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The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults at risk for coronavirus disease 2019 (COVID-19) comprising 14 established United States (US) prospective cohort studies. For decades, C4R cohorts have collected extensive data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R will link this pre-COVID phenotyping to information on SARS-CoV-2 infection and acute and post-acute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and broadly reflects the racial, ethnic, socioeconomic, and geographic diversity of the US. C4R is ascertaining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations, and high-quality events surveillance. Extensive pre-pandemic data minimize referral, survival, and recall bias. Data are being harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these will be pooled and shared widely to expedite collaboration and scientific findings. This unique resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including post-acute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term trajectories of health and aging.

Background and Purpose: Studies of carotid artery disease have suggested that high-grade stenosis can affect cognition, even without stroke. The presence and degree of cognitive impairment in such patients have not been reported and compared with a demographically matched population-based cohort. Methods: We studied cognition in 1000 consecutive CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) patients, a treatment trial for asymptomatic carotid disease. Cognitive assessment was after randomization but before assigned treatment. The cognitive battery was developed in the general population REGARDS Study (Reasons for Geographic and Racial Differences in Stroke), involving Word List Learning Sum, Word List Recall, and Word List fluency for animal names and the letter F. The carotid stenosis patients were >45 years old with ≥70% asymptomatic carotid stenosis and no history of prevalent stroke. The distribution of cognitive performance for the patients was standardized, accounting for age, race, and education using performance from REGARDS, and after further adjustment for hypertension, diabetes, dyslipidemia, and smoking. Using the Wald Test, we tabulated the proportion of Z scores less than the anticipated deviate for the population-based cohort for representative percentiles. Results: There were 786 baseline assessments. Mean age was 70 years, 58% men, and 52% right-sided stenosis. The overall Z score for patients was significantly below expected for higher percentiles ( P P =0.015). Lower performance was attributed largely to Word List Recall ( P P ≤0.01). The scores for left versus right carotid disease were similar. Conclusions: Baseline cognition of patients with severe carotid stenosis showed below normal cognition compared to the population-based cohort, controlling for demographic and cardiovascular risk factors. This cohort represents the largest group to date to demonstrate that poorer cognition, especially memory, in this disease. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02089217.

Background and ObjectivesWomen have been underrepresented in cardiovascular disease clinical trials but there is less certainty over the level of disparity specifically in stroke. We examined the participation of women in trials according to stroke prevalence in the population.MethodsPublished randomized controlled trials with ≥100 participants enrolled between 1990 and 2020 were identified from ClinicalTrials.gov. To quantify sex disparities in enrollment, we calculated the participation to prevalence ratio (PPR), defined as the percentage of women participating in a trial vs the prevalence of women in the disease population.ResultsThere were 281 stroke trials eligible for analyses with a total of 588,887 participants, of whom 37.4% were women. Overall, women were represented at a lower proportion relative to their prevalence in the underlying population (mean PPR 0.84; 95% confidence interval [CI] 0.81–0.87). The greatest differences were observed in trials of intracerebral hemorrhage (PPR 0.73; 95% CI 0.71–0.74), trials with a mean age of participants p for trend = 0.201).DiscussionWomen are disproportionately underrepresented in stroke trials relative to the burden of disease in the population. Clear guidance and effective implementation strategies are required to improve the inclusion of women and thus broader knowledge of the impact of interventions in clinical trials.

INTRODUCTION Television (TV) viewing may be associated with increased venous thromboembolism (VTE) risk independent of VTE risk factors including physical activity. This association was assessed in a large biracial US cohort of Black and White adults. METHODS Between 2003 and 2007 The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study recruited 30,239 participants aged ≥45 years, who were surveyed for baseline TV viewing and followed for VTE events. TV viewing was categorized as

ObjectiveTo investigate sex and race differences in the association between fasting blood glucose (FBG) and risk of ischemic stroke (IS).MethodsThis prospective longitudinal cohort study included adults age ≥45 years at baseline in the Reasons for Geographic And Racial Differences in Stroke Study, followed for a median of 11.4 years. The exposure was baseline FBG (mg/dL); suspected IS events were ascertained by phone every 6 months and were physician-adjudicated. Cox proportional hazards were used to assess the adjusted sex/race-specific associations between FBG (by category and as a restricted cubic spline) and incident IS.ResultsOf 20,338 participants, mean age was 64.5 (SD 9.3) years, 38.7% were Black, 55.4% were women, 16.2% were using diabetes medications, and 954 IS events occurred. Compared to FBG pFBG×race/sex = 0.004). Analyses using FBG splines suggest that sex was the major contributor to differences by race/sex subgroups.ConclusionsSex differences in the strength and shape of the association between FBG and IS are likely driving the significant differences in the association between FBG and IS across race/sex subgroups. These findings should be explored further and may inform tailored stroke prevention guidelines.

ObjectiveTo test the hypothesis that silent myocardial infarction (MI) is a risk factor for ischemic stroke, we evaluated the association between silent MI and subsequent ischemic stroke in the Cardiovascular Health Study.MethodsThe Cardiovascular Health Study prospectively enrolled community-dwelling individuals ≥65 years of age. We included participants without prevalent stroke or baseline evidence of MI. Our exposures were silent and clinically apparent, overt MI. Silent MI was defined as new evidence of Q-wave MI, without clinical symptoms of MI, on ECGs performed during annual study visits from 1989 to 1999. The primary outcome was incident ischemic stroke. Secondary outcomes were ischemic stroke subtypes: nonlacunar, lacunar, and other/unknown. Cox proportional hazards analysis was used to model the association between time-varying MI status (silent, overt, or no MI) and stroke after adjustment for baseline demographics and vascular risk factors.ResultsAmong 4,224 participants, 362 (8.6%) had an incident silent MI, 421 (10.0%) an incident overt MI, and 377 (8.9%) an incident ischemic stroke during a median follow-up of 9.8 years. After adjustment for demographics and comorbidities, silent MI was independently associated with subsequent ischemic stroke (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.03–2.21). Overt MI was associated with ischemic stroke both in the short term (HR, 80; 95% CI, 53–119) and long term (HR, 1.60; 95% CI, 1.04–2.44). In secondary analyses, the association between silent MI and stroke was limited to nonlacunar ischemic stroke (HR, 2.40; 95% CI, 1.36–4.22).ConclusionIn a community-based sample, we found an association between silent MI and ischemic stroke.

ObjectiveTo examine the joint associations of daily time spent in different intensities of physical activity, sedentary behaviour and sleep with all-cause mortality.MethodsFederated pooled analysis of six prospective cohorts with device-measured time spent in different intensities of physical activity, sedentary behaviour and sleep following a standardised compositional Cox regression analysis.Participants130 239 people from general population samples of adults (average age 54 years) from the UK, USA and Sweden.Main outcomeAll-cause mortality (follow-up 4.3–14.5 years).ResultsStudies using wrist and hip accelerometer provided statistically different results (I2=92.2%, Q-test pConclusionThis federated analysis shows a joint dose–response association between the daily balance of time spent in physical activity of different intensities and sedentary behaviour with all-cause mortality, while sleep duration does not appear to be significant. The strongest association is with time spent in moderate to vigorous physical activity, but it is modified by the balance of time spent in light physical activity relative to sedentary behaviour.

Introduction Diabetes incidence differs by race in the U.S., with a persistent reported Black–White disparity. However, the factors that contribute to this excess risk in middle-aged and older adults are unclear. Methods This prospective cohort study included 7,171 Black and White adults aged ≥45 years without diabetes at baseline (2003‒2007) who completed a follow-up examination (2013‒2016). Modified Poisson regression was used to obtain sex-stratified RRs for diabetes. Mediation analyses using a change in β coefficient assessed individual and neighborhood factors that contribute to the racial disparity in diabetes incidence. Statistical analyses were conducted in 2018–2019. Results The cumulative incidence of diabetes was higher for Black men (16.2%) and women (17.7%) than for White men (11.0%) and women (8.1%). Adjusting for age and prediabetes, diabetes risk was higher for Black women than for White women (RR=1.75, 95% CI=1.47, 2.07) and for Black men than for White men (RR=1.33, 95% CI=1.09, 1.64). The individual factors that attenuated the racial disparity the most were Southern dietary pattern (change in β=42.8%) and neighborhood socioeconomic environment (change in β=26.3%) among men and BMI (change in β=34.4%) and waist circumference (change in β=32.4%) among women. When including all factors collectively, the racial disparity in diabetes incidence was similar for men (RR=1.38, 95% CI=1.04, 1.83) and was attenuated for women (RR=1.41, 95% CI=1.11, 1.81). Conclusions The racial disparity in diabetes incidence remained after accounting for individual and neighborhood factors. Further investigation of additional factors underlying this racial disparity is needed to inform multilevel strategies for diabetes prevention.

Background and Purpose: CREST (Carotid Revascularization Endarterectomy Versus Stenting Trial) reported a higher periprocedural risk for any stroke, death, or myocardial infarction for women randomized to carotid artery stenting (CAS) compared with women randomized to carotid endarterectomy (CEA). No difference in risk by treatment was detected for women relative to men in the 4-year primary outcome. We aimed to conduct a pooled analysis among symptomatic patients in large randomized trials to provide more precise estimates of sex differences in the CAS-to-CEA risk for any stroke or death during the 120-day periprocedural period and ipsilateral stroke thereafter. Methods: Data from the Carotid Stenosis Trialists’ Collaboration included outcomes from symptomatic patients in EVA-3S (Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis), SPACE (Stent-Protected Angioplasty Versus Carotid Endarterectomy in Symptomatic Patients), ICSS (International Carotid Stenting Study), and CREST. The primary outcome was any stroke or death within 120 days after randomization and ipsilateral stroke thereafter. Event rates and relative risks were estimated using Poisson regression; effect modification by sex was assessed with a sex-by-treatment-by-trial interaction term, with significant interaction defined a priori as P ≤0.10. Results: Over a median 2.7 years of follow-up, 433 outcomes occurred in 3317 men and 1437 women. The CAS-to-CEA relative risk of the primary outcome was significantly lower for women compared with men in 1 trial, nominally lower in another, and nominally higher in the other two. The sex-by-treatment-by-trial interaction term was significant ( P =0.065), indicating heterogeneity among trials. Contributors to this heterogeneity are primarily differences in periprocedural period. When the trials are nevertheless pooled, there were no significant sex differences in risk in any follow-up period. Conclusions: There were significant differences between trials in the magnitude of sex differences in treatment effect (CAS-to-CEA relative risk), indicating pooling data from these trials to estimate sex differences might not be valid. Whether sex is acting as an effect modifier of the CAS-to-CEA treatment effect in symptomatic patients remains uncertain. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00190398 (EVA-3S) and NCT00004732 (CREST). URL: https://www.isrctn.com ; Unique identifier: ISRCTN57874028 (SPACE) and ISRCTN25337470 (ICSS).

Funder: National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care East Midlands, Funder: National Institute on Aging, Funder: Stockholms Läns Landsting; FundRef: http://dx.doi.org/10.13039/501100004348, Funder: Norwegian Directorate for Public Health, Funder: Centrum for Idrottsforskning; FundRef: http://dx.doi.org/10.13039/501100005350, Funder: The Coca-Cola Company, Objectives: To examine the joint associations of accelerometer-measured physical activity and sedentary time with all-cause mortality. Methods: We conducted a harmonised meta-analysis including nine prospective cohort studies from four countries. 44 370 men and women were followed for 4.0 to 14.5 years during which 3451 participants died (7.8% mortality rate). Associations between different combinations of moderate-to-vigorous intensity physical activity (MVPA) and sedentary time were analysed at study level using Cox proportional hazards regression analysis and summarised using random effects meta-analysis. Results: Across cohorts, the average time spent sedentary ranged from 8.5 hours/day to 10.5 hours/day and 8 min/day to 35 min/day for MVPA. Compared with the referent group (highest physical activity/lowest sedentary time), the risk of death increased with lower levels of MVPA and greater amounts of sedentary time. Among those in the highest third of MVPA, the risk of death was not statistically different from the referent for those in the middle (16%; 95% CI 0.87% to 1.54%) and highest (40%; 95% CI 0.87% to 2.26%) thirds of sedentary time. Those in the lowest third of MVPA had a greater risk of death in all combinations with sedentary time; 65% (95% CI 1.25% to 2.19%), 65% (95% CI 1.24% to 2.21%) and 263% (95% CI 1.93% to 3.57%), respectively. Conclusion: Higher sedentary time is associated with higher mortality in less active individuals when measured by accelerometry. About 30–40 min of MVPA per day attenuate the association between sedentary time and risk of death, which is lower than previous estimates from self-reported data.

The tridecapeptide neurotensin has been implicated in the pathogenesis of cardiometabolic disease. Its stable precursor, pro-neurotensin/neuromedin N (pro-NT/NMN), has been associated with composite cardiovascular outcomes including coronary heart disease (CHD) and stroke. The exclusive association of pro-NT/NMN with ischemic stroke has not been evaluated. We conducted a prospective case-cohort study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. From 2003 to 2007, REGARDS enrolled 30,239 white or black adults aged ⩾ 45 years. Baseline fasting pro-NT/NMN was measured by immunoassay in the analytic sample including 448 incident ischemic stroke cases and 818 random cohort sample participants. A total of 464 ischemic strokes occurred. Risk of stroke was assessed with a Cox proportional-hazards model incorporating demographic covariates and a second adding stroke risk factors. Increased pro-NT/NMN was associated with ischemic stroke in the demographic model overall (hazard ratio (HR) per standard deviation (SD) pro-NT/NMN 1.16, 95% confidence interval (CI) 1.01–1.33) and in men (HR per SD pro-NT/NMN 1.25, 95% CI 1.04–1.50); HRs were attenuated in the risk factor model. Pre-existing diabetes mellitus and CHD were the largest confounders of ischemic stroke risk, each accounting for an estimated 19% of the association of pro-NT/NMN with ischemic stroke observed in the demographic model. There were no significant interactions of race or sex with pro-NT/NMN. Further research on associations of pro-NT/NMN with stroke risk factors such as diabetes mellitus is indicated.

Background: Hypertension awareness, treatment, and control programs were initiated in the United States during the 1960s and 1970s. Whereas blood pressure (BP) control in the population and subsequent reduced hypertension-related disease risks have improved since the implementation of these interventions, it is unclear whether these BP changes can be generalized to diverse and high-risk populations. This report describes the 4-decade change in BP levels for the population in a high disease risk southeastern region of the United States. The objective is to determine the magnitude of the shift in systolic BP (SBP) among Blacks and Whites from the Southeast between 1960 and 2005 with the assessment of the unique population cohorts. Methods: A multicohort study design compared BPs from the CHS (Charleston Heart Study) and ECHS (Evans County Heart Study) in 1960 and the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) 4 decades later. The analyses included participants ≥45 years of age from CHS (n=1323), ECHS (n=1842), and REGARDS (n=6294) with the main outcome of SBP distribution. Results: Among Whites 45 to 54 years of age, the median SBP was 18 mm Hg (95% CI, 16–21 mm Hg) lower in 2005 than 1960. The median shift was a 45 mm Hg (95% CI, 37–51 mm Hg) decline for those ≥75 years of age. The shift was larger for Blacks, with median declines of 38 mm Hg (95% CI, 32–40 mm Hg) at 45 to 54 years of age and 50 mm Hg (95% CI, 33–60 mm Hg) for ages ≥75 years. The 95th percentile of SBP decreased 60 mm Hg for Whites and 70 mm Hg for Blacks. Conclusions: The results of the current analyses of the unique cohorts in the Southeast confirm the improvements in population SBP levels since 1960. This assessment provides new evidence of improvement in SBP, suggesting that strategies and programs implemented to improve hypertension treatment and control have been extraordinarily successful for both Blacks and Whites residing in a high-risk region of the United States. Severe BP elevations commonly observed in the 1960s have been nearly eliminated, with the current 75th percentile of BP generally less than the 25th percentile of BP in 1960.

Dietary modification of insulin resistance may be a strategy for reducing chronic disease. For this study, we tested the hypothesis that higher fasting insulin, a marker for insulin resistance, would be related to diet patterns with a high proportion of carbohydrates, those with a high glycemic index, and those characterized by added sugar and processed starches. Data were analyzed on 13,528 nondiabetic participants of the REasons for Geographic and Ethnic Differences in Stroke (REGARDS), an observational study of adults aged ≥45 years residing in 1855 counties across the continental USA. Information on habitual diet was collected using the Block 98 Food Frequency Questionnaire. Percent energy from carbohydrate, glycemic index, and glycemic load were determined for each participant, as well as adherence to five established diet patterns. Logistic regression was used to examine associations of baseline diet characteristics with odds for high fasting insulin [quartiles 3 and 4 (median = 98.9 pmol/L) vs. quartile 1], after adjusting for covariates. Greater percent carbohydrate, glycemic index, and glycemic load, and adherence to sweets/fat and southern diet patterns, was associated with greater odds for high insulin (P for trend

Objectives:We aimed to compare incident family caregivers and matched controls on change in social network variables and satisfaction with social activities. Methods: A total of 479 participants from the Caregiving Transitions Study were included in the analysis, 244 (50.9%) of whom began substantial and sustained caregiving between baseline and follow-up interviews. We assessed associations between incident caregiving and change in social network size, change in monthly social contact, and satisfaction with social activities. Results: Incident caregivers reported lower satisfaction with social activities and greater decline in social network size than controls. Among only the caregivers, dementia caregivers reported greater decline in social network size while caregivers who were spouses, experienced higher strain, and provided more hours of care reported lower satisfaction with social activities. Discussion: Social engagement declined more among incident caregivers than controls. Future studies should aim to understand why subgroups of caregivers reported lower social engagement.

Background and Objectives Few population-based studies have directly compared caregivers of persons with dementia to caregivers of persons with other disabilities (nondementia caregivers). We enrolled dementia and nondementia caregivers who were providing substantial and sustained care and compared these groups on measures of caregiver stressors, appraisals of burden, and well-being. Research Design and Methods Caregivers (N = 251) who provided continuous care for at least 1 year and at least 5 h per week were recruited from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Caregivers reported on dementia caregiving status, stressors, burden, and well-being. Results Forty-seven percent (n = 117) reported caring for a person with dementia. Dementia caregivers reported more stressors, providing more care for self-care and behavioral problems than nondementia caregivers. Dementia caregivers also reported higher appraisals of stress and burden, and more depressive symptoms, but did not differ from nondementia caregivers on mental and physical health quality of life. In multivariable-adjusted models, adjustment for the total number of care recipient problems attenuated differences between dementia and nondementia caregivers on burden and depression measures. Discussion and Implications Dementia and nondementia caregivers showed relatively few differences in indicators of overall well-being in this population-based sample, perhaps because both groups of caregivers in this study were providing substantial care. Dementia caregivers may require special assistance with dementia-specific problems such as behavioral problems. Clinical interventions and policy changes targeting highly burdened caregivers are needed to support them in allowing their care recipients to age in place at home.

Background The neuropeptide neurotensin (NT) has been linked to cardiometabolic disease. Cardiovascular risk factors are being recognized as risk factors for cognitive impairment. Objective To examine the association of the stable precursor of NT, pro-neurotensin/neuromedin N (pro-NT/NMN), with incident cognitive impairment (ICI). Methods We conducted a prospective nested case-control study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. In 2003-2007, REGARDS enrolled 30,239 Black and White adults aged ≥45 years. ICI was identified using a 3-test cognitive battery administered biannually. Baseline pro-NT/NMN was measured by immunoassay in 393 cases of ICI and 490 controls after 3.4 years follow up. Multivariable logistic regression was used to calculate odds ratios (OR) of ICI by pro-NT/NMN quartiles. Race, age, and sex differences were studied with stratified models and interaction testing. Results Pro-NT/NMN was higher in Black participants and those with hypertension and diabetes. Women with a 4th versus 1st-quartile pro-NT/NMN had 2.28-fold increased odds of ICI (95% CI 1.08-4.78) after adjusting for risk factors and incident stroke. There was no association of higher pro-NT/NMN quartiles with ICI in the overall group or men. There were no race or age differences in associations. Conclusion In this biracial population-based study, elevated systemic pro-NT/NMN was associated with more than doubled risk of ICI in women but not men. Others reported sex-specific associations in women for cardiovascular mortality and diabetes with higher pro-NT/NMN, supporting a role for future research on sex differences in the neurotensinergic system.

Objective:The current study aims to describe the Mediterranean diet (MD) adherence across the US regions, and explore the predictive factors of MD adherence among US adults.Design:Cross-sectional secondary data analysis. MD adherence score (0–9) was calculated using the Block 98 FFQ. Hot spot analysis was conducted to describe the geospatial distribution of MD adherence across the US regions. Logistic regression explored predictors of MD adherence.Setting:Nationwide community-dwelling residency in the USA.Participants:Adults aged ≥45 years (n20 897) who participated in the REasons for Geographic and Racial Differences in Stroke study and completed baseline assessment during January 2003 and October 2007.Results:The mean of MD adherence score was 4·36 (sd1·70), and 46·5 % of the sample had high MD adherence (score 5–9). Higher MD adherence clusters were primarily located in the western and northeastern coastal areas of the USA, whereas lower MD adherence clusters were majorly observed in south and east-north-central regions. Being older, black, not a current smoker, having a college degree or above, an annual household income ≥ $US 75K, exercising ≥4 times/week and watching TV/video Conclusions:There were significant geospatial and population disparities in MD adherence across the US regions. Future studies are needed to explore the causes of MD adherence disparities and develop effective interventions for MD promotion in the USA.

Background and Purpose: Social determinants of health (SDOH) have been previously associated with incident stroke. Although SDOH often cluster within individuals, few studies have examined associations between incident stroke and multiple SDOH within the same individual. The objective was to determine the individual and cumulative effects of SDOH on incident stroke. Methods: This study included 27 813 participants from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study, a national, representative, prospective cohort of black and white adults aged ≥45 years. SDOH was the primary exposure. The main outcome was expert adjudicated incident stroke. Cox proportional hazards models examined associations between incident stroke and SDOH, individually and as a count of SDOH, adjusting for potential confounders. Results: The mean age was 64.7 years (SD 9.4) at baseline; 55.4% were women and 40.4% were blacks. Over a median follow-up of 9.5 years (IQR, 6.0–11.5), we observed 1470 incident stroke events. Of 10 candidate SDOH, 7 were associated with stroke ( P Conclusions: Incremental increases in the number of SDOH were independently associated with higher incident stroke risk in adults aged

Objective The aim of the study was to examine the relationship between longitudinally assessed cognitive functioning and self-reported dementia status using the Ascertain Dementia 8-item questionnaire (AD8) in a national population-based sample. Methods The analysis included 14,453 participants from the REasons for Geographic and Racial Differences in Stroke study. A validated cutoff of ≥2 symptoms endorsed on the AD8 (administered 10 years after enrollment) represented positive AD8 status. Incident cognitive impairment was defined as change from intact to impaired status in the Six-Item Screener score, and cognitive decline was defined by trajectories of Letter “F” Fluency from the Montreal Cognitive Assessment, and Animal Fluency, Word List Learning, and Word List Delayed recall, all from the Consortium to Establish a Registry for Alzheimer’s Disease battery. Logistic regression models controlled for demographics, health variables, and depressive symptoms. Results Sensitivity and specificity of the AD8 to detect incident cognitive impairment were 45.2% and 78.4%, respectively. Incident cognitive impairment and a one-word decline in WLL increased the odds of self-reported positive AD8 by 96% (95% CI: 1.68–2.28) and 27% (95% CI: 1.17–1.37), respectively. There was a strong association between high depression risk and self-reported positive AD8 in sensitivity analyses. Conclusions Incident cognitive impairment and high depression risk were the strongest predictors of self-reported positive AD8 in this population-based sample. Our results inform the utility of the AD8 as a self-report measure in a large, national sample that avoids selection biases inherent in clinic-based studies. The AD8 is screening measure and should not be used to diagnose dementia clinically.

Chronic stress has been widely proposed to increase systemic inflammation, a pathway that may link stress with a heightened risk for many diseases. The chronic stress–inflammation relationship has been challenging to study in humans, however, and family caregiving has been identified as one type of stressful situation that might lead to increased inflammation. Previous studies of caregiving and inflammation have generally used small convenience samples, compared caregivers with poorly characterized control participants, and assessed inflammation only after caregivers provided care for extended periods of time. In the current project, changes over a 9-y period were examined on six circulating biomarkers of inflammation for 480 participants from a large population-based study. All participants reported no involvement in caregiving prior to the first biomarker assessment, and 239 participants then took on extensive and prolonged family caregiving responsibilities at some point prior to the second biomarker assessment. Incident caregivers were individually matched on multiple demographic and health history variables with participants who reported no caregiving responsibilities. Of the six biomarkers examined, only tumor necrosis factor alpha receptor 1 showed a significantly greater increase in caregivers compared with controls. This effect was small (d = 0.14), and no effects were found for a subset of 45 caregivers who were living with a spouse with dementia. These results are consistent with recent meta-analytic findings and challenge the widespread belief that caregiving is a substantial risk factor for increased inflammation. Future research is warranted on factors that may account for stress resilience in family caregivers.

Background N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), a commonly used clinical marker of cardiac function, is associated with the presence of stroke symptoms and is a strong risk factor for future atrial fibrillation, stroke, and all‐cause mortality. Few data are available on the association between NT‐proBNP levels and stroke recurrence. Objective We studied the relationship between NT‐proBNP and risk of future ischemic stroke across the continuum of preexisting cerebrovascular conditions: asymptomatic, prior stroke symptoms, prior transient ischemic attack (TIA), and prior stroke. Methods The Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort enrolled 30,239 black and white Americans aged 45 years and older from 2003 to 2007. With 5.4 years follow‐up, baseline NT‐proBNP was measured in 892 participants who developed ischemic stroke and a 4328‐person cohort random sample. Hazard ratios of stroke by baseline NT‐proBNP were calculated in groups based on the presence of prebaseline cerebrovascular conditions. Results In the fully adjusted model, elevated NT‐proBNP was associated with stroke risk in participants without a preexisting cerebrovascular condition (hazard ratio [HR], 2.32; 95% confidence interval [CI], 1.84‐2.94) and in participants with a history of stroke symptoms (HR, 1.67; 95% CI, 1.01‐2.78) or transient ischemic attack (HR, 2.66; 95% CI, 1.00‐7.04) but not among those with prior stroke (HR, 1.26; 95% CI, 0.71‐2.21). Conclusions These findings support the potential for NT‐proBNP testing to identify people who are at highest risk for future stroke.

Patients with hypertension who develop atrial premature complexes (APCs) are at a particularly high risk for atrial fibrillation (AF). We sought to identify medications and modifiable risk factors that could reduce the risk of AF imposed by presence of APCs in such a high risk group. This analysis included 4,331 participants with treated hypertension from the Reasons for Geographic and Racial Differences in Stroke study who were free of AF and cardiovascular disease at the time of enrollment (2003-2007). APCs were detected in 8.2% (n = 356) of the participants at baseline. During a median follow-up of 9.4 years, 9.9% (n = 429) of the participants developed AF. Participants with APCs, compared with those without, were more than twice as likely to develop AF (Odds ratio [95% confidence interval]: 2.36[1.75, 3.19]). This association was significantly weaker in statin users than nonusers (Odds ratio [95% confidence interval]:1.42[0.81,2.48] vs 3.01[2.11,4.32], respectively; interaction p-value = 0.02), and in angiotensin-II receptor blocker users than nonusers (Odds ratio [95% confidence interval]:1.31[0.66,2.61] vs 2.78[1.99,3.89], respectively; interaction p-value = 0.05). Borderline weaker associations between APCs and AF were also observed in alpha-blocker users than nonusers, nondiabetics than diabetics, and in those with systolic blood pressure level 130 to 139 mm Hg compared with those with other systolic blood pressure levels. No significant effect modifications were observed by use of other medications or by presence of other cardiovascular risk factors. In conclusion, the significant AF risk associated with APCs in patients with hypertension could potentially be reduced by treatment with angiotensin-II receptor blockers and statins along with lowering blood pressure and management of diabetes.

The coronavirus disease 2019 pandemic has disrupted the lives of whole communities and nations. The multinational multicenter National Institute of Neurological Disorders and Stroke Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial stroke prevention trial rapidly experienced the effects of the pandemic and had to temporarily suspend new enrollments and shift patient follow-up activities from in-person clinic visits to telephone contacts. There is an ethical obligation to the patients to protect their health while taking every feasible step to ensure that the goals of the trial are successfully met. Here, we describe the effects of the pandemic on the trial and steps that are being taken to mitigate the effects of the pandemic so that trial objectives can be met.

Background and Purpose— In previous studies, isolated nonspecific ST-segment and T-wave abnormalities (NSSTTAs), a common finding on ECGs, were associated with greater risk for incident coronary artery disease. Their association with incident stroke remains unclear. Methods— The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a population-based, longitudinal study of 30 239 white and black adults enrolled from 2003 to 2007 in the United States. NSSTTAs were defined from baseline ECG using the standards of Minnesota ECG Classification (Minnesota codes 4-3, 4-4, 5-3, or 5-4). Participants with prior stroke, coronary heart disease, and major and minor ECG abnormalities other than NSSTTAs were excluded from analysis. Multivariable Cox proportional hazards regression was used to examine calculate hazard ratios of incident ischemic stroke by presence of baseline NSSTTAs. Results— Among 14 077 participants, 3111 (22.1%) had NSSTTAs at baseline. With a median of 9.6 years follow-up, 106 (3.4%) with NSSTTAs had ischemic stroke compared with 258 (2.4%) without NSSTTAs. The age-adjusted incidence rates (per 1000 person-years) of stroke were 2.93 in those with NSSTTAs and 2.19 in those without them. Adjusting for baseline age, sex, race, geographic location, and education level, isolated NSSTTAs were associated with a 32% higher risk of ischemic stroke (hazard ratio, 1.32 [95% CI, 1.05–1.67]). With additional adjustment for stroke risk factors, the risk of stroke was increased 27% (hazard ratio, 1.27 [95% CI, 1.00–1.62]) and did not differ by age, race, or sex. Conclusions— Presence of NSSTTAs in persons with an otherwise normal ECG was associated with a 27% increased risk of future ischemic stroke.

Background Data on stroke epidemiology and availability of hospital-based stroke services around the world are important for guiding policy decisions and healthcare planning. Aims To provide the most current incidence, mortality and case–fatality data on stroke and describe current availability of stroke units around the world by country. Methods We searched multiple databases (based on our existing search strategy) to identify new original manuscripts and review articles published between 1 June 2016 and 31 October 2018 that met the ideal criteria for data on stroke incidence and case–fatality. For data on the availability of hospital-based stroke services, we searched PubMed for all literature published up until 31 June 2018. We further screened reference lists, citation history of manuscripts and gray literature for this information. Mortality codes for International Classification of Diseases-9 and International Classification of Diseases-10 were extracted from the World Health Organization mortality database for each country providing these data. Population denominators were obtained from the World Health Organization, and when these were unavailable within a two-year period of mortality data, population denominators within a two-year period were obtained from the United Nations. Using country-specific population denominators and the most recent years of mortality data available for each country, we calculated both the crude mortality from stroke and mortality adjusted to the World Health Organization world population. Results Since our last report in 2017, there were two countries with new incidence studies, China ( n = 1) and India ( n = 2) that met the ideal criteria. New data on case–fatality were found for Estonia and India. The most current mortality data were available for the year 2015 (39 countries), 2016 (43 countries), and 2017 (7 countries). No new data on mortality were available for six countries. Availability of stroke units was noted for 63 countries, and the proportion of patients treated in stroke units was reported for 35/63 countries. Conclusion Up-to-date data on stroke incidence, case–fatality, and mortality statistics provide evidence of variation among countries and changing magnitudes of burden among high and low–middle income countries. Reporting of hospital-based stroke units remains limited and should be encouraged.

Background Relative to White adults, Black adults have a substantially higher prevalence of hypertension and diabetes, both key risk factors for stroke, cardiovascular disease, cognitive impairment, and dementia. Blood biomarkers have shown promise in identifying contributors to racial disparities in many chronic diseases. Methods We outline the study design and related statistical considerations for a nested cohort study, the Biomarker Mediators of Racial Disparities in Risk Factors (BioMedioR) study, within the 30,239-person biracial REasons for Geographic And Racial Differences in Stroke (REGARDS) study (2003-present). Selected biomarkers will be assessed for contributions to racial disparities in risk factor development over median 9.4 years of follow-up, with initial focus on hypertension and diabetes. Here we outline study design decisions and statistical considerations for the sampling of 4,400 BioMedioR participants. Results The population for biomarker assessment was selected using a random sample study design balanced across race and sex to provide the optimal opportunity to describe association of biomarkers with the development of hypertension and diabetes. Descriptive characteristics of the BioMedioR sample and analytic plans are provided for this nested cohort study. Conclusions This nested biomarker study will examine pathways with the target to help explain racial differences in hypertension and diabetes incidence.

Background and Purpose: When reporting primary results from randomized controlled trials, recommendations include reporting results by sex. We reviewed the reporting of results by sex in contemporary acute stroke randomized controlled trials. Methods: We searched MEDLINE for articles reporting the primary results of phase 2 or 3 stroke randomized controlled trials published between 2010 and June 2020 in one of nine major clinical journals. Eligible trials were restricted to those with a therapeutic intervention initiated within one month of stroke onset. Of primary interest was the reporting of results by sex for the primary outcome. We performed bivariate analyses using Fisher exact tests to identify study-level factors associated with reporting by sex and investigated temporal trends using an exact test for trend. Results: Of the 115 studies identified, primary results were reported by sex in 37% (n=42). Reporting varied significantly by journal, with the New England Journal of Medicine (61%) and Lancet journals (40%) having the highest rates ( P =0.03). Reporting also differed significantly by geographic region (21% Europe versus 48% Americas, P =0.03), trial phase (13% phase 2 versus 40% phase 3, P =0.05), and sample size (24% 750 participants, P P =0.11), there was a temporal trend in favor of greater reporting among later publications (25% 2010–2012 versus 48% 2019–2020). Conclusions: Although reporting of primary trial results by sex improved from 2010 to 2020, the prevalence of reporting in major journals is still low. Further efforts are required to encourage journals and authors to comply with current reporting recommendations.

Low socioeconomic position (SEP) across the lifecourse is associated with Type 2 diabetes (T2DM). We examined whether these economic disparities differ by race and sex. We included 5448 African American (AA) and white participants aged ≥45 years from the national (United States) REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort without T2DM at baseline (2003–07). Incident T2DM was defined by fasting glucose ≥126 mg/dL, random glucose ≥200 mg/dL, or using T2DM medications at follow-up (2013–16). Derived SEP scores in childhood (CSEP) and adulthood (ASEP) were used to calculate a cumulative (CumSEP) score. Social mobility was defined as change in SEP. We fitted race-stratified logistic regression models to estimate the association between each lifecourse SEP indicator and T2DM, adjusting for covariates; additionally, we tested SEP-sex interactions. Over a median of 9.0 (range 7–14) years of follow-up, T2DM incidence was 167.1 per 1000 persons among AA and 89.9 per 1000 persons among white participants. Low CSEP was associated with T2DM incidence among AA (OR = 1.61; 95%CI 1.05–2.46) but not white (1.06; 0.74–2.33) participants; this was attenuated after adjustment for ASEP. In contrast, low CumSEP was associated with T2DM incidence for both racial groups. T2DM risk was similar for stable low SEP and increased for downward mobility when compared with stable high SEP in both groups, whereas upward mobility increased T2DM risk among AAs only. No differences by sex were observed. Among AAs, low CSEP was not independently associated with T2DM, but CSEP may shape later-life experiences and health risks.

Background and Purpose: In the general population, Black adults are less likely than White adults to have controlled blood pressure (BP), and when not controlled, they are at greater risk for stroke compared with White adults. High BP is a major modifiable risk factor for recurrent stroke, but few studies have examined racial differences in BP control among stroke survivors. Methods: We used data from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) to examine disparities in BP control between Black and White adults, with and without a history of stroke. We studied participants taking antihypertensive medication who did and did not experience an adjudicated stroke (n=306 and 7693 participants, respectively) between baseline (2003–2007) and a second study visit (2013–2016). BP control at the second study visit was defined as systolic BP Results: Among participants with a history of stroke, 50.3% of White compared with 39.3% of Black participants had controlled BP. Among participants without a history of stroke, 56.0% of White compared with 50.2% of Black participants had controlled BP. After multivariable adjustment, there was a tendency for Black participants to be less likely than White participants to have controlled BP (prevalence ratio, 0.77 [95% CI, 0.59–1.02] for those with a history of stroke and 0.92 [95% CI, 0.88–0.97] for those without a history of stroke). Conclusions: There was a lower proportion of controlled BP among Black compared with White adults with or without stroke, with no statistically significant differences after multivariable adjustment.

ObjectiveThe purpose of this study was to examine depressive symptoms as a risk factor for incident stroke and determine whether depressive symptomatology was differentially predictive of stroke among Black and White participants.MethodsThe study comprised 9,529 Black and 14,516 White stroke-free participants, aged 45 and older, enrolled in the REasons for Geographic and Racial Differences in Stroke (2003–2007). Incident stroke was the first occurrence of stroke. Association between baseline depressive symptoms (assessed via the 4-item Center for Epidemiologic Studies Depression Scale [CES-D-4]: 0, 1–3, or ≥4) and incident stroke was analyzed with Cox proportional hazards models adjusted for demographics, stroke risk factors, and social factors.ResultsThere were 1,262 strokes over an average follow-up of 9.21 (SD 4.0) years. Compared to participants with no depressive symptoms, after demographic adjustment, participants with CES-D-4 scores of 1–3 had 39% increased stroke risk (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.23–1.57), with slight attenuation after full adjustment (HR = 1.27, 95% CI = 1.11–1.43). Participants with CES-D-4 scores of ≥4 experienced 54% higher risk of stroke after demographic adjustment (HR = 1.54, 95% CI = 1.27–1.85), with risk attenuated in the full model similar to risk with 1–3 symptoms (HR = 1.25, 95% CI = 1.03–1.51). There was no evidence of a differential effect by race (p = 0.53).ConclusionsThe association of depressive symptoms with increased stroke risk was similar among a national sample of Black and White participants. These findings suggest that assessment of depressive symptoms should be considered in primary stroke prevention for both Black and White participants.

Background Atrial fibrillation is associated with increased stroke risk; available risk prediction tools have modest accuracy. We hypothesized that circulating stroke risk biomarkers may improve stroke risk prediction in atrial fibrillation. Methods and Results The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a prospective cohort study of 30 239 Black and White adults age ≥45 years. A nested study of stroke cases and a random sample of the cohort included 175 participants (63% women, 37% Black adults) with baseline atrial fibrillation and available blood biomarker data. There were 81 ischemic strokes over 5.2 years in these participants. Adjusted for demographics, stroke risk factors, and warfarin use, the following biomarkers were associated with stroke risk (hazard ratio [HR]; 95% CI for upper versus lower tertile): cystatin C (3.16; 1.04–9.58), factor VIII antigen (2.77; 1.03–7.48), interleukin‐6 (9.35; 1.95–44.78), and NT‐proBNP (N‐terminal B‐type natriuretic peptide) (4.21; 1.24–14.29). A multimarker risk score based on the number of blood biomarkers in the highest tertile was developed; adjusted HRs of stroke for 1, 2, and 3+ elevated blood biomarkers, compared with none, were 1.75 (0.57–5.40), 4.97 (1.20–20.5), and 9.51 (2.22–40.8), respectively. Incorporating the multimarker risk score to the CHA 2 DS 2 VASc score resulted in a net reclassification improvement of 0.34 (95% CI, 0.04–0.65). Conclusions Findings in this biracial cohort suggested the possibility of substantial improvement in stroke risk prediction in atrial fibrillation using blood biomarkers or a multimarker risk score.

Purpose We previously described the magnitude of rural-urban differences in the prevalence of stroke risk factors and stroke mortality. In this report, we sought to extend the understanding of rural-urban differences in the prevalence of stroke risk factors by using an enhanced definition of rural-urban status and assessing the impact of neighborhood socioeconomic status (nSES) on risk factor differences. Methods This analysis included 28,242 participants without a history of stroke from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Participants were categorized into the 6-level ordinal National Center for Health Statistics Urban-Rural Classification Scheme. The prevalence of stroke risk factors (hypertension, diabetes, smoking, atrial fibrillation, left ventricular hypertrophy, and heart disease) was assessed across the rural-urban scale with adjustment for demographic characteristics and further adjustment for nSES score. Findings Hypertension, diabetes, and heart disease were more prevalent in rural than urban regions. Higher odds were observed for these risk factors in the most rural compared to the most urban areas (odds ratios [95% CI]: 1.25 [1.11-1.42] for hypertension, 1.15 [0.99-1.33] for diabetes, and 1.19 [1.02-1.39] for heart disease). Adjustment for nSES score partially attenuated the odds of hypertension and heart disease with rurality, completely attenuated the odds of diabetes, and unmasked an association of current smoking. Conclusions Some of the higher stroke mortality in rural areas may be due to the higher burden of stroke risk factors in rural areas. Lower nSES contributed most notably to rural-urban differences for diabetes and smoking.

A healthy brain is critical for living a longer and fuller life. The projected aging of the population, however, raises new challenges in maintaining quality of life. As we age, there is increasing compromise of neuronal activity that affects functions such as cognition, also making the brain vulnerable to disease. Once pathology-induced decline begins, few therapeutic options are available. Prevention is therefore paramount, and primary care can play a critical role. The purpose of this American Heart Association scientific statement is to provide an up-to-date summary for primary care providers in the assessment and modification of risk factors at the individual level that maintain brain health and prevent cognitive impairment. Building on the 2017 American Heart Association/American Stroke Association presidential advisory on defining brain health that included “Life’s Simple 7,” we describe here modifiable risk factors for cognitive decline, including depression, hypertension, physical inactivity, diabetes, obesity, hyperlipidemia, poor diet, smoking, social isolation, excessive alcohol use, sleep disorders, and hearing loss. These risk factors include behaviors, conditions, and lifestyles that can emerge before adulthood and can be routinely identified and managed by primary care clinicians.

BACKGROUND AND AIM: Providing care to an older adult with a disability has been associated with increased risk to the caregiver’s health, but most previous studies of caregiving and health compare persons who are already caregivers with poorly matched non-caregiving controls and are often based on convenience samples. In this report, we describe the enrollment of persons who transitioned into a family caregiving role while participating in a national epidemiological study. METHODS: Participants in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were asked on two occasions 9-14 years apart if they were providing care on an ongoing basis to a family member with a chronic illness or disability. Those who answered “no” and “yes,” respectively, to this caregiving question and reported sufficient caregiving responsibilities after their transitions were enrolled in the present study as incident caregivers (N = 251). Participants matched on multiple demographic and health history variables and who reported no history of caregiving were enrolled as non-caregiving controls (N = 251). RESULTS: Among eligible participants, 84% agreed to participate, and 47% of caregivers reported caring for a person with dementia. Descriptive analyses confirmed the success of the matching procedures for balancing the groups on multiple demographic and pre-caregiving health variables. Depressive symptoms and perceived stress increased significantly after the transition to caregiving. CONCLUSION: Comparable, population-based samples of incident caregivers and matched non-caregivers have been enrolled. Future analyses will examine within-person changes in health and circulating biomarkers as a function of the transition to caregiving.

Little is known about whether the relationship between hypertension and ischemic stroke differs by sex. We examined sex differences in the association between hypertension severity and treatment and ischemic stroke risk. We used a longitudinal cohort study in the continental United States, with oversampling of black individuals and those living in the stroke belt. We included 26 461 participants recruited from 2003 to 2007 without prevalent stroke at baseline. The main outcome was incident ischemic stroke ascertained by telephone surveillance (with physician adjudication for suspected events). Proportional hazards regression was used to assess the sex-specific association between systolic blood pressure and stroke and between classes of antihypertensive medications and stroke after adjustment for age, race, sex, and age-by-race and sex-by-treatment interaction terms. A priori, P 140 mm Hg) was higher in women (hazard ratio, 1.25; 95% CI, 1.16–1.34) than men (hazard ratio, 1.14; 95% CI, 1.05–1.23; sex–systolic blood pressure interaction term, P =0.09). Compared with no medications, with each additional class of medications, stroke risk increased by 23% (hazard ratio, 1.23; 95% CI, 1.14–1.33) for women and 21% (hazard ratio, 1.21; 95% CI, 1.12–1.31) for men ( P =0.79). Further work on the biological mechanisms for sex differences in stroke risk associated with hypertension severity and a need for sex-specific clinical guidelines may be warranted.

// Tomi Akinyemiju 1 , Justin X. Moore 2 , Daniel Tefera Dibaba 3 , Maria Pisu 4 , Michael Goodman 5 , Virginia J. Howard 6 , Monika Safford 7 , Susan C. Gilchrist 8 , Mary Cushman 9 , LeAnn Long 10 and Suzanne E. Judd 10 1 Department of Population Health Sciences, Duke University School of Medicine, Durham, NC, USA 2 Division of Public Health Sciences and Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA 3 Tennessee Clinical and Translational Science Institute, University of Tennessee Health Science Center, Memphis, TN, USA 4 Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham AL, USA 5 Department of Epidemiology, Emory University Rollins School of Public Health, Atlanta, GA, USA 6 Department of Epidemiology, University of Alabama at Birmingham, Birmingham AL, USA 7 Department of Medicine, Weill Cornell Medical College, New York, NY, USA 8 Department of Clinical Cancer Prevention and Cardiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Department of Medicine and Vermont Cancer Center, Larner College of Medicine at the University of Vermont, Burlington, VT, USA 10 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA Correspondence to: Tomi Akinyemiju, email: tomi.akinyemiju@duke.edu Keywords: inflammatory biomarkers; racial disparities; cancer mortality; obesity Received: December 12, 2018 Accepted: June 29, 2019 Published: August 06, 2019 ABSTRACT This study examines the association between inflammatory biomarkers and risk of cancer mortality by race. Data were obtained from 1,856 participants in the prospective REGARDS cohort who were cancer-free at baseline, and analyzed in relation to cancer mortality prospectively. Biomarkers were log-transformed and categorized into tertiles due to non-normal distributions, and Cox proportional hazard regression models were utilized to compute hazard ratios with 95% confidence intervals using robust sandwich methods. Individuals in the highest tertile of IL-6 had over a 12-fold increased risk of cancer mortality (HR: 12.97, 95% CI: 3.46–48.63); those in the highest tertile of IL-8 had over a 2-fold increased risk of cancer mortality (HR: 2.21, 95% CI: 0.86–5.71), while those in the highest tertile of IL-10 had over a 3-fold increased risk of cancer mortality (HR: 3.06, 95% CI: 1.35–6.89). In race-stratified analysis, each unit increase in IL-6 was associated with increased risk of cancer mortality among African-Americans (HR: 3.88, 95% CI: 1.17–12.88) and Whites (5.25, 95% CI: 1.24–22.31). If replicated in larger, racially diverse prospective cohorts, these results suggest that cancer patients may benefit from clinical or lifestyle approaches to regulate systemic inflammation as a cancer prevention strategy.

Background Most carotid revascularization studies define asymptomatic as symptom-free for more than 180 days; however, it is unknown if intervention carries similar risk among those currently asymptomatic but with previous symptoms (PS) vs those who were always asymptomatic (AA). Methods We compared the periprocedural and 4-year risks of PS vs AA patients in the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) randomized to carotid endarterectomy (CEA) or carotid artery stenting (CAS)/angioplasty. Proportional hazards models adjusting for age, sex, and treatment were used to assess the risk of periprocedural stroke and/or death (S+D; any S+D during periprocedural period), stroke and death at 4 years (any S+D within the periprocedural period and ipsilateral stroke out to 4 years) and the primary end point at 4 years (any stroke, death, and myocardial infarction within the periprocedural period and ipsilateral stroke out to 4 years). Analysis was performed pooling the CEA-treated and CAS-treated patients, and separately for each treatment. Results Of 1181 asymptomatic patients randomized in CREST, 1104 (93%) were AA and 77 (7%) were PS. There was no difference in risk when comparing the AA and PS cohorts in the pooled CAS+CEA population for periprocedural S+D (2.0% vs 1.3%), S+D at 4 years (3.6% vs 3.2%), or the primary end point (5.2% vs 5.8%). There were also no differences among those assigned to CEA (periprocedural S+D, 1.5% vs 0%; S+D at 4 years, 2.7% vs 0%; or primary end point, 5.1% vs 2.4%) or CAS (periprocedural S+D, 2.5% vs 2.8%; S+D at 4 years, 4.4% vs 6.9%; or primary end point, 5.3% vs 9.8%) when analyzed separately. Conclusions In CREST, only a small minority of asymptomatic patients had previous ipsilateral symptoms. The outcomes of periprocedural S+D, periprocedural S+D, and ipsilateral stroke up to 4 years, and the primary end point did not differ for AA patients compared with PS patients.

Background Retrospective studies have reported an association between cancer and arterial thromboembolic event (ATE) risk. Objectives We sought to confirm this in a prospective cohort with adjudicated outcomes. Methods We evaluated participants enrolled in the REGARDS (REasons for Geographic and Racial Differences in Stroke) study with Medicare coverage for 365 days before their baseline visit (2003-2007). Medicare claims were used to identify new cancer diagnoses during follow-up. Using incidence-density sampling, participants who developed cancer were matched by age, sex, race, and education 1:4 to control participants who had not developed cancer. Participants were prospectively followed through 2015 for an expert-adjudicated ATE, defined as acute myocardial infarction or ischemic stroke. Cox regression was performed to evaluate the association between incident cancer and subsequent ATE. Results In this analysis, 836 REGARDS participants with incident cancer were matched to 3339 control participants without cancer. In the 30 days after cancer diagnosis, 0.60% (n = 5) of the participants had an ATE; most of these events occurred near the time of cancer diagnosis. After adjustment for demographics, geographic region, and cardiovascular risk factors, compared to the noncancer controls, participants with incident cancer had an increased risk of ATE in the first 30 days after diagnosis (hazard ratio, 5.8; 95% confidence interval, 2.1-15.9). There was no association between cancer diagnosis and ATE beyond 30 days. Cancers with known metastases and types considered high risk for venous thromboembolism had the strongest associations with ATE. Conclusions Incident cancer is associated with an increased short-term risk of ATE independent of vascular risk factors.

Background and Purpose— It is unclear whether disparities in mortality among stroke survivors exist long term. Therefore, the purpose of the current study is to describe rates of longer term mortality among stroke survivors (ie, beyond 30 days) and to determine whether socioeconomic disparities exist. Methods— This analysis included 1329 black and white participants, aged ≥45 years, enrolled between 2003 and 2007 in the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) who suffered a first stroke and survived at least 30 days after the event. Long-term mortality among stroke survivors was defined in person-years as time from 30 days after a first stroke to date of death or censoring. Mortality rate ratios (MRRs) were used to compare rates of poststroke mortality by demographic and socioeconomic characteristics. Results— Among adults who survived ≥30 days poststroke, the age-adjusted rate of mortality was 82.3 per 1000 person-years (95% CI, 75.4–89.2). Long-term mortality among stroke survivors was higher in older individuals (MRR for 75+ versus 50k, 1.4; 95% CI, 1.1–1.9), and lower neighborhood socioeconomic status (SES; MRR for low versus high neighborhood SES, 1.4; 95% CI, 1.1–1.7). There were no differences in age-adjusted rates of long-term poststroke mortality by race, rurality, or US region. Conclusions— Rates of long-term mortality among stroke survivors were higher among individuals with lower SES and among those residing in neighborhoods of lower SES. These results emphasize the need for improvements in long-term care poststroke, especially among individuals of lower SES.

BackgroundThere have been mixed findings regarding the relationship between walkability and level of physical activity in adults.MethodsParticipants from The REasons for Geographic and Racial Differences in Stroke (REGARDS) national cohort (N=7561) were used to examine the association between Walk Score and physical activity measured via accelerometry. The subsample included geographically diverse adults, who identified as black or white, and were over the age of 45. Linear regression was used to examine the direct effects, as well as the interaction, of Walk Score by sex, age and race.ResultsThe majority of participants lived in a ‘Very Car-Dependent’ location (N=4115). Only 527 lived in a location that was ‘Very Walkable/Walker’s Paradise’. Living in a location with a Walk Score of ‘Very Car-Dependent’ compared with ‘Very Walkable/Walker’s Paradise’ was associated with 19% (0.81; 95% CI 0.73 to 0.90) lower predicted minutes of moderate to vigorous physical activity per day, after adjustment for covariates. There was no evidence of statistically significant interactions between Walk Score and sex, age or race (p>0.05).ConclusionAccumulated daily time in moderate to vigorous physical activity was higher for participants living in neighbourhoods designated as ‘Very Walkable/Walker’s Paradise’. This effect was not moderated by sex, age or race of participants.

Objective: To describe the relationship between metabolic health parameters and depressive symptoms and perceived stress, and whether the co-occurrence of these two psychological stressors has an additive influence on metabolic dysregulation in adults at different levels of body mass index (BMI) without diabetes. Methods: Participants without diabetes (N=20,312) from the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) study (recruited between 2003–2007) who had a body mass index (BMI) ≥18.5 kg/m2 were included in this cross-sectional analysis. Mean age of sample was 64.4 years, with 36% African American, and 56% women. Depressive symptoms and perceived stress were measured using brief versions of the Center for Epidemiologic Studies Depression (CES-D-4 item) questionnaire and Cohen Perceived Stress Scale (PSS), respectively. Metabolic health parameters included waist circumference, blood pressure (systolic and diastolic), low- and high-density lipoprotein (LDL, HDL) cholesterol, triglycerides, fasting glucose, and high sensitivity C-reactive protein (hs-CRP). Sequentially adjusted General Linear Regression Models (GLM) for each metabolic parameter were used to assess the association between having both elevated depressive symptoms and stress, either of these psychological risk factors, or none with all analyses stratified by BMI category (i.e., normal, overweight, and obesity). Results: The presence of elevated depressive symptoms and/or perceived stress was generally associated with increased waist circumference, higher CRP, and lower HDL. The combination of depressive symptoms and perceived stress, compared to either alone, was typically associated with poorer metabolic health outcomes. However, sociodemographic and lifestyle factors generally attenuated the associations between psychological factors and metabolic parameters. Conclusions: Elevated depressive symptoms in conjunction with high levels of perceived stress were more strongly associated with several parameters of metabolic health than only one of these psychological constructs in a large, diverse cohort of adults. Findings suggest that healthy lifestyle factors may attenuate the association between psychological distress and metabolic health impairment.

Background: Hypertension is a leading cause of disability-adjusted life years lost in the United States. Adiponectin is a cytokine secreted by adipocytes that increases insulin sensitivity, maintains vascular homeostasis, and is inversely associated with adiposity. We sought to determine the risk of incident hypertension by level of adiponectin at baseline. Methods: The REasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black and White US adults in 2003-2006, with a second visit ~9 years later. Adiponectin was measured at the baseline visit among a random sample of 4,400 participants who attended the second visit. Modified Poisson regression estimated the relative risk (RR) for incident hypertension by each 1 SD higher of log-transformed adiponectin level adjusting for age, race, and sex in a minimally adjusted model. The fully adjusted model added Southern Diet pattern, dietary ratio of sodium to potassium, BMI, waist circumference, and systolic blood pressure. Restricted cubic splines visualized RR of hypertension by level of adiponectin, relative to the median. Results: After excluding those with prevalent hypertension (threshold 140/90 mm Hg or blood pressure medication use; n=2477) and missing adiponectin (n =129), 1,877 participants remained (mean age 62 years, 49% male, 36% Black, with lower adiponectin in Black participants pFigure ). Conclusions: In a cohort of Black and White US adults without hypertension, level of adiponectin did not associate with risk of incident hypertension 9 years later after adjusting for other hypertension risk factors.

Importance Intracerebral hemorrhage and arterial ischemic disease share risk factors, to our knowledge, but the association between the 2 conditions remains unknown. Objective To evaluate whether intracerebral hemorrhage was associated with an increased risk of incident ischemic stroke and myocardial infarction. Design, Setting, and Participants An analysis was conducted of pooled longitudinal participant-level data from 4 population-based cohort studies in the United States: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Northern Manhattan Study (NOMAS), and the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. Patients were enrolled from 1987 to 2007, and the last available follow-up was December 31, 2018. Data were analyzed from September 1, 2019, to March 31, 2020. Exposure Intracerebral hemorrhage, as assessed by an adjudication committee based on predefined clinical and radiologic criteria. Main Outcomes and Measures The primary outcome was an arterial ischemic event, defined as a composite of ischemic stroke or myocardial infarction, centrally adjudicated within each study. Secondary outcomes were ischemic stroke and myocardial infarction. Participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction at their baseline study visit were excluded. Cox proportional hazards regression was used to examine the association between intracerebral hemorrhage and subsequent arterial ischemic events after adjustment for baseline age, sex, race/ethnicity, vascular comorbidities, and antithrombotic medications. Results Of 55 131 participants, 47 866 (27 639 women [57.7%]; mean [SD] age, 62.2 [10.2] years) were eligible for analysis. During a median follow-up of 12.7 years (interquartile range, 7.7-19.5 years), there were 318 intracerebral hemorrhages and 7648 arterial ischemic events. The incidence of an arterial ischemic event was 3.6 events per 100 person-years (95% CI, 2.7-5.0 events per 100 person-years) after intracerebral hemorrhage vs 1.1 events per 100 person-years (95% CI, 1.1-1.2 events per 100 person-years) among those without intracerebral hemorrhage. In adjusted models, intracerebral hemorrhage was associated with arterial ischemic events (hazard ratio [HR], 2.3; 95% CI, 1.7-3.1), ischemic stroke (HR, 3.1; 95% CI, 2.1-4.5), and myocardial infarction (HR, 1.9; 95% CI, 1.2-2.9). In sensitivity analyses, intracerebral hemorrhage was associated with arterial ischemic events when updating covariates in a time-varying manner (HR, 2.2; 95% CI, 1.6-3.0); when using incidence density matching (odds ratio, 2.3; 95% CI, 1.3-4.2); when including participants with prevalent intracerebral hemorrhage, ischemic stroke, or myocardial infarction (HR, 2.2; 95% CI, 1.6-2.9); and when using death as a competing risk (subdistribution HR, 1.6; 95% CI, 1.1-2.1). Conclusions and Relevance This study found that intracerebral hemorrhage was associated with an increased risk of ischemic stroke and myocardial infarction. These findings suggest that intracerebral hemorrhage may be a novel risk marker for arterial ischemic events.

The underenrollment of women in randomized clinical trials represents a threat to the validity of the evidence supporting clinical guidelines and potential disparities in access to novel treatments.To determine whether women were underenrolled in contemporary randomized clinical trials of acute stroke therapies published in 9 major journals after accounting for their representation in underlying stroke populations.MEDLINE was searched for acute stroke therapeutic trials published between January 1, 2010, and June 11, 2020.Eligible articles reported the results of a phase 2 or 3 randomized clinical trial that enrolled patients with stroke and/or transient ischemic attack and examined a therapeutic intervention initiated within 1 month of onset.Data extraction was performed by 2 independent authors in duplicate. Individual trials were matched to estimates of the proportion of women in underlying stroke populations using the Global Burden of Disease database.The primary outcome was the enrollment disparity difference (EDD), the absolute difference between the proportion of trial participants who were women and the proportion of strokes in the underlying disease populations that occurred in women. Random-effects meta-analyses of the EDD were performed, and multivariable metaregression was used to explore the associations of trial eligibility criteria with disparity estimates.The search returned 1529 results, and 115 trials (7.5%) met inclusion criteria. Of 121 105 randomized patients for whom sex was reported, 52 522 (43.4%) were women. The random-effects summary EDD was -0.053 (95% CI, -0.065 to -0.040), indicating that women were underenrolled by 5.3 percentage points. This disparity persisted across virtually all geographic regions, intervention types, and stroke types, apart from subarachnoid hemorrhage (0.117 [95% CI, 0.084 to 0.150]). When subarachnoid hemorrhage trials were excluded, the summary EDD was -0.067 (95% CI, -0.078 to -0.057). In the multivariable metaregression analysis, an upper age limit of 80 years as an eligibility criterion was associated with a 6-percentage point decrease in the enrollment of women.Further research is needed to understand the causes of the underenrollment of women in acute stroke trials. However, to maximize representation, investigators should avoid imposing age limits on enrollment.

Four seminal randomized controlled trials (RCTs) have investigated aspirin, aspirin plus extended-release dipyridamole, and clopidogrel for the prevention of recurrent vascular events. Despite studying over 32,000 patients with stroke in these trials, the decision on which antiplatelet agent to select for secondary stroke prevention remains controversial. Attempts to translate the results of these RCTs into clinical practice are complicated by each trial's selection of participants and choice of primary outcome. Herein, we argue that by examining RCT results with participant selection limited to patients with ischemic stroke or TIA and by focusing on recurrent stroke as our outcome, we can use the standard epidemiology 2 × 2 table to assist in selecting an antiplatelet agent for secondary stroke prevention.

ObjectiveNo systematic review of the literature has dedicated itself to looking at the management of symptomatic carotid stenosis in female patients. In this scoping review, we aimed to identify all randomised controlled trials (RCTs) that reported sex-specific outcomes for patients who underwent carotid revascularisation, and determine whether sufficient information is reported within these studies to assess short-term and long-term outcomes in female patients.Design, setting and participantsWe systematically searched Medline, Embase, Pubmed and Cochrane libraries for RCTs published between 1991 and 2020 that included female patients and compared either endarterectomy with stenting, or any revascularisation (endarterectomy or stenting) with medical therapy in patients with symptomatic high-grade (>50%) carotid stenosis.ResultsFrom 1537 references examined, 27 eligible studies were identified. Sex-specific outcomes were reported in 13 studies. Baseline patient characteristics of enrolled female patients were reported in 2 of those 13 studies. Common outcomes reported included stroke and death, however, there was significant heterogeneity in the reporting of both periprocedural and long-term outcomes. Sex-specific differences relating to the degree of stenosis and time from index event to treatment are largely limited to studies comparing endarterectomy to medical therapy. Adverse events were not reported by sex.ConclusionsOnly half of the previously published RCTs and systematic reviews report sex-specific outcomes. Detailed analyses on the results of carotid artery intervention for female patients with symptomatic stenosis are limited.

Background and Purpose: No systematic review of the literature has dedicated itself to looking at the management of symptomatic carotid stenosis in women. In this scoping review, we aimed to identify all randomized controlled trials (RCTs) that reported sex-specific outcomes for patients who underwent carotid revascularization, and determine whether sufficient information is reported within these studies to assess women’s short and long-term outcomes. Methods: We systematically searched Medline, Embase, Pubmed, and Cochrane libraries for RCTs published between 1991 and 2020 that included women and compared either endarterectomy with stenting, or any revascularization (endarterectomy or stenting) with medical therapy in patients with symptomatic high grade (greater than 50%) carotid stenosis. Results: From 1,537 references examined, 27 eligible studies were identified. Sex-specific outcomes were reported in 13 studies. Baseline patient characteristics of enrolled women were reported in 2 of those 13 studies. Common outcomes reported included stroke and death, however there was significant heterogeneity in the reporting of both periprocedural and long-term outcomes. Sex-specific differences relating to the degree of stenosis and time from index event to treatment were limited to studies comparing endarterectomy to medical therapy. Adverse events were not reported by sex. Conclusions: Half of the previously published RCTs and systematic reviews report sex-specific outcomes. Detailed analysis on the benefits of carotid artery intervention for women with symptomatic stenosis is limited . Further analysis with individual patient data and a network meta-analysis is the necessary next step to better assess the treatment effects of carotid management in women.

Introduction: When reporting primary results, it is recommended that RCTs report sex-specific outcomes. We reviewed the reporting of sex-specific outcomes in contemporary acute stroke RCTs. Methods: We searched MEDLINE for manuscripts published between 2010 and June 2020 in one of nine major clinical journals reporting the primary results of phase 2 or 3 stroke RCTs. Eligible trials tested a therapeutic intervention initiated within one month of stroke onset. Reporting of sex-specific primary results was the outcome of interest. We also investigated whether the trial formally tested for an interaction between sex and treatment and if that interaction test was statistically significant. We performed bivariate analyses using Fisher’s exact tests to identify study-level factors associated with sex-specific reporting including journal, geographic region, trial phase, sample size, stroke type, trial type (e.g. thrombolytic, EVT, secondary prevention), and industry funding. Temporal trends using two-year time periods were also explored. Results: Of the 115 studies identified, sex-specific primary outcome data were reported in 37% (n=42). Reporting varied significantly by journal, with NEJM (61%) and Lancet journals (40%) having the highest rates (p=0.03) (Table). Reporting also differed by geographic region (p=0.03), trial phase (p=0.05), and sample size (p Conclusions: Although reporting of sex-specific outcomes improved from 2010 to 2020, the prevalence of reporting in major journals is still low. Further efforts are required to ensure that journals and authors comply with reporting guidelines.