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Background It is unknown how blood pressure (BP) relates to stroke risk across levels of hypertension daily dose (HDD)‐quantified antihypertensive medication intensity. Methods and Results The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study enrolled 30 239 participants from the 48 contiguous US states in 2003 to 2007 with in‐person follow‐up in 2013 to 2016 (Visit 2). We included those without prior stroke at Visit 2, treating this visit as T0. Biannual phone calls and medical record review ascertained incident stroke events. Cox proportional hazard models estimated the hazard ratio (HR) of incident stroke by treatment intensity defined by systolic BP stages and HDD groupings. There were 344 stroke events over a median 5.5 years. Relative to systolic BP

Background Cognitive impairment after stroke is common and is present in up to 60% of survivors. Stroke severity, indicated by both volume and location, is the most consequential predictor of cognitive impairment, with severe strokes predicting higher chances of cognitive impairment. The current investigation examines the associations of 2 stroke severity ratings and a caregiver‐report of poststroke functioning with longitudinal cognitive outcomes. Methods and Results One hundred fifty‐seven caregivers and stroke survivor dyads participated in the CARES (Caring for Adults Recovering From the Effects of Stroke) project, an ancillary study of the REGARDS (Reasons for Geographic and Racial Differences in Stroke) national cohort study. The Glasgow Outcome Scale and modified Rankin Scale scores collected at hospitalization discharge were included as 2 primary predictors of cognitive impairment. The number of caregiver‐reported problems and impairments at 9 months following stroke were included as a third predictor. Cognition was measured using a biennial telephone battery and included the domains of learning, memory, and executive functioning. Multiple cognitive assessments were analyzed up to 5 years poststroke, controlling for prestroke cognition and demographic variables of the stroke survivor. Separate mixed models showed significant main effects of the Glasgow Outcome Scale (b=0.3380 [95% CI, 0.14–0.5]; P=0.0009), modified Rankin Scale (b=−0.2119 [95% CI, −0.32 to −0.10]; P=0.0002), and caregiver‐reported problems (b=−0.0671 [95% CI, −0.09 to −0.04]; P

Rationale & Objective: Plasma proneurotensin/neuromedin N (pro-NT/NMN) is a precursor of neurotensin, a tridecapeptide linked with type 2 diabetes mellitus and other comorbid conditions associated with kidney disease. Whether pro-NT/NMN is directly associated with incident chronic kidney disease (CKD), and whether that association differs by race, is uncertain. We evaluated whether pro-NT/NMN levels were associated with increased risk of kidney outcomes. Study Design: Prospective cohort. Setting & Participants: Participants in Biomarker Mediators of Racial Disparities in Risk Factors, a nested cohort from the REasons for Geographic And Racial Differences in Stroke study, with available stored serum and urine samples from baseline and second visits for biomarker measurement. Exposure: Baseline log-transformed pro-NT/NMN. Outcomes: Incident CKD, progressive estimated glomerular filtration rate (eGFR) decline, incident albuminuria, and incident kidney failure within median follow-up time of 9.4 years. Analytical Approach: Logistic regression. Results: Among 3,914 participants, the mean ± SD age was 64 ± 8 (SD) years, 48% were women, and 51% were Black. Median baseline eGFR was 90 (IQR, 77-102) mL/min/1.73 m2. Each SD higher of pro-NT/NMN was associated with 9% higher odds of progressive eGFR decline (OR, 1.09; 95% CI, 1.00-1.20). There was no association observed with incident CKD (OR, 1.10; 95% CI, 0.96-1.27), incident albuminuria (OR, 1.08; 95% CI, 0.96-1.22), or incident kidney failure (OR, 1.10; 95% CI, 0.83-1.46). There were no differences in results by race or sex. Limitations: Single measurement of pro-NT/NMN and limited generalizability. Conclusions: Higher pro-NT/NMN was associated with progressive eGFR decline but no other manifestations of kidney disease incidence. Plain-Language Summary: Neurotensin is a peptide secreted by the small intestine in response to a meal. Higher levels of neurotensin and its stable precursor, proneurotensin/neuromedin N (pro-NT/NMN), have been associated with cardiovascular disease and type 2 diabetes mellitus, important risk factors for the development of kidney disease. Whether pro-NT/NMN is directly associated with kidney outcomes has been less studied and has been done so in largely homogenous cohorts of White participants. Using the REasons for Geographic And Racial Differences in Stroke study, we followed Black and White participants and evaluated the risk of developing kidney outcomes. We found that elevated levels of pro-NT/NMN were associated with kidney function decline. Pro-NT/NMN may help individuals who may benefit from closer monitoring of kidney function.

Abstract Background The relationships between psychosocial stress and diet with gut microbiota composition and diversity deserve ongoing investigation. The primary aim of this study was to examine the associations of psychosocial stress measures and dietary variables with gut microbiota genera abundance and alpha diversity among young adult, black and white females. The secondary aim was to explore mediators of psychosocial stress and gut microbiota diversity and abundance. Methods Data on 60 females who self-identified as African American (AA; n = 29) or European American (EA; n = 31) aged 21–45 years were included. Cortisol was measured in hair and saliva, and 16S analysis of stool samples were conducted. Discrimination experiences (recent and lifetime), perceived stress, and depression were evaluated based on validated instruments. Spearman correlations were performed to evaluate the influence of psychosocial stressors, cortisol measures, and dietary variables on gut microbiota genus abundance and alpha diversity measured by amplicon sequence variant (ASV) count. Mediation analyses assessed the role of select dietary variables and cortisol measures on the associations between psychosocial stress, Alistipes and Blautia abundance, and ASV count. Results AA females were found to have significantly lower ASV count and Blautia abundance. Results for the spearman correlations assessing the influence of psychosocial stress and dietary variables on gut microbiota abundance and ASV count were varied. Finally, diet nor cortisol was found to partially or fully mediate the associations between subjective stress measures, ASV count, and Alistipes and Blautia abundance. Conclusion In this cross-sectional study, AA females had lower alpha diversity and Blautia abundance compared to EA females. Some psychosocial stressors and dietary variables were found to be correlated with ASV count and few gut microbiota genera. Larger scale studies are needed to explore the relationships among psychosocial stress, diet and the gut microbiome.

Abstract African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele.

Abstract Background Communities in the United States (US) exist on a continuum of urbanicity, which may inform how individuals interact with their food environment, and thus modify the relationship between food access and dietary behaviors. Objective This cross-sectional study aims to examine the modifying effect of community type in the association between the relative availability of food outlets and dietary inflammation across the US. Methods Using baseline data from the REasons for Geographic and Racial Differences in Stroke study (2003–2007), we calculated participants’ dietary inflammation score (DIS). Higher DIS indicates greater pro-inflammatory exposure. We defined our exposures as the relative availability of supermarkets and fast-food restaurants (percentage of food outlet type out of all food stores or restaurants, respectively) using street-network buffers around the population-weighted centroid of each participant’s census tract. We used 1-, 2-, 6-, and 10-mile (~ 2-, 3-, 10-, and 16 km) buffer sizes for higher density urban, lower density urban, suburban/small town, and rural community types, respectively. Using generalized estimating equations, we estimated the association between relative food outlet availability and DIS, controlling for individual and neighborhood socio-demographics and total food outlets. The percentage of supermarkets and fast-food restaurants were modeled together. Results Participants (n = 20,322) were distributed across all community types: higher density urban (16.7%), lower density urban (39.8%), suburban/small town (19.3%), and rural (24.2%). Across all community types, mean DIS was − 0.004 (SD = 2.5; min = − 14.2, max = 9.9). DIS was associated with relative availability of fast-food restaurants, but not supermarkets. Association between fast-food restaurants and DIS varied by community type (P for interaction = 0.02). Increases in the relative availability of fast-food restaurants were associated with higher DIS in suburban/small towns and lower density urban areas (p-values

Objective: Worse neighborhood socioeconomic environment (NSEE) may contribute to an increased risk of type 2 diabetes (T2D). We examined whether the relationship between NSEE and T2D differs by sex and age in three study populations. Research design and methods: We conducted a harmonized analysis using data from three independent longitudinal study samples in the US: 1) the Veteran Administration Diabetes Risk (VADR) cohort, 2) the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort, and 3) a case-control study of Geisinger electronic health records in Pennsylvania. We measured NSEE with a z-score sum of six census tract indicators within strata of community type (higher density urban, lower density urban, suburban/small town, and rural). Community type-stratified models evaluated the likelihood of new diagnoses of T2D in each study sample using restricted cubic splines and quartiles of NSEE. Results: Across study samples, worse NSEE was associated with higher risk of T2D. We observed significant effect modification by sex and age, though evidence of effect modification varied by site and community type. Largely, stronger associations between worse NSEE and diabetes risk were found among women relative to men and among those less than age 45 in the VADR cohort. Similar modification by age group results were observed in the Geisinger sample in small town/suburban communities only and similar modification by sex was observed in REGARDS in lower density urban communities. Conclusions: The impact of NSEE on T2D risk may differ for males and females and by age group within different community types.

Abstract Background Lipid accumulation product (LAP) and visceral adiposity index (VAI) are novel, non-imaging markers of visceral adiposity that are calculated by using body mass index (BMI), waist circumference (WC) and serum lipid concentrations. We hypothesized that LAP and VAI are more strongly associated with adverse kidney outcomes than BMI and WC. Methods Using data from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, we used multivariable logistic regression to evaluate associations of LAP, VAI, BMI and WC with incident chronic kidney disease (CKD), (incident eGFR 25% decline). Results Among the overall cohort of 27,550 participants, the mean baseline age was 65 years; 54% were women; and 41% were African American. After a median of 9.4 years (IQR 8.6, 9.9) of follow-up, a total of 1127 cases of incident CKD were observed. Each two-fold higher value of VAI (OR 1.12, 95% CI 1.04, 1.20), LAP (OR 1.21, 95% CI 1.13, 1.29), WC (OR 2.10, 95% CI 1.60, 2.76) and BMI (OR: 2.66, 95% CI 1.88, 3.77), was associated with greater odds of incident CKD. Conclusions LAP and VAI as measures of visceral adiposity are associated with higher odds of incident CKD but may not provide information beyond WC and BMI.

Objectives This study sought first to empirically define dietary patterns and to apply the novel Dietary Inflammation Score (DIS) in data from rural and metropolitan populations in Australia, and second to investigate associations with cardiovascular disease (CVD) risk factors.Design Cross-sectional study.Setting Rural and metropolitan Australia.Participants Adults over the age of 18 years living in rural or metropolitan Australia who participated in the Australian Health survey.Primary outcomes A posteriori dietary patterns for participants separated into rural and metropolitan populations using principal component analysis. Secondary outcomes: association of each dietary pattern and DIS with CVD risk factors was explored using logistic regression.Results The sample included 713 rural and 1185 metropolitan participants. The rural sample was significantly older (mean age 52.7 compared with 48.6 years) and had a higher prevalence of CVD risk factors. Two primary dietary patterns were derived from each population (four in total), and dietary patterns were different between the rural and metropolitan areas. None of the identified patterns were associated with CVD risk factors in metropolitan or rural areas, aside diet pattern 2 being strongly associated with from self-reported ischaemic heart disease (OR 13.90 95% CI 2.29 to 84.3) in rural areas. There were no significant differences between the DIS and CVD risk factors across the two populations, except for a higher DIS being associated with overweight/obesity in rural areas.Conclusion Exploration of dietary patterns between rural and metropolitan Australia shows differences between the two populations, possibly reflective of distinct cultures, socioeconomic factors, geography, food access and/or food environments in the different areas. Our study provides evidence that action targeting healthier dietary intakes needs to be tailored to rurality in the Australian context.

Rationale & Objective: Dietary factors may impact inflammation and interferon production, which could influence phenotypic expression of Apolipoprotein1 (APOL1) genotypes. We investigated whether associations of dietary patterns with kidney outcomes differed by APOL1 genotypes. Study Design: Prospective cohort. Settings & Participants: 5,640 Black participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS). Exposures: Five dietary patterns derived from food frequency questionnaires: Convenience foods, Southern, Sweets and Fats, Plant-based, and Alcohol/Salads. Outcomes: Incident chronic kidney disease (CKD), CKD progression, and kidney failure. Incident CKD was defined as a change in estimated glomerular filtration rate (eGFR) to

Abstract Background Studies have shown neighborhood walkability is associated with obesity. To advance this research, study designs involving longer follow-up, broader geographic regions, appropriate neighborhood characterization, assessment of exposure length and severity, and consideration of stayers and movers are needed. Using a cohort spanning the conterminous United States, this study examines the longitudinal relationship between a network buffer-derived, duration-weighted neighborhood walkability measure and two adiposity-related outcomes. Methods This study included 12,846 Black/African American and White adults in the REasons for Geographic And Racial Differences in Stroke study. Body mass index (BMI) and waist circumference (WC) were assessed at baseline and up to 13.3 years later (M (SD) = 9.4 (1.0) years). BMI and WC were dichotomized. Walk Score® was duration-weighted based on time at each address and categorized as Very Car-Dependent, Car-Dependent, Somewhat Walkable, Very Walkable, and Walker’s Paradise. Unadjusted and adjusted logistic regression models tested each neighborhood walkability-adiposity association. Adjusted models controlled for demographics, health factors, neighborhood socioeconomic status, follow-up time, and either baseline BMI or baseline WC. Adjusted models also tested for interactions. Post-estimation Wald tests examined whether categorical variables had coefficients jointly equal to zero. Orthogonal polynomial contrasts tested for a linear trend in the neighborhood walkability-adiposity relationships. Results The odds of being overweight/obese at follow-up were lower for residents with duration-weighted Walk Score® values in the Walker’s Paradise range and residents with values in the Very Walkable range compared to residents with values in the Very Car-Dependent range. Residents with duration-weighted Walk Score® values classified as Very Walkable had significantly lower odds of having a moderate-to-high risk WC at follow-up relative to those in the Very Car-Dependent range. For both outcomes, the effects were small but meaningful. The negative linear trend was significant for BMI but not WC. Conclusion People with cumulative neighborhood walkability scores in the Walker’s Paradise range were less likely to be overweight/obese independent of other factors, while people with scores in the Very Walkable range were less likely to be overweight/obese and less likely to have a moderate-to-high risk WC. Addressing neighborhood walkability is one approach to combating obesity.

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.MethodsRECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.DiscussionRECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.RegistrationNCT05172024.

Background & aimsNonalcoholic fatty liver disease (NAFLD) is prevalent and may affect cognitive function. We studied associations of NAFLD with risk of cognitive impairment. Secondarily we evaluated liver biomarkers (alanine aminotransferase (ALT), aspartate aminotransferase (AST), their ratio, and gamma-glutamyl transpeptidase).MethodsIn a prospective cohort study, the REasons for Geographic and Racial Differences in Stroke, among 30,239 black and white adults aged ≥45,495 cases of incident cognitive impairment were identified over 3.4 years follow up. Cognitive impairment was identified as new impairment in two of three cognitive tests administered every two years during follow up; word list learning and recall, and verbal fluency. 587 controls were selected from an age, race, sex-stratified sample of the cohort. The fatty liver index was used to define baseline NAFLD. Liver biomarkers were measured using baseline blood samples.ResultsNAFLD at baseline was associated with a 2.01-fold increased risk of incident cognitive impairment in a minimally adjusted model (95% CI 1.42, 2.85). The association was largest in those aged 45-65 (p interaction by age = 0.03), with the risk 2.95-fold increased (95% CI 1.05, 8.34) adjusting for cardiovascular, stroke and metabolic risk factors. Liver biomarkers were not associated with cognitive impairment, except AST/ALT >2, with an adjusted OR 1.86 (95% CI 0.81, 4.25) that did not differ by age.ConclusionsA laboratory-based estimate of NAFLD was associated with development of cognitive impairment, particularly in mid-life, with a tripling in risk. Given its high prevalence, NAFLD may be a major reversible determinant of cognitive health.

Abstract Background Understanding health care experiences during the COVID-19 pandemic may provide insights into patient needs and inform policy. The objective of this study was to describe health care experiences by race and social determinants of health. Methods We conducted a telephone survey (July 6, 2020-September 4, 2021) among 9492 Black and White participants in the longitudinal REasons for Geographic And Racial Differences in Stroke cohort study, age 58–105 years, from the continental United States. Among participants with symptoms of COVID-19, outcomes were: 1. Sought care or advice for the illness; 2. Received a SARS-CoV-2 test for the illness; and 3. Tested positive. Among participants without symptoms of COVID-19, outcomes were: 1. Wanted a test; 2. Wanted and received a test; 3. Did not want but received a test; and 4. Tested positive. We examined these outcomes overall and in subgroups defined by race, household income, marital status, education, area-level poverty, rural residence, Medicaid expansion, public health infrastructure ranking, and residential segregation. Results The average age of participants was 76.8 years, 36% were Black, and 57% were female. Among participants with COVID-19 symptoms (n = 697), 74% sought care or advice for the illness, 50% received a SARS-CoV-2 test, and 25% had a positive test (50% of those tested). Among participants without potential COVID-19 symptoms (n = 8795), 29% wanted a SARS-CoV-2 test, 22% wanted and received a test, 8% did not want but received a test, and 1% tested positive; a greater percentage of participants who were Black compared to White wanted (38% vs 23%, p

Abstract Background Despite a growing burden of Alzheimer’s Disease and related dementias (ADRD) in the US, the relationship between health care and cognitive impairment prevention is unclear. Primary care manages risk causing conditions and risk reducing behaviors for dementia, so we examine the association between individual and area-level access to primary care and cognitive impairment in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Methods REGARDS participants with a cognitive assessment and vascular measurements at their baseline visit were included in this cross-sectional analysis. Cognitive impairment was defined as a Six-Item Screener (SIS) score

BackgroundSome but not all African-Americans (AA) who carry APOL1 nephropathy risk variants (APOL1) develop kidney failure (end-stage kidney disease, ESKD). To identify genetic modifiers, we assessed gene–gene interactions in a large prospective cohort of the REasons for Geographic and Racial Differences in Stroke (REGARDS) study.MethodsGenotypes from 8,074 AA participants were obtained from Illumina Infinium Multi-Ethnic AMR/AFR Extended BeadChip. We compared 388 incident ESKD cases with 7,686 non-ESKD controls, using a two-locus interaction approach. Logistic regression was used to examine the effect of APOL1 risk status (using recessive and additive models), single nucleotide polymorphism (SNP), and APOL1*SNP interaction on incident ESKD, adjusting for age, sex, and ancestry. APOL1*SNP interactions that met the threshold of 1.0 × 10−5 were replicated in the Genetics of Hypertension Associated Treatment (GenHAT) study (626 ESKD cases and 6,165 controls). In a sensitivity analysis, models were additionally adjusted for diabetes status. We conducted additional replication in the BioVU study.ResultsTwo APOL1 risk alleles prevalence (recessive model) was similar in the REGARDS and GenHAT studies. Only one APOL1–SNP interaction, for rs7067944 on chromosome 10, ~10 KB from the PCAT5 gene met the genome-wide statistical threshold (Pinteraction = 3.4 × 10−8), but this interaction was not replicated in the GenHAT study. Among other relevant top findings (with Pinteraction < 1.0 × 10−5), a variant (rs2181251) near SMOC2 on chromosome six interacted with APOL1 risk status (additive) on ESKD outcomes (REGARDS study, Pinteraction =5.3 × 10−6) but the association was not replicated (GenHAT study, Pinteraction = 0.07, BioVU study, Pinteraction = 0.53). The association with the locus near SMOC2 persisted further in stratified analyses. Among those who inherited ≥1 alternate allele of rs2181251, APOL1 was associated with an increased risk of incident ESKD (OR [95%CI] = 2.27[1.53, 3.37]) but APOL1 was not associated with ESKD in the absence of the alternate allele (OR [95%CI] = 1.34[0.96, 1.85]) in the REGARDS study. The associations were consistent after adjusting for diabetes.ConclusionIn a large genome-wide association study of AAs, a locus SMOC2 exhibited a significant interaction with the APOL1 locus. SMOC2 contributes to the progression of fibrosis after kidney injury and the interaction with APOL1 variants may contribute to an explanation for why only some APOLI high-risk individuals develop ESKD.

Background Corin enzyme contributes to the processing of inactive natriuretic peptides to bioactive hormones. In Black individuals, Corin gene variants (rs111253292 [Q568P] and rs75770792 [T555I]) have been previously reported to have a modest association with blood pressure (BP) and hypertension. Methods and Results We evaluated the association of Corin genotype with BP traits, prevalent hypertension, and incident hypertension among self‐identified 11 322 Black Americans in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study and the JHS (Jackson Heart Study) using multivariable‐adjusted regression modeling. Multivariable‐adjusted genotype‐stratified differences in NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) and BNP (B‐type natriuretic peptide) levels were assessed. Genotype‐stratified NPPA and NPPB expression differences in healthy organ donor left atrial and left ventricular heart tissue (N=15) were also examined. The rs111253292 genotype was not associated with systolic BP (β±SE, 0.42±0.58; −1.24±0.82), diastolic BP (0.51±0.33; −0.41±0.46), mean arterial pressure (0.48±0.38; −0.68±0.51), and prevalent hypertension (odds ratio [OR], 0.93 [95% CI, 0.80–1.09]; OR, 0.79 [95% CI, 0.61–1.01]) in both REGARDS and JHS, respectively. The rs75770792 genotype was not associated with systolic BP (0.48±0.58; −1.26±0.81), diastolic BP (0.52±0.33; −0.33±0.45), mean arterial pressure (0.50±0.38; −0.63±0.50), and prevalent hypertension (OR, 1.02 [95% CI, 0.84–1.23]; OR, 0.87 [95% CI, 0.67–1.13]) in both cohorts, respectively. The Corin genotype was also not associated with incident hypertension (OR, 1.35 [95% CI, 0.94–1.93]; OR, 0.95 [95% CI, 0.64–1.39]) in the study cohorts. The NT‐proBNP levels in REGARDS and BNP levels in JHS were similar between the Corin genotype groups. In heart tissue, the NPPA and NPPB expression was similar between the genotype groups. Conclusions Corin gene variants observed more commonly in Black individuals are not associated with differences in NP expression, circulating NP levels, and BP or hypertension as previously reported in candidate gene studies. Understanding the genetic determinants of complex cardiovascular traits in underrepresented populations requires further evaluation.

Objective: The association between neighborhood disadvantage and health is well-documented. However, whether these associations may differ across rural and urban areas is unclear. This study examines the association between a multi-item neighborhood social and economic environment (NSEE) measure and diabetes prevalence across urban and rural communities in the US. Methods: This study included 27,159 Black and White participants aged ≥45 years at baseline (2003–2007) from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. Each participant's residential address was geocoded. NSEE was calculated as the sum of z-scores for six US Census tract variables (% of adults with less than high school education; % of adults unemployed; % of households earning

Abstract 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.

Abstract Background Many older adults in the U.S. do not achieve the recommended amount of physical activity (PA) to fully realize a myriad of health benefits. Adiposity is one of those important correlates of PA and sedentary behaviors. However, the full extent to which adiposity is associated with PA and stationary time (STA) is uncertain. Therefore, we examined the association of adiposity with objectively measured PA and STA in black and white older adults. Methods We conducted a cross-sectional study of older adults enrolled in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study 2003–2007 who participated in an ancillary accelerometer study 2009–2013. Assessment of body mass index (BMI) and waist circumference (WC) was completed during an in-home visit in the parent study. PA was measured by Actical™ accelerometers, which provided estimates of moderate-to-vigorous-intensity PA (MVPA), light-intensity PA (LPA), and STA for 4–7 consecutive days. Data from accelerometers were standardized to square root percentages of total wear time per day (SqrtMVPA%, SqrtLPA%, and SqrtSTA%). Interactions were tested for BMI and WC by race and sex, separately. Results Data were available for 7873 participants (69.8 ± 8.7 yr, 54.2% women, 31.5% African American). In mixed linear regression models, significant interactions existed in BMI by race and sex for the SqrtMVPA%, WC by race and sex for the SqrtMVPA% and the SqrtLPA% model(p

Abstract Background Higher D‐dimer is a risk factor for cardiovascular diseases and venous thromboembolism. In the general population, D‐dimer and other thrombo‐inflammatory biomarkers are higher among Black individuals, who also have higher risk of these conditions compared to White people. Objective To assess whether Black individuals have an exaggerated correlation between D‐dimer and thrombo‐inflammatory biomarkers characteristic of cardiovascular diseases. Methods Linear regression was used to assess correlations of 11 thrombo‐inflammatory biomarkers with D‐dimer in a cross‐sectional study of 1068 participants of the biracial Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Results Adverse levels of most biomarkers, especially fibrinogen, factor VIII, C‐reactive protein, N‐terminal pro‐B‐type natriuretic peptide, and interleukin (IL)‐6, were associated with higher D‐dimer. Several associations with D‐dimer differed significantly by race. For example, the association of factor VIII with D‐dimer was more than twice as large in Black compared to White participants. Specifically, D‐dimer was 26% higher per standard deviation (SD) higher factor VIII in Black adults and was only 11% higher per SD higher factor VIII in White adults. In Black but not White adults, higher IL‐10 and soluble CD14 were associated with higher D‐dimer. Conclusions Findings suggest that D‐dimer might relate to Black/White differences in cardiovascular diseases and venous thromboembolism because it is a marker of amplified thrombo‐inflammatory response in Black people. Better understanding of contributors to higher D‐dimer in the general population is needed.

Background: Epidemiological studies utilize residential histories to assess environmental exposure risk. The validity from using commercially-sourced residential histories within national longitudinal studies remains unclear. Our study assessed predictors of non-agreement between baseline addresses from the commercially-sourced LexisNexis database and participants in the national longitudinal study, REasons for Geographic and Racial Differences in Stroke (REGARDS). Additionally, we assessed differences in stroke risk by neighborhood socioeconomic score (nSES) based on participant reported address compared to nSES from LexisNexis/REGARDS matched baseline address. Methods: From January 2003–October 2007, REGARDS enrolled 30,239 black and white adults aged 45 and older within the continental United States and collected their baseline address. ArcGIS Desktop 10.5.1 with ESRI 2016 Business Analyst Data was used to geocode baseline addresses from LexisNexis and REGARDS. Logistic regression was used to estimate the likelihood that LexisNexis address matched REGARDS baseline address for each participant. Survival analysis was used to estimate association between nSES and incident stroke. Results: Approximately 91% of REGARDS participants had a LexisNexis address. Of these geocoded addresses, 93% of REGARDS baseline addresses matched LexisNexis addresses. Odds of agreement between LexisNexis and REGARDS was higher for older-aged participants (OR = 1.02 per year, 95% CI: 1.01, 1.02), blacks compared to whites (OR = 1.16, 95% CI: 1.05, 1.29), females compared to males (OR = 1.15, 95% CI: 1.04, 1.26), participants with an income of $34k-74k compared to an income less than $20k (OR = 1.62, 95% CI: 1.39, 1.89). Odds of agreement were lower for residents in Midwest compared to residents in the south (OR = 0.82, 95% CI: 0.73, 0.94). No significant differences in nSES-stroke associations were observed between REGARDS only and LexisNexis/REGARDS matched addresses; however, differences in interactions were observed. Conclusion: Agreement between LexisNexis and REGARDS addresses varied by sociodemographic groups, potentially introducing bias in studies reliant on LexisNexis alone for residential address data.

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 CHA2DS2VASc 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.

Background Sudden cardiac death (SCD) is a common cause of death in the United States. Few previous studies have investigated the associations of diet scores and dietary patterns with risk of SCD. We investigated the associations of the Mediterranean diet score and various dietary patterns with risk of SCD in participants in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study cohort. Methods and Results Diet was assessed with a food frequency questionnaire administered at baseline in REGARDS. The Mediterranean diet score was derived based on the consumption of specific food groups considered beneficial or detrimental components of that diet. Dietary patterns were derived previously using factor analysis, and adherence to each pattern was scored. SCD events were ascertained through regular contacts. Cox proportional hazards regression was used to examine the risk of SCD events associated with the Mediterranean diet score and adherence to each of the 5 dietary patterns overall and stratifying on history of coronary heart disease at baseline. The analytic sample included 21 069 participants with a mean 9.8±3.8 years of follow‐up. The Mediterranean diet score showed a trend toward an inverse association with risk of SCD after multivariable adjustment (hazard ratio [HR] comparing highest with lowest group, 0.74; 95% CI, 0.55–1.01; Ptrend=0.07). There was a trend toward a positive association of the Southern dietary pattern with risk of SCD (HR comparing highest with lowest quartile of adherence, 1.46; 95% CI, 1.02–2.10; Ptrend=0.06). Conclusions In REGARDS participants, we identified trends toward an inverse association of the Mediterranean diet score and a positive association of adherence to the Southern dietary pattern with risk of SCD.

Abstract 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 Data on the association between calcium (Ca) and ischemic stroke are sparse and inconsistent. This study aimed to examine Ca intake and serum Ca levels in relation to risk of ischemic stroke. Methods The primary analysis included 19,553 participants from the Reasons for Geographic And Racial Differences in Stroke (REGARDS) study. A subcohort was randomly selected to create a case-cohort study (n=3,016), in which serum Ca levels were measured. Ischemic stroke cases were centrally adjudicated by physicians based on medical records. Cox proportional hazards regression for the cohort and weighted Cox proportional hazard regression with robust sandwich estimation method for the case-cohort analysis with adjustment for potential confounders were performed. Results During a mean 8.3-year follow-up, 808 incident cases of ischemic stroke were documented. Comparing the highest quintile to the lowest, a statistically significant inverse association was observed between total Ca intake and risk of ischemic stroke (hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.55 to 0.95; Plinear-trend=0.183); a restricted cubic spline analysis indicated a threshold effect like non-linear association of total Ca intake with ischemic stroke (Pnon-linear=0.006). In the case-cohort, serum Ca was inversely associated with the risk of ischemic stroke. Compared to the lowest, the highest quintile of serum Ca had a 27% lower risk of ischemic stroke (HR, 0.73; 95% CI, 0.53 to 0.99; Plinear-trend=0.013). Observed associations were mainly mediated by type 2 diabetes, hypertension, and cholesterol. Conclusions These findings suggest that serum Ca has inverse and Ca intake has threshold effect like association with risk of ischemic stroke.

Background: Sickle cell anemia may be associated with cognitive dysfunction, and some complications of sickle cell anemia might affect those with sickle cell trait (SCT), so we hypothesized that SCT is a risk factor for cognitive impairment. Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled a national cohort of 30,239 white and black Americans from 2003 to 7, who are followed every 6 months. Baseline and annual global cognitive function testing used the Six-Item Screener (SIS), a validated instrument (scores range 0–6; ≤4 indicates cognitive impairment). Participants with baseline cognitive impairment and whites were excluded. Logistic regression was used to calculate the association of SCT with incident cognitive impairment, adjusted for risk factors. Linear mixed models assessed multivariable-adjusted change in test scores on a biennially administered 3-test battery measuring learning, memory, and semantic and phonemic fluency. Findings: Among 7743 participants followed for a median of 7·1 years, 85 of 583 participants with SCT (14·6%) developed incident cognitive impairment compared to 902 of 7160 (12·6%) without SCT. In univariate analysis, the odds ratio (OR) of incident cognitive impairment was 1·18 (95% CI: 0·93, 1·51) for those with SCT vs. those without. Adjustment did not impact the OR. There was no difference in change on 3-test battery scores by SCT status (all p > 0·11). Interpretation: In this prospective cohort study of black Americans, SCT was not associated with incident cognitive impairment or decline in test scores of learning, memory and executive function. Funding: National Institutes of Health, American Society of Hematology. Keywords: Sickle cell trait, Cognitive dysfunction, Cognition, Prospective studies, Risk factors, Epidemiology

The built environment (BE) has been associated with health outcomes in prior studies. Few have investigated the association between neighborhood walkability, a component of BE, and hypertension. We examined the association between neighborhood walkability and incident hypertension in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Walkability was measured using Street Smart Walk Score based on participants' residential information at baseline (collected between 2003 and 2007) and was dichotomized as more (score ≥70) and less (score

Background The Life’s Simple 7 (LS7) metric incorporates health behaviors (body mass index, diet, smoking, physical activity) and health factors (blood pressure, cholesterol, glucose) to estimate an individual’s level of cardiovascular health. The association between cardiovascular health and incident hypertension is unresolved. Hypertension’s threshold was recently lowered and it is unclear if better cardiovascular health is associated with lower risk of incident hypertension with the updated threshold or in a multirace cohort. We sought to assess the association between better LS7 score and risk of incident hypertension among Black and White adults using a 130/80 mm Hg hypertension threshold. Methods and Results We determined the association between LS7 metric and incident hypertension in the REGARDS (Reasons for Geographic and Racial Disparities in Stroke) study, including participants free of baseline hypertension (2003–2007) who completed a second visit between 2013 and 2016. Hypertension was defined as systolic/diastolic blood pressure ≥130/80 mm Hg or antihypertensive medication use. Each LS7 component was assigned 0 (poor), 1 (intermediate), or 2 (ideal) points. We generated a 14‐point score by summing points. Among 2930 normotensive participants (20% Black, 80% White), the median (25th–75th percentiles) LS7 total score was 9 (8–10) points. Over a median follow‐up of 9 years, 42% developed hypertension. In the fully adjusted model, each 1‐point higher LS7 score had a 6% lower risk of incident hypertension (risk ratio, 0.94 per 1 point; 95% CI, 0.92–0.96). Conclusions Better cardiovascular health was associated with lower risk of incident hypertension using a 130/80 mm Hg hypertension threshold among Black and White adults.

Background Atrial fibrillation (AF) is associated with a 5‐fold increased stroke risk. While most patients with AF warrant anticoagulation, optimal treatment remains uncertain for patients with AF without cardiovascular comorbidities because the risk of stroke in this population has not been well‐characterized. Methods and Results Participants (N=28 253; 55% women, mean age 64.6±9.4 years), from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study (2003–present) were classified into 1 of 4 groups based on the presence or absence of AF and the presence or absence of cardiovascular comorbidities. Cox proportional hazards analysis was used to compare the risk of stroke between groups. During 244 560 person‐years of follow‐up (median 8.7 years), 1206 strokes occurred. Compared with patients with neither AF nor cardiovascular comorbidities, we did not find an increased stroke risk (hazard ratio [HR], 1.23; 95% CI, 0.62–2.18 [P=0.511]) among participants with AF alone. Participants without AF but with cardiovascular comorbidities had both an elevated stroke risk (HR, 1.77; 95% CI, 1.48–2.18 [P

Background Soluble CD14 (sCD14), a circulating pattern recognition receptor, has been suggested as a cardiovascular disease risk factor. Prospective studies evaluating sCD14 with incident cardiovascular disease events are limited, particularly among racially diverse populations. Methods and Results Between 2003 and 2007, the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study recruited 30 239 black and white participants across the United States. In a nested case–cohort study, sCD14 was measured in baseline serum from 548 cases of incident ischemic stroke, 612 cases of incident coronary heart disease (CHD), and a cohort random sample (n=1039). Cox models estimated hazards ratios (HR) of incident ischemic stroke or CHD per 1 SD higher sCD14, adjusting for cardiovascular disease risk factors. There was a differential association of sCD14 with ischemic stroke and CHD risk by race. Among blacks, the adjusted HR of stroke per SD increment of sCD14 was 1.42 (95% CI: 1.12, 1.80), with no association among whites (HR 1.02 [95% CI: 0.82, 1.27]). Higher sCD14 was associated with increased CHD risk in blacks but not whites, and relationships between sCD14 and CHD were stronger at younger ages. Adjusted for risk factors, the HR of CHD per SD higher sCD14 among blacks at age 45 years was 2.30 (95% CI: 1.45, 3.65) compared with 1.56 (95% CI: 0.94, 2.57) among whites. At age 65 years, the CHD HR was 1.51 (95% CI: 1.20, 1.91) among blacks and 1.02 (95% CI: 0.80, 1.31) among whites. Conclusions sCD14 may be a race‐specific stroke and CHD risk marker.

Vitamin D deficiency is highly prevalent in children and adults with cystic fibrosis (CF). Recent studies have found an association between vitamin D status and risk of pulmonary exacerbations in children and adults with CF. The ongoing Vitamin D for enhancing the Immune System in Cystic fibrosis (DISC) study, a multi-center, double-blind, randomized, placebo-controlled trial, will test the hypothesis of whether high dose vitamin D given as a single oral bolus of 250,000 IU to adults with CF during a pulmonary exacerbation followed by a maintenance dose of vitamin D will improve time to next pulmonary exacerbation and re-hospitalization, improve survival and lung function compared to placebo and reduce the rates of pulmonary exacerbation. Subjects will be randomized 1:1 at each clinical site to vitamin D or placebo within 72 h of hospital admission for pulmonary exacerbation. Clinical follow-up visits will occur at 1, 2, 3, and 7 days, and 1, 3, 6 and 12 months after randomization. Blood and sputum will be collected and determination of clinical outcomes will be assessed at each visit. The primary endpoint will be the time to next pulmonary exacerbation requiring antibiotics, re-hospitalization or death. The secondary endpoints will include lung function assessed by forced expiratory volume in 1 s (FEV1), blood markers of inflammatory cytokines, anti-microbial peptide expression by peripheral blood mononuclear cells and circulating concentrations in blood. Other exploratory endpoints will examine the phenotype of neutrophils and monocyte/macrophages in sputum. Nutritional status will be assessed by 3 day food records and food frequency questionnaire.

Aims: Vitamin D is a fat-soluble vitamin classically known for its role in calcium absorption and bone health. Growing evidence indicates that vitamin D deficiency may be associated with inflammation, insulin resistance, and obesity. However, prior studies examining the association of vitamin D with metabolic risk factors had relatively low representation of individuals of black race, limiting their ability to characterize associations of vitamin D and parameters of metabolic health in black vs. white individuals. Methods: We examined associations of 25-hydroxyvitamin D (25(OH)D) concentrations with markers of inflammation (interleukin [IL]-6, IL-10, high sensitivity C-reactive protein [hsCRP]), insulin sensitivity (adiponectin, resistin, HOMA-IR), and obesity (body mass index [BMI], waist circumference) in 1042 participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a large national cohort of black and white adults 45 years or older. Results: In unadjusted analyses, lower 25(OH)D concentrations were associated with higher IL-6 and hsCRP concentrations; lower adiponectin concentrations; higher HOMA-IR; and higher BMI and waist circumference (P 0.1). Conclusions: Lower 25(OH)D concentrations are associated with disturbances in metabolic health in both blacks and whites. Whether correcting vitamin D deficiency could offer a beneficial therapy for disease prevention requires further study.