Strategies for Improving Enrollment of Diverse Populations with a Focus on Lipid-Lowering Clinical Trials.

PURPOSE OF REVIEW: We review under-representation of key demographic groups in cardiovascular clinical trials, focusing on lipid-lowering trials. We outline multilevel strategies to recruit and retain diverse populations in cardiovascular trials. RECENT FINDINGS: Barriers to participation in trials occur at the study, participant, health system, sponsor, and policy level, requiring a multilevel approach to effectively increase participation of under-represented groups in research. Increasing the representation of marginalized and under-represented groups in leadership positions in clinical trials can ensure that their perspectives and experiences are considered. Trial design should prioritize patient- and community-indicated needs. Women and individuals from racially/ethnically diverse populations remain under-represented in lipid-lowering and other cardiovascular clinical trials relative to their disease burden in the population. This limits the generalizability of trial results to the broader population in clinical practice. Collaboration between community stakeholders, researchers, and community members can facilitate shared learning about trials and build trust.

The Effects of Four Doses of Vitamin D Supplements on Falls in Older Adults : A Response-Adaptive, Randomized Clinical Trial.

BACKGROUND: Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences. OBJECTIVE: To compare the effects of 4 doses of vitamin D3 supplements on falls. DESIGN: 2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333). SETTING: 2 community-based research units. PARTICIPANTS: 688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D [25-(OH)D] level of 25 to 72.5 nmol/L. INTERVENTION: 200 (control), 1000, 2000, or 4000 IU of vitamin D3 per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D3 doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose. MEASUREMENTS: Time to first fall or death over 2 years (primary outcome). RESULTS: During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d; n = 308) and those randomly assigned to receive 200 IU/d (n = 339) (hazard ratio [HR], 0.94 [95% CI, 0.76 to 1.15]; P = 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 [CI, 1.03 to 3.41]; fall with hospitalization: HR, 2.48 [CI, 1.13 to 5.46]). LIMITATIONS: The control group received 200 IU of vitamin D3 per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached. CONCLUSION: In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D3 supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D3 doses of 1000 IU/d or higher. PRIMARY FUNDING SOURCE: National Institute on Aging.

Influence of Opioid Prescription Policy on Overdoses and Related Adverse Effects in a Primary Care Population.

BACKGROUND: In response to the opioid epidemic, many states have enacted policies limiting opioid prescriptions. There is a paucity of evidence of the impact of opioid prescribing interventions in primary care populations, including whether unintended consequences arise from limiting the availability of prescribed opioids. OBJECTIVE: Our aim was to compare changes in opioid overdose and related adverse effects rate among primary care patients following the implementation of state-level prescribing policies. DESIGN: A cohort of primary care patients within an interrupted time series model. PARTICIPANTS: Electronic medical record data for 62,776 adult (18+ years) primary care patients from a major medical center in Vermont from January 1, 2016, to June 30, 2018. INTERVENTIONS: State-level opioid prescription policy changes limiting dose and duration. MAIN MEASURES: Changes in (1) opioid overdose rate and (2) opioid-related adverse effects rate per 100,000 person-months following the July 1, 2017, prescription policy change. KEY RESULTS: Among primary care patients, there was no change in opioid overdose rate following implementation of the prescribing policy (incidence rate ratio; IRR: 0.64, 95% confidence interval; CI: 0.22-1.88). There was a 78% decrease in the opioid-related adverse effects rate following the prescribing policy (IRR: 0.22, 95%CI: 0.09-0.51). This association was moderated by opioid prescription history, with decreases observed among opioid-naïve patients (IRR: 0.18, 95%CI: 0.06-0.59) and among patients receiving chronic opioid prescriptions (IRR: 0.17, 95%CI: 0.03-0.99), but not among those with intermittent opioid prescriptions (IRR: 0.51, 95%CI: 0.09-2.82). CONCLUSIONS: Limiting prescription opioids did not change the opioid overdose rate among primary care patients, but it reduced the rate of opioid-related adverse effects in the year following the state-level policy change, particularly among patients with chronic opioid prescription history and opioid-naïve patients. Limiting the quantity and duration of opioid prescriptions may have beneficial effects among primary care patients.

Use of electronic recruitment methods in a clinical trial of adults with gout.

BACKGROUND/AIMS: Electronic-based recruitment methods are increasingly utilized in clinical trials to recruit and enroll research participants. The cost-effectiveness of electronic-based methods and impact on sample generalizability is unknown. We compared recruitment yields, cost-effectiveness, and demographic characteristics across several electronic and traditional recruitment methods. METHODS: We analyzed data from the diet gout trial recruitment campaign. The diet gout trial was a randomized, controlled, cross-over trial that examined the effects of a dietary approaches to stop hypertension (DASH)-like diet on uric acid levels in adults with gout. We used four electronic medical record and four non-electronic medical record-based recruitment methods to identify and recruit potentially eligible participants. We calculated the response rate, screening visit completion rate, and randomization rate for each method. We also determined cost per response, the screening, and randomization for each method. Finally, we compared the demographic characteristics among individuals who completed the screening visit by recruitment method. RESULTS: Of the 294 adults who responded to the recruitment campaign, 51% were identified from electronic medical record-based methods. Patient portal messaging, an electronic medical record-based method, resulted in the highest response rate (4%), screening visit completion rate (37%), and randomization rate (21%) among these eight methods. Electronic medical record-based methods ($60) were more cost-effective per response than non-electronic medical record-based methods ($107). Electronic-based methods, including patient portal messaging and Facebook, had the highest proportion of White individuals screened (52% and 60%). Direct mail to non-active patient portal increased enrollment of traditionally under-represented groups, including both women and African Americans. CONCLUSION: An electronic medical record-based recruitment strategy that utilized the electronic medical record for participant identification and postal mailing for participant outreach was cost-effective and increased participation of under-represented groups. This hybrid strategy represents a promising approach to improve the timely execution and broad generalizability of future clinical trials.

Health care experiences during the COVID-19 pandemic by race and social determinants of health among adults age ≥ 58 years in the REGARDS study.

BACKGROUND: Understanding health care experiences during the COVID-19 pandemic may provide insights into patient needs and inform policy. The objective of this study was to describe health care experiences by race and social determinants of health. METHODS: We conducted a telephone survey (July 6, 2020-September 4, 2021) among 9492 Black and White participants in the longitudinal REasons for Geographic And Racial Differences in Stroke cohort study, age 58-105 years, from the continental United States. Among participants with symptoms of COVID-19, outcomes were: 1. Sought care or advice for the illness; 2. Received a SARS-CoV-2 test for the illness; and 3. Tested positive. Among participants without symptoms of COVID-19, outcomes were: 1. Wanted a test; 2. Wanted and received a test; 3. Did not want but received a test; and 4. Tested positive. We examined these outcomes overall and in subgroups defined by race, household income, marital status, education, area-level poverty, rural residence, Medicaid expansion, public health infrastructure ranking, and residential segregation. RESULTS: The average age of participants was 76.8 years, 36% were Black, and 57% were female. Among participants with COVID-19 symptoms (n = 697), 74% sought care or advice for the illness, 50% received a SARS-CoV-2 test, and 25% had a positive test (50% of those tested). Among participants without potential COVID-19 symptoms (n = 8795), 29% wanted a SARS-CoV-2 test, 22% wanted and received a test, 8% did not want but received a test, and 1% tested positive; a greater percentage of participants who were Black compared to White wanted (38% vs 23%, p < 0.001) and received tests (30% vs 18%, p < 0.001) and tested positive (1.4% vs 0.8%, p = 0.005). CONCLUSIONS: In this national study of older US adults, many participants with potential COVID-19 symptoms and asymptomatic participants who desired testing did not receive COVID-19 testing.

Health Information Technology Use Among Persons With Self-reported Atherosclerotic Cardiovascular Disease: Analysis of the 2011-2018 National Health Interview Survey.

BACKGROUND: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality in the United States. Health information technologies (HITs) have recently emerged as a viable intervention to mitigate the burden of ASCVD. Approximately 60% of US adults report searching the internet for health information; however, previous research has not examined the prevalence of general technology or HIT use among adults with and without ASCVD. In addition, social determinants in HIT use among adults with ASCVD are not well understood. OBJECTIVE: The aim of this study was to evaluate the prevalence and social determinants of HIT use among US adults with versus without self-reported ASCVD. METHODS: We pooled cross-sectional data from the 2011-2018 National Health Interview Survey (NHIS) to examine the general technology and HIT use among adults aged ≥18 years with and without self-reported ASCVD (coronary heart disease, stroke, or both). General technology use was defined as mobile phone ownership, internet use, and computer use. HIT use was defined as looking up health information on the internet, filling a web-based prescription, scheduling a medical appointment on the internet, communicating with a health care provider by email, or using web-based group chats to learn about health topics. We evaluated sociodemographic differences in HIT use among respondents by using Poisson regression. Analyses were weighted according to NHIS standards. RESULTS: A total sample of 256,117 individuals were included, of which 2194 (0.9%) reported prior ASCVD. Among adults with prior ASCVD, the mean age was 70.6 (SD 11.5) years, and 47.4% (1048/2194) of the adults were females. General technology use differed between participants with and without prior ASCVD, with 36.0% (614/1826) and 76.2% (157,642/213,816) indicating internet usage and 24.6% (374/1575) and 60.7% (107,742/184,557) indicating using a computer every day, respectively. Similarly, adults with ASCVD were less likely to use HIT than those without ASCVD (515/2194, 25.1% vs 123,966/253,923, 51.0%; P<.001). Among adults with prior ASCVD, social determinants that were associated with HIT use included younger age, higher education, higher income, being employed, and being married. CONCLUSIONS: HIT use was low among adults with a history of ASCVD, which may represent a barrier to delivering care via emerging HIT. Given the associations with social determinants such as income, education, and employment, targeted strategies and policies are needed to eliminate barriers to impact HIT usage.

Recruitment of trial participants through electronic medical record patient portal messaging: A pilot study.

BACKGROUND/AIM: Cost-efficient methods are essential for successful participant recruitment in clinical trials. Patient portal messages are an emerging means of recruiting potentially eligible patients into trials. We assessed the response rate and complaint rate from direct-to-patient, targeted recruitment through patient portals of an electronic medical record for a clinical trial, and compared response rates by differences in message content. METHODS: The Study to Understand Fall Reduction and Vitamin D in You (STURDY) trial is a National Institutes of Health-sponsored, community-based study of vitamin D supplementation for fall prevention in older adults conducted at Johns Hopkins. Potential participants were identified using the Epic electronic medical record at the Johns Hopkins Health System based on age (≥70 years), ZIP code (30-mile radius of study site), and prior activation of a patient portal account. We prepared a shorter message and a longer message. Both had basic information about study participation, but the longer message also contained information about the significance of the study and a personal invitation from the STURDY principal investigator. The Hopkins Institutional Review Board did not require prior consent from the patient or their providers. We calculated the response rate and tracked the number of complaints and requests for removal from future messages. We also determined response rate according to message content. RESULTS: Of the 5.5 million individuals receiving care at the Johns Hopkins Health System, a sample of 6896 met our inclusion criteria and were sent one patient portal recruitment message between 6 April 2017 and 3 August 2017. Assessment of enrollment by this method ended on 1 December 2017. There were 116 patients who expressed interest in the study (response rate: 1.7%). Twelve (0.2%) recipients were randomized. There were two complaints (0.03%) and one request to unsubscribe from future recruitment messages (0.01%). Response rate was higher with the longer message than the shorter message (2.1% vs 1.2%; p = 0.005). CONCLUSION: Patient portal messages inviting seniors to participate in a randomized controlled trial resulted in a response rate similar to commercial email marketing and resulted in very few complaints or opt-out requests. Furthermore, a longer message with more content enhanced response rate. Recruitment through patient portals might be an effective strategy to enroll trial participants.

Development and External Validation of a Machine Learning Tool to Rule Out COVID-19 Among Adults in the Emergency Department Using Routine Blood Tests: A Large, Multicenter, Real-World Study.

BACKGROUND: Conventional diagnosis of COVID-19 with reverse transcription polymerase chain reaction (RT-PCR) testing (hereafter, PCR) is associated with prolonged time to diagnosis and significant costs to run the test. The SARS-CoV-2 virus might lead to characteristic patterns in the results of widely available, routine blood tests that could be identified with machine learning methodologies. Machine learning modalities integrating findings from these common laboratory test results might accelerate ruling out COVID-19 in emergency department patients. OBJECTIVE: We sought to develop (ie, train and internally validate with cross-validation techniques) and externally validate a machine learning model to rule out COVID 19 using only routine blood tests among adults in emergency departments. METHODS: Using clinical data from emergency departments (EDs) from 66 US hospitals before the pandemic (before the end of December 2019) or during the pandemic (March-July 2020), we included patients aged ≥20 years in the study time frame. We excluded those with missing laboratory results. Model training used 2183 PCR-confirmed cases from 43 hospitals during the pandemic; negative controls were 10,000 prepandemic patients from the same hospitals. External validation used 23 hospitals with 1020 PCR-confirmed cases and 171,734 prepandemic negative controls. The main outcome was COVID 19 status predicted using same-day routine laboratory results. Model performance was assessed with area under the receiver operating characteristic (AUROC) curve as well as sensitivity, specificity, and negative predictive value (NPV). RESULTS: Of 192,779 patients included in the training, external validation, and sensitivity data sets (median age decile 50 [IQR 30-60] years, 40.5% male [78,249/192,779]), AUROC for training and external validation was 0.91 (95% CI 0.90-0.92). Using a risk score cutoff of 1.0 (out of 100) in the external validation data set, the model achieved sensitivity of 95.9% and specificity of 41.7%; with a cutoff of 2.0, sensitivity was 92.6% and specificity was 59.9%. At the cutoff of 2.0, the NPVs at a prevalence of 1%, 10%, and 20% were 99.9%, 98.6%, and 97%, respectively. CONCLUSIONS: A machine learning model developed with multicenter clinical data integrating commonly collected ED laboratory data demonstrated high rule-out accuracy for COVID-19 status, and might inform selective use of PCR-based testing.

Use of online recruitment strategies in a randomized trial of cancer survivors.

BACKGROUND/AIMS: Despite widespread Internet adoption, online advertising remains an underutilized tool to recruit participants into clinical trials. Whether online advertising is a cost-effective method to enroll participants compared to other traditional forms of recruitment is not known. METHODS: Recruitment for the Survivorship Promotion In Reducing IGF-1 Trial, a community-based study of cancer survivors, was conducted from June 2015 through December 2016 via in-person community fairs, advertisements in periodicals, and direct postal mailings. In addition, "Right Column" banner ads were purchased from Facebook to direct participants to the Survivorship Promotion In Reducing IGF-1 Trial website. Response rates, costs of traditional and online advertisements, and demographic data were determined and compared across different online and traditional recruitment strategies. Micro-trials optimizing features of online advertisements were also explored. RESULTS: Of the 406 respondents to our overall outreach efforts, 6% (24 of 406) were referred from online advertising. Facebook advertisements were shown over 3 million times (impressions) to 124,476 people, which resulted in 4401 clicks on our advertisement. Of these, 24 people ultimately contacted study staff, 6 underwent prescreening, and 4 enrolled in the study. The cost of online advertising per enrollee was $794 when targeting a general population versus $1426 when accounting for strategies that specifically targeted African Americans or men. By contrast, community fairs, direct mail, or periodicals cost $917, $799, or $436 per enrollee, respectively. Utilization of micro-trials to assess online ads identified subtleties (e.g. use of an advertisement title) that substantially impacted viewer interest in our trial. CONCLUSION: Online advertisements effectively directed a relevant population to our website, which resulted in new enrollees in the Survivorship Promotion In Reducing IGF-1 Trial at a cost comparable to traditional methods. Costs were substantially greater with online recruitment when targeting under-represented populations, however. Additional research using online micro-trial tools is needed to evaluate means of more precise recruitment to improve yields in under-represented groups. Potential gains from faster recruitment speed remain to be determined.

Effects of Continuous Accelerated Pacing on Cardiac Structure and Function in Patients With Heart Failure With Preserved Ejection Fraction: Insights From the myPACE Randomized Clinical Trial.

BACKGROUND: Heart failure with preserved ejection fraction ≥50% is prevalent with few evidence-based therapies. In a trial of patients with heart failure with preserved ejection fraction with specialized pacemakers, treatment with accelerated personalized pacing averaging 75 bpm (myPACE) markedly improved quality of life, NT-proBNP (N-terminal pro-brain natriuretic peptide), physical activity, and atrial fibrillation burden compared with the standard lower rate setting of 60 bpm (usual care). METHODS AND RESULTS: In this exploratory study, provider-initiated echocardiographic studies obtained before and after the trial were assessed for changes in left ventricular (LV) structure and function among participants who continued their pacing assignment. The analytic approach aimed to detect differences in standard and advanced echocardiographic parameters within and between study arms. Of the 100 participants, 16 myPACE and 20 usual care arm had a qualifying set of echocardiograms performed a mean (SD) 3 (2.0) years apart. Despite similar baseline echocardiogram measures, sustained exposure to moderately accelerated pacing resulted in reduced septal wall thickness (in cm: myPACE 1.1 [0.2] versus usual care 1.2 [0.2], P=0.008) and lower LV mass to systolic volume ratio (in g/mL: myPACE 4.8 [1.9] versus usual care 6.8 [3.1], P=0.038) accompanied by a minor reduction in LV ejection fraction (in %: myPACE 55 [5] versus usual care 60 [5], P=0.015). These changes were paralleled by improvements in heart failure-related quality of life (myPACE Minnesota Living with Heart Failure Questionnaire improved by 16.1 [13.9] points, whereas usual care worsened by 6.9 [11.6] points, P<0.001). Markers of diastolic function and LV performance were not affected. CONCLUSIONS: Exposure to continuous accelerated pacing in heart failure with preserved ejection fraction is associated with a reduced LV wall thickness and a small amount of LV dilation with small reduction in ejection fraction.

Soluble CD14 and Incident Diabetes Risk: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Study.

Context: Soluble CD14 (sCD14) is an inflammation biomarker with higher concentrations in White than Black adults. Higher sCD14 is seen in insulin resistance and diabetes. There are limited data on the relationship between sCD14 and incident diabetes. Objective: To determine the association of sCD14 with incident diabetes risk in a large biracial US cohort and evaluate whether relationships differ by race. Design: This study included 3401 Black and White participants from the REasons for Geographic And Racial Differences in Stroke (REGARDS) study without baseline diabetes who completed baseline and follow-up in-home visits. Modified Poisson regression models estimated risk ratios (RR) of incident diabetes per 1-SD increment sCD14, with adjustment for risk factors. A sCD14-by-race interaction evaluated whether associations differed by race. Results: There were 460 cases of incident diabetes over a mean 9.5 years of follow-up. The association of sCD14 with diabetes differed by race (P for interaction < .09). Stratifying by race, adjusting for age, sex, and region, higher sCD14 was associated with incident diabetes in White (RR: 1.15; 95% CI: 1.01, 1.33) but not Black participants (RR: 0.96; 95% CI: 0.86, 1.08). In models adjusted for clinical and sociodemographic diabetes risk factors, the association was attenuated among White participants (RR: 1.10; 95% CI: 0.95, 1.28) and remained null among Black participants (RR: 0.90; 95% CI: 0.80, 1.01). Conclusion: sCD14 was associated with incident diabetes risk in White but not Black adults, but this association was explained by diabetes risk factors.

Factor VIII and Incident Hypertension in Black and White Adults: The REasons for Geographic and Racial Differences in Stroke (REGARDS) Cohort.

BACKGROUND: Nearly half of all Americans have hypertension, and Black adults experience a disproportionate burden. Hypercoagulability may relate to hypertension risk, and higher levels of factor VIII increase thrombosis risk. Black adults have higher factor VIII and more hypertension than other groups. Whether higher factor VIII associates with incident hypertension is unknown. METHODS: The Biomarkers as Mediators of Racial Disparities in Risk Factors (BioMedioR) study measured certain biomarkers in a sex-race stratified sample of 4,400 REGARDS participants who attended both visits. We included BioMedioR participants, excluding those with prevalent hypertension, missing factor VIII level, or covariates of interest. Modified Poisson regression estimated risk ratios (RR) for incident hypertension by higher log-transformed factor VIII level per SD (SD of log-transformed factor VIII, 0.33). Weighting was applied to take advantage of REGARDS sampling design. RESULTS: Among the 1,814 participants included (55% female, 24% Black race), median follow-up was 9.5 years and 35% (2,146/6,138) developed hypertension. Black participants had a higher median (IQR) factor VIII level (105.6%; 87.1 to 126.9%) than White participants (95.6%; 79.8% to 115.9%; p<0.001). . The age and sex-adjusted Black-White hypertension RR was 1.45 (95% CI 1.28, 1.63). Higher factor VIII was not associated with more hypertension (final model RR 1.01; 95% CI 0.94, 1.07). CONCLUSIONS: In a prospective study of Black and White adults without prevalent hypertension, factor VIII was not associated with greater hypertension risk.

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

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

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

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

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

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

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

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

Development and validation of a risk model for hospital-acquired venous thrombosis: the Medical Inpatients Thrombosis and Hemostasis study.

BACKGROUND: Regulatory organizations recommend assessing hospital-acquired (HA) venous thromboembolism (VTE) risk for medical inpatients. OBJECTIVES: To develop and validate a risk assessment model (RAM) for HA-VTE in medical inpatients using objective and assessable risk factors knowable at admission. METHODS: The development cohort included people admitted to medical services at the University of Vermont Medical Center (Burlington, Vermont) between 2010 and 2019, and the validation cohorts included people admitted to Hennepin County Medical Center (Minneapolis, Minnesota), University of Michigan Medical Center (Ann Arbor, Michigan), and Harris Health Systems (Houston, Texas). Individuals with VTE at admission, aged <18 years, and admitted for <1 midnight were excluded. We used a Bayesian penalized regression technique to select candidate HA-VTE risk factors for final inclusion in the RAM. RESULTS: The development cohort included 60 633 admissions and 227 HA-VTE, and the validation cohorts included 111 269 admissions and 651 HA-VTE. Seven HA-VTE risk factors with t statistics ≥1.5 were included in the RAM: history of VTE, low hemoglobin level, elevated creatinine level, active cancer, hyponatremia, increased red cell distribution width, and malnutrition. The areas under the receiver operating characteristic curve and calibration slope were 0.72 and 1.10, respectively. The areas under the receiver operating characteristic curve and calibration slope were 0.70 and 0.93 at Hennepin County Medical Center, 0.70 and 0.87 at the University of Michigan Medical Center, and 0.71 and 1.00 at Harris Health Systems, respectively. The RAM performed well stratified by age, sex, and race. CONCLUSION: We developed and validated a RAM for HA-VTE in medical inpatients. By quantifying risk, clinicians can determine the potential benefits of measures to reduce HA-VTE.

Effects of Diet on 10-Year Atherosclerotic Cardiovascular Disease Risk (from the DASH Trial).

Although modern risk estimators, such as the American College of Cardiology/American Heart Association Pooled Cohort Equation, play a central role in the decisions of patients to start pharmacologic therapy to prevent atherosclerotic cardiovascular disease (ASCVD), there is limited evidence to inform expectations for 10-year ASCVD risk reduction from established lifestyle interventions. Using data from the original DASH (Dietary Approaches to Stop Hypertension) trial, we determined the effects of adopting the DASH diet on 10-year ASCVD risk compared with adopting a control or a fruits and vegetables (F/V) diet. The DASH trial included 459 adults aged 22 to 75 years without CVD and not taking antihypertensive or diabetes mellitus medications, who were randomized to controlled feeding of a control diet, an F/V diet, or the DASH diet for 8 weeks. We determined 10-year ASCVD risk with the American College of Cardiology/American Heart Association Pooled Cohort Equation based on blood pressure and lipids measured before and after the 8-week intervention. Compared with the control diet, the DASH and F/V diets changed 10-year ASCVD risk by -10.3% (95% confidence interval [CI] -14.4 to -5.9) and -9.9% (95% CI -14.0 to -5.5) respectively; these effects were more pronounced in women and Black adults. There was no difference between the DASH and F/V diets (-0.4%, 95% CI -6.9 to 6.5). ASCVD reductions attributable to the difference in systolic blood pressure alone were -14.6% (-17.3 to -11.7) with the DASH diet and -7.9% (-10.9 to -4.8) with the F/V diet, a net relative advantage of 7.2% greater relative reduction from DASH compared with F/V. This was offset by the effects on high-density lipoprotein of the DASH diet, which increased 10-year ASCVD by 8.8% (5.5 to 12.3) compared with the more neutral effect of the F/V diet of -1.9% (-5.0 to 1.2). In conclusion, compared with a typical American diet, the DASH and F/V diets reduced 10-year ASCVD risk scores by about 10% over 8 weeks. These findings are informative for counseling patients on both choices of diet and expectations for 10-year ASCVD risk reduction.

Validating cuffless continuous blood pressure monitoring devices.

Cuff-based home blood pressure (BP) devices, which have been the standard for BP monitoring for decades, are limited by physical discomfort, convenience, and their ability to capture BP variability and patterns between intermittent readings. In recent years, cuffless BP devices, which do not require cuff inflation around a limb, have entered the market, offering the promise of continuous beat-to-beat measurement of BP. These devices take advantage of a variety of principles to determine BP, including (1) pulse arrival time, (2) pulse transit time, (3) pulse wave analysis, (4) volume clamping, and (5) applanation tonometry. Because BP is calculated indirectly, these devices require calibration with cuff-based devices at regular intervals. Unfortunately, the pace of regulation of these devices has failed to match the speed of innovation and direct availability to patient consumers. There is an urgent need to develop a consensus on standards by which cuffless BP devices can be tested for accuracy. In this narrative review, we describe the landscape of cuffless BP devices, summarize the current status of validation protocols, and provide recommendations for an ideal validation process for these devices.