Harlan M. Krumholz

Background: The AoU (All of Us) Research Program aims to accelerate precision‐medicine research. To provide context for the generalizability of findings we benchmarked cardiovascular risk factors and established cardiovascular disease prevalence in AoU against nationally representative estimates. Methods: We included AoU participants enrolled between May 2017 and June 2022 and the NHANES (National Health and Nutrition Examination Survey) 2017 to March 2020 cycle. The AoU Survey cohort included participants who completed the Personal and Family Health History survey (N=185 232). AoU EHR included participants with linked electronic health record (EHR) (N=287 012). We identified cardiovascular risk factors and cardiovascular disease through survey questions in AoU Survey and NHANES, and Systematized Nomenclature of Medicine codes for AoU EHR. Results: AoU Survey and AoU EHR were older than NHANES (56.1±17 years and 57.6±17 years versus 47.5±18 years) with more female participants (64% and 60% versus 51.8%). Black participants were underrepresented in AoU Survey (9.1%) and overrepresented in AoU EHR (19.9%); 11.5% in NHANES. Prevalence of cardiovascular comorbidities in AoU Survey and NHANES were similar but lower in AoU Survey when age adjusted (eg, hypertension 31.7% in NHANES versus 19.7% in AoU Survey, diabetes 11.3% versus 8%). Black participants had higher unadjusted rates of hypertension, diabetes, coronary artery disease and congestive heart failure than NHANES. AoU EHR with its code‐based identification had higher unadjusted prevalence of most cardiovascular comorbidities; differences attenuated with age‐adjustment. Conclusions: AoU includes more historically underrepresented groups, but representation varies by whether cohorts are defined by survey versus EHR availability. Further, disease prevalence can change based on how conditions are ascertained.

Background: Randomized trials show substantial weight loss with semaglutide and tirzepatide under structured care, but little is known about whether patients in routine practice continue therapy, reach a maintenance dose, and have their weight measured. Objectives: To describe the first year after initiation of semaglutide or tirzepatide for obesity, including care patterns, maintenance-dose attainment, weight documentation, and total body weight loss (TBWL). Methods: This retrospective cohort study used Epic Cosmos, an electronic health record network of >350 US health systems, to identify adults with obesity and without diabetes who initiated injectable semaglutide or tirzepatide in 2024. Outcomes over 12 months included prescribing persistence, discontinuation, switching, add-on therapy, and reinitiation; attainment of Food and Drug Administration (FDA)-labeled maintenance doses; availability of follow-up weight; and TBWL across progressively restricted populations. Results: Among 743,153 adults (60.1% semaglutide; mean age, 48.5 years; 72.5% female), 12-month prescribing persistence was 29.9% for semaglutide and 35.9% for tirzepatide. FDA-labeled maintenance-dose attainment was 28.3% and 55.0%, respectively, and only 8.8% and 16.4% remained prescribing persistent at a maintenance dose with a recorded weight at 12 months. About half of initiators lacked a 12-month weight. Among all initiators, ≥5% TBWL was documented in 25.6% (semaglutide) and 30.4% (tirzepatide), rising to 51.9% and 61.9% among those with recorded weight, 66.1% and 79.5% among those also prescribing persistent, and 82.9% and 87.3% among those further at a maintenance dose. Conclusions: In routine practice, most patients initiating semaglutide or tirzepatide did not remain on therapy, reach a maintenance dose, and have weight documented through the first year. Documented weight loss was greatest among those completing each step of care, suggesting continuation, dose escalation, and monitoring as targets for improvement. CENTRAL ILLUSTRATION: Care Cascade and Weight-Loss Outcomes Among Semaglutide and Tirzepatide Initiators, Standardized to 100 Initiators. Numbers are per 100 initiators and were rounded so that categories at each step sum to the preceding step. At the 12-month dose step, prescribed dose was missing for 1 per 100 semaglutide initiators and <1 per 100 tirzepatide initiators.

Background: Hypertension is the leading modifiable risk factor for ischemic stroke, yet the adequacy of preventative hypertension care in routine clinical practice remains suboptimal, potentially representing missed opportunities for stroke prevention. We evaluated the association between hypertension care delivery and incident ischemic stroke. Methods: We conducted a retrospective, matched, nested case–control study among adults with hypertension using data from a large regional health system (2010–2024). Patients with a first‐ever ischemic stroke were matched 1:2 to controls on age, sex, race and ethnicity, and calendar time. Three care metrics were assessed: (1) outpatient visits with blood pressure measurement per year; (2) number of antihypertensive medication ingredients; and (3) medication intensification score. Conditional logistic regression estimated adjusted odds ratios. Results: The study included 13 476 cases and 26 952 matched controls. Cases had fewer blood pressure visits per year (median, 2.50 versus 3.01), similar number of medication ingredients (2.00 versus 2.00), and lower treatment intensification scores (−0.211 versus −0.125). Compared with ≤1 visit, >5 blood pressure visits per year was associated with lower stroke odds (adjusted odds ratio, 0.55 [95% CI, 0.51–0.59]). Use of 2 to 3 medication ingredients (versus 0) was also associated with reduced stroke odds (adjusted odds ratio, 0.80 [95% CI, 0.75–0.86]), whereas >3 ingredients was not. The highest quartile of treatment intensification showed the strongest association (adjusted odds ratio, 0.47 [95% CI, 0.44–0.51]). Findings were consistent across subgroup and sensitivity analyses. Conclusions: Greater engagement in hypertension care was associated with lower odds of ischemic stroke, suggesting that gaps in routine management may represent missed opportunities for prevention.

BACKGROUND: Antiphospholipid antibodies (aPL) are associated with an increased risk of thrombosis. However, individual studies have reported conflicting findings regarding the prevalence of aPL in patients with ischemic stroke and their association with first or recurrent events. METHODS: Systematic searches of PubMed and Embase through May 13, 2025 were conducted to identify case-control, cohort, or cross-sectional studies investigating 3 questions related to aPL seropositivity (defined as positivity for either immunoglobulin G/immunoglobulin M anticardiolipin antibody, immunoglobulin G/immunoglobulin M anti-β2 glycoprotein I antibody, or a lupus anticoagulant): (1) the prevalence of aPL seropositivity among individuals with ischemic stroke; (2) the association between aPL seropositivity and the risk of first ischemic stroke; and (3) the association between aPL seropositivity and the risk of recurrent ischemic stroke. Random-effects models with inverse weighting were used to calculate pooled prevalences and odds ratios (OR) with 95% CIs. Risk of bias was assessed using the ROBINS-I tool. RESULTS: A total of 52 studies were included (40 case-control, 12 cohort). The pooled prevalence of seropositivity for any aPL among patients with ischemic stroke (51 studies, 9438 patients) was 19.1% (95% CI, 15.4%–23.0%; I ² =95.8%). aPL seropositivity was associated with higher odds of first ischemic stroke (43 studies, 19 097 patients; OR, 2.93 [95% CI, 2.31–3.73]; I ² =68.7%). The strongest associations were for lupus anticoagulant (OR, 6.69 [95% CI, 2.94–15.2]; I ² =92.6%) and immunoglobulin G anticardiolipin antibody (OR, 2.56 [95% CI, 1.96–3.35]; I ² =92.5%). The odds of recurrent ischemic stroke among patients with versus without any aPL seropositivity were not significantly different (OR, 1.20 [95% CI, 0.87–1.67]; 9 studies, 2873 patients, I ² =11.4%). CONCLUSIONS: Seropositivity for any aPL was present in nearly 1-in-5 patients with ischemic stroke and was associated with increased odds of ischemic stroke at presentation.

Venous thromboembolism (VTE), including deep-vein thrombosis and pulmonary embolism, is the third most common cause of vascular death worldwide and a major contributor to costly and debilitating non-fatal complications. Despite the changing landscape of risk factors, preventive and diagnostic strategies, risk stratification and therapies, no contemporary global summary of the burden of VTE is available. In a collaborative, multinational effort, we provide a global overview of the incidence and outcomes of VTE. Reliable data were available for only a limited number of countries (predominantly in Northern America, Western Europe and Oceania), with notable regional differences. During 2012–2016, the global annual incidence of deep-vein thrombosis ranged from 25.1 to 131.5 per 100,000 of the population. The incidence of pulmonary embolism rose from 2012–2016 to 2017–2022 in Northern America and Asia but remained stable in Oceania. Among patients with pulmonary embolism, 30-day all-cause mortality ranged globally from 1.0% to 9.0%, and the 1-year cumulative incidence of recurrent VTE ranged from 2.9% to 8.1%. These findings reveal the substantial global burden of VTE, sources of heterogeneity and stark regional gaps in the data, demanding coordinated surveillance, standardized reporting and research into local and global drivers to curb worldwide morbidity and mortality.

Aims: Although enteric-coated aspirin is widely used instead of chewable formulations in patients with atherosclerotic cardiovascular disease (ASCVD), its effects on cardiovascular and gastrointestinal outcomes remain uncertain. Separately, air pollution is a driver of cardiovascular risk, yet individual-level interventions have not been tested in outcomes trials. Methods and results: The Coated Or Chewable Aspirin in Patients with Established AThErosclerotic Disease and a Hybrid Strategy to Mitigate the Adverse Effects of AIR Pollution (COATED-AIR) is a randomized trial with a 2 × 2 factorial design planned to address these knowledge gaps. Patients with ASCVD receiving low-dose aspirin are considered for inclusion. Major exclusion criteria consist of being within 72 h of acute/unstable ASCVD or revascularization, triple antithrombotic therapy, active/recent bleeding, life expectancy <1 year, or other barriers or unwillingness for enrolment. Eligible consenting patients are randomized, in a double-blind fashion, to enteric-coated vs. chewable aspirin 81 mg daily and (via factorial randomization) to a hybrid strategy to mitigate the adverse effects of air pollution vs. usual care. The hybrid strategy includes (i) an educational flashcard, (ii) real-time air quality alerts via cellular text messages, and (iii) recommendations to (a) limit outdoor activity or (b) use a KN-95 facemask when outdoors, or (c) increase citrus fruit intake on days with elevated pollution levels. The primary efficacy outcome for the aspirin randomization is a composite of fatal/non-fatal ischaemic stroke, thrombotic/thromboembolic myocardial infarction, and acute limb ischaemia. For the AIR randomization, other forms of cardiovascular death are additionally included in the primary composite outcome. The median planned duration of follow-up is 2 years. Enrolment was completed on 28 January 2026. Clinical follow-up and blinded event adjudications are ongoing. Conclusion: COATED-AIR will determine whether aspirin coating affects its safety or effectiveness, and whether individual-level strategies can mitigate cardiovascular risks from air pollution in patients with ASCVD.

For a more comprehensive understanding of health disparities, consideration must be given not only to morbidity and mortality outcomes but also to more holistic health-related constructs, such as well-being. We assessed differences in well-being across sociodemographic subgroups in the United States (US). We used data from the Gallup National Health and Well-being Index (2014–2016, n = 530,920) to assess independent cross-sectional associations of self-reported race, ethnicity, educational attainment, and rural residence with measures of well-being for non-institutionalized residents from 50 US states and the District of Columbia. Our outcome measures are thriving, calculated from self-reported current and future life evaluation, and the composite Well-Being Index (WBI), calculated from 38 self-reported metrics spanning 5 domains of well-being (Career, Community, Physical, Financial, Social). We summarized these measures for race-education-urban subgroups and tested for interactions among these three factors, before and after adjustment for year of survey completion, age, sex, marital status, household size, and income. Among our sample, 55% were thriving. After adjustment, higher levels of education were associated with increased odds of thriving: compared with those with no high school degree, we found higher odds of thriving for respondents reporting completion of high school/technical school/some college (OR=1.61(1.57,1.66)), college (OR=2.77(2.69,2.85)), and postgraduate (OR=3.38 (3.29,3.49)) education. Compared with White respondents, Black (OR (95% CI)=1.15 (1.12,1.17)) and Hispanic (OR=1.26 (1.23,1.29)) respondents had higher odds of thriving; results were similar for WBI, except Asian respondents had also higher WBI after adjustment for all covariates (OR=2.54 (2.28,2.80)). Across race-education-urban subgroups, non-White respondents with a college degree living in urban and rural areas had the highest odds of thriving; White respondents with no college degree living in urban areas had the lowest odds of thriving (p < 0.001 for each), after adjustment. These findings raise questions about how well-being is mediated given the known worse clinical health measures among minoritized groups.

The medical management of obesity has been transformed by the introduction of obesity medicines (OMs), based on the actions of glucagon-like peptide-1 and other nutrient-stimulated hormones, enabling the achievement of unprecedented weight reduction through pharmacotherapy. Here we review our current understanding of key issues surrounding obesity treatment, weight reduction, and improving health for people living with obesity. Key gaps in our knowledge of fundamental aspects of energy homeostasis are identified with a focus on their translational importance for improving outcomes. We discuss the utility of weight and health metrics, heterogeneity in achievement of clinical outcomes, individualization of treatment targets and goals, strengths and limitations of clinical trial, observational and real-world data (RWD), opportunities for improving the joint use of lifestyle management and OMs, gaps in our understanding of the long-term safety and side effects of current and emerging medicines, and the potential negative effects of losing weight. Collectively, while not intended as guidance for treatment, this document highlights the considerable progress and new research opportunities for interrogating basic and clinical science with the goal of translating advances in endocrine science into optimized outcomes for a broad range of individuals along the continuum of the weight journey.