Publications by authors named "Mary Cushman"

586 Publications

Television Viewing, physical activity and Venous Thromboembolism Risk: the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

J Thromb Haemost 2021 Jun 2. Epub 2021 Jun 2.

Department of Pathology & Laboratory Medicine, Larner College of Medicine, University of Vermont.

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 United States cohort of Black and White adults.

Methods: Between 2003-2007 The REasons for Geographic and Racial Differences in Stroke (REGARDS) recruited 30,239 participants aged ≥45 years, who were surveyed for baseline TV viewing and followed for VTE events. TV viewing was categorized as <2 hours (light), 2 to 4 hours (moderate), and ≥4 hours (heavy) per day. Physical activity was classified as poor, intermediate, or ideal based on reported weekly activity. Hazard ratios of TV viewing and physical activity were calculated adjusting for VTE risk factors. Multiple imputation for missingness was used as a sensitivity analysis.

Results: Over 96,813 person-years (median: 5.06 years) of follow up there were 214 VTE events. Heavy TV viewing was not associated with VTE risk in the unadjusted and fully adjusted model (aHR: 0.92 [95%CI: 0.62, 1.36]). Ideal physical activity trended towards a reduced VTE risk (HR: 0.71 [95%CI: 0.51,1.01]). There was no evidence of an interaction between TV viewing, physical activity and risk of VTE.

Conclusions: In this contemporary racially and geographically diverse United States cohort, there was no association between TV viewing and VTE risk, before and after accounting for physical activity. The high burden of traditional VTE risk factors in REGARDS may mask any association of TV viewing with VTE, or TV viewing may have only a modest association with VTE risk.
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http://dx.doi.org/10.1111/jth.15408DOI Listing
June 2021

Pro-Neurotensin/Neuromedin N and Risk of Incident Metabolic Syndrome and Diabetes Mellitus in the REGARDS Cohort.

J Clin Endocrinol Metab 2021 May 20. Epub 2021 May 20.

Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, USA.

Context: The peptide neurotensin is implicated in insulin resistance, diabetes mellitus (DM), and cardiovascular disease.

Objective: We studied the association of neurotensin's stable precursor, pro-neurotensin/neuromedin N (pro-NT/NMN) with incident metabolic syndrome (MetS) and DM.

Design/setting/participants: We included 3,772 participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study who completed the baseline exam (2003-2007), the follow-up exam (2013-2016), and had pro-NT/NMN measured by immunoassay. Weighted logistic regression models were fitted to incident DM, incident MetS, and each MetS component, separately, incorporating demographics, metabolic risk factors, HOMA-IR, and diet scores.

Main Outcome Measures: Incident MetS was defined by ≥3 harmonized criteria at follow-up in those with <3 at baseline. Incident DM was defined by use of hypoglycemic drugs/insulin, fasting glucose ≥126 mg/dL, or random glucose ≥200 mg/dL, in those without these at baseline.

Results: Median [IQR] plasma pro-NT/NMN was 160 [118-218] pmol/L. 564 (of 2,770 without baseline MetS) participants developed MetS and 407 (of 3,030 without baseline DM) developed DM. Per standard deviation (SD) higher log-Pro-NT/NMN, the demographic-adjusted odds ratio (OR) and 95% confidence interval (CI) of incident MetS was 1.22 (1.11-1.35); 1.16 (1.00-1.35) for incident low HDL, and 1.25 (1.11-1.40) for incident dysglycemia. The association of pro-NT/NMN with MetS was attenuated in the model adding HOMA-IR (OR per SD log-pro-NT/NMN 1.14, 95% CI 1.00-1.30). There was no association with incident DM (OR per SD log-pro-NT/NMN 1.06, 95% CI 0.94-1.19).

Conclusions: Pro-NT/NMN was associated with MetS and two components, dysglycemia and low HDL, likely explained by insulin resistance.
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http://dx.doi.org/10.1210/clinem/dgab355DOI Listing
May 2021

Whole-genome sequencing association analysis of quantitative red blood cell phenotypes: The NHLBI TOPMed program.

Am J Hum Genet 2021 May 21;108(5):874-893. Epub 2021 Apr 21.

Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.

Whole-genome sequencing (WGS), a powerful tool for detecting novel coding and non-coding disease-causing variants, has largely been applied to clinical diagnosis of inherited disorders. Here we leveraged WGS data in up to 62,653 ethnically diverse participants from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and assessed statistical association of variants with seven red blood cell (RBC) quantitative traits. We discovered 14 single variant-RBC trait associations at 12 genomic loci, which have not been reported previously. Several of the RBC trait-variant associations (RPN1, ELL2, MIDN, HBB, HBA1, PIEZO1, and G6PD) were replicated in independent GWAS datasets imputed to the TOPMed reference panel. Most of these discovered variants are rare/low frequency, and several are observed disproportionately among non-European Ancestry (African, Hispanic/Latino, or East Asian) populations. We identified a 3 bp indel p.Lys2169del (g.88717175_88717177TCT[4]) (common only in the Ashkenazi Jewish population) of PIEZO1, a gene responsible for the Mendelian red cell disorder hereditary xerocytosis (MIM: 194380), associated with higher mean corpuscular hemoglobin concentration (MCHC). In stepwise conditional analysis and in gene-based rare variant aggregated association analysis, we identified several of the variants in HBB, HBA1, TMPRSS6, and G6PD that represent the carrier state for known coding, promoter, or splice site loss-of-function variants that cause inherited RBC disorders. Finally, we applied base and nuclease editing to demonstrate that the sentinel variant rs112097551 (nearest gene RPN1) acts through a cis-regulatory element that exerts long-range control of the gene RUVBL1 which is essential for hematopoiesis. Together, these results demonstrate the utility of WGS in ethnically diverse population-based samples and gene editing for expanding knowledge of the genetic architecture of quantitative hematologic traits and suggest a continuum between complex trait and Mendelian red cell disorders.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.003DOI Listing
May 2021

FGL1 as a modulator of plasma D-dimer levels: Exome-wide marker analysis of plasma tPA, PAI-1, and D-dimer.

J Thromb Haemost 2021 Apr 20. Epub 2021 Apr 20.

Faculty of Health and Medical Sciences, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.

Background: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA, and D-dimer.

Objectives: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach.

Methods: Cohort-level analyses and fixed effects meta-analyses of PAI-1 (n = 15 603), tPA (n = 6876,) and D-dimer (n = 19 306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing.

Results: Five variants located in NME7, FGL1, and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10 ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10 in the discovery using an independent cohort. Replication was observed for three out of the five significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (fibrinogen-like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels.

Conclusion: This work provides new evidence for a role of FGL1 in hemostasis.
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http://dx.doi.org/10.1111/jth.15345DOI Listing
April 2021

Innovation via social media - The importance of Twitter to science.

Res Pract Thromb Haemost 2021 Mar 11;5(3):373-375. Epub 2021 Mar 11.

Department of Medicine Larner College of Medicine at the University of Vermont Burlington VT USA.

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http://dx.doi.org/10.1002/rth2.12493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8035792PMC
March 2021

Liver Fibrosis is Associated with Ischemic Stroke Risk in Women but not Men: The REGARDS Study.

J Stroke Cerebrovasc Dis 2021 Jul 16;30(7):105788. Epub 2021 Apr 16.

Department of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT USA; Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT USA.

Background: Nonalcoholic fatty liver disease is inconsistently associated with ischemic stroke, with one study suggesting an association in women and not men. The relative importance of liver fibrosis, as opposed to fatty liver, for cardiovascular risk is increasingly appreciated. We hypothesized that advanced liver fibrosis is associated with incident ischemic stroke risk, and especially in women.

Methods: We performed a case-cohort study in the REasons for Geographic and Racial Differences in Stroke cohort. Black and white individuals aged 45 and older were recruited between 2003 and 2007 and followed for ischemic stroke. The Fibrosis-4 (FIB-4) score and Nonalcoholic Fatty Liver Disease Fibrosis Score (NFS) were calculated using baseline data for stroke cases and a cohort random sample; advanced liver fibrosis was classified using validated cutoffs. Cox proportional hazards models were used to estimate hazard ratios (HR) of stroke after adjusting for potential confounders. Sex differences were assessed.

Results: There were 572 incident ischemic strokes (285 in women) over 5.4 (SD, 2.2) years. Advanced liver fibrosis was not significantly associated with ischemic stroke overall using the FIB-4 (HR 1.44; 95% CI 0.49-4.28) or NFS (HR 1.76; 95% CI 0.67-4.61). However, liver fibrosis was associated with stroke in women (HR 3.51; 95% CI 1.00-12.34) but not men (HR 0.70, 95% CI 0.16-3.16) (P = 0.098 for interaction) when using FIB-4. A similar but non-significant sex difference was seen for NFS.

Conclusion: Advanced liver fibrosis may be associated with a higher risk of ischemic stroke in women but not men.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184639PMC
July 2021

Venous thrombosis with oral postmenopausal hormone therapy: Roles of activated protein C resistance and tissue factor pathway inhibitor.

J Thromb Haemost 2021 Mar 28. Epub 2021 Mar 28.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.

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 hormone trials. Women were randomized to hormone therapy or placebo. Biomarkers were measured at baseline and after 1 year in 217 cases and 817 controls.

Results: Increased APC resistance and decreased TFPI at baseline were associated with VT (odds ratio 1.20-2.06). However, women with such prothrombotic profile at baseline did not have further increased risk of VT when randomized to HT compared with placebo. Although there was no change in APC resistance or TFPI in placebo group after 1 year, HT group showed prothrombotic changes in the biomarkers (i.e., an increase in APC resistance) (mean [standard deviation] 0.39 [0.54]) and decrease in TFPI (-0.21 [0.50]: free TFPI, -0.24 [0.22]: TFPI activity -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 before 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.
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http://dx.doi.org/10.1111/jth.15319DOI Listing
March 2021

Hemostatic factors, inflammatory markers, and risk of incident venous thromboembolism: The Multi-Ethnic Study of Atherosclerosis.

J Thromb Haemost 2021 Mar 27. Epub 2021 Mar 27.

Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN, USA.

Background: Several 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.

Objectives: We aimed to prospectively confirm previous findings and explore less studied biomarkers in relation to VTE risk in a multi-racial/multi-ethnic cohort.

Methods: Circulating 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.

Results: There were 227 events during a median of 14 years 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 < .001) for D-dimer, 1.49 (95% CI 0.84-2.63; p = .02) for factor VIII, 1.32 (95% CI 0.76-2.28; p = .99) for fibrinogen, 1.92 (95% CI 1.08-3.42; p = .15) for PAP, 1.68 (95% CI 0.81-3.48; p = .08) for CRP, and 2.55 (95% CI 1.15-5.66; p = .07) for IL-6, after adjustment for demographics and body mass index. For CRP and IL-6, follow-up was restricted to 10 years because of violations of the proportional hazards assumption. No significant interactions by age/ethnicity were observed.

Conclusions: We demonstrated a fairly novel association between PAP and risk of incident VTE, and contributed further prospective confirmation regarding the associations of D-dimer, factor VIII, and IL-6 with VTE.
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http://dx.doi.org/10.1111/jth.15315DOI Listing
March 2021

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

medRxiv 2021 Mar 20. Epub 2021 Mar 20.

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.
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http://dx.doi.org/10.1101/2021.03.19.21253986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987050PMC
March 2021

Recent Randomized Trials of Antithrombotic Therapy for Patients With COVID-19: JACC State-of-the-Art Review.

J Am Coll Cardiol 2021 04 16;77(15):1903-1921. Epub 2021 Mar 16.

Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA; Clinical Trials Center, Cardiovascular Research Foundation, New York, New York, USA; Center for Outcomes Research and Evaluation (CORE), Yale School of Medicine, New Haven, Connecticut, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jacc.2021.02.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963001PMC
April 2021

Hemostatic factor levels and cognitive decline in older adults: The Cardiovascular Health Study.

J Thromb Haemost 2021 05 29;19(5):1219-1227. Epub 2021 Mar 29.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

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-α -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 β = -0.65, 95% confidence interval [CI]: -1.08 to -0.21; TFPI β = -0.55, 95% CI: -0.90 to -0.19; FXc β = 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.
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http://dx.doi.org/10.1111/jth.15300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136364PMC
May 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Coagulopathy of hospitalised COVID-19: A Pragmatic Randomised Controlled Trial of Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID COVID COAG - RAPID Trial): A structured summary of a study protocol for a randomised controlled trial.

Trials 2021 Mar 10;22(1):202. Epub 2021 Mar 10.

St. Michael's Hospital, Applied Health Research Centre, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Canada.

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: 1) 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; 2) Admitted to hospital for COVID-19; 3) One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: a. D-Dimer ≥2 times ULN OR b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4) > 18 years of age; 5) Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: 1) pregnancy; 2) hemoglobin <80 g/L in the last 72 hours; 3) platelet count <50 x 10/L in the last 72 hours; 4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6) 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); 7) 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)]; 8) patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11) known history of heparin-induced thrombocytopenia; 12) known allergy to UFH or LMWH; 13) admitted to the intensive care unit at the time of screening; 14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; 15) Imminent death according to the judgement of the most responsible physician; 16) 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): 1. All-cause death 2. Composite of ICU admission or all-cause death 3. Composite of mechanical ventilation or all-cause death 4. Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; 5. Red blood cell transfusion (>1 unit); 6. Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; 7. Renal replacement therapy; 8. Hospital-free days alive; 9. ICU-free days alive; 10. Ventilator-free days alive; 11. Organ support-free days alive; 12. Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 13. Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); 14. Heparin induced thrombocytopenia; 15. 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 11, 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.
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http://dx.doi.org/10.1186/s13063-021-05076-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943934PMC
March 2021

Correlates of a southern diet pattern in a national cohort study of blacks and whites: the REasons for Geographic And Racial Differences in Stroke (REGARDS) study.

Br J Nutr 2021 Feb 26:1-7. Epub 2021 Feb 26.

Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, USA.

The Southern dietary pattern, derived within the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort, is characterised by high consumption of added fats, fried food, organ meats, processed meats and sugar-sweetened beverages and is associated with increased risk of several chronic diseases. The aim of the present study was to identify characteristics of individuals with high adherence to this dietary pattern. We analysed data from REGARDS, a national cohort of 30 239 black and white adults ≥45 years of age living in the USA. Dietary data were collected using the Block 98 FFQ. Multivariable linear regression was used to calculate standardised beta coefficients across all covariates for the entire sample and stratified by race and region. We included 16 781 participants with complete dietary data. Among these, 34·6 % were black, 45·6 % male, 55·2 % resided in stroke belt region and the average age was 65 years. Black race was the factor with the largest magnitude of association with the Southern dietary pattern (Δ = 0·76 sd, P < 0·0001). Large differences in Southern dietary pattern adherence were observed between black participants and white participants in the stroke belt and non-belt (stroke belt Δ = 0·75 sd, non-belt Δ = 0·77 sd). There was a high consumption of the Southern dietary pattern in the US black population, regardless of other factors, underlying our previous findings showing the substantial contribution of this dietary pattern to racial disparities in incident hypertension and stroke.
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http://dx.doi.org/10.1017/S0007114521000696DOI Listing
February 2021

Contrasting Associations of Prudent and Western Dietary Patterns with Risk of Developing Venous Thromboembolism.

Am J Med 2021 Jun 17;134(6):763-768.e3. Epub 2021 Feb 17.

University of Minnesota School of Public Health; Minneapolis.

Background: Published studies are inconsistent about whether differences in diet are associated with risk of venous thromboembolism. We studied the association between dietary patterns and incident venous thromboembolism in a large US cohort.

Methods: The Atherosclerosis Risk in Communities study followed 14,818 middle-aged males and females for incident venous thromboembolism over an average of 22 years between 1987 and 2015. Trained interviewers assessed dietary intake at visits 1 and 3, using a food frequency questionnaire. We derived 2 dietary pattern scores using principal component analysis and ascertained and verified hospitalized venous thromboembolism. In separate proportional hazards regression analyses, we examined associations of quintiles of the prudent and the Western dietary pattern scores with risk of developing non-cancer-related and total venous thromboembolism, adjusting for demographic characteristics, lifestyle factors, body mass index, and diabetes.

Results: With 860 total incident venous thromboembolism events, the hazard ratios (95% confidence intervals) of incident non-cancer-related venous thromboembolism (n = 631) across quintiles of the prudent dietary pattern score were 1 (reference), 1.04 (0.81-1.32), 0.84 (0.65-1.08), 0.70 (0.53-0.91), and 0.88 (0.67-1.15), P = .04. Across quintiles of the Western dietary pattern score, hazard ratios of non-cancer-related venous thromboembolism were 1 (reference), 1.13 (0.87-1.45), 1.20 (0.92-1.56), 1.03 (0.77-1.39), and 1.58 (1.13-2.21), P = .04. Associations were similar for total venous thromboembolism.

Conclusions: In this community-based cohort, a prudent dietary pattern was associated with a lower risk of future venous thromboembolism, whereas a Western dietary pattern was associated with a higher risk.
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http://dx.doi.org/10.1016/j.amjmed.2021.01.016DOI Listing
June 2021

Response: Patient and caregiver engagement in venous thromboembolism research.

Res Pract Thromb Haemost 2021 Jan 8;5(1):247. Epub 2020 Dec 8.

Department of Medicine Department of Pathology & Laboratory Medicine Larner College of Medicine at the University of Vermont Burlington VT USA.

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http://dx.doi.org/10.1002/rth2.12452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845054PMC
January 2021

Goodbye 2020, hello to our future.

Authors:
Mary Cushman

Res Pract Thromb Haemost 2021 Jan 28;5(1):6-8. Epub 2021 Jan 28.

Department of Medicine Larner College of Medicine at the University of Vermont Burlington VT USA.

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http://dx.doi.org/10.1002/rth2.12477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845055PMC
January 2021

Cancer and Embolic Stroke of Undetermined Source.

Stroke 2021 Mar 28;52(3):1121-1130. Epub 2021 Jan 28.

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY (B.B.N., L.M.D.).

One-quarter to one-third of ischemic strokes have no established mechanism after standard diagnostic evaluation and are classified as embolic stroke of undetermined source (ESUS). Failure of randomized trials to demonstrate a benefit of direct oral anticoagulants over aspirin for the treatment of ESUS as a single homogeneous entity has led to renewed interest by stroke experts to divide ESUS into subgroups. Emerging data suggest that active cancer, which is present in 5% to 10% of patients with ESUS, is a distinct and important subgroup of ESUS with unique clinical characteristics, underlying pathophysiologies, and treatment and prognostic considerations. Furthermore, the prevalence of cancer-related ESUS is expected to increase as patients with cancer, even those with distant metastases, survive longer due to improvements in cancer treatments. In this topical review, we examine the epidemiological link between ESUS and cancer, the clinical features and potential mechanistic underpinnings of ESUS with cancer (with a focus on novel biomarkers and their relationship to recurrent stroke and other thromboembolic events), and the potential treatment strategies for cancer-related ESUS. We include a critical appraisal of existing data and ongoing or planned clinical trials of different antithrombotic approaches. As cancer-related ESUS is a dynamic disease with variable course, we recommend close collaboration between neurologists and oncologists to develop individualized management plans.
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http://dx.doi.org/10.1161/STROKEAHA.120.032002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902455PMC
March 2021

Change in Life's Simple 7 Measure of Cardiovascular Health After Incident Stroke: The REGARDS Study.

Stroke 2021 Mar 20;52(3):878-886. Epub 2021 Jan 20.

University of Vermont Medical Center, Burlington, VT (M.C.).

Background And Purpose: Life's Simple 7 (LS7) is a metric for cardiovascular health based on the 7 domains of smoking, diet, physical activity, body mass index, blood pressure, total cholesterol, and fasting glucose. Because they may be targeted for secondary prevention purposes, we hypothesized that stroke survivors would experience improvement in LS7 score over time compared with people who did not experience a stroke. We addressed this hypothesis in the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) cohort of Black and White adults enrolled between 2003 and 2007.

Methods: Participants who had LS7 data at baseline, were stroke-free at baseline, had a 10-year follow-up visit, and either did not have a stroke or had an ischemic stroke >1 year before follow-up were included (N=7569). Among these participants, 149 (2.0%) had an adjudicated ischemic stroke between the LS7 assessments. LS7 scores were classified as 0 to 2 points for each domain for a maximum score of 14, with higher scores representing better health. Multivariable linear regression was used to test the association of ischemic stroke with change in LS7 score. Covariates included baseline LS7 score, age, race, sex, education, and geographic region.

Results: The 149 stroke survivors had an average of 4.9 years (SD=2.5) of follow-up from the stroke event to the second LS7 assessment. After adjusting for covariates, participants who experienced an ischemic stroke showed 0.28 points more decline in total LS7 score (=0.03) than those who did not experience a stroke.

Conclusions: Stroke survivors did not experience improvements in cardiovascular health due to secondary prevention after ischemic stroke. On the contrary, they experienced significantly greater decline, indicating the need for greater efforts in secondary prevention after a stroke.
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http://dx.doi.org/10.1161/STROKEAHA.120.030836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902464PMC
March 2021

Lipoprotein (a) and coronary artery calcification: prospective study assessing interactions with other risk factors.

Metabolism 2021 03 7;116:154706. Epub 2021 Jan 7.

Lipid Research Group, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia. Electronic address:

Background: Elevated plasma lipoprotein (a) [Lp(a)] and coronary artery calcification (CAC) are established cardiovascular risk factors that correlate with each other. We hypothesized that other cardiovascular risk factors could affect their relationship.

Methods: We tested for interactions of 24 study variables related to dyslipidemia, diabetes, insulin resistance, hypertension, inflammation and coagulation with baseline Lp(a) on change in CAC volume and density over 9.5 years in 5975 Multi-Ethnic Study of Atherosclerosis (MESA) participants, free of apparent cardiovascular disease at baseline.

Results: Elevated Lp(a) was associated with larger absolute increase in CAC volume (3.21 and 4.45 mm/year higher for Lp(a) ≥30 versus <30 mg/dL, and Lp(a) ≥50 versus <50 mg/dL, respectively), but not relative change in CAC volume. No association was found with change in CAC density when assessing continuous ln-transformed Lp(a). The association between elevated Lp(a) (≥30 mg/dL) and absolute change in CAC volume was greater in participants with higher circulating levels of interleukin-2 soluble receptor α, soluble tumor necrosis factor alpha receptor 1 and fibrinogen (15.33, 11.81 and 7.02 mm/year in quartile 4, compared to -3.44, -0.59 and 1.91 mm/year in quartile 1, respectively). No significant interaction was found for other study variables. Similar interactions were seen when assessing Lp(a) levels ≥50 mg/dL.

Conclusions: Elevated Lp(a) was associated with an absolute increase in CAC volume, especially in participants with higher levels of selected markers of inflammation and coagulation. These results suggest Lp(a) as a potential biomarker for CAC volume progression.
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http://dx.doi.org/10.1016/j.metabol.2021.154706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853621PMC
March 2021

Association of Sickle Cell Trait With Incidence of Coronary Heart Disease Among African American Individuals.

JAMA Netw Open 2021 01 4;4(1):e2030435. Epub 2021 Jan 4.

Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson.

Importance: The incidence of and mortality from coronary heart disease (CHD) are substantially higher among African American individuals compared with non-Hispanic White individuals, even after adjusting for traditional factors associated with CHD. The unexplained excess risk might be due to genetic factors related to African ancestry that are associated with a higher risk of CHD, such as the heterozygous state for the sickle cell variant or sickle cell trait (SCT).

Objective: To evaluate whether there is an association between SCT and the incidence of myocardial infarction (MI) or composite CHD outcomes in African American individuals.

Design, Setting, And Participants: This cohort study included 5 large, prospective, population-based cohorts of African American individuals in the Women's Health Initiative (WHI) study, the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, the Multi-Ethnic Study of Atherosclerosis (MESA), the Jackson Heart Study (JHS), and the Atherosclerosis Risk in Communities (ARIC) study. The follow-up periods included in this study were 1993 and 1998 to 2014 for the WHI study, 2003 to 2014 for the REGARDS study, 2002 to 2016 for the MESA, 2002 to 2015 for the JHS, and 1987 to 2016 for the ARIC study. Data analysis began in October 2013 and was completed in October 2020.

Exposures: Sickle cell trait status was evaluated by either direct genotyping or high-quality imputation of rs334 (the sickle cell variant). Participants with sickle cell disease and those with a history of CHD were excluded from the analyses.

Main Outcomes And Measures: Incident MI, defined as adjudicated nonfatal or fatal MI, and incident CHD, defined as adjudicated nonfatal MI, fatal MI, coronary revascularization procedures, or death due to CHD. Cox proportional hazards regression models were used to estimate the hazard ratio for incident MI or CHD comparing SCT carriers with noncarriers. Models were adjusted for age, sex (except for the WHI study), study site or region of residence, hypertension status or systolic blood pressure, type 1 or 2 diabetes, serum high-density lipoprotein level, total cholesterol level, and global ancestry (estimated from principal components analysis).

Results: A total of 23 197 African American men (29.8%) and women (70.2%) were included in the combined sample, of whom 1781 had SCT (7.7% prevalence). Mean (SD) ages at baseline were 61.2 (6.9) years in the WHI study (n = 5904), 64.0 (9.3) years in the REGARDS study (n = 10 714), 62.0 (10.0) years in the MESA (n = 1556), 50.3 (12.0) years in the JHS (n = 2175), and 53.2 (5.8) years in the ARIC study (n = 2848). There were no significant differences in the distribution of traditional factors associated with cardiovascular disease by SCT status within cohorts. A combined total of 1034 participants (76 with SCT) had incident MI, and 1714 (137 with SCT) had the composite CHD outcome. The meta-analyzed crude incidence rate of MI did not differ by SCT status and was 3.8 per 1000 person-years (95% CI, 3.3-4.5 per 1000 person-years) among those with SCT and 3.6 per 1000 person-years (95% CI, 2.7-5.1 per 1000 person-years) among those without SCT. For the composite CHD outcome, these rates were 7.3 per 1000 person-years (95% CI, 5.5-9.7 per 1000 person-years) among those with SCT and 6.0 per 1000 person-years (95% CI, 4.9-7.4 per 1000 person-years) among those without SCT. Meta-analysis of the 5 study results showed that SCT status was not significantly associated with MI (hazard ratio, 1.03; 95% CI, 0.81-1.32) or the composite CHD outcome (hazard ratio, 1.16; 95% CI, 0.92-1.47).

Conclusions And Relevance: In this cohort study, there was not an association between SCT and increased risk of MI or CHD in African American individuals. These disorders may not be associated with sickle cell trait-related sudden death in this population.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.30435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786247PMC
January 2021

C-reactive protein and risk of cognitive decline: The REGARDS study.

PLoS One 2020 31;15(12):e0244612. Epub 2020 Dec 31.

Departments of Medicine and Pathology & Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, Vermont, United States of America.

Markers of systemic inflammation are associated with increased risk of cognitive impairment, but it is unclear if they are associated with a faster rate of cognitive decline and whether this relationship differs by race. Our objective was to examine the association of baseline C-reaction protein (CRP) with cognitive decline among a large racially diverse cohort of older adults. Participants included 21,782 adults aged 45 and older (36% were Black, Mean age at baseline 64) from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. CRP was measured at baseline and used as a continuous variable or a dichotomous grouping based on race-specific 90th percentile cutoffs. Cognitive measures of memory and verbal fluency were administered every 2 years for up to 12 years. Latent growth curve models evaluated the association of CRP on cognitive trajectories, adjusting for relevant demographic and health factors. We found that higher CRP was associated with worse memory (B = -.039, 95% CI [-.065,-.014]) and verbal fluency at baseline (B = -.195, 95% CI [-.219,-.170]), but not with rate of cognitive decline. After covariate adjustment, the association of CRP on memory was attenuated (B = -.005, 95% CI [-.031,-.021]). The association with verbal fluency at baseline, but not over time, remained (B = -.042, 95% CI [-.067,-.017]). Race did not modify the association between CRP and cognition. Findings suggest that levels of CRP at age 45+, are a marker of cognitive impairment but may not be suitable for risk prediction for cognitive decline.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244612PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774911PMC
March 2021

N-Terminal Pro-B-Type Natriuretic Peptide and Longitudinal Risk of Hypertension.

Am J Hypertens 2021 May;34(5):476-483

Department of Medicine, University of Vermont Larner College of Medicine, Burlington, Vermont, USA.

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.
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http://dx.doi.org/10.1093/ajh/hpaa224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140656PMC
May 2021

C-reactive protein and hypertension incidence in black and white Americans: REasons for Geographic And Racial Differences in Stroke (REGARDS) study.

Am J Hypertens 2020 Dec 16. Epub 2020 Dec 16.

Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT.

Background: More inflammation is associated with greater risk incident hypertension, and black US adults have excess burden of hypertension. We investigated whether increased inflammation as quantified by higher C-reactive protein (CRP) explains the excess incidence in hypertension experienced by black US adults.

Methods: We included 6,548 black and white REGARDS participants without hypertension at baseline (2003-2007) who attended a second visit (2013-2016). Sex-stratified risk ratios (RR) for incident hypertension at the second exam in black compared to white individuals were estimated using Poisson regression adjusted for groups of factors known to partially explain the black-white differences in incident hypertension. We calculated the percent mediation by CRP of the racial difference in hypertension.

Results: Baseline CRP was higher in black participants. The black-white RR for incident hypertension in the minimally adjusted model was 1.33 (95% CI 1.22, 1.44) for males and 1.15 (1.04, 1.27) for females. CRP mediated 6.6% (95% CI 2.7, 11.3%) of this association in females and 19.7% (9.8, 33.2%) in males. In females, CRP no longer mediated the black-white RR in a model including waist circumference and body mass index, while in males the black-white difference was fully attenuated in models including income, education and dietary patterns.

Conclusions: Elevated CRP attenuated a portion of the unadjusted excess risk of hypertension in black adults, but this excess risk was attenuated when controlling for measures of obesity in females and diet and socioeconomic factors in males. Inflammation related to these risk factors might explain part of the black-white disparity in hypertension.
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http://dx.doi.org/10.1093/ajh/hpaa215DOI Listing
December 2020

Life's Simple 7 and Nonalcoholic Fatty Liver Disease: The Multiethnic Study of Atherosclerosis.

Am J Med 2021 04 5;134(4):519-525. Epub 2020 Dec 5.

Preventive Cardiology, Houston Methodist DeBakey Cardiology Associates, Houston Tex.

Background: The American Heart Association (AHA) has defined Life's Simple 7 (LS7) as a measure of overall cardiovascular health . Nonalcoholic fatty liver disease (NAFLD) has been involved as a risk factor for cardiovascular disease. We evaluated the association between LS7 and NAFLD.

Methods: We evaluated participants form the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Cardiovascular health score was calculated from the Life's Simple 7 metrics. A score of 0-8 was considered inadequate, 9-10 average, and 11-14 optimal. NAFLD was defined using noncontrast cardiac computed tomography (CT) and a liver/spleen attenuation ratio (L/S) < 1. Multivariable regression were performed to evaluate the association.

Results: Our cross-sectional analysis of 3901 participants showed 19% (n = 747) had optimal cardiovascular health, 33% (n = 1270) had average, and 48% (n = 1884) had inadequate. White participants were most likely to have an optimal score (51%, n = 378), whereas African American participants had the lowest proportion with optimal scores (16%, n = 120; P < 0.001). The overall prevalence of NAFLD was 18% with a distribution of 7%, 14%, and 25% in the optimal, average, and inadequate score categories, respectively (P < 0.001). Adjusted for risk factors, average and optimal health categories had lower odds of NAFLD compared to those with inadequate scores: odds ratio for average, 0.44 (95% confidence interval 0.36-0.54); optimal, odds ratio 0.19 (95% confidence interval 0.14-0.26). This association was similar across gender, race and age groups.

Conclusion: A more favorable cardiovascular health score was associated with a lower prevalence of NAFLD. This study may suggest a potential of Life's Simple 7 in the prevention of liver disease.
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http://dx.doi.org/10.1016/j.amjmed.2020.09.023DOI Listing
April 2021

Sex Differences in Factors Contributing to the Racial Disparity in Diabetes Risk.

Am J Prev Med 2021 04 2;60(4):e169-e177. Epub 2020 Dec 2.

Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, Vermont.

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.
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http://dx.doi.org/10.1016/j.amepre.2020.09.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987785PMC
April 2021

Coagulation factor VIII, white matter hyperintensities and cognitive function: Results from the Cardiovascular Health Study.

PLoS One 2020 16;15(11):e0242062. Epub 2020 Nov 16.

Charité -Universitätsmedizin Berlin, Center for Stroke Research Berlin, Berlin, Germany.

Objective: To investigate the relationship between high FVIII clotting activity (FVIII:C), MRI-defined white matter hyperintensities (WMH) and cognitive function over time.

Methods: Data from the population-based Cardiovascular Health Study (n = 5,888, aged ≥65) were used. FVIII:C was measured in blood samples taken at baseline. WMH burden was assessed on two cranial MRI scans taken roughly 5 years apart. Cognitive function was assessed annually using the Modified Mini-Mental State Examination (3MSE) and Digit Symbol Substitution Test (DSST). We used ordinal logistic regression models adjusted for demographic and cardiovascular factors in cross-sectional and longitudinal WMH analyses, and adjusted linear regression and linear mixed models in the analyses of cognitive function.

Results: After adjustment for confounding, higher levels of FVIII:C were not strongly associated with the burden of WMH on the initial MRI scan (OR>p75 = 1.20, 95% CI 0.99-1.45; N = 2,735) nor with WMH burden worsening over time (OR>p75 = 1.18, 95% CI 0.87-1.59; N = 1,527). High FVIII:C showed no strong association with cognitive scores cross-sectionally (3MSE>p75 β = -0.06, 95%CI -0.45 to 0.32, N = 4,005; DSST>p75 β = -0.69, 95%CI -1.52 to 0.13, N = 3,954) or over time (3MSE>p75 β = -0.07,95% CI -0.58 to 0.44, N = 2,764; DSST>p75 β = -0.22, 95% CI -0.97 to 0.53, N = 2,306) after confounding adjustment.

Interpretation: The results from this cohort study of older adult participants indicate no strong relationships between higher FVIII:C levels and WMH burden or cognitive function in cross-sectional and longitudinal analyses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242062PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668572PMC
January 2021

Exploring Opportunities for Primary Prevention of Unprovoked Venous Thromboembolism: Ready for Prime Time?

J Am Heart Assoc 2020 12 16;9(23):e019395. Epub 2020 Nov 16.

Departments of Medicine and Pathology & Laboratory Medicine Larner College of Medicine at the University of Vermont Burlington VT.

Venous thromboembolism (VTE) is an important vascular disease and public health problem. Prevention of VTE has focused mainly on using thromboprophylaxis to avoid provoked VTE or recurrent VTE, with little attention paid to the possibility of preventing the one third to one half of VTEs that are unprovoked. We review growing research suggesting that unhealthy lifestyle risk factors may cause a considerable proportion of unprovoked VTE. Using epidemiologic data to calculate population attributable risks, we estimate that in the United States obesity may contribute to 30% of VTEs, physical inactivity to 4%, current smoking to 3%, and Western dietary pattern to 11%. We also review possibilities for VTE primary prevention either through a high-risk individual approach or a population-wide approach. Interventions for outpatients at high VTE risk but without VTE provoking factors have not been fully tested; yet, improving patient awareness of risk and symptoms, lifestyle counseling, and possibly statins or direct oral anticoagulants may prove useful in primary prevention of unprovoked VTE. A population approach to prevention would bolster awareness of VTE and aim to shift lifestyle risk factors downward in the whole population using education, environmental changes, and policy. Assuming the epidemiological associations are accurate, causal, and independent of each other, a reduction of obesity, physical inactivity, current smoking, and Western diet by 25% in the general population might reduce the incidence of unprovoked VTE by 12%. We urge further research and consideration that primary prevention of unprovoked VTE may be a worthwhile public health aim.
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http://dx.doi.org/10.1161/JAHA.120.019395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763794PMC
December 2020

Diversity, equity, and inclusion in publishing: Calling thrombosis and hemostasis journals to action in support of women.

Res Pract Thromb Haemost 2020 Oct 16;4(7):1076-1079. Epub 2020 Oct 16.

Larner College of Medicine at the University of Vermont Burlington VT USA.

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http://dx.doi.org/10.1002/rth2.12434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590272PMC
October 2020