Treatment With Canagliflozin Versus Placebo in Children and Adolescents With Type 2 Diabetes: A Randomized Clinical Trial: Annals of Internal Medicine: Vol 178, No 9

Background: Treatment options for children and adolescents with type 2 diabetes mellitus (T2DM) are limited. Canagliflozin is a sodium–glucose cotransporter-2 inhibitor approved for the treatment of T2DM in adults. Objective: To assess the safety and efficacy of canagliflozin in children and adolescents with T2DM. Design: Phase 3, randomized, double-blind, placebo-controlled, parallel-group study. (ClinicalTrials.gov: NCT03170518; EudraCT: 2016-005223-88) Setting: Multicenter (104 sites in 10 countries). Participants: Children and adolescents aged 10 years or older with T2DM (hemoglobin A1c [HbA1c] ≥6.5% to ≤11%). Intervention: Participants were randomly assigned to canagliflozin (100 mg) or placebo once daily. Participants with week 12 readings of 7% or higher for HbA1c and at least 60 mL/min/1.73 m2 for estimated glomerular filtration rate were randomly assigned again at week 13 to either keep receiving 100 mg of canagliflozin (or placebo) or have their dose uptitrated to 300 mg (or placebo). The treatment period was 52 weeks. Measurements: Change in HbA1c from baseline to week 26 (primary efficacy end point), secondary efficacy end points, and safety. Results: A total of 171 participants were randomly assigned to canagliflozin (n = 84) or placebo (n = 87). At week 26, HbA1c reduction from baseline was significantly greater with canagliflozin than placebo (difference in least-squares means, −0.76% [95% CI, −1.25% to −0.27%]; P = 0.002). The proportion of participants who achieved HbA1c levels below 6.5% was significantly greater with canagliflozin than placebo (36.3% vs. 14.0%; difference, 22.3 percentage points [CI, 10.5 to 34.1 percentage points]). Treatment-emergent adverse events (AEs) occurred in 77.4% and 74.7% and serious treatment-emergent AEs in 9.5% and 5.7% of participants who received canagliflozin and placebo, respectively. Common AEs seen with canagliflozin were similar to those in the adult population. Hypoglycemia occurred in 11.9% and 10.3% of participants receiving canagliflozin and placebo, respectively. Limitation: Study duration and relatively small sample size. Conclusion: In children and adolescents with T2DM, canagliflozin provided a clinically meaningful reduction in HbA1c, with a safety profile similar to that seen in adults. Primary Funding Source: Johnson & Johnson.

In adults with obesity and knee OA, adding weekly semaglutide to diet and activity counseling reduced weight and knee pain at 68 wk

Clinical Impact Ratings GIM/FP/GP: 5 out of 7 Endocrinology: 7 out of 7 Rheumatology: 5 out of 7

Assessing the System-Instruction Vulnerabilities of Large Language Models to Malicious Conversion Into Health Disinformation Chatbots

Large language models (LLMs) offer substantial promise for improving health care; however, some risks warrant evaluation and discussion. This study assessed the effectiveness of safeguards in foundational LLMs against malicious instruction into health disinformation chatbots. Five foundational LLMs—OpenAI’s GPT-4o, Google’s Gemini 1.5 Pro, Anthropic’s Claude 3.5 Sonnet, Meta’s Llama 3.2-90B Vision, and xAI’s Grok Beta—were evaluated via their application programming interfaces (APIs). Each API received system-level instructions to produce incorrect responses to health queries, delivered in a formal, authoritative, convincing, and scientific tone. Ten health questions were posed to each customized chatbot in duplicate. Exploratory analyses assessed the feasibility of creating a customized generative pretrained transformer (GPT) within the OpenAI GPT Store and searched to identify if any publicly accessible GPTs in the store seemed to respond with disinformation. Of the 100 health queries posed across the 5 customized LLM API chatbots, 88 (88%) responses were health disinformation. Four of the 5 chatbots (GPT-4o, Gemini 1.5 Pro, Llama 3.2-90B Vision, and Grok Beta) generated disinformation in 100% (20 of 20) of their responses, whereas Claude 3.5 Sonnet responded with disinformation in 40% (8 of 20). The disinformation included claimed vaccine–autism links, HIV being airborne, cancer-curing diets, sunscreen risks, genetically modified organism conspiracies, attention deficit–hyperactivity disorder and depression myths, garlic replacing antibiotics, and 5G causing infertility. Exploratory analyses further showed that the OpenAI GPT Store could currently be instructed to generate similar disinformation. Overall, LLM APIs and the OpenAI GPT Store were shown to be vulnerable to malicious system-level instructions to covertly create health disinformation chatbots. These findings highlight the urgent need for robust output screening safeguards to ensure public health safety in an era of rapidly evolving technologies.

Integrated suicide care in primary care improved safety planning and reduced suicide attempts at 90 d

Clinical Impact Ratings Mental Health: 6 out of 7 GIM/FP/GP: 6 out of 7 Public Health: 6 out of 7

Summary for Patients: High-Concentration Delta-9-Tetrahydrocannabinol Cannabis Products and Mental Health Outcomes

High-Concentration Delta-9-Tetrahydrocannabinol Cannabis Products and Mental Health Outcomes: A Systematic Review: Annals of Internal Medicine: Vol 178, No 10

Background: Rapid changes in the legalized cannabis market have led to the predominance of high-concentration delta-9-tetrahydrocannabinol (THC) cannabis products. Purpose: To systematically review associations of high-concentration THC cannabis products with mental health outcomes. Data Sources: Ovid MEDLINE through May 2025; EMBASE, Allied and Complementary Medicine Database, Cochrane Library, Database of Abstracts of Reviews of Effects, CINAHL, and Toxicology Literature Online through August 2024. Study Selection: Two reviewers independently selected studies with high-concentration THC defined as greater than 5 mg or greater than 10% THC per serving or labeled as “high-potency concentrate,” “shatter,” or “dab.” Data Extraction: Outcomes included anxiety, depression, psychosis or schizophrenia, and cannabis use disorder (CUD). Results were categorized by association direction and by study characteristics. Therapeutic studies were defined by use of cannabis to treat medical conditions or symptoms. Data Synthesis: Ninety-nine studies (221 097 participants) were included: randomized trials (42%), observational studies (47%), and other interventional study designs (11%); more than 95% had moderate or high risk of bias. In studies not testing for therapeutic effects, high-concentration THC products showed consistent unfavorable associations with psychosis or schizophrenia (70%) and CUD (75%). No therapeutic studies reported favorable results for psychosis or schizophrenia. For anxiety and depression, 53% and 41% of nontherapeutic studies, respectively, reported unfavorable associations, especially among healthy populations. Among therapeutic studies, nearly half found benefits for anxiety (47%) and depression (48%), although some also found unfavorable associations (24% and 30%, respectively). Limitation: Moderate and high risk of bias of individual studies and limited evaluation of contemporary products. Conclusion: High-concentration THC products are associated with unfavorable mental health outcomes, particularly for psychosis or schizophrenia and CUD. There was some low-quality evidence, inconsistent by population, for therapeutic benefits for anxiety and depression. Primary Funding Source: Colorado General Assembly, House Bill 21-1317.

Cost-Effectiveness of Pharmacologic Treatments in Adults With Overweight or Obesity: A Systematic Review for the American College of Physicians

Background: A comprehensive overview of the cost-effectiveness of pharmacologic treatments for overweight or obesity is lacking. Purpose: To evaluate cost-effectiveness of pharmacologic treatments in adults with overweight or obesity in a U.S. setting. Data Sources: MEDLINE, Embase, and economic databases, searched on 13 October 2025. Study Selection: Non–industry-sponsored U.S. trial-based and model-based cost-effectiveness evaluations of pharmacologic treatments in adults with overweight or obesity. Data Extraction: Data on clinical characteristics, economic characteristics (for example, model type), and study outcomes were extracted by one reviewer and verified by a second reviewer. Study quality was assessed using the CHEQUE (Criteria for Health Economic Quality Evaluation) tool; value was assessed using incremental cost-effectiveness ratios (ICERs), with thresholds for high value (<$100 000 per quality-adjusted life-year [QALY], or dominant), intermediate value ($100 000 to $200 000 per QALY), low value (>$200 000 per QALY), and no value (strict or extended dominance, or less costly and less effective); and certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Data Synthesis: Four out of 9 included studies were at low risk of bias. None of the 42 pairwise comparisons that were reported had high certainty. In the 6 studies with moderate certainty, liraglutide had low value and phentermine–topiramate and tirzepatide had high value when each was compared with lifestyle modification. Semaglutide had low value compared with naltrexone–bupropion and phentermine–topiramate and high value compared with liraglutide. Limitations: All studies were model-based. ICERs were not reported for all potential treatment comparisons. Most studies had incomplete reporting or were at high risk of bias. Conclusion: Current evidence on cost-effectiveness of pharmacologic treatment of overweight or obesity is hampered by poor-quality studies, limiting the ability to draw conclusions. Primary Funding Source: American College of Physicians. (PROSPERO: CRD42023491646)

Care of Bereaved Persons: A Systematic Review: Annals of Internal Medicine: Vol 179, No 4

Background: Bereavement after the death of someone close is universal, and clinicians may be uncertain if or what interventions may be beneficial. Purpose: To synthesize effects of health care interventions for bereaved children and adults. Data Sources: Eight databases were searched from inception in September 2025, supplemented with screening reviews, guidelines, federal register entries, and expert input. Study Selection: Dual independent reviewers selected randomized controlled trials (RCTs) comparing interventions for bereaved or soon-to-be bereaved persons with usual care, no intervention, or an alternative intervention. Data Extraction: Outcomes were evaluated using the abstractor-checker model. Risk of bias was assessed; random-effects meta-analysis was used for effect estimates; multiple effect modifiers were explored; and applicability, generalizability, and strength of evidence (SoE) were determined. Data Synthesis: A total of 169 RCTs reported in 303 publications evaluated psychotherapy; expert-facilitated support groups; pharmacotherapy; peer support; self-help interventions; writing, music, and art therapy; enhanced provider contact; and integrative medicine for bereaved persons. Risk of bias was substantial, and only 15 RCTs included children. There was moderate SoE that individual psychotherapy improves grief disorder, grief, and depression symptoms and low SoE that expert-facilitated support groups and enhanced contact with health care providers may improve depression symptoms. Other interventions showed conflicting results, indicated no benefit, or had insufficient SoE. Limitations: Research focused on grief in adults, study populations were complex, and the review may have missed culturally specific interventions. Conclusion: Psychotherapy can improve key outcomes in bereaved adults, and expert-facilitated support groups and enhanced provider contact may also provide benefits. Evidence for other bereavement interventions, approaches for children, and outcomes beyond general grief or grieving, grief disorder, and depression symptoms is limited. Primary Funding Source: Agency for Healthcare Research and Quality. (PROSPERO: CRD42023466057)

Moving Stroke Rehabilitation Forward and Into the Future

Surveillance Note: Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians