AIMS:Pulmonary abnormalities are commonly reported in heart failure (HF) and may have prognostic implications. Current evidence is limited to high-income countries. We examined the relationship between forced expiratory volume in 1 second (FEV1), HF burden, and long-term clinical outcomes in a diverse multi-national HF cohort. METHODS AND RESULTS:In a sub-study within the multinational Global Congestive Heart Failure registry, which collected clinical data including spirometry from HF participants in 28 high-, middle-, and low-income countries, and followed for a median 3.8 (IQR 2.1, 5.0) years. Baseline FEV1 was transformed into z-scores standardized for age, sex, and height. The association between baseline FEV1 with all-cause mortality, cardiovascular (CV) deaths, and all-cause hospitalizations was examined. FINDINGS:The analysis included 3359 HF participants (mean age 61.9 [SD 14.1] years, 66.4% males). Participants with lower FEV1 z-scores, even within the normal range (z-score>-2), showed increasing burden of HF, cardiac structural and functional impairment, and lower health-related quality of life. FEV1 z-score ≤ -2 was independently associated with higher risks of all-cause (HR 2.20 [95%CI 1.61-3.01]), CV mortality (HR 2.45 [1.64-3.66]), and hospitalizations (HR 1.40 [1.12-1.74]). The effect sizes were comparable to those of other major prognostic factors. The association was consistent across populations from diverse socio-economic development, HF aetiology, HF types, and airflow obstruction. CONCLUSION:In a diverse, multi-national HF cohort, reductions in FEV1 were independently associated with higher HF burden and poor health outcomes. The effect of lower FEV1 was generalizable across the HF spectrum and comparable to other major established HF prognostic factors.

Background: Anticoagulation did not reduce the risk of stroke recurrence compared with antiplatelet therapy in randomized controlled trial (RCT) participants with embolic stroke of undetermined source (ESUS). Subsequent analyses of individual RCTs suggested a benefit of anticoagulation in particular subgroups, but these findings have not been consistently replicated. We aimed to determine the effect of anticoagulation in ESUS patients and pre-specified subgroups using pooled RCT data. Methods: We performed an individual participant data meta-analysis (IPD-MA) of published RCTs comparing anticoagulation with antiplatelet therapy after ESUS on the primary outcomes of stroke recurrence and major bleeding, in addition to other secondary cardiovascular endpoints. The effect of anticoagulation on the risk for stroke recurrence compared with aspirin was further explored in subgroups predefined by baseline demographics, medical comorbidities, concomitant medication use, and echocardiographic and electrocardiographic parameters. Databases from individual RCTs were obtained and hazard ratios (HRs) with corresponding 95% confidence intervals (95%CIs) in the overall trial population and subgroups were estimated following adjustment for predefined covariates, using Cox proportional hazard models. Adjusted HRs were then combined into pooled estimates using the random-effects model. Differences between subgroups were assessed using Cochran's Q test of heterogeneity. The protocol of the IPD-MA is published in PROSPERO (CRD42025644724). Results: We included 4 RCTs with a total of 13,970 participants (mean age 66 years; 39% female). Baseline characteristics were well balanced between the treatment groups (Figure 1). Participants allocated to anticoagulant therapy (n=6,989) had comparable risks of stroke recurrence (adjusted HR=0.94, 95%CI: 0.78-1.14) and major bleeding (adjusted HR=1.21, 95%CI: 0.52-2.80) compared with participants allocated to antiplatelet therapy (n=6,981). We identified no significant difference in secondary efficacy or safety cardiovascular endpoints (Figure 2). We did not identify any predefined subgroup in which the effect of anticoagulation significantly differed from antiplatelet therapy (Figure 3). Conclusion: Anticoagulation did not reduce the risk for stroke recurrence or other cardiovascular events after ESUS when compared with antiplatelet therapy. None of the predefined subgroups benefitted from anticoagulation.

Background Most population studies examining heart failure (HF) have been conducted in Western high-income countries (HICs), with limited comparable data from lower-income settings. Objectives The aims of this study were to describe differences in HF incidence and 30-day, 1-year, and 5-year case fatality rates among HF patients from countries at different income levels and in different global regions and to examine the impact of common and potentially modifiable risk factors for incident HF. Methods This analysis of the PURE (Prospective Urban Rural Epidemiology) study included 172,653 individuals from 25 HICs, upper middle-income countries (UMICs), lower middle-income countries (LMICs), and low-income countries (LICs) and 8 geographic regions of the world, followed for a median of 15 years. Age- and sex-standardized HF incidence, as well as 30-day, 1-year, and 5-year HF case fatality, were compared by income group and by geographic region. The population attributable fractions (PAFs) for incident HF related to 13 cardiometabolic, lifestyle, socioeconomic, environmental, and psychosocial risk factors were also estimated. Results The standardized rate of incident HF was 0.39 (95% CI: 0.36-0.41) per 1,000 person-years overall; the rate was highest in UMICs (0.58; 95% CI: 0.52-0.64), followed by HICs (0.36; 95% CI: 0.30-0.43), then LMICs (0.34; 95% CI: 0.30-0.38), and then LICs (0.26; 95% CI: 0.22-0.30). Among regions, the highest HF incidence was in sub-Saharan Africa (1.18; 95% CI: 0.95- 1.41) and Europe and Central Asia (0.86; 95% CI: 0.72-1.00) and lowest in South Asia (0.19; 95% CI: 0.15-0.22). Thirty-day case fatality was highest in LICs (59%) and lowest in HICs (11%); it was highest in South Asia (63%) and sub-Saharan Africa (63%) and lowest in North America (12%). Five-year case fatality after HF diagnosis was highest in LICs (77%) and lowest in HICs (28%); it was highest in South Asia (81%) and sub-Saharan Africa (75%) and lowest in North America (25%). More than 71% of the PAF for HF was attributable to the 13 modifiable risk factors studied, the largest being hypertension (PAF = 25%). Conclusions HF incidence and associated mortality vary substantially across countries at different levels of economic development and by geographic region. Hypertension is the largest population-level risk factor for HF globally. Preventive measures, early diagnosis, and access to guideline-directed medical therapy should be prioritized to reduce global disparities in HF incidence and mortality.

BACKGROUND & AIMS:Gastrointestinal bleeding (GIB) is common in patients with cardiovascular (CV) disease, but a complete understanding of subsequent outcomes is unknown. We assessed outcomes after GIB in patients with CV disease. METHODS:INTERBLEED is an international multicenter prospective study comparing adults with CV disease (coronary or peripheral arterial disease, heart failure, atrial fibrillation, cerebrovascular disease, or venous thromboembolic disease) with GIB to those without. Outcomes included major adverse cardiovascular events (MACE; myocardial infarction, stroke, or CV-related death), all-cause death, and recurrent GIB at 12 months. Multivariable regression modelling yielded odds ratios (ORs) with 95% confidence intervals (CIs), and reverse Kaplan-Meier curves were created. RESULTS:A total of 3814 patients were enrolled: 1612 patients with GIB and 2202 without. On multivariable analyses, patients with CV disease experiencing GIB were more likely to die within 12 months (OR, 2.29; 95% CI, 1.24-4.19). GIB was associated with recurrent GIB (OR, 4.28; 95% CI, 2.80-6.53) but not MACE. However, resumption of antithrombotic therapy between 4 and 7 days (OR, 0.37; 95% CI, 0.17-0.83) or 8 and 30 days (OR, 0.37; 95% CI, 0.17-0.81) after GIB were associated with lower odds of MACE within 12 months compared with discontinuation or lack of resumption within 60 days. Any antithrombotic use after enrollment was associated with lower all-cause death (OR, 0.45; 95% CI, 0.28-0.71). Neither antithrombotic use nor early resumption was associated with higher odds of recurrent GIB. CONCLUSIONS:GIB in patients with CV disease is independently associated with subsequent morbidity and mortality. Patterns in antithrombotic resumption were associated with outcomes. Further research into optimal antithrombotic management after GIB is essential.

BACKGROUND:Uptake of drugs for primary and secondary prevention of cardiovascular disease is low in many countries. Single-pill combination (SPC) therapies consisting of a statin and 1 or more antihypertensive drugs, with or without aspirin, can reduce rates of fatal and nonfatal cardiovascular disease, but their use is currently limited. OBJECTIVES:The authors modeled the potential impact of widespread adoption of SPC therapies over 2023 to 2050. METHODS:We used state-transition and demographic modeling approaches to project ischemic heart disease- and stroke-related deaths and nonfatal events in 182 countries. We modeled the effects of programs to roll out primary and secondary prevention SPCs in 2 scenarios, compared to non-SPC (current) care: 1) targeted strategies to improve adherence and reduce therapeutic inertia among persons already in care; and 2) population-based strategies to provide SPC therapies to most persons at intermediate-to-high risk. We conducted sensitivity analyses around our assumptions on adoption, long-term adherence, and the effect of aspirin. RESULTS:Over 2023-2050, use of SPC therapies could prevent up to 29 million deaths and 51 million cases in the targeted scenario and up to 72 million deaths and 130 million cases in the population scenario. The greatest share of fatal and nonfatal events prevented would be in South and East Asia and the Pacific because of population size. SPC therapies could reduce all-cause premature mortality by 2.0% (targeted) to 3.2% (population), facilitating achievement of global health targets. CONCLUSIONS:SPC therapies could substantially accelerate progress on cardiovascular disease mortality by increasing use of preventive drugs, especially in settings where uptake is currently low.

Objectives Dose-response meta-analysis (DRMA) is a crucial clinical and epidemiological research tool for synthesizing exposure-risk relationships. Despite its growing use, facilitated by the availability of statistical software, the appropriateness of the underlying statistical methods has not been thoroughly explored. This study aims to evaluate the reporting quality of key statistical measures in DRMA and compare their performance using empirical datasets. Study Design and Setting We performed a systematic literature search to identify relevant studies, from which we extracted datasets and study characteristics. We fitted linear, quadratic polynomial and restricted cubic spline (RCS) models with fixed and non-fixed knots selection procedures. Key measures assessed included non-linearity, goodness-of-fit (GoF), model comparison, and the impact of outlying studies on statistical results. We compared P-values for non-linearity, GoF test for each model pair, and used the Akaike information criterion for model comparison. We evaluated the influence of individual studies on non-linearity and GoF using a leave-one-out (LOO) approach. Results We included 146 unique DRMA studies, from which 242 datasets were extracted with median (interquartile range) of 9 (7, 14) individual studies. While the non-linearity test was conducted in 102/124 (82.3%) studies, other measures were infrequently reported. Only 13/146 (10.0%) studies assessed GoF, 10/79 (12.7%) provided model comparison results, and 46/146 (31.5%) examined the impact of outlying studies. Our reanalysis of 242 datasets demonstrated that the RCS model with a non-fixed knots selection procedure identified more non-linearity (110/242, 45.5%) and fitted well (205/242, 84.7%) than other models. The LOO approach showed that conclusions regarding non-linearity and GoF changed in approximately 50% of cases after excluding a single study, regardless of the model used. Conclusion Our analysis reveals suboptimal attention to key statistical issues in published DRMA studies. RCS with non-fixed knots selection have shown potential advantages than a few other alternative modeling approaches. To strengthen the credibility of meta-analytic findings, it is advisable for researchers to integrate both clinical judgment and rigorous statistical model evaluation in their analyses. The LOO assessment underscores the necessity for methods that can identify and accommodate outlying studies in DRMA.

Abstract Aims Risk prediction indices used in worsening heart failure (HF) vary in complexity, performance, and the type of datasets in which they were validated. We compared the performance of seven risk prediction indices in a contemporary cohort of patients hospitalized for HF. Methods and results We assessed the performance of the Length of stay and number of Emergency department visits in the prior 6 months (LE), Length of stay, number of Emergency department visits in the prior 6 months, and admission N‐Terminal prohormone of brain natriuretic peptide (NT‐proBNP (LENT), Length of stay, Acuity, Charlson co‐morbidity index, and number of Emergency department visits in the prior 6 months (LACE), Get With The Guidelines Heart Failure (GWTG), Readmission Risk Score (RRS), Enhanced Feedback for Effective Cardiac Treatment model (EFFECT), and Acute Decompensated Heart Failure National Registry (ADHERE) risk indices among consecutive patients hospitalized for HF and discharged alive from January 2017 to December 2019 in a network of hospitals in England. The primary composite outcome was 30‐day all‐cause mortality or readmission. We assessed model discrimination and overall accuracy using the C‐statistic (higher values, better) and Brier score (lower values, better), respectively. Among 1206 patients in the cohort, 45.0% were female, mean (SD) age was 76.6 (11.7) years, and mean (SD) left ventricular ejection fraction was 43.0% (11.6). At 30 days, 236 (19.6%) patients were readmitted and 28 (2.3%) patients died, with 264 (21.9%) patients experiencing either readmission or death. The LENT index offered the combination of greatest risk discrimination and accuracy for the primary composite outcome (C‐statistic: 0.97; 95% CI 0.96, 0.98; 0.29; Brier score: 0.05). The LE (C‐statistic: 0.95; 95% CI 0.93, 0.96; Brier score: 0.06) and LACE (C‐statistic: 0.90; 95% CI 0.88, 0.92; Brier score 0.09) indices had high discrimination and accuracy. Discrimination and accuracy were modest with the RRS (C‐statistic: 0.65; 95% CI 0.61, 0.69; Brier score: 0.16) and EFFECT (C‐statistic: 0.64; 95% CI 0.60, 0.67; Brier score: 0.16) score; and poor with the GWTG‐HF (C‐statistic: 0.62; 95% CI 0.58, 0.66; Brier score: 0.17) and ADHERE (C‐statistic: 0.54; 95% CI 0.50, 0.57; Brier score: 0.17) scores. Conclusions In a study that compared the performance of seven risk prediction indices in a contemporary cohort of patients hospitalized for HF, the simple LENT index offered the greatest combination of discrimination and accuracy for the primary composite outcome of 30‐day all‐cause mortality or readmission. This three‐variable index ‐using length of hospital stay, preceding emergency department visits and admission NT‐proBNP level‐ is a practical and reliable way to assess prognosis following hospitalization for HF.

AIMS:This study aimed to identify and quantify the importance of risk factors for gastrointestinal (GI) bleeding in patients with CV disease. METHODS:We conducted a case-control study in 9 countries in Asia, America, Europe, and Australia. Cases were patients with CV disease with GI bleeding. Controls were patients with CV without a history of GI bleeding. All participants completed a baseline standardized assessment. We calculated adjusted odds ratios (ORs) and average population attributable fractions (aPAFs) with 95% confidence intervals (CIs). RESULTS:Between September 2015 and December 2022, we enrolled 2,519 cases and 2,202 controls. Independent risk factors for GI bleeding were age (age 71+: OR 4.16, 95% CI 3.48-4.97; age 61-70: OR 1.69, 95% CI 1.39-2.04; age ≤60 as reference), underweight (OR 3.38, 95% CI 2.24-5.10; aPAF 1.6%, 95% CI 1.0-2.0%), current smoker (OR 1.31; 95% CI 1.09-1.58; aPAF 1.5%, 95% CI 0.6-2.5); chronic kidney disease (OR 1.86, 95% CI 1.62-2.14; aPAF 8.8%, 95% CI 7.0-9.6%), prior stroke (OR 1.56, 95% CI 1.30-1.88, aPAF 2.6%, 95% CI 1.2-4.0%), glucocorticoids (OR 1.71, 95% CI 1.34-2.16, aPAF 1.8%, 95% CI 1.3-2.9%), NSAIDs or COX-2 inhibitors (OR 1.82, 95% CI 1.45-2.29; aPAF 2.2%, 95% CI 1.3-3.0%), liver disease (OR 3.68, 95% CI 2.77-4.89; aPAF 3.5%, 95% CI 2.8-4.2%), peptic ulcer disease (OR 3.38, 95% CI 2.66-4.31; aPAF 4.8%, 95% CI 3.8-5.7%), diverticular disease (OR 1.81, 95% CI 1.46-2.24; aPAF 2.8%, 1.9-3.6%) and antithrombotic therapy within 6 months (aPAF 7.6%, 95% CI 4.3-12.8%). Overall aPAF adjusted for age, sex and region was 37.3% (95% CI 33.0-42.2%). CONCLUSION:Potentially modifiable risk factors are associated with only about one third of the aPAF for GI bleeding.

BACKGROUND:The HOPE 4 trial (Heart Outcomes Prevention and Evaluation 4) investigated the effectiveness of a comprehensive, collaborative model of care, implemented in Colombia and Malaysia, which aimed to reduce cardiovascular disease risk in individuals with hypertension. One component of this intervention was the nomination of a treatment supporter, where participants could select a family member or friend to assist them with their care. The purpose of this study was to investigate the impact of these individuals on participant outcomes, as well as the relationship dynamics between participants and their treatment supporter.METHODS:Participants in the HOPE 4 intervention group with baseline and 12 months of follow-up were included for analysis. They were divided into Every Visit (n=339) and <Every Visit (n=268) groups based on whether they had a treatment supporter for all 5 or for <5 follow-up visits, respectively. Outcomes were stratified between groups and tested for significance using a generalized linear mixed-effects model. A survey investigating participant satisfaction with their treatment supporter was administered at 12 months.RESULTS:Groups were majority female (53% versus 62%) with a mean age of 63 and 66 years. Country of origin differed between groups (22% versus 86%; Colombia). A 15.5% ([95% CI, 6.2%-24.8%] P=0.004) greater increase in statin medication use was reported in the Every Visit group at 12 months compared with the <Every Visit group. Sixty-one percent versus 48.2% of participants reported high medication adherence at 12 months (P<0.003). The difference in change in systolic blood pressure between groups was not found to be significant at 12 months, though it favored the Every Visit group (-2.3 [95% CI, -6.1 to 1.5]; P=0.045). The majority of survey respondents from either study group strongly agreed that having a treatment supporter positively influenced their health.CONCLUSIONS:Long-term support from a nominated treatment supporter was associated with improved adherence, risk factor management, and medication use among individuals with hypertension.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01826019.

Background The focus of most epidemiological studies has been mortality or clinical events, with less information on activity limitations related to basic daily functions and their consequences. Standardised data from multiple countries at different economic levels in different regions of the world on activity limitations and their associations with clinical outcomes are sparse. We aimed to quantify the prevalence of activity limitations and use of assistive devices and the association of limitations with adverse outcomes in 25 countries grouped by different economic levels. Methods In this analysis, we obtained data from individuals in 25 high-income, middle-income, and low-income countries from the Prospective Urban Rural Epidemiological (PURE) study (175 660 participants). In the PURE study, individuals aged 35-70 years who intended to continue living in their current home for a further 4 years were invited to complete a questionnaire on activity limitations. Participant follow-up was planned once every 3 years either by telephone or in person. The activity limitation screen consisted of questions on self-reported difficulty with walking, grasping, bending, seeing close, seeing far, speaking, hearing, and use of assistive devices (gait, vision, and hearing aids). We estimated crude prevalence of self-reported activity limitations and use of assistive devices, and prevalence standardised by age and sex. We used logistic regression to additionally adjust prevalence for education and socioeconomic factors and to estimate the probability of activity limitations and assistive devices by age, sex, and country income. We used Cox frailty models to evaluate the association between each activity limitation with mortality and clinical events (cardiovascular disease, heart failure, pneumonia, falls, and cancer). The PURE study is registered with ClinicalTrials.gov, NCT03225586. Findings Between Jan 12, 2001, and May 6, 2019, 175 584 individuals completed at least one question on the activity limitation questionnaire (mean age 506 years [SD 98]; 103 625 [59%] women). Of the individuals who completed all questions, mean follow-up was 107 years (SD 44). The most common self-reported activity limitations were difficulty with bending (23 921 [136%] of 175 515 participants), seeing close (22 532 [134%] of 167 801 participants), and walking (22 805 [130%] of 175 554 participants); prevalence of limitations was higher with older age and among women. The prevalence of all limitations standardised by age and sex, with the exception of hearing, was highest in low-income countries and middle-income countries, and this remained consistent after adjustment for socioeconomic factors. The use of gait, visual, and hearing aids was lowest in low-income countries and middle-income countries, particularly among women. The prevalence of seeing close limitation was four times higher (6257 [165%] of 37 926 participants vs 717 [40%] of 18 039 participants) and the prevalence of seeing far limitation was five times higher (4003 [106%] of 37 923 participants vs 391 [22%] 2 2%] of 18 038 participants) in low-income countries than in high- income countries, but the prevalence of glasses use in low-income countries was half that in high-income countries. Walking limitation was most strongly associated with mortality (adjusted hazard ratio 132 [95% CI 125-139]) and most consistently associated with other clinical events, with other notable associations observed between seeing far limitation and mortality, grasping limitation and cardiovascular disease, bending limitation and falls, and between speaking limitation and stroke. Interpretation The global prevalence of activity limitations is substantially higher in women than men and in lowincome countries and middle-income countries compared with high-income countries, coupled with a much lower use of gait, visual, and hearing aids. Strategies are needed to prevent and mitigate activity limitations globally, with particular emphasis on low-income countries and women.

Importance Rheumatic heart disease (RHD) remains a public health issue in low- and middle-income countries (LMICs). However, there are few large studies enrolling individuals from multiple endemic countries. Objective To assess the risk and predictors of major patient-important clinical outcomes in patients with clinical RHD. Design, Setting, and Participants Multicenter, hospital-based, prospective observational study including 138 sites in 24 RHD-endemic LMICs. Main Outcomes and Measures The primary outcome was all-cause mortality. Secondary outcomes were cause-specific mortality, heart failure (HF) hospitalization, stroke, recurrent rheumatic fever, and infective endocarditis. This study analyzed event rates by World Bank country income groups and determined the predictors of mortality using multivariable Cox models. Results Between August 2016 and May 2022, a total of 13 696 patients were enrolled. The mean age was 43.2 years and 72% were women. Data on vital status were available for 12 967 participants (94.7%) at the end of follow-up. Over a median duration of 3.2 years (41 478 patient-years), 1943 patients died (15% overall; 4.7% per patient-year). Most deaths were due to vascular causes (1312 [67.5%]), mainly HF or sudden cardiac death. The number of patients undergoing valve surgery (604 [4.4%]) and HF hospitalization (2% per year) was low. Strokes were infrequent (0.6% per year) and recurrent rheumatic fever was rare. Markers of severe valve disease, such as congestive HF (HR, 1.58 [95% CI, 1.50-1.87]; P < .001), pulmonary hypertension (HR, 1.52 [95% CI, 1.37-1.69]; P < .001), and atrial fibrillation (HR, 1.30 [95% CI, 1.15-1.46]; P < .001) were associated with increased mortality. Treatment with surgery (HR, 0.23 [95% CI, 0.12-0.44]; P < .001) or valvuloplasty (HR, 0.24 [95% CI, 0.06-0.95]; P = .042) were associated with lower mortality. Higher country income level was associated with lower mortality after adjustment for patient-level factors. Conclusions and Relevance Mortality in RHD is high and is correlated with the severity of valve disease. Valve surgery and valvuloplasty were associated with substantially lower mortality. Study findings suggest a greater need to improve access to surgical and interventional care, in addition to the current approaches focused on antibiotic prophylaxis and anticoagulation.

New-onset post-operative atrial fibrillation (POAF) occurs in 25-50% of patients after cardiac surgery. In some patients, POAF is a transient entity, while in others it represents a first presentation of paroxysmal or persistent AF. The long-term AF recurrence rate in patients with POAF is unknown. This study estimates the AF recurrence rate in patients with new-onset POAF following cardiac surgery as evaluated with an implantable loop recorder (ILR).

Investigators often conduct randomized controlled trials (RCTs) at multiple centers/sites when determining the effect of a treatment or an intervention. Diversifying recruitment across multiple institutions allows investigators to make recruitment go faster within a shorter timeframe and allows generalizing the study results across diverse populations. Despite having a common study protocol across multiple centers, the eligible participants may be heterogeneous, site policies and practices may vary, and the investigators’ experience, training, and expertise may also vary across sites. These factors may contribute to the heterogeneity in effect estimates across centers. As a result, we usually observe some degree of heterogeneity in effect estimates across centers, despite all centers following the same study protocol. During the analysis of such a trial, investigators typically ignore center effects, but some have suggested considering centers as fixed or random effects in the model. It is not clear how considering the effects of centers, either as fixed or random effects, impacts the test of the primary hypothesis. In this article, we first review the practice of accounting for center effects in the analyses of published RCTs and illustrate the extent of heterogeneity observed in a few preexisting multicenter RCTs. To determine the impact of heterogeneity on the test of a primary hypothesis of an RCT, we considered continuous and binary outcomes and the corresponding appropriate model, namely, a simple linear regression model for a continuous outcome and a logistic regression model for the binary outcome. For each model type, we considered three methods: (a) ignore the center effect, (b) account for centers as fixed effects, or (c) account for centers as random effects. Based on simulation studies of these models, we then examine whether considering the center as a fixed or random effect in the model helps to preserve or reduce the type I and type II error rates during the analysis phase of an RCT. Finally, we outline the threshold at which center-level effects are negligible and thus negligible and provide recommendations on when it may be necessary to account for center effects during the analyses of multicenter randomized controlled trials.

Background The drivers of cardiovascular disease (CVD) and all-cause mortality may differ around the world. Regional-level prospective data can help guide policies to reduce CVD and all-cause mortality. Objectives This study examined the incidence of CVD and mortality in Malaysia and the Philippines and estimated the population-level risks attributable to common risk factors for each outcome. Methods This prospective cohort study included 20,272 participants from Malaysia and the Philippines. The mean follow-up was 8.2 years. The incidences of CVD and mortality rates were calculated for the overall cohort and in key subgroups. For each outcome, population-attributable fractions (PAFs) were calculated to compare risks associated with 12 modifiable risk factors. Results The mean age of the cohort was 51.8 years (59% women). Leading causes of mortality were CVD (37.9%) and cancer (12.4%). The incidence of CVD (per 1,000 person-years) was higher in the Philippines (11.0) than Malaysia (8.3), and CVD contributed to a higher proportion of deaths in the Philippines (58% vs 36%). By contrast, all-cause mortality rates were higher in Malaysia (14.1) than in the Philippines (10.9). Approximately 78% of the PAF for CVD and 68% of the PAF for all-cause mortality were attributable to 12 modifiable risk factors. For CVD, the largest PAF was from hypertension (24.2%), whereas for all-cause mortality, the largest PAF was from low education (18.4%). Conclusions CVD and cancer account for one-half of adult mortality in Malaysia and the Philippines. Hypertension was the largest population driver of CVD, whereas low education was associated with the largest burden of overall mortality.

BACKGROUND & AIMS: Several medications have been suspected to contribute to the etiology of inflammatory bowel disease (IBD). This study assessed the association between medication use and the risk of developing IBD using the Prospective Urban Rural Epidemiology cohort.METHODS: This was a prospective cohort study of 133,137 individuals between the ages of 20 and 80 from 24 countries. Country-specific validated questionnaires documented baseline and follow-up medication use. Participants were followed up prospectively at least every 3 years. The main outcome was the development of IBD, including Crohn's disease (CD) and ulcerative colitis (UC). Short-term (baseline but not follow-up use) and long-term use (baseline and subsequent followup use) were evaluated. Results are presented as adjusted odds ratios (aORs) with 95% CIs. RESULTS: During a median follow-up period of 11.0 years (interquartile range, 9.2-12.2 y), there were 571 incident IBD cases (143 CD and 428 UC). Incident IBD was associated significantly with baseline antibiotic (aOR, 2.81; 95% CI, 1.67-4.73; P = .0001) and hormonal medication use (aOR, 4.43; 95% CI, 1.78-11.01; P = .001). Among females, previous or current oral contraceptive use also was associated with IBD development (aOR, 2.17; 95% CI, 1.70-2.77; P < .001). Nonsteroidal anti-inflammatory drug users also were observed to have increased odds of IBD (aOR, 1.80; 95% CI, 1.23-2.64; P = .002), which was driven by long-term use (aOR, 5.58; 95% CI, 2.26-13.80; P < .001). All significant results were consistent in direction for CD and UC with low heterogeneity.CONCLUSIONS: Antibiotics, hormonal medications, oral contraceptives, and long-term nonsteroidal antiinflammatory drug use were associated with increased odds of incident IBD after adjustment for covariates.

Background Although several epidemiological studies have linked social isolation to increased risk of mortality, the magnitude of any effect is unclear, in part because of the use of different measures of social isolation. Objective To examine the association between social isolation and all-cause mortality and investigate whether it differs in various subgroups or populations. Data sources We searched for relevant studies in electronic databases: MEDLINE (1946 to December 31, 2021), EMBASE (1974 to December 31, 2021), and PsycINFO (1806 to December 31, 2021). Selection criteria We included both prospective and retrospective cohort studies that examined the association between social isolation and all-cause mortality among adults. Data collection and analysis Two reviewers screened and extracted data independently. We contacted study authors to obtain missing information whenever possible. Data were pooled using a random effect model to calculate estimates of the effects of social isolation on all-cause mortality. Results Data from studies involving 1.30 million individuals were included. The pooled hazard ratio of social isolation for all-cause mortality was 1.33 (95% confidence interval; 1.26–1.41, heterogeneity: Chi² = 112.51, P < 0.00001, I² = 76%). Conclusion Social isolation is associated with increased risk for all-cause mortality. Registration PROSPERO (CRD42020152351).

AIM:To examine the incidence of cardiovascular disease (CVD), of death, and the comparative effects of 12 common modifiable risk factors for both outcomes in South Asia.METHODS AND RESULTS:Prospective study of 33 583 individuals 35-70 years of age from India, Bangladesh, or Pakistan. Mean follow-up period was 11 years. Age and sex adjusted incidence of a CVD event and mortality rates were calculated for the overall cohort, by urban or rural location, by sex, and by country. For each outcome, mutually adjusted population attributable fractions (PAFs) were calculated in 32 611 individuals without prior CVD to compare risks associated with four metabolic risk factors (hypertension, diabetes, abdominal obesity, high non-HDL cholesterol), four behavioural risk factors (tobacco use, alcohol use, diet quality, physical activity), education, household air pollution, strength, and depression. Hazard ratios were calculated using Cox regression models, and average PAFs were calculated for each risk factor or groups of risk factors. Cardiovascular disease was the most common cause of death (35.5%) in South Asia. Rural areas had a higher incidence of CVD (5.41 vs. 4.73 per 1000 person-years) and a higher mortality rate (10.27 vs. 6.56 per 1000 person-years) compared with urban areas. Males had a higher incidence of CVD (6.42 vs. 3.91 per 1000 person-years) and a higher mortality rate (10.66 vs. 6.85 per 1000 person-years) compared with females. Between countries, CVD incidence was highest in Bangladesh, while the mortality rate was highest in Pakistan. The modifiable risk factors studied contributed to approximately 64% of the PAF for CVD and 69% of the PAF for death. Largest PAFs for CVD were attributable to hypertension (13.1%), high non-HDL cholesterol (11.1%), diabetes (8.9%), low education (7.7%), abdominal obesity (6.9%), and household air pollution (6.1%). Largest PAFs for death were attributable to low education (18.9%), low strength (14.6%), poor diet (6.4%), diabetes (5.8%), tobacco use (5.8%), and hypertension (5.5%).CONCLUSION:In South Asia, both CVD and deaths are highest in rural areas and among men. Reducing CVD and premature mortality in the region will require investment in policies that target a broad range of health determinants.

Background: Self-collection of nasal swabs for the detection of SARS-CoV-2 RNA by reverse transcription-polymerase chain reaction (RT-PCR) would considerably increase the testing capability and decrease the risk of transmission among healthcare workers (HCW) and the use of personal protective equipment (PPE). Objectives: This study aimed to evaluate the performance of self-collected nasal swabs compared with professionally collected nasopharyngeal (NP) swabs for detection of SARS-CoV-2 RNA by RT-PCR. Materials and methods: We performed a cross-sectional study where the suspected cases of coronavirus disease 2019 (COVID-19) were instructed about the self-collection of nasal swabs from their mid-turbinate. The results were compared to a nasopharyngeal swab collected by a trained healthcare worker in the same patient at the same sitting. Results: We enrolled 100 participants, of which, 69 (69%) were male and 31 (31%) were female. The median age of the study participant was 36 years. Of the participants, 58 (58%) were symptomatic, and the commonest clinical presentation was cough, which was present in 42 (42%) participants. Out of 100 samples, 31 (31%) professionally collected nasopharyngeal swabs and 28 (28%) self-collected nasal swabs were positive for SARS-CoV-2 by RT-PCR. Out of 31 professionally collected positive samples, three samples were negative in self-collection. Out of 28 self-collected positive samples, no sample was negative in the professional collection. The sensitivity and specificity of self-collected nasal swabs compared to professionally collected nasopharyngeal swabs were 90.32% and 100.00%, respectively. The sensitivity of self-collected nasal was 100% when the cycle threshold (Ct) value of the professionally collected NP swab was less than 30. Conclusion: Our study showed that self-collected nasal swabs' sensitivities were similar to professionally collected NP swabs with a high viral load (low Ct value). Hence, this method could be used when the patient is symptomatic and come to the health providers in the early stage of COVID-19 illness.

Background:Bleeding is the most common adverse event in those with cardiovascular (CV) disease receiving antithrombotic therapy, and it most commonly occurs in the gastrointestinal (GI) tract. Clinicians often dismiss bleeding as an adverse event that is reversible with effective antithrombotic therapy, but bleeding is associated with substantial morbidity and mortality, most likely mediated through an increased risk of CV events. Reducing the burden of bleeding requires knowledge of the potentially modifiable risk factors for bleeding and the potentially modifiable risk factors for adverse outcomes after bleeding.Methods:INTERBLEED is an international, multicentre, 2-component, observational study, with an incident case-control study examining the risk factors for GI bleeding, and a prospective cohort study of risk factors for CV events after GI bleeding. Cases either have CV disease and present to the hospital with GI bleeding or develop GI bleeding during hospitalization. Controls have CV disease, but no history of GI bleeding. We use a questionnaire to obtain detailed information on known and potential risk factors for GI bleeding and for CV events and outcomes after bleeding. We obtain CV and anthropometric measurements, perform functional and cognitive assessments, and follow participants at 3 months and 12 months.Results:As of April 1, 2022, the study is ongoing in 10 countries at 31 centres and has recruited 2407 cases and 1478 controls.Conclusions:Knowledge of risk factors for bleeding, and risk factors for CV events and functional decline after bleeding, will help develop strategies to prevent bleeding and subsequent complications.