Proneurotensin/Neuromedin N and Risk of Incident CKD and Other Kidney Outcomes in Community-Living Individuals: The REGARDS Study.

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.

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.

N-Terminal Pro-B-Type Natriuretic Peptide and Risk for Diabetes Mellitus and Metabolic Syndrome.

CONTEXT: Natriuretic peptide concentrations are inversely associated with risk of diabetes mellitus and may be protective from metabolic dysfunction. OBJECTIVE: We studied associations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) with incident diabetes, metabolic syndrome (MetS), and MetS components. DESIGN/SETTING/PARTICIPANTS: 2,899 participants with baseline (2003-2007) and follow-up (2013-2016) examinations and baseline NT-proBNP measurement in the REasons for Geographic And Racial Differences in Stroke study. Logistic regression models were fitted to incident MetS, MetS components, and diabetes; covariates included demographics, risk and laboratory factors. MAIN OUTCOME MEASURES: Incident diabetes, defined as fasting glucose ≥126 mg/dL, random glucose ≥200 mg/dL, or use of insulin or hypoglycemic drugs at follow-up but not baseline. Incident MetS, in participants with ≥3 harmonized criteria at follow-up and <3 at baseline. RESULTS: 310 participants (2,364 at risk) developed diabetes and 361 (2,059 at risk) developed MetS over mean 9.4 years follow-up. NT-proBNP was inversely associated with odds of incident diabetes (fully-adjusted OR per-SD higher log NT-proBNP 0.80, 95% CI 0.69-0.93) and MetS in the highest vs. lowest quartile only (fully-adjusted OR 0.59, 95% CI 0.37-0.92); the linear association with incident MetS was not statistically significant. NT-proBNP was inversely associated with incident dysglycemia in all models (fully-adjusted OR per-SD log NT-proBNP 0.65, 95% CI 0.53-0.79), but not with other MetS components. Effect modification by sex, race, age, or BMI was not observed. CONCLUSIONS: NT-proBNP was inversely associated with odds of diabetes, MetS, and the MetS dysglycemia component. The metabolic implications of B-type natriuretic peptides appear important for glycemic homeostasis.

Omega-3 Fatty Acids and Risk of Ischemic Stroke in REGARDS.

We examined associations between lipidomic profiles and incident ischemic stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. Plasma lipids (n = 195) were measured from baseline blood samples, and lipids were consolidated into underlying factors using exploratory factor analysis. Cox proportional hazards models were used to test associations between lipid factors and incident stroke, linear regressions to determine associations between dietary intake and lipid factors, and the inverse odds ratio weighting (IORW) approach to test mediation. The study followed participants over a median (IQR) of 7 (3.4-11) years, and the case-cohort substudy included 1075 incident ischemic stroke and 968 non-stroke participants. One lipid factor, enriched for docosahexaenoic acid (DHA, an omega-3 fatty acid), was inversely associated with stroke risk in a base model (HR = 0.84; 95%CI 0.79-0.90; P = 8.33 × 10-8) and fully adjusted model (HR = 0.88; 95%CI 0.83-0.94; P = 2.79 × 10-4). This factor was associated with a healthy diet pattern (ß = 0.21; 95%CI 0.12-0.30; P = 2.06 × 10-6), specifically with fish intake (ß = 1.96; 95%CI 0.95-2.96; P = 1.36 × 10-4). DHA was a mediator between fish intake and incident ischemic stroke (30% P = 5.78 × 10-3). Taken together, DHA-containing plasma lipids were inversely associated with incident ischemic stroke and mediated the relationship between fish intake and stroke risk.

Hepatocyte growth factor and risk of incident stroke in Black and White Americans in the Reasons for Geographic and Racial Differences in Stroke study.

Background: Hepatocyte growth factor (HGF) is a cytokine produced in response to endothelial damage. Higher levels correlate with cardiovascular risk factors, including hypertension and diabetes. Objectives: We hypothesized that HGF is associated with stroke. Methods: The Reasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black and White Americans aged ≥45 years from 2003 to 2007. In this case-cohort study, after 5.5 years of follow-up, circulating baseline HGF was measured in 557 participants with incident ischemic stroke and in a cohort random sample of 964 participants. Hazard ratios (HRs) per SD log-transformed HGF and by HGF quintile were calculated using Cox proportional hazards models adjusting for stroke risk factors and other correlates of HGF. Differences by race and sex were tested using interaction terms. Results: Median HGF was 295 (IQR, 209-402) pg/mL. HGF was higher with older age, male sex, prevalent cardiovascular disease, smoking, and warfarin use, but did not differ by race. The adjusted HR of incident ischemic stroke per SD higher baseline HGF (145 pg/mL) was 1.30 (CI, 1.00-1.70), with no difference by sex or race. HGF in the highest (>434 pg/mL) vs lowest quintile (<135 pg/mL) was associated with an adjusted HR of incident stroke of 2.12 (CI, 1.31-3.41). Conclusion: In the REGARDS study, higher HGF was associated with increased risk of incident ischemic stroke in Black and White adults, with a doubling in risk of HGF in the top quintile compared with the lowest quintile after adjusting for other stroke risk factors.

Plasma Metabolites and Life's Simple 7 in REGARDS.

BACKGROUND: The American Heart Association's Life's Simple 7 (LS7) is a health metric that captures important factors associated with cardiovascular and cerebrovascular health. Previous studies highlight the potential of plasma metabolites to serve as a marker for lifestyle and health behavior that could be a target for stroke prevention. The objectives of this study were to identify metabolites that were associated with LS7 and incident ischemic stroke and mediate the relationship between the two. METHODS: Targeted metabolomic profiling of 162 metabolites by liquid chromatography-tandem mass spectrometry was used to identify candidate metabolites in a stroke case-cohort nested within the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). Weighted linear regression and weighted Cox proportional hazard models were used to identify metabolites that were associated with LS7 and incident ischemic stroke, respectively. Effect measures were based on a 1-SD change in metabolite level. Metabolite mediators were examined using inverse odds ratio weighting mediation analysis. RESULTS: The study comprised 1075 ischemic stroke cases and 968 participants in the random cohort sample. Three out of 162 metabolites were associated with the overall LS7 score including guanosine (ß, -0.46 [95% CI, -0.65 to -0.27]; P=2.87×10-6), cotinine (ß, -0.49 [95% CI, -0.70 to -0.28]; P=7.74×10-6), and acetylneuraminic acid (ß, -0.59 [95% CI, -0.77 to -0.42]; P=4.29×10-11). Guanosine (hazard ratio, 1.47 [95% CI, 1.31-1.65]; P=6.97×10-11), cotinine (hazard ratio, 1.30 [95% CI, 1.16-1.44]; P=2.09×10-6), and acetylneuraminic acid (hazard ratio, 1.29 [95% CI, 1.15-1.45]; P=9.24×10-6) were associated with incident ischemic stroke. The mediation analysis identified guanosine (27% mediation, indirect effect; P=0.002), cotinine (30% mediation, indirect effect; P=0.004), and acetylneurminic acid (22% mediation, indirect effect; P=0.041) partially mediated the relationship between LS7 and ischemic stroke. CONCLUSIONS: We identified guanosine, cotinine, and acetylneuraminic acid that were associated with LS7, incident ischemic stroke, and mediated the relationship between LS7 and ischemic stroke.

Cytokines, C-Reactive Protein, and Risk of Incident Hypertension in the REGARDS Study.

BACKGROUND: Hypertension is a highly prevalent cardiovascular disease risk factor that may be related to inflammation. Whether adverse levels of specific inflammatory cytokines relate to hypertension is unknown. The present study sought to determine whether higher levels of IL (interleukin)-1ß, IL-6, TNF (tumor necrosis factor)-α, IFN (interferon)-γ, IL-17A, and CRP (C-reactive protein) are associated with a greater risk of incident hypertension. METHODS: The REGARDS study (Reasons for Geographic and Racial Difference in Stroke) is a prospective cohort study that recruited 30 239 community-dwelling Black and White adults from the contiguous United States in 2003 to 2007 (visit 1), with follow-up 9 years later in 2013 to 2016 (visit 2). We included participants without prevalent hypertension who attended follow-up 9 years later and had available laboratory measures and covariates of interest. Poisson regression estimated the risk ratio of incident hypertension by level of inflammatory biomarkers. RESULTS: Among 1866 included participants (mean [SD] aged of 62 [8] years, 25% Black participants, 55% women), 36% developed hypertension. In fully adjusted models comparing the third to first tertile of each biomarker, there was a greater risk of incident hypertension for higher IL-1ß among White (1.24 [95% CI, 1.01-1.53]) but not Black participants (1.01 [95% CI, 0.83-1.23]) and higher TNF-α (1.20 [95% CI, 1.02-1.41]) and IFN-γ (1.22 [95% CI, 1.04-1.42]) among all participants. There was no increased risk with IL-6, IL-17A, or CRP. CONCLUSIONS: Higher levels of IL-1ß, TNF-α, and IFN-γ, representing distinct inflammatory pathways, are elevated in advance of hypertension development. Whether modifying these cytokines will reduce incident hypertension is unknown.

Neighborhood Disadvantage and Risk of Heart Failure: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

BACKGROUND: Heart failure (HF) affects >6 million US adults, with recent increases in HF hospitalizations. We aimed to investigate the association between neighborhood disadvantage and incident HF events and potential differences by diabetes status. METHODS: We included 23 645 participants from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke), a prospective cohort of Black and White adults aged ≥45 years living in the continental United States (baseline 2005-2007). Neighborhood disadvantage was assessed using a Z score of 6 census tract variables (2000 US Census) and categorized as quartiles. Incident HF hospitalizations or HF-related deaths through 2017 were adjudicated. Multivariable-adjusted Cox regression was used to examine the association between neighborhood disadvantage and incident HF. Heterogeneity by diabetes was assessed using an interaction term. RESULTS: The mean age was 64.4 years, 39.5% were Black adults, 54.9% females, and 18.8% had diabetes. During a median follow-up of 10.7 years, there were 1125 incident HF events with an incidence rate of 3.3 (quartile 1), 4.7 (quartile 2), 5.2 (quartile 3), and 6.0 (quartile 4) per 1000 person-years. Compared to adults living in the most advantaged neighborhoods (quartile 1), those living in neighborhoods in quartiles 2, 3, and 4 (most disadvantaged) had 1.30 (95% CI, 1.06-1.60), 1.36 (95% CI, 1.11-1.66), and 1.45 (95% CI, 1.18-1.79) times greater hazard of incident HF even after accounting for known confounders. This association did not significantly differ by diabetes status (interaction P=0.59). For adults with diabetes, the adjusted incident HF hazards comparing those in quartile 4 versus quartile 1 was 1.34 (95% CI, 0.92-1.96), and it was 1.50 (95% CI, 1.16-1.94) for adults without diabetes. CONCLUSIONS: In this large contemporaneous prospective cohort, neighborhood disadvantage was associated with an increased risk of incident HF events. This increase in HF risk did not differ by diabetes status. Addressing social, economic, and structural factors at the neighborhood level may impact HF prevention.

A cross-sectional study observing the association of psychosocial stress and dietary intake with gut microbiota genera and alpha diversity among a young adult cohort of black and white women in Birmingham, Alabama.

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.

Closing the Last Mile Gap in Access to Multimodality Imaging in Rural Settings: Design of the Imaging Core of the Risk Underlying Rural Areas Longitudinal Study.

Achieving optimal cardiovascular health in rural populations can be challenging for several reasons including decreased access to care with limited availability of imaging modalities, specialist physicians, and other important health care team members. Therefore, innovative solutions are needed to optimize health care and address cardiovascular health disparities in rural areas. Mobile examination units can bring imaging technology to underserved or remote communities with limited access to health care services. Mobile examination units can be equipped with a wide array of assessment tools and multiple imaging modalities such as computed tomography scanning and echocardiography. The detailed structural assessment of cardiovascular and lung pathology, as well as the detection of extracardiac pathology afforded by computed tomography imaging combined with the functional and hemodynamic assessments acquired by echocardiography, yield deep phenotyping of heart and lung disease for populations historically underrepresented in epidemiological studies. Moreover, by bringing the mobile examination unit to local communities, innovative approaches are now possible including engagement with local professionals to perform these imaging assessments, thereby augmenting local expertise and experience. However, several challenges exist before mobile examination unit-based examinations can be effectively integrated into the rural health care setting including standardizing acquisition protocols, maintaining consistent image quality, and addressing ethical and privacy considerations. Herein, we discuss the potential importance of cardiac multimodality imaging to improve cardiovascular health in rural regions, outline the emerging experience in this field, highlight important current challenges, and offer solutions based on our experience in the RURAL (Risk Underlying Rural Areas Longitudinal) cohort study.

Interleukin-6, Diabetes, and Metabolic Syndrome in a Biracial Cohort: The Reasons for Geographic and Racial Differences in Stroke Cohort.

OBJECTIVE: Black Americans have a greater risk of type 2 diabetes than White Americans. The proinflammatory cytokine interleukin-6 (IL-6) is implicated in diabetes pathogenesis, and IL-6 levels are higher in Black individuals. This study investigated associations of IL-6 with incident diabetes and metabolic syndrome in a biracial cohort. RESEARCH DESIGN AND METHODS: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black and White adults age ≥45 years in 2003-2007, with a follow-up ∼9.5 years later. Baseline plasma IL-6 was measured in 3,399 participants at risk of incident diabetes and 1,871 at risk of metabolic syndrome. Relative risk (RR) by IL-6 was estimated with modified Poisson regression for both groups. RESULTS: Incident diabetes occurred in 14% and metabolic syndrome in 20%; both rates rose across IL-6 quartiles. There was a three-way interaction of IL-6, race, and central adiposity for incident diabetes (P = 8 × 10-5). In Black participants with and without central adiposity, RRs were 2.02 (95% CI 1.00-4.07) and 1.66 (1.00-2.75) for the fourth compared with first IL-6 quartile, respectively. The corresponding RRs were 1.73 (0.92-3.26) and 2.34 (1.17-4.66) in White participants. The pattern was similar for IL-6 and metabolic syndrome. CONCLUSIONS: Although IL-6 was higher in Black than in White participants and those with central adiposity, the association of IL-6 with diabetes risk was statistically significant only among White participants without central adiposity. The association with metabolic syndrome risk was similarly stronger in low-risk groups. The results support the concept of interventions to lower inflammation in diabetes prevention, but to reduce race disparities, better biomarkers are needed.

Long-term exposure to air pollution and risk of stroke by ecoregions: The REGARDS study.

Several cohort studies have found associations between long-term exposure to air pollution and stroke risk. However, it is unclear whether the surrounding ecology may modify these associations. This study evaluates associations of air pollution with stroke risk by ecoregions, which are areas of similar type, quality, and quantity of environmental resources in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study. We assessed the incidence of stroke in 26,792 participants (45+ yrs) from the REGARDS study, a prospective cohort recruited across the contiguous United States. One-yr and 3-yr means of PM2.5, PM10, O3, NO2, SO2, and CO were estimated at baseline using data from the Center for Air, Climate, & Energy Solution, and assigned to participants at the census block group level. Incident stroke was ascertained through September 30, 2020. Relations of air pollutants with the risk of incident stroke were estimated using Cox proportional hazards models, adjusting for relevant demographics, behavioral risk factors, and neighborhood urbanicity. Models were stratified by EPA designated ecoregions. A 5.4 µg/m3 (interquartile range) increase in 1-yr PM10 was associated with a hazard ratio (95 %CI) for incident stroke of 1.07 (1.003, 1.15) in the overall study population. We did not find evidence of positive associations for PM2.5, O3, NO2, SO2, and CO in the fully adjusted models. In our ecoregion-specific analysis, associations of PM2.5 with stroke were stronger in the Great Plains ecoregion (HR = 1.44) than other ecoregions, while associations for PM10 were strongest in the Eastern Temperate Forests region (HR = 1.15). The associations between long-term exposure to air pollution and risk of stroke varied by ecoregion. Our results suggests that the type, quality, and quantity of the surrounding ecology can modify the effects of air pollution on risk of stroke.

Associations between dietary habits, socio-demographics and gut microbial composition in adolescents.

The relationship between dietary habits and microbiota composition during adolescence has not been well examined. This is a crucial knowledge gap to fill considering that diet-microbiota interactions influence neurodevelopment, immune system maturation and metabolic regulation. This study examined the associations between diet and the gut microbiota in a school-based sample of 136 adolescents (Mage = 12·1 years; age range 11-13 years; 48 % female; 47 % Black, 38 % non-Hispanic White, 15 % Hispanic or other minorities) from urban, suburban and rural areas in the Southeast USA. Adolescents completed the Rapid Eating Assessment for Participants and provided stool samples for 16S ribosomal RNA gene sequencing. Parents reported their child and family socio-demographic characteristics. The associations between diet and socio-demographics with gut microbiota diversity and abundance were analysed using multivariable regression models. Child race and ethnicity, sex, socio-economic status and geographic locale contributed to variation within microbiota composition (ß-diversity). Greater consumption of processed meat was associated with a lower microbial α-diversity after adjusting for socio-demographic variables. Multi-adjusted models showed that frequent consumption of nutrient-poor, energy-dense foods (e.g. sugar-sweetened beverages, fried foods, sweets) was negatively associated with abundances of genera in the family Lachnospiraceae (Anaerostipes, Fusicatenibacter and Roseburia), which are thought to play a beneficial role in host health through their production of short-chain fatty acids (SCFAs). These results provide new insights into the complex relationships among socio-demographic factors, diet and gut microbiota during adolescence. Adolescence may represent a critical window of opportunity to promote healthy eating practices that shape a homoeostatic gut microbiota with life-long benefits.

Comparative Discrimination of Life's Simple 7 and Life's Essential 8 to Stratify Cardiovascular Risk: Is the Added Complexity Worth It?

BACKGROUND: Life's Simple 7 (LS7) is an easily calculated and interpreted metric of cardiovascular health based on 7 domains: smoking, diet, physical activity, body mass index, blood pressure, cholesterol, and fasting glucose. The Life's Essential 8 (LE8) metric was subsequently introduced, adding sleep metrics and revisions of the previous 7 domains. Although calculating LE8 requires additional information, we hypothesized that it would be a more reliable index of cardiovascular health. METHODS: Both the LS7 and LE8 metrics yield scores with higher values indicating lower risk. These were calculated among 11 609 Black and White participants free of baseline cardiovascular disease (CVD) in the Reasons for Geographic and Racial Differences in Stroke study, enrolled in 2003 to 2007, and followed for a median of 13 years. Differences in 10-year risk of incident CVD (coronary heart disease or stroke) were calculated as a function LS7, and LE8 scores were calculated using Kaplan-Meier and proportional hazards analyses. Differences in incident CVD discrimination were quantified by difference in the c-statistic. RESULTS: For both LS7 and LE8, the 10-year risk was approximately 5% for participants around the 99th percentile of scores, and a 4× higher 20% risk for participants around the first percentile. Comparing LS7 to LE8, 10-year risk was nearly identical for individuals at the same relative position in score distribution. For example, the "cluster" of 2013 participants with an LS7 score of 7 was at the 35.8th percentile in distribution of LS7 scores, and had an estimated 10-year CVD risk of 8.4% (95% CI, 7.2%-9.8%). In a similar location in the LE8 distribution, the 1457 participants with an LE8 score of 60±2.5 at the 39.4th percentile of LE8 scores had a 10-year risk of CVD of 8.5% (95% CI, 7.1%-10.1%), similar to the cluster defined by LS7. The age-race-sex adjusted c-statistic of the LS7 model was 0.691 (95% CI, 0.667-0.705), and 0.695 for LE8 (95% CI, 0.681-0.709) (P for difference, 0.12). CONCLUSIONS: Both LS7 and LE8 were associated with incident CVD, with discrimination of the 2 indices practically indistinguishable. As a simpler metric, LS7 may be favored for use by the general population and clinicians.

Stroke Severity, Caregiver Feedback, and Cognition in the REGARDS-CARES Study.

Objective: Cognitive impairment after stroke is common, present 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 two stroke severity ratings and a caregiver-report of post-stroke functioning with longitudinal cognitive outcomes. Methods: The analysis was conducted on 157 caregivers and stroke survivor dyads who participated in the Caring for Adults Recovering from the Effects of Stroke (CARES) project, an ancillary study of the REasons for Geographic and Racial Differences in Stroke (REGARDS) national cohort study. Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) collected at hospitalization discharge were included as two primary predictors of cognitive impairment. The number of caregiver-reported problems and impairments at nine months following stroke were included as a third predictor. Cognition was assessed using a biennial telephone battery, incorporating multiple cognitive assessments to assess learning, memory, and executive functioning. Longitudinal cognitive scores were analyzed up to five years post-stroke, controlling for baseline (pre-stroke) cognitive scores and demographic variables of each stroke survivor collected at CARES baseline. Results: Separate mixed models showed significant main effects of GOS (b=0.3280, p=0.0009), mRS (b=-0.2119, p=0.0002), and caregiver-reported impairments (b=-0.0671, p<0.0001) on longitudinal cognitive scores. In a combined model including all three predictors, only caregiver-reported problems significantly predicted cognitive outcomes (b=-0.0480, p<0.0001). Impact: These findings underscore the importance of incorporating caregivers feedback in understanding cognitive consequences of stroke.

A Segmented Regression Analysis of Household Income and Recurrent Falls Among Adults in a National Cohort Study.

Falls can have life-altering consequences for older adults, including extended recovery periods and compromised independence. Higher household income may mitigate the risk of falls by providing financial resources for mobility tools, remediation of environmental hazards, and needed supports, or it may buffer the impact of an initial fall on subsequent risk through improved assistance and care. Household income has not had a consistently observed association with falls in older adults; however, a segmented association may exist such that associations are attenuated above a certain income threshold. In this study, we utilized segmented negative binomial regression analysis to examine the association between household income and recurrent falls among 2,302 participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study recruited between 2003 and 2007. Income-fall association segments separated by changes in slope were considered. Model results indicated a 2-segment association between household income and recurrent falls in the past year. In the range below the breakpoint, household income was negatively associated with the rate of recurrent falls across all age groups examined; in a higher income range (from $20,000-$49,999 to ≥$150,000), the association was attenuated (weaker negative trend) or reversed (positive trend). These findings point to potential benefits of ensuring that incomes for lower-income adults exceed the threshold needed to confer a reduced risk of recurrent falls.

Tubule dysfunction and injury and future risk of sepsis-associated acute kidney injury.

BACKGROUND: Novel biomarkers can quantify both kidney tubule function, including proximal tubule reabsorptive (urine α-1 microglobulin (uα1m)) and tubule protein synthesis capacities (urine uromodulin (uUMOD)), and tubular injury (urine neutrophil gelatinase-associated lipocalin (uNGAL)). In a blood pressure trial, we reported that lower reabsorptive and synthetic protein capacity at times of health predicted future risk of acute kidney injury (AKI), but most AKI was related to hemodynamic causes in this trial. Associations between tubular function and injury and future AKI related to other causes is unknown. MATERIALS AND METHODS: We performed a case-control study in REGARDS, a population-based cohort study, among participants who provided urine at the baseline visit. We matched each septic AKI case by age, sex, race, and time from baseline to hospital admission 1 : 1 to a participant with sepsis who did not develop AKI (controls). Using conditional logistic regression, we evaluated the associations of uα1m, uUMOD, urine ammonium, and uNGAL with septic AKI. RESULTS: Mean age was 69 ± 8 years, 44% were female, and 39% were Black participants. Median baseline eGFR among cases and controls was 73 (55, 90) and 82 (65, 92) mL/min/1.73m2, and median albuminuria was 19 (8, 87) vs. 9 (5, 22) mg/g, respectively. No independent associations were observed between the tubule function or injury markers and subsequent risk of septic AKI once models were adjusted for baseline albuminuria, estimated glomerular filtration rate, and other risk factors. CONCLUSION: Among community participants, tubule function and injury markers at times of health were not independently associated with future risk of septic AKI.

Changes in Adiposity and Cognitive Function in Older Adults: The REGARDS Study.

OBJECTIVES: Adiposity may have a role in the risk of dementia. Fewer studies have focused on the relationship between change in adiposity and cognitive decline. Our study aimed to explore the association between the change in adiposity and cognitive function in Black and White older adults. METHODS: The participants were 12,204 older adults without cognitive impairment (62.8 ±â€…8.0 years) in the United States. The percent body mass index change (%BMI change) and percent waist circumference change (%WC change) were measured at 2 in-home visits (first: 2003-2007, second: 2013-2016). Cognitive status was assessed by the Six-Item Screener annually. Memory and executive function were measured by word list learning, MOCA recall and orientation, and letter and animal fluency every 2 years. Logistic regression or linear regression models were used to estimate the relationship between percent change in adiposity and cognitive function. RESULTS: After 12.7 ±â€…1.7 years, a greater decrease in %BMI change or %WC change was significantly associated with a higher risk of cognitive impairment. Compared to older adults with -5% ≤ change ≤ 5% from baseline, a significantly higher risk of cognitive impairment and greater loss in memory and executive function were found among those who experienced more than a 10% decline in %BMI change or %WC change. Older adults who experienced a 5%-10% decrease in %BMI change had a higher risk of cognitive impairment and greater loss of memory compared to those with -5% ≤ change ≤ 5%. DISCUSSION: A greater decrease in %BMI (>5%) and %WC (>10%) change was associated with greater cognitive loss observed over time.

Age and sex differences in the association between neighborhood socioeconomic environment and incident diabetes: Results from the diabetes location, environmental attributes and disparities (LEAD) network.

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.

Strong protective effect of the APOL1 p.N264K variant against G2-associated focal segmental glomerulosclerosis and kidney disease.

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.