disease, and sleep apnea. Resistant hypertension is associated with increased risk of cardiovascular death vs controlled blood pressure at 5 years to 10 years (absolute risk increase, 10.3% [95% CI, 8.7%-12.1%]). Lifestyle modifications for resistant hypertension include a low-sodium diet (<1500 mg/d), reducing or avoiding alcohol, 150 min/wk or more of aerobic exercise, and weight loss. Illicit drugs (eg, cocaine) and medications that increase blood pressure (eg, nonsteroid anti-inflammatory drugs, serotonin-norepinephrine reuptake inhibitors) should be avoided. Sleep apnea should be treated when diagnosis is confirmed. Pharmacologic optimization includes use of combination tablets of antihypertensives; intensifying diuretic therapy by using chlorthalidone; and sequential addition of antihypertensive medications using evidence-based algorithms. In a meta-analysis of 20 studies (9 randomized clinical trials [RCTs] and 11 observational studies [331 participants]), use of antihypertensive therapies that combine 2 to 3 medications into a single formulation reduced SBP by −3.99 mm Hg (95% CI, −7.92 to −0.07) vs equivalent doses given separately. For patients with apparent or true resistant hypertension who have an estimated glomerular filtration rate of 45 mL/min/1.73 m2 or greater and a serum potassium level of 4.5 mmol/L or less, adding spironolactone (25-50 mg/d) compared with placebo lowers office SBP by −13.3 mm Hg (95% CI, −17.89 to −8.72 [4 RCTs]) and 24-hour ambulatory SBP by −8.46 mm Hg (95% CI, −12.54 to −4.38 [2 RCTs]) in a network meta-analysis of 24 RCTs (3485 patients with resistant hypertension). A meta-analysis of 10 RCTs (2478 participants) reported that compared with a sham procedure, catheter-based renal denervation, which disrupts the sympathetic nerves in the renal artery walls, decreased 24-hour ambulatory SBP by −4.4 mm Hg (95% CI, −6.1 to −2.7) and office SBP by −6.6 mm Hg (95% CI, −9.7 to −3.6).

    Conclusions and Relevance

    True resistant hypertension affects 10% of patients treated for hypertension and is diagnosed after excluding white-coat hypertension, medication nonadherence, and secondary hypertension such as primary aldosteronism. First-line treatment includes lifestyle modifications, diuretic therapy with chlorthalidone, and combination tablets of antihypertensives. Spironolactone and renal denervation decrease blood pressure in patients with true resistant hypertension.

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    Peptic Ulcer Disease

    JAMA. December 3, 2024: 332(21):1832-1842

    Importance

    In the US, peptic ulcer disease affects 1% of the population and approximately 54 000 patients are admitted to the hospital annually for bleeding peptic ulcers.

    Observations

    Approximately 10% of patients presenting with upper abdominal pain in a primary care setting have a peptic ulcer as the cause of their symptoms. The principal causes of peptic ulcer disease are Helicobacter pylori infection, which affects approximately 42% of patients with peptic ulcer disease, and aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, which are etiologic factors in approximately 36% of people with peptic ulcer disease. Complications of peptic ulcer include bleeding (73% of patients), perforation (9% of patients), and pyloric obstruction (3% of patients). Annually, 10 000 people die of peptic ulcer disease in the US. Endoscopy definitively diagnoses peptic ulcer disease. Acid blockers, such as omeprazole, can heal peptic ulcers in approximately 80% to 100% of patients within 4 weeks, but gastric ulcers larger than 2 cm may require 8 weeks of treatment. Eradication of H pylori decreases peptic ulcer recurrence rates from approximately 50% to 60% to 0% to 2%. Discontinuing NSAIDs heals 95% of ulcers identified on endoscopy and reduces recurrence from 40% to 9%. When discontinuing an NSAID is not desirable, changing the NSAID (eg, from ketorolac to ibuprofen), adding a proton pump inhibitor such as omeprazole or lansoprazole, and eradicating H pylori with treatment such as bismuth, metronidazole, and tetracycline combined with omeprazole can reduce recurrence rates.

    Conclusions and Relevance

    Peptic ulcer disease is associated with increased hospitalization rates and mortality. Acid blocking with proton pump inhibitors, such as omeprazole or lansoprazole, is the primary treatment. Recurrence of ulcers can be prevented by eradicating H pylori if present and discontinuing aspirin or NSAIDs if applicable.

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    Povidone Iodine vs Chlorhexidine Gluconate in Alcohol for Preoperative Skin Antisepsis

    JAMA. August 20, 2024: 332(7):541-549

    Importance

    Preoperative skin antisepsis is an established procedure to prevent surgical site infections (SSIs). The choice of antiseptic agent, povidone iodine or chlorhexidine gluconate, remains debated.

    Objective

    To determine whether povidone iodine in alcohol is noninferior to chlorhexidine gluconate in alcohol to prevent SSIs after cardiac or abdominal surgery.

    Design, Setting, and Participants

    Multicenter, cluster-randomized, investigator-masked, crossover, noninferiority trial; 4403 patients undergoing cardiac or abdominal surgery in 3 tertiary care hospitals in Switzerland between September 2018 and March 2020 were assessed and 3360 patients were enrolled (cardiac, n = 2187 [65%]; abdominal, n = 1173 [35%]). The last follow-up was on July 1, 2020.

    Interventions

    Over 18 consecutive months, study sites were randomly assigned each month to either use povidone iodine or chlorhexidine gluconate, each formulated in alcohol. Disinfectants and skin application processes were standardized and followed published protocols.

    Main Outcomes and Measures

    Primary outcome was SSI within 30 days after abdominal surgery and within 1 year after cardiac surgery, using definitions from the US Centers for Disease Control and Prevention’s National Healthcare Safety Network. A noninferiority margin of 2.5% was used. Secondary outcomes included SSIs stratified by depth of infection and type of surgery.

    Results

    A total of 1598 patients (26 cluster periods) were randomly assigned to receive povidone iodine vs 1762 patients (26 cluster periods) to chlorhexidine gluconate. Mean (SD) age of patients was 65.0 years (39.0-79.0) in the povidone iodine group and 65.0 years (41.0-78.0) in the chlorhexidine gluconate group. Patients were 32.7% and 33.9% female in the povidone iodine and chlorhexidine gluconate groups, respectively. SSIs were identified in 80 patients (5.1%) in the povidone iodine group vs 97 (5.5%) in the chlorhexidine gluconate group, a difference of 0.4% (95% CI, −1.1% to 2.0%) with the lower limit of the CI not exceeding the predefined noninferiority margin of −2.5%; results were similar when corrected for clustering. The unadjusted relative risk for povidone iodine vs chlorhexidine gluconate was 0.92 (95% CI, 0.69-1.23). Nonsignificant differences were observed following stratification by type of surgical procedure. In cardiac surgery, SSIs were present in 4.2% of patients with povidone iodine vs 3.3% with chlorhexidine gluconate (relative risk, 1.26 [95% CI, 0.82-1.94]); in abdominal surgery, SSIs were present in 6.8% with povidone iodine vs 9.9% with chlorhexidine gluconate (relative risk, 0.69 [95% CI, 0.46-1.02]).

    Conclusions and Relevance

    Povidone iodine in alcohol as preoperative skin antisepsis was noninferior to chlorhexidine gluconate in alcohol in preventing SSIs after cardiac or abdominal surgery.

    Trial Registration

    ClinicalTrials.gov Identifier: NCT03685604

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