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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 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.

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.

AIMS: Recent findings have demonstrated the important contribution of inflammation to the risk of cardiovascular disease (CVD) in individuals with optimally managed low density lipoprotein cholesterol (LDL-C). We explored relationships between LDL-C, high sensitivity C-reactive protein (hs-CRP), and clinical outcomes in a free-living US population. METHODS AND RESULTS: We used data from the REasons for Geographical And Racial Differences in Stroke (REGARDS), and selected individuals at ‘high risk’ for coronary events with a Framingham Coronary Risk Score of ≥10% or atherosclerotic cardiovascular disease (ASCVD) risk ≥7.5% in order to explore relationships between low LDL-C [

One of the benefits of this large, national cohort study with black and white participants is the opportunity to involve a breadth of researchers in the science. REGARDS actively solicits and engages early career and minority investigators to lead or participate in manuscripts as well as ancillary studies. REGARDS has provided opportunities for >175 ancillary studies, including those that enrich existing outcomes, provide new outcomes, assess new exposures, link with other national data, support extended analyses, and assess genetic associations. Over 70% of the 500+ publications to date have a lead author who was not a funded REGARDS investigator. In this presentation, we will discuss some of the innovative ancillary studies and high-impact manuscripts that have grown out of REGARDS, the processes for developing an ancillary study/manuscript, and the procedures for obtaining REGARDS data. We will describe opportunities for mentored research for junior investigators, as well as independent research projects.

Major life events, such as retirement, may lead to dramatic shifts in physical activity (PA) patterns. However, there are limited empirical data quantifying the magnitude of these changes. Our aims were to objectively measure PA before and after retirement and to describe changes in participation in various types of PA. Participants were employed black and white men and women enrolled in REGARDS (REasons for Geographic and Racial Differences in Stroke), a national prospective cohort study (n=581, mean age 64 years, 25% black, 51% women). Participants met inclusion criteria if they retired between their first and second accelerometer wearing (2009-2013 and 2017-2018, respectively) and had valid accelerometer data (>4 days with >10 hours/day pre- and post-retirement). Accelerometer-based PA was categorized into average minutes per day spent in sedentary, light-intensity, and moderate-to-vigorous PA. Participants reported changes (less, same, more) in 12 types of PA. After retirement, participants decreased both sedentary time (by 36.3 minutes/day) and moderate-to-vigorous PA (by 5.6 minutes/day). Conversely, there was an increase in light-intensity PA (+18.1 minutes/day) after retirement. Participants reported changes in their participation level in various PA activities. For example, 41% reported an increased amount of TV viewing, 42% reported less walking, and 31% reported increased participation in volunteer activities. Findings indicate that retirement coincides with a change in the time spent in each intensity category and the time spent across a range of activity types. Further research is warranted to examine how these changes in physical activity patterns influence post-retirement health status.

Investigators in the NIH-funded REGARDS (REasons for Geographic and Racial Differences in Stroke) project have taken a novel approach to break the paradigm of epidemiologic studies limited to clinic-based convenience samples, by developing a national cohort of 30,239 black and white participants recruited from communities across all lower 48 US states, including 1,855 of the 3,033 counties. Mean age at enrollment (Jan 2003-Oct 2007) was 65.3 years. The four initial aims were to further understanding of: 1) geographic and racial differences in stroke risk factors; 2) geographic and racial differences in stroke incidence and mortality; 3) association of stroke risk factors and stroke risk (incidence and mortality) focusing on effect modification by race or region; and 4) establishment of a repository of serum, plasma, urine and DNA for use in future studies. When the grant was awarded, the study goals were broadened to include longitudinal remote assessment of cognitive function. A second in-home visit was completed May 2013-Dec 2016 including measures of functional status. The cohort is in its 17th year of follow-up. We will detail recruitment and enrollment methods, characteristics of the cohort and status, with brief overview of the biological, medical, psychosocial, environmental, and contextual data collected in the parent study. Speakers will discuss in more detail the stroke and cognitive data, ancillary studies focused on caregiver and heart disease outcomes, and provide examples of national and international mentoring that has leveraged REGARDS data. Finally, we will describe opportunities for additional data sharing and new ancillary studies.

Objectives This study examines the relationship between alcohol consumption and incident stroke among older adults and tests whether alcohol consumption contributes to observed race and sex differences in stroke. Method Data are from a U.S. national cohort of black and white adults aged 45 and older, the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Current and past drinking levels were reported at baseline (2003-2007). Participants who had never had a stroke were followed for adjudicated stroke events through September 2015 (n = 27,265). We calculated Cox proportional hazard models for stroke, adjusting for demographic, socioeconomic, behavioral, and health characteristics. Results Participants, mean age 64.7 years, consumed on average 2.2 drinks/week and experienced 1,140 first-time stroke events over median 9.1 years follow-up. Nondrinkers had a 12% higher risk of stroke than current drinkers; the risk of stroke among nondrinkers largely reflected high risks among past drinkers; these differences were explained by socioeconomic characteristics. Among current drinkers, light drinkers had significantly lower stroke risks than moderate drinkers after accounting for demographic, socioeconomic, behavioral, and health characteristics. Implications of alcohol did not differ between blacks and whites but did differ by sex: Especially among women, nondrinkers, and specifically past drinkers, had higher risks; these differences were largely explained by health characteristics and behaviors. Alcohol did not explain race and sex differences in stroke incidence. Discussion Among older adults, those who used to, but no longer, drink had higher risks of stroke, especially among women; current light drinkers had the lowest risk of stroke.

Participants in the national Reasons for Geographic and Racial Differences in Stroke (REGARDS) study were asked about family caregiving responsibilities at enrollment (2003-2007). Among the 88% of participants who were not caregivers at enrollment, 1,229 reported becoming caregivers before a follow-up interview 12 years later. The Caregiving Transitions Study screened these participants and enrolled 251 as incident caregivers. All reported 5 or more hours of care per week, provided assistance with at least one ADL or IADL, and were caregivers for at least 3 months before a 2nd blood sample was obtained in the REGARDS study. A total of 251 noncaregiving control participants who reported no caregiving responsibilities over this 12-year period were also enrolled. Each control was matched to a caregiver on age (+ 5 years), sex, race, other demographics, and baseline (pre-caregiving) health variables. Descriptive analyses confirm the unique comparability of the samples compared to previous caregiving studies.

The association between perceived stress and atrial fibrillation (AF) remains unclear. The aim of this study was to examine the association between perceived stress and AF. A total of 25,530 participants (mean age 65 ± 9.4 years; 54 % women; 41 % blacks) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study were included in this analysis. Logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for the association between the short version of the Cohen Perceived Stress Scale and AF. In a multivariable analysis adjusted for demographics, cardiovascular risk factors, and potential confounders, the prevalence of AF was found to increase with higher levels of stress (none: OR = 1.0, referent; low stress: OR = 1.12, 95 % CI = 0.98, 1.27; moderate stress OR = 1.27, 95 % CI = 1.11, 1.47; high stress: OR = 1.60, 95 % CI = 1.39, 1.84). Increasing levels of perceived stress are associated with prevalent AF in REGARDS.

Introduction: Recent findings have demonstrated the important contribution of inflammation to the risk of cardiovascular disease (CVD) in individuals with optimally managed low density lipoprotein cholesterol (LDL-C). We explored relationships between LDL-C, high sensitivity C-reactive protein (hsCRP) and clinical outcomes in a free-living US population. Methods: We used data from the REasons for Geographical And Racial Differences in Stroke (REGARDS), and selected individuals at “high risk” for coronary events with a Framingham Coronary Risk Score of >10% or atherosclerotic cardiovascular disease (ASCVD) risk >7.5% in order to explore relationships between low LDL-C ( 70 mg/dl [1.8 mmol/L]); hs-CRP 70 mg/dl) and low hs-CRP (

AIMS: Relatively little is known about the health outcomes associated with very low plasma concentrations of high density lipoprotein cholesterol (HDL-C) mainly because of the small numbers of individuals with such extreme values included in clinical trials. We therefore investigated the association between low and very low HDL-C concentration at baseline and incident all-cause-mortality, death from malignant disease (i.e. cancer), and with fatal or non-fatal incident coronary heart disease (CHD) in individuals from the Reasons for Geographical And Racial Differences in Stroke (REGARDS) study. METHODS AND RESULTS: Analysis was based on 21,751 participants from the REGARDS study who were free of CHD, other cardiovascular disease and cancer at baseline and were categorized by baseline HDL-C into

Longitudinal cohort studies normally identify and adjudicate incident events detected during follow-up by retrieving medical records. There are several reasons why the adjudication process may not be successfully completed for a suspected event including the inability to retrieve medical records from hospitals and an insufficient time between the suspected event and data analysis. These “incomplete adjudications” are normally assumed not to be events, an approach which may be associated with loss of precision and introduction of bias. In this article, the authors evaluate the use of multiple imputation methods designed to include incomplete adjudications in analysis. Using data from the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study, 2008−2009, they demonstrate that this approach may increase precision and reduce bias in estimates of the relations between risk factors and incident events.

Reduced glomerular filtration rate and albuminuria are associated with an increased risk for stroke. Their association with stroke symptoms is not known.The incidence of stroke symptoms was determined in 20 386 participants ≥45 years of age in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study who were free of a history of stroke, transient ischemic attack and stroke symptoms at baseline. Six stroke symptoms were assessed via telephone interviews at baseline and every 6 months. Participants were followed over a median of 2.1 years (maximum follow-up of 6 years). Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI equation and the albumin-to-creatinine ratio from spot urine samples.The incidence of any stroke symptom (n = 2548 cases) was 10.8, 12.9, 18.2 and 20.7% among participants with an eGFR ≥90, 60-89, 45-59 and45 mL/min/1.73m(2), respectively, and 10.8, 14.4, 17.0 and 18.8 for participants with albumin-to-creatinine ratios10, 10-29, 30-299 and ≥300 mg/g, respectively (each P-trend0.001). The multivariable-adjusted hazard ratio (95% confidence interval) for any stroke symptom was 1.02 (0.91-1.14), 1.22 (1.01-1.48) and 1.26 (0.98-1.62) for those with an eGFR of 60-89, 45-59 and45 mL/min/1.73m(2), respectively, versus ≥90 mL/min/1.73m(2) (P-trend = 0.022) and 1.16 (1.03-1.31), 1.29 (1.12-1.50) and 1.11 (0.82-1.49) for those with albumin-to-creatinine ratios of 10-29, 30-299 and ≥300 versus10 mg/g, respectively (P-trend = 0.005).Reduced eGFR and higher albuminuria levels are associated with an increased risk for incident stroke symptoms.

Death certificates may lack accuracy and misclassify the cause of death. The validity of proxy-reported cause of death is not well established. The authors examined death records on 336 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, a national cohort study of 30,239 community-dwelling US adults (2003–2010). Trained experts used study data, medical records, death certificates, and proxy reports to adjudicate causes of death. The authors computed agreement on cause of death from the death certificate, proxy, and adjudication, as well as sensitivity and specificity for certain diseases. Adjudicated cause of death had a higher rate of agreement with proxy reports (73%; Cohen's kappa (κ) statistic = 0.69) than with death certificates (61%; κ = 0.54). The agreement between proxy reports and adjudicators was better than agreement with death certificates for all disease-specific causes of death. Using the adjudicator assessments as the “gold standard,” for disease-specific causes of death, proxy reports had similar or higher specificity and higher sensitivity (sensitivity = 50%–89%) than death certificates (sensitivity = 31%–81%). Proxy reports may be more concordant with adjudicated causes of death than with the causes of death listed on death certificates. In many settings, proxy reports may represent a better strategy for determining cause of death than reliance on death certificates.

Abdominal obesity prevalence is increasing rapidly in the United States, particularly among adults 88 cm for women and >102 cm for men).2-5 High WC is associated with an increased risk of hypertension, stroke, coronary heart disease, diabetes mellitus, and cardiovascular-related death, independent of body mass index (BMI).6-11 Recognizing these important cardiovascular risks, the National Institutes of Health recommends screening for high WC in persons who are overweight (BMI 25–29.9) or obese class I (BMI 30–34.9) and to consider screening for high WC in persons with normal weight (BMI 18.5–24.9).2,4 However, many adults have moderate WC (80–88 cm for women and 94–102 cm for men).11-13 Less is known about the cardiovascular risks of moderate WC. Although WC appears to increase the risk of obesity-related complications in a graded fashion rather than only at high WC thresholds, previous studies have examined different moderate-range WC values based on empirically defined categories making translation of these findings into clinical practice challenging.8,9,14-15 Sex-specific WC cutoffs that predict obesity-related risk independent of BMI, that account for the graded relationship between WC and obesity-related risk, and that involve simple criteria (e.g., three strata) are needed for clinical practice and public health promotion. In 1995, Lean and colleagues identified two WC “action levels” associated with increased cardiovascular risk: (i) 80 cm in women and 94 cm in men, and (ii) 88 cm in women and 102 cm in men.14,16 However, few studies have tested whether these action levels predict cardiovascular risk independent of BMI in blacks and whites. The inclusion of blacks is important because US data (all pre-1990) have not found a consistent association between abdominal obesity and cardiovascular risk for blacks, after controlling for BMI.9,17,18 Therefore, we examined hypertension prevalence which is positively associated with obesity and abdominal obesity,2,6,19 by BMI and WC, with a focus on moderate WC, in a large biracial, national cohort of community-dwelling US adults aged 45–84 years. We tested the relationship between WC strata developed by Lean and colleagues and hypertension prevalence after adjusting for BMI and hypertension risk factors. We explored age variability because the relative proportion of lean body mass to fat mass may decrease with age7 and the relationship between abdominal obesity and cardiovascular risk may not persist in older adults after controlling for BMI.20 We hypothesized that moderate WC would be associated with prevalent hypertension among persons with normal, over-weight, or obese class I BMI.

BACKGROUND There are few available data on the epidemiology of prehypertension (preHTN).To determine racial, clinical, and demographic differences in the prevalence of preHTN and its cross-sectional association with vascular risk factors. METHODS Cross-sectional analysis of 5,553 prehypertensives, 20,351 hypertensive's, and 4,246 nonhypertensive participants (age ≥45), from a population-based national cohort study (REasons for Geographic And Racial Differences in Stroke (REGARDS) total population 30,239, of whom 30,150 had adequate blood pressure (BP) measurements) enrolled from January 2003-October 2007 with oversampling from the southeastern stroke belt, and black individuals. Baseline data were collected using a combination of telephone interview and in-home evaluation. preHTN was defined according to The Seventh Report of the Joint national Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) guidelines. RESULTS The prevalence of preHTN was associated with age and black race (62.9% in blacks compared to 54.1 % in whites). A higher prevalence of preHTN was observed in obese individuals, self-reported heart disease; and, those with elevated high-sensitivity C reactive protein (hsCRP), diabetes, and microalbuminuria compared to those without these factors. Heavy alcohol consumption in white participants was associated with increased odds of preHTN (odds ratio (OR) = 1 . 3 2) but was even greater in black participants (OR =2.27). CONCLUSION The prevalence of preHTN increased by age and African-American race. In addition, a higher prevalence of preHTN was observed with elevated hsCRP, diabetes, microalbuminuria, and those with heavy alcohol consumption compared to those without these factors.

Social support may be important for cognitive aging, but studies incorporating life course data are rare. Latent growth curve models estimated 10-year cognitive trajectories in 9,538 participants (baseline ages 45–94; mean=64) in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) project. Retrospective report of greater childhood social support was associated with better initial episodic memory (standardized estimate=0.08; 95% CI=0.05–0.10) and verbal fluency (standardized estimate=0.05; 95% CI=0.03–0.07), but not with subsequent rates of cognitive decline. Childhood social support effects on initial cognition were larger than or similar to independent effects of self-reported parental education. Effects were partially or fully mediated by higher education, lower body mass index, less perceived stress, and fewer depressive symptoms later in life. Childhood social support was more strongly associated with memory in Black participants, compared with White participants. These results suggest broad and enduring effects of childhood social support across the life course.

Background/Objectives Social support can prevent or delay long-term nursing home placement (NHP). The purpose of our study was to understand how the availability of a caregiver can affect NHP after ischemic stroke and how this affects different subgroups differently. Design Nested cohort study. Setting Nationally based REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Participants Stroke survivors aged 65 to 100 (256 men, 304 women). Measurements Data were from Medicare claims from January 2003 to December 2013 and REGARDS baseline interviews conducted from January 2003 to October 2007. Caregiver support was measured by asking, “If you had a serious illness or became disabled, do you have someone who would be able to provide care for you on an on-going basis?” Diagnosis of ischemic stroke was derived from inpatient claims. NHP was determined using a validated claims algorithm for stays of 100 days and longer. Risk was estimated using Cox regression. Results Within 5 years of stroke, 119 (21.3%) participants had been placed in a nursing home. Risk of NHP was greater in those lacking available caregivers (log-rank P = .006). After adjustment for covariates, lacking an available caregiver increased the risk of NHP after stroke within 1 year by 70% (hazard ratio (HR) = 1.70, 95% confidence interval (CI) = 0.97–2.99) and within 5 years by 68% (HR = 1.68, 95% CI = 1.10–2.58). The effect of caregiver availability on NHP within 5 years was limited to men (HR = 3.15, 95% CI = 1.49–6.67). Conclusion In men aged 65 and older who have survived an ischemic stroke, the lack of an available caregiver is associated with triple the risk of NHP within 5 years.