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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.

Purpose The association between CVD risk factors and mortality is well established, however, current tools for addressing subgroups have focused on the overall burden of disease. The identification of risky combinations of characteristics may lead to a better understanding of physiologic pathways that underlie morbidity and mortality in older adults. Methods Participants included 5067 older adults from the Cardiovascular Health Study, followed for up to 6 years. Using latent class analysis (LCA), we created CV damage phenotypes based on probabilities of abnormal brain infarctions, major echocardiogram abnormalities, N-terminal probrain natriuretic peptide, troponin T, interleukin-6, c reactive-protein, galectin-3, cystatin C. We assigned class descriptions based on the probability of having an abnormality among risk factors, such that a healthy phenotype would have low probabilities in all risk factors. Participants were assigned to phenotypes based on the maximum probability of membership. We used Cox-proportional hazards regression to evaluate the association between the categorical CV damage phenotype and all-cause and CVD-mortality. Results The analysis yielded 5 CV damage phenotypes consistent with the following descriptions: healthy (59%), cardio-renal (11%), cardiac (15%), multisystem morbidity (6%), and inflammatory (9%). All four phenotypes were statistically associated with a greater risk of all-cause mortality when compared with the healthy phenotype. The multisystem morbidity phenotype had the greatest risk of all-cause death (HR: 4.02; 95% CI: 3.44, 4.70), and CVD-mortality (HR: 4.90, 95% CI: 3.95, 6.06). Conclusions Five CV damage phenotypes emerged from CVD risk factor measures. CV damage across multiple systems confers a greater mortality risk compared to damage in any single domain.

Background Previous studies are inconsistent about whether chronic coronary artery disease or generalized atherosclerosis is a causal risk factor for venous thromboembolism. No study seems to have taken a genomic approach to this question. Objective To test in a prospective study whether a polygenic risk score for coronary artery disease is associated with risk of venous thromboembolism. Participants/methods Within the Atherosclerosis Risk in Communities Study cohort, we computed a previously validated polygenic risk score for coronary artery disease among 9144 White participants at baseline in 1987-1989. We followed the participants through 2015 for incident hospitalized venous thromboembolism events, validated by physician review. We used Cox proportional hazards regression to associate quintiles of the polygenic risk score to venous thromboembolism incidence rates. Results Over the median of 26 years of follow-up, 476 participants had a venous thromboembolism event. There was no apparent association between the coronary artery disease polygenic risk score and incident venous thromboembolism, with age, sex, body mass index adjusted hazard ratios across quintiles being 1 (reference), 0.87 (0.65, 1.15), 1.08 (0.82, 1.42), 0.96 (0.72, 1.27), and 1.03 (0.78, 1.37). Conclusions A genetic disposition to coronary artery disease did not confer an increased risk of venous thromboembolism in this prospective study.

Background Neurotensin, a neuropeptide with direct cardiac effects, has been associated with prospective risk of hypertension-related conditions through measurement of its precursor, pro-neurotensin/neuromedin N (pro-NT/NMN). Its association with incident hypertension has not been evaluated. Methods From 2003 to 2007, the REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 Black or White adults age ≥45. Pro-NT/NMN was measured in 1,692 participants without baseline hypertension (self-reported antihypertensive use or blood pressure ≥140/90 mm Hg) who underwent follow-up assessment in 2013–2016. A sensitivity analysis was conducted using a lower threshold (≥130/80 mm Hg) to define hypertension. Three robust Poisson regression models were fitted to risk of incident hypertension, adding demographics, cardiometabolic risk factors, and dietary covariates. Results Six hundred and fourteen participants developed hypertension over 9.4 years of follow-up. Pro-NT/NMN ranged from 14 to 1,246 pmol/l, with median [interquartile range] 154 [112, 206] pmol/l. Pro-NT/NMN was not associated with hypertension overall (fully adjusted incidence rate ratio per SD increment log pro-NT/NMN 1.03, 95% confidence interval 0.95–1.11). Results of sensitivity analysis did not differ substantially. Conclusions Baseline pro-NT/NMN was not associated with incident hypertension. This may be a result of neurotensin’s long-term interactions with other molecular regulators of blood pressure, such as the renin–angiotensin–aldosterone system.

Author(s): Shabani, Mahsima; Bakhshi, Hooman; Ostovaneh, Mohammad R; Ma, Xiaoyang; Wu, Colin O; Ambale-Venkatesh, Bharath; Blaha, Michael J; Allison, Matthew A; Budoff, Matthew J; Cushman, Mary; Tracy, Russell P; Herrington, David M; Szklo, Moyses; Cox, Christopher; Bluemke, David A; Lima, Joao AC | Abstract: AimsLittle is known about the association of temporal changes in inflammatory biomarkers and the risk of death and cardiovascular diseases. We aimed to evaluate the association between temporal changes in C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) and risk of heart failure (HF), cardiovascular disease (CVD), and all-cause mortality in individuals without a history of prior CVD.Methods and resultsParticipants from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort with repeated measures of inflammatory biomarkers and no CVD event prior to the second measure were included. Quantitative measures, annual change, and biomarker change categories were used as main predictors in Cox proportional hazard models stratified based on sex and statin use. A total of 2258 subjects (50.6% female, mean age of 62nyears) were studied over an average of 8.1nyears of follow-up. The median annual decrease in CRP levels was 0.08nmg/L. Fibrinogen and IL-6 levels increased by a median of 30nmg/dL and 0.24npg/mL annually. Temporal changes in CRP were positively associated with HF risk among females (HR: 1.18 per each standard deviation increase, Pnln0.001) and other CVD in both female (HR: 1.12, Pn=n0.004) and male participants (HR: 1.24, Pn=n0.003). The association of CRP change with HF and other CVD was consistently observed in statin users (HR: 1.23 per SD increase, Pn=n0.001 for HF and HR: 1.19 per SD increase, Pnln0.001 for other CVD). There were no significant associations between temporal changes of fibrinogen or IL-6 with HF or other CVD. Men with sustained high values of IL-6 had a 2.3-fold higher risk of all-cause mortality (Pnln0.001) compared with those with sustained low values.ConclusionsTemporal change in CRP is associated with HF only in women and statin users, and other CVD in both women and men, and statin users. Annual changes in fibrinogen and IL-6 were not predictive of cardiovascular outcomes in either sex.

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

Background Oral postmenopausal hormone therapy (HT) increases the risk of venous thrombosis (VT). We postulated that activated protein C (APC) resistance induced by HT is one of the mechanisms causing VT, and also assessed the role of one of the main determinants of APC resistance, i.e., tissue factor pathway inhibitor (TFPI). Methods We performed a nested case-control study embedded within two Women's Health Initiative (WHI) hormone trials. Women were randomized to hormone therapy or placebo. Biomarkers were measured at baseline and after one-year, in 217 cases and 817 controls. Results Increased APC resistance and decreased TFPI at baseline were associated with VT (OR ranging from 1.20 to 2.06). However, women with such prothrombotic profile at baseline did not have further increased risk of VT when randomized to HT compared with placebo. While there was no change in APC resistance or TFPI in placebo group after one-year, HT group showed prothrombotic changes in the biomarkers, i.e., an increase in APC resistance (mean(sd):0.39 (0.54)) and decrease in TFPI (-0.21(0.50): free TFPI, -0.24(0.22): TFPI activity and -0.22(0.20): total TFPI). However, HT induced prothrombotic change in biomarkers did not increase risk of VT. Conclusion Women with prothrombotic levels of APC resistance and TFPI at baseline were not at increased risk of VT when randomized to HT compared with placebo. This suggests that testing for these biomarkers prior to starting HT is not required. HT led to prothrombotic change in these biomarkers after one year, but this did not relate to increased risk of VT.

BackgroundSeveral hemostatic factors and inflammatory markers are associated with the risk of incident venous thromboembolism (VTE), however, most existing data are from case-control studies in Caucasian populations.ObjectivesWe aimed to prospectively confirm previous findings and explore less studied biomarkers in relation to VTE risk in a multi-racial/multi-ethnic cohort.MethodsCirculating levels of factor VIII, fibrinogen, D-dimer, plasmin-antiplasmin complex (PAP), C-reactive protein (CRP), and interleukin-6 (IL-6) were measured at baseline (2000-2002) in 6706 participants of the Multi-Ethnic Study of Atherosclerosis. Incident VTE was identified using hospitalization discharge codes from baseline to December 31, 2015. Hazard ratios (HRs) of VTE were estimated in Cox regression models.ResultsThere were 227 events during a median of 14years of follow-up. Compared with participants in the lowest quartile, the HRs for those above the 95th percentile and p for trend across categories were 3.50 (95% confidence interval [CI] 1.98-6.19; p&nbsp

Background Hemostasis is a key factor in cerebrovascular disease, but the association of hemostatic factors with cognitive decline is unclear.Objective To prospectively evaluate associations of 20 hemostatic factor levels with changes in cognition during >= 8 years of follow-up in the Cardiovascular Health Study (CHS) of older adults.Methods We included participants of an existing CHS cross-sectional substudy (n = 400) with hemostatic factors measured in 1989-1990. Between 1989-1990 and 1998-1999, cognitive function was measured using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Tests. Mixed-effects linear regression models estimated change in cognitive function over time, adjusting for sociodemographic and clinical factors and APOE genotype, using Bonferroni adjustment. We also derived principal components to account for the interrelationship among factors.Results Of 20 factors evaluated individually, only higher levels of plasmin-alpha(2)-antiplasmin complex (PAP), tissue factor pathway inhibitor (TFPI), and lower factor X (FXc) levels were associated with faster cognitive decline, estimated by annual change in 3MSE points (1 standard deviation PAP beta = -0.65, 95% confidence interval [CI]: -1.08 to -0.21; TFPI beta = -0.55, 95% CI: -0.90 to -0.19; FXc beta = 0.52, 95% CI: 0.21-0.84). One of four principal components, loading positively on D-dimer, prothrombin fragment 1.2 (F1.2), and PAP was significantly associated with change in 3MSE.Conclusions Levels of PAP, TPFI, and FXc and a combination of factors driven by PAP, D-dimer, and F1.2 were associated with cognitive decline. Whether these findings can be used to improve dementia prevention or prediction requires further study.

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

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

BACKGROUND Hypertension is a common condition that increases risk for future cardiovascular disease. N-terminal B-type natriuretic peptide (NT-proBNP) is higher in individuals with hypertension, but studies of its association with hypertension risk have been mixed. METHODS The REasons for Geographic And Racial Differences in Stroke (REGARDS) study enrolled 30,239 U.S. Black or White adults aged ≥45 years from 2003 to 2007. A subcohort included 4,400 participants who completed a second assessment in 2013–2016. NT-proBNP was measured by immunoassay in 1,323 participants without baseline hypertension, defined as blood pressure ≥140/90 or self-reported antihypertensive prescriptions. Two robust Poisson regression models assessed hypertension risk, yielding incidence rate ratios (IRRs): Model 1 included behavioral and demographic covariates and Model 2 added risk factors. A sensitivity analysis using a less conservative definition of hypertension (blood pressure ≥130/80 or self-reported antihypertensive prescriptions) was conducted. RESULTS Four hundred and sixty-six participants developed hypertension after mean follow-up of 9.4 years. NT-proBNP was not associated with hypertension (Model 2 IRR per SD log NT-proBNP 1.01, 95% confidence interval 0.92–1.12), with no differences by sex, body mass index, age, or race. Similar findings were seen in lower-threshold sensitivity analysis. CONCLUSIONS NT-proBNP was not associated with incident hypertension in REGARDS; this did not differ by race or sex.

In the United States, causes of racial differences in stroke and its risk factors remain only partly understood, and there is a long-standing disparity in stroke incidence and mortality impacting Black Americans. Only half of the excess risk of stroke in the United States Black population is explained by traditional risk factors, suggesting potential effects of other factors including genetic and biological characteristics. Here, we nonsystematically reviewed candidate laboratory biomarkers for stroke and their relationships to racial disparities in stroke. Current evidence indicates that IL-6 (interleukin-6), a proinflammatory cytokine, mediates racial disparities in stroke through its association with traditional risk factors. Only one reviewed biomarker, Lp(a) (lipoprotein[a]), is a race-specific risk factor for stroke. Lp(a) is highly genetically determined and levels are substantially higher in Black than White people; clinical and pharmaceutical ramifications for stroke prevention remain uncertain. Other studied stroke risk biomarkers did not explain racial differences in stroke. More research on Lp(a) and other biological and genetic risk factors is needed to understand and mitigate racial disparities in stroke.

Objective: Venous thromboembolism (VTE) is a common disease that has a genetic basis. Lifestyle factors contribute to risk, but it is unknown whether healthy lifestyle can mitigate the genetic risk. We studied whether greater adherence to the American Heart Association’s cardiovascular health metric, Life’s Simple 7 (LS7), is associated with lower incidence of VTE in individuals across categories of a genetic risk score (GRS) for VTE. Approach AND RESULTS: We followed 9026 White participants from the ARIC (Atherosclerosis Risk in Communities) Study, a prospective cohort enrolled in 1987 to 1989 until 2015. We tested the joint associations with VTE of a validated VTE GRS comprising 5 well-known gene variants and baseline LS7 categories. There were 466 incident VTE events over 22.8 years. Participants with an optimal LS7 score had a lower incidence of VTE (3.9%) than those with inadequate LS7 (5.7%). Compared with the high GRS and inadequate LS7 group (hazard ratio=1), those with high GRS and optimal LS7 indeed had a reduced hazard ratio of VTE: 0.65 (95% CI, 0.48–0.89). The group with low GRS and optimal LS7 had the lowest hazard ratio of VTE (0.39 [95% CI, 0.25–0.61]). Of the LS7 components, in all GRS groups, the factor most strongly protective for VTE was normal weight. Conclusions: Among people at low or high genetic risk for VTE, healthier lifestyle factors, particularly normal weight, were associated with a lower incidence of VTE. Further studies should determine the impact of lifestyle changes among patients at high genetic risk of VTE, such as in thrombophilic families.

Background Coronavirus disease‐19 (COVID‐19) spans a wide spectrum of illness. Severe cases of COVID‐19 can manifest inflammation in organs other than the lung, in tissues not known to support viral replication, and also in a hypercoagulable state. These observations have suggested that SARS‐CoV‐2 can provoke a hyperimmune response in some cases that could lead to secondary organ damage. Methods With evidence of elevated levels of interleuking‐6 (IL‐6) in patients with severe COVID‐19, we conducted a small pilot off‐label compassionate care study of the IL‐6 receptor inhibitor tocilizumab patients with severe COVID‐19. Results Following a single infusion of tocilizumab in patients with severe manifested rapid declines in C‐reactive protein (CRP), D‐Dimer, and gradual rises in lymphocyte and platelet counts. Conclusions These findings suggest both pathophysiological mechanisms as well as clinical benefit that might be seen with IL‐6 inhibition in severe COVID‐19.

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

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

Background Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear. Objectives The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF. Methods The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio. Results Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p, Central Illustration

PURPOSE: Guidelines recommend venous thromboembolism (VTE) risk assessment in outpatients with cancer and pharmacologic thromboprophylaxis in selected patients at high risk for VTE. Although validated risk stratification tools are available, < 10% of oncologists use a risk assessment tool, and rates of VTE prophylaxis in high-risk patients are low in practice. We hypothesized that implementation of a systems-based program that uses the electronic health record (EHR) and offers personalized VTE prophylaxis recommendations would increase VTE risk assessment rates in patients initiating outpatient chemotherapy. PATIENTS AND METHODS: Venous Thromboembolism Prevention in the Ambulatory Cancer Clinic (VTEPACC) was a multidisciplinary program implemented by nurses, oncologists, pharmacists, hematologists, advanced practice providers, and quality partners. We prospectively identified high-risk patients using the Khorana and Protecht scores (≥ 3 points) via an EHR-based risk assessment tool. Patients with a predicted high risk of VTE during treatment were offered a hematology consultation to consider VTE prophylaxis. Results of the consultation were communicated to the treating oncologist, and clinical outcomes were tracked. RESULTS: A total of 918 outpatients with cancer initiating cancer-directed therapy were evaluated. VTE monthly education rates increased from < 5% before VTEPACC to 81.6% (standard deviation [SD], 11.9; range, 63.6%-97.7%) during the implementation phase and 94.7% (SD, 4.9; range, 82.1%-100%) for the full 2-year postimplementation phase. In the postimplementation phase, 213 patients (23.2%) were identified as being at high risk for developing a VTE. Referrals to hematology were offered to 151 patients (71%), with 141 patients (93%) being assessed and 93.8% receiving VTE prophylaxis. CONCLUSION: VTEPACC is a successful model for guideline implementation to provide VTE risk assessment and prophylaxis to prevent cancer-associated thrombosis in outpatients. Methods applied can readily translate into practice and overcome the current implementation gaps between guidelines and clinical practice.

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

PURPOSE: To examine the prospective association between serum Mg level and the incidence of cognitive impairment. METHODS: A random sub-cohort (n=2,063) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) cohort was included in this study. Baseline serum Mg concentration was measured using inductively coupled plasma mass spectrometry. According to the current reference interval of serum magnesium (0.75-0.95 mmol/L), we classified participants below the interval as Level 1 and used it as the referent. The rest of the study population were equally divided into three groups, named Level 2 to 4. Incident cognitive impairment was identified using the Six-Item Screener. Multivariable-adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using logistic regression models. RESULTS: After adjustment for potential confounders, an inverse threshold association between serum Mg level and incident cognitive impairment was observed. Compared to those with hypomagnesemia (Level 1

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.

Coronavirus disease 2019 (COVID‐19) is associated with significant hypercoagulability. However, despite prophylactic anticoagulation, critically ill patients with this condition develop thromboses. This forum discusses the lungs as the epicenter for the hemostatic issues, puts forward a proposal for staging COVID‐19 coagulopathy based on available diagnostic markers, and suggest considering current and future treatment options based on these different stages.

Venous thromboembolism is a major cause of morbidity and mortality. The impact of the US Surgeon General’s The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism in 2008 has been lower than expected given the public health impact of this disease. This scientific statement highlights future research priorities in venous thromboembolism, developed by experts and a crowdsourcing survey across 16 scientific organizations. At the fundamental research level (T0), researchers need to identify pathobiological causative mechanisms for the 50% of patients with unprovoked venous thromboembolism and to better understand mechanisms that differentiate hemostasis from thrombosis. At the human level (T1), new methods for diagnosing, treating, and preventing venous thromboembolism will allow tailoring of diagnostic and therapeutic approaches to individuals. At the patient level (T2), research efforts are required to understand how foundational evidence impacts care of patients (eg, biomarkers). New treatments, such as catheter-based therapies, require further testing to identify which patients are most likely to experience benefit. At the practice level (T3), translating evidence into practice remains challenging. Areas of overuse and underuse will require evidence-based tools to improve care delivery. At the community and population level (T4), public awareness campaigns need thorough impact assessment. Large population-based cohort studies can elucidate the biological and environmental underpinnings of venous thromboembolism and its complications. To achieve these goals, funding agencies and training programs must support a new generation of scientists and clinicians who work in multidisciplinary teams to solve the pressing public health problem of venous thromboembolism.

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

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

Background Prospective studies have suggested higher factor VIII (FVIII) levels are an independent risk factor for coronary heart disease (CHD) and stroke. However, limited information, including on genetic and epigenetic contributors to FVIII variation, is available specifically among African Americans (AAs), who have higher FVIII levels than Europeans. Objectives We measured FVIII levels in ~3400 AAs from the community-based Jackson Heart Study and assessed genetic, epigenetic, and epidemiological correlates of FVIII, as well as incident cardiovascular disease (CVD) associations. Methods We assessed cross-sectional associations of FVIII with CVD risk factors as well as incident CHD, stroke, heart failure, and mortality associations. We additionally assessed associations with TOPMed whole genome sequencing data and an epigenome-wide methylation array. Results Our results confirmed associations between FVIII and risk of incident CHD events and total mortality in AAs; mortality associations were largely independent of traditional risk factors. We also demonstrate an association of FVIII with incident heart failure, independent of B-type natriuretic peptide. Two genomic regions were strongly associated with FVIII (ABO and VWF). The index variant at VWF is specific to individuals of African descent and is distinct from the previously reported European VWF association signal. Epigenome-wide association analysis showed significant FVIII associations with several CpG sites in the ABO region. However, after adjusting for ABO genetic variants, ABO CpG sites were not significant. Conclusions Larger sample sizes of AAs will be required to discover additional genetic and epigenetic contributors to FVIII phenotypic variation, which may have consequences for CVD health disparities.

Coronavirus disease-2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), may predispose patients to thrombotic disease, both in the venous and arterial circulations, because of excessive inflammation, platelet activation, endothelial dysfunction, and stasis. In addition, many patients receiving antithrombotic therapy for thrombotic disease may develop COVID-19, which can have implications for choice, dosing, and laboratory monitoring of antithrombotic therapy. Moreover, during a time with much focus on COVID-19, it is critical to consider how to optimize the available technology to care for patients without COVID-19 who have thrombotic disease. Herein, the authors review the current understanding of the pathogenesis, epidemiology, management, and outcomes of patients with COVID-19 who develop venous or arterial thrombosis, of those with pre-existing thrombotic disease who develop COVID-19, or those who need prevention or care for their thrombotic disease during the COVID-19 pandemic.

There may be many predictors of venous thromboembolism (VTE) and bleeding in hospitalized medical patients, but until now, systematic reviews and assessments of the certainty of the evidence have not been published. We conducted a systematic review to identify prognostic factors for VTE and bleeding in hospitalized medical patients and searched Medline and EMBASE from inception through May 2018. We considered studies that identified potential prognostic factors for VTE and bleeding in hospitalized adult medical patients. Reviewers extracted data in duplicate and independently and assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. Of 69 410 citations, we included 17 studies in our analysis: 14 that reported on VTE, and 3 that reported on bleeding. For VTE, moderate-certainty evidence showed a probable association with older age; elevated C-reactive protein (CRP), D-dimer, and fibrinogen levels; tachycardia; thrombocytosis; leukocytosis; fever; leg edema; lower Barthel Index (BI) score; immobility; paresis; previous history of VTE; thrombophilia; malignancy; critical illness; and infections. For bleeding, moderate-certainty evidence showed a probable association with older age, sex, anemia, obesity, low hemoglobin, gastroduodenal ulcers, rehospitalization, critical illness, thrombocytopenia, blood dyscrasias, hepatic disease, renal failure, antithrombotic medication, and presence of a central venous catheter. Elevated CRP, a lower BI, a history of malignancy, and elevated heart rate are not included in most VTE risk assessment models. This study informs risk prediction in the management of hospitalized medical patients for VTE and bleeding; it also informs guidelines for VTE prevention and future research.

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

Aims Soluble tumour necrosis factor‐α receptor 1 (sTNF‐αR1) and interleukin‐2 receptor α (sIL‐2Rα) predict incident heart failure (HF) in the elderly population. However, the association of these biomarkers with HF in a multi‐ethnic asymptomatic population is unclear. We aimed to investigate the association of sTNF‐αR1 and sIL‐2Rα with incident HF in a multi‐ethnic population of middle age and older participants. Methods and results The multi‐ethnic study of atherosclerosis is a prospective population‐based study of 6814 participants aged 45–84 years who were free of clinical cardiovascular disease at enrolment. We included 2869 participants with available sTNF‐αR1 or sIL‐2Rα level measurement at baseline multi‐ethnic study of atherosclerosis exam (2000–2002). We used Cox proportional‐hazards model to investigate the association between sTNF‐αR1 and sIL‐2Rα with incident HF after adjusting for traditional cardiovascular risk factors and coronary artery calcium score measured by cardiac computed tomography. Among the included participants, the mean (standard deviation) age was 61.6 (10.2) years and 46.7% were men. The median (interquartile range) sTNF‐αR1 and sIL‐2Rα were 1293 (1107–1547) and 901 (727–1154) pg/mL. During a median follow‐up of 14.2 (interquartile range: 11.7–14.8) years, 130 participants developed HF. In multivariable analysis, the hazard ratio (95% confidence interval, P value) of incident HF for each standard deviation increment of log‐transformed sTNF‐αR1 and sIL‐2Rα was 1.43 (1.21–1.7, P ≤ 0.001) and 1.26 (1.04–1.53, P = 0.02), respectively. Excluding participants with interim coronary heart disease, we found a statistically significant association between sTNF‐αR1 and HF with hazard ratio of 1.39 (95% confidence interval: 1.11 to 1.74, P = 0.005) and sIL‐2Rα and HF showing a hazard ratio of 1.39 (95% confidence interval: 1.09 to 1.76, P = 0.007). Conclusions sTNF‐αR1 and sIL‐2Rα are associated with a higher risk of incident HF in a multi‐ethnic cohort without a previous history of cardiovascular disease.

Background. Polycythemia vera patients with high hematocrit have increased risk of venous thromboembolism (VTE). We tested whether high hematocrit in the general population is also associated with elevated VTE risk. Methods. The prospective Atherosclerosis Risk in Communities (ARIC) Study performed a complete blood count in 13,891 adults aged 45-64 at baseline in 1987-89. We identified and validated incident hospitalized VTEs through 2015, with provoked VTE defined as occurring within 90 days of surgery, trauma, immobilization or with cancer. We performed proportional hazards regression analyses using race-sex specific categorization of hematocrit percentiles (i.e., Results. At baseline, higher hematocrit was associated with smoking prevalence, greater pack years smoked, higher body-mass index and higher prevalence of diabetes. With 26 years median follow-up, 800 participants had incident deep vein thrombosis of the leg and/or pulmonary embolism. The figure shows a J-shaped association of hematocrit with VTE incidence. The VTE incidence at the highest level of hematocrit was approximately double that at the mid level. Low hematocrit also was associated with elevated VTE incidence but the confidence interval overlapped 1. The Table shows modeling results. Accounting for other risk factors, the risk of overall VTE was elevated 72% for participants above the 95th percentile of hematocrit compared with the reference. Specifically, hazard ratios (95% confidence interval) of incident VTE were 1.27 (0.91,1.76), 1.06 (0.87,1.28), 1 (reference), 1.17 (0.98, 1.40) and 1.72 (1.30, 2.27) across the five hematocrit percentiles, adjusted for age, race, sex, body mass index, and other potential confounding variables including smoking status and pack-years. The association of high hematocrit with VTE was limited to provoked VTE, with little evidence for unprovoked VTE. Results were similar for hemoglobin (not shown). Discussion. High hematocrit and hemoglobin in a general middle-aged population sample were associated with increased long-term risk of VTE, particularly provoked VTE. The reasons for this pattern require further study. Disclosures No relevant conflicts of interest to declare.

BACKGROUND Rare coding mutations underlying deficiencies of antithrombin and proteins C and S contribute to familial venous thromboembolism (VTE). It is uncertain whether rare variants play a role in the etiology of VTE in the general population. OBJECTIVES We conducted a deep whole-exome sequencing (WES) study to investigate the associations between rare coding variants and the risk of VTE in two population-based prospective cohorts. PATIENTS/METHODS Whole-exome sequencing was performed in the Longitudinal Investigation of Thromboembolism Etiology (LITE), which combines the Atherosclerosis Risk in Communities (ARIC) study (316 incident VTE events among 3159 African Americans [AAs] and 458 incident VTEs among 7772 European Americans [EAs]) and the Cardiovascular Healthy Study (CHS; 60 incident VTEs among 1751 EAs). We performed gene-based tests of rare variants (allele frequency

Background/Objectives Higher resting heart rate is a risk factor for arterial cardiovascular diseases. We assessed whether higher heart rate is a risk factor for venous thromboembolism (VTE). Methods In a prospective epidemiologic cohort, the Atherosclerosis Risk in Communities (ARIC) Study, we associated resting heart rate by electrocardiogram with physician‐validated incident hospitalized VTE through 2015. We also examined whether lower heart rate variability (HRV), a marker of cardiac autonomic imbalance, might be a risk factor for VTE. Results Resting heart rate at Visit 1 (1987‐1989), when participants were 45 to 64 years old (mean, 54 years), was not associated with incidence of VTE (n = 882 cases). However, heart rate at Visit 4 (1996‐1998; mean age, 63 years) was associated positively with VTE (n = 557 cases). The adjusted hazard ratios (95% confidence intervals) of VTE across Visit 4 heart rate categories of

Background Heart failure (HF) hospitalization places patients at increased short-term risk for venous thromboembolism (VTE). Long-term risk for VTE associated with incident HF, HF subtypes, or structural heart disease is unknown. Objectives In the ARIC (Atherosclerosis Risk In Communities) cohort, VTE risk associated with incident HF, HF subtypes, and abnormal echocardiographic measures in the absence of clinical HF was assessed. Methods During follow-up, ARIC identified incident HF and subcategorized HF with preserved ejection fraction or reduced ejection fraction. At the fifth clinical examination, echocardiography was performed. Physicians adjudicated incident VTE using hospital records. Adjusted Cox proportional hazards models were used to evaluate the association between HF or echocardiographic exposures and VTE. Results Over a mean of 22 years in 13,728 subjects, of whom 2,696 (20%) developed incident HF, 729 subsequent VTE events were identified. HF was associated with increased long-term risk for VTE (adjusted hazard ratio: 3.13; 95% confidence interval: 2.58 to 3.80). In 7,588 subjects followed for a mean of 10 years, the risk for VTE was similar for HF with preserved ejection fraction (adjusted hazard ratio: 4.71; 95% CI: 2.94 to 7.52) and HF with reduced ejection fraction (adjusted hazard ratio: 5.53; 95% confidence interval: 3.42 to 8.94). In 5,438 subjects without HF followed for a mean of 3.5 years, left ventricular relative wall thickness and mean left ventricular wall thickness were independent predictors of VTE. Conclusions In this prospective population-based study, incident hospitalized HF (including both heart failure with preserved ejection fraction and reduced ejection fraction), as well as echocardiographic indicators of left ventricular remodeling, were associated with greatly increased risk for VTE, which persisted through long-term follow-up. Evidence-based strategies to prevent long-term VTE in patients with HF, beyond time of hospitalization, are needed.

Previous studies do not widely support hyperuricemia as a risk factor for stroke and other cardiovascular diseases. We assessed the relationship between hyperuricemia and ischemic stroke (≈900 cases) using a large data set from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). We employed a case-cohort design (incident stroke cases and randomly selected cohort participants) and weighted Cox-proportional hazard models to estimate the association of serum urate level ≥6.8 mg/dL (ie, hyperuricemia) and 6.0 to

Background: The majority of people with chronic kidney disease (CKD) are unaware of their kidney disease. Assessing the clinical significance of increasing CKD awareness has critical public health and healthcare delivery implications. Whether CKD awareness among persons with CKD is associated with longitudinal health behaviors, disease management, and health outcomes is unknown. Methods: We analyzed data from participants with CKD in the REasons for Geographic And Racial Differences in Stroke study, a national, longitudinal, population-based cohort. Our predictor was participant CKD awareness. Outcomes were (1) health behaviors (smoking avoidance, exercise, and nonsteroidal anti-inflammatory drug use); (2) CKD management indicators (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, statin use, systolic blood pressure, fasting blood glucose, and body mass index); (3) change in estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR); and (4) health outcomes (incident end-stage kidney disease [ESKD], coronary heart disease [CHD], stroke, and death). Logistic and linear regressions were used to examine the association of baseline CKD awareness with outcomes of interest, adjusted for CKD stage and participant demographic and clinical factors. Results: Of 6,529 participants with baseline CKD, 285 (4.4%) were aware of their CKD. Among the 3,586 participants who survived until follow-up (median 9.5 years), baseline awareness was not associated with subsequent odds of health behaviors, CKD management indicators, or changes in eGFR and UACR in adjusted analyses. Baseline CKD awareness was associated with increased risk of ESKD (adjusted hazard ratio [aHR] 1.44; 95% CI 1.08–1.92) and death (aHR 1.18; 95% CI 1.00–1.39), but not with subsequent CHD or stroke, in adjusted models. Conclusions: Individuals aware of their CKD were more likely to experience ESKD and death, suggesting that CKD awareness reflects disease severity. Most persons with CKD, including those that are high-risk, remain unaware of their CKD. There was no evidence of associations between baseline CKD awareness and longitudinal health behaviors, CKD management indicators, or eGFR decline and albuminuria.

BACKGROUND: α-Globin is expressed in endothelial cells of resistance arteries, where it limits endothelial nitric oxide signaling and enhances α-adrenergic–mediated vasoconstriction. α-Globin gene (HBA) copy number is variable in people of African descent and other populations worldwide. Given the protective effect of nitric oxide in the kidney, we hypothesized that HBA copy number would be associated with kidney disease risk. METHODS: Community-dwelling Black Americans aged ≥45 years old were enrolled in a national longitudinal cohort from 2003 through 2007. HBA copy number was measured using droplet digital PCR. The prevalence ratio (PR) of CKD and the relative risk (RR) of incident reduced eGFR were calculated using modified Poisson multivariable regression. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression. RESULTS: Among 9908 participants, HBA copy number varied from 2 to 6. In analyses adjusted for demographic, clinical, and genetic risk factors, a one-copy increase in HBA was associated with 14% greater prevalence of CKD (PR, 1.14; 95% CI, 1.07 to 1.21; P

Objectives To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. Trial design Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial Participants The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; Admitted to hospital for COVID-19; One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: D-Dimer ≥2 times ULN OR D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; > 18 years of age; Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: pregnancy; hemoglobin platelet count 9/L in the last 72 hours; known fibrinogen known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; known bleeding within the last 30 days requiring emergency room presentation or hospitalization; known history of a bleeding disorder of an inherited or active acquired bleeding disorder; known history of heparin-induced thrombocytopenia; known allergy to UFH or LMWH; admitted to the intensive care unit at the time of screening; treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; Imminent death according to the judgement of the most responsible physician; enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. Intervention and comparator Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician’s discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. Main outcomes The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): All-cause death Composite of ICU admission or all-cause death Composite of mechanical ventilation or all-cause death Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; Red blood cell transfusion (>1 unit); Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; Renal replacement therapy; Hospital-free days alive; ICU-free days alive; Ventilator-free days alive; Organ support-free days alive; Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); Heparin induced thrombocytopenia; Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. Randomisation Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. Blinding (masking) No blinding involved. This is an open-label trial. Numbers to be randomised (sample size) 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. Trial Status Protocol Version Number 1.4. Recruitment began on May 11th, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. Trial registration ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Contains fulltext : 245735.pdf (Publisher’s version ) (Closed access) BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with macro- and micro-thromboses, which are triggered by endothelial cell activation, coagulopathy, and uncontrolled inflammatory response. Conventional antithrombotic agents are under assessment in dozens of randomized controlled trials (RCTs) in patients with COVID-19, with preliminary results not demonstrating benefit in several studies. OBJECTIVES: Given the possibility that more novel agents with antithrombotic effects may have a potential utility for management of patients with COVID-19, we assessed ongoing RCTs including these agents with their potential mechanism of action in this population. METHODS: We searched clinicaltrials.gov and the World Health Organization International Clinical Trials Registry Platform to identify RCTs of novel antithrombotic agents in patients with COVID-19. RESULTS: Based on a systematic literature search, 27 RCTs with 10 novel antithrombotic agents (including nafamostat, dociparstat, rNAPc2, and defibrotide) were identified. The results from these trials have not been disseminated yet. The studied drugs in the ongoing or completed RCTs include agents affecting the coagulation cascade, drugs affecting endothelial activation, and mixed acting agents. Their postulated antithrombotic mechanisms of action and their potential impact on patient management are summarized. CONCLUSION: Some novel antithrombotic agents have pleiotropic anti-inflammatory and antiviral effects, which may help reduce the viral load or fibrosis, and improve oxygenation. Results from ongoing RCTs will elucidate their actual role in the management of patients with COVID-19.

Social vulnerabilities increase the risk of developing hypertension and lower life expectancy, but the effect of an individual’s overall vulnerability burden is unknown. Our objective was to determine the association of social vulnerability count and the risk of developing hypertension or dying over 10 years and whether these associations vary by race. We used the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) and included participants without baseline hypertension. The primary exposure was the count of social vulnerabilities defined across economic, education, health and health care, neighborhood and built environment, and social and community context domains. Among 5425 participants of mean age 64±10 SD years of which 24% were Black participants, 1468 (31%) had 1 vulnerability and 717 (15%) had ≥2 vulnerabilities. Compared with participants without vulnerabilities, the adjusted relative risk ratio for developing hypertension was 1.16 (95% CI, 0.99–1.36) and 1.49 (95% CI, 1.20–1.85) for individuals with 1 and ≥2 vulnerabilities, respectively. The adjusted relative risk ratio for death was 1.55 (95% CI, 1.24–1.93) and 2.30 (95% CI, 1.75–3.04) for individuals with 1 and ≥2 vulnerabilities, respectively. A greater proportion of Black participants developed hypertension and died than did White participants (hypertension, 38% versus 31%; death, 25% versus 20%). The vulnerability count association was strongest in White participants ( P value for vulnerability count×race interaction: hypertension=0.046, death=0.015). Overall, a greater number of socially determined vulnerabilities was associated with progressively higher risk of developing hypertension, and an even higher risk of dying over 10 years.

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

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

BACKGROUND: Low levels of high-density lipoprotein cholesterol (HDL-C) have been associated with incident cognitive impairment (ICI) in some, but not all studies. METHODS: We examine the association between HDL-C and ICI among 18,378 Reasons for Geographic and Racial Differences in Stroke (REGARDS) study participants without cognitive impairment or stroke at baseline in 2003 to 2007, and who did not have a stroke event during follow-up. RESULTS: Over a median follow-up of 9.6 years, 1,359 participants developed ICI. In fully adjusted models, the RR for ICI was 1.51 (95% CI 1.06, 2.15) in White women and 1.25 (95% CI 0.95, 1.65) in Black women. The association was not statistically significant afrter adjustment for triglycerides. There was no evidence of an association between HDL-C and ICI among White or Black men. CONCLUSIONS: Low HDL-C was associated with a higher risk of ICI in White and Black women in models not including triglycerides.

Context: Mechanisms explaining documented associations of 25-hydroxyvitamin D [25(OH)D] deficiency with increased risks of cardiovascular disease (CVD) and venous thromboembolism may relate to adverse hemostatic and inflammatory responses. Objective: To evaluate whether 25(OH)D deficiency is associated with a prothrombotic and proinflammatory biological profile. Design: Cross-sectional analyses. Setting: The Multi-Ethnic Study of Atherosclerosis, a multicenter prospective cohort of American adults. Participants: Up to 6554 adults free of CVD. Main Outcome Measures: Ten hemostatic biomarkers (D-dimer, fibrinogen, factor VIII, plasmin-antiplasmin, and homocysteine [n = 6443]; von Willebrand factor, soluble tissue factor, plasminogen activator inhibitor-1 (PAI-1), total tissue factor pathway inhibitor (TFPI), and soluble thrombomodulin [n = 814]), and three inflammatory biomarkers (IL-6, C-reactive protein [n = 6443], and TNF-α soluble receptor [n = 3802]). Results: Among 6443 subjects (46.6% men; mean age, 62.1 years; mean body mass index, 28.3 kg/m2) of White (37.8%), Black (27.2%), Chinese (12.2%), and Hispanic (21.8%) race/ethnicity, mean 25(OH)D was 25.3 ng/mL. After multiple adjustment, 25(OH)D concentrations were associated with concentrations of IL-6 and homocysteine and also with concentrations of PAI-1 and TFPI: per 10 ng/mL decrement in 25(OH)D, 5.1% higher IL-6 (95% confidence interval [CI], 3.4-6.9; P < .001); 3.7% higher homocysteine (95% CI, 3.0-4.3; P < .001); 7.0% higher PAI-1 (95% CI, 0.9-13.6; P = .025); and 2.1% higher TFPI (95% CI, 0.0-4.2; P = .047), without racial/ethnic heterogeneity. No significant associations were observed for other hemostatic and inflammatory biomarkers. Conclusions: Increased inflammation as reflected by higher circulating IL-6 and increased homocysteine concentrations may represent mechanisms linking 25(OH)D deficiency to greater risks of CVD and perhaps venous thromboembolism. Low concentrations of 25(OH)D were also associated with PAI-1 and TFPI concentrations, but not with other hemostatic biomarkers.

Background Individual blood cell count abnormalities have been associated with cardiovascular disease and increased mortality. In this study, we defined a “cytopenia phenotype,” reflecting bone marrow hypoproliferation, to determine if peripheral blood cytopenia is associated with increased cardiovascular disease and mortality risk. Methods and Results Study participants were derived from a biracial observational cohort study, REGARDS (Reasons for Geographic and Racial Differences in Stroke), that enrolled 30 239 Black and White participants aged ≥45 years between 2003 and 2007. Median follow up was ≈9 years. The current study included 19 864 participants from REGARDS study (37.9% men, 40% Black participants) who have complete blood count available at study enrollment. We defined a cytopenia phenotype based on age‐, sex‐, and race‐adjusted lowest fifth percentile of blood counts. Multivariable Cox proportional hazards models estimated the hazard ratios (HR) and 95% CI of cytopenia for mortality and incident cardiovascular disease in adjusted models. Mean age of the study participants was 64 years (SD:9.7). The prevalence of cytopenia was 1.9% (n=378). Cytopenia was associated with increased risk of all‐cause mortality (HR, 1.73; 95% CI, 1.34–2.22) and cardiovascular disease mortality (HR, 1.56; 95% CI, 1.11–2.29). Cytopenia was associated with stroke risk in Black but not White participants (HR, 1.96 versus 0.86; P ‐interaction for race=0.08) and was not associated with coronary heart disease risk. Conclusions We defined a cytopenia phenotype with clinical implications for mortality and stroke risk in a large biracial and geographically diverse population. Whether generated through somatic mutations or decreased organ function, cytopenia was associated with mortality risk and was a race‐specific risk factor for stroke.

The 300 000+ deaths from COVID‐19 in the United States (now) 1 provide stark illustration of the well‐known fact that despite great wealth, and that we spend more than any other country on health care when compared to other high‐income nations, for decades we have ranked near the bottom in several metrics of health starting from birth 5 There are myriad reasons, including sexism, implicit bias, and structural racism [ ]the National Heart, Lung, and Blood Institute selected researchers to collaborate on antithrombotic trials based on submitted letters of intent and research progress over the first months of the pandemic, forming the Accelerating COVID‐19 Therapeutic Interventions and Vaccines (ACTIV)‐4 program At Research and Practice in Thrombosis and Haemostasis, we waived article publication charges and published original COVID‐19 research and articles that raise hypotheses relevant to treatment 9 We studied the authorship gender gap during the first COVID wave 10 and published articles on new ways to disseminate science 11 Dobson and Wolberg eloquently discussed scientific silver linings of COVID‐19 and considered the impact on institutional racism and increasing diversity in science 4 I call on you to continue to submit science to us;we are also interested in Forum articles on the social impact of COVID‐19 and the events of 2020