Abstract Background and objectives Residence in the United States Stroke Belt has been linked to a higher stroke mortality rate, raising the question of whether this increased risk is also associated with other brain health outcomes, such as cognitive change, defined as within-person changes in cognitive performance over time. This study aimed to investigate if residing in the Stroke Belt is associated with cognitive decline compared to residing outside this region in a large cohort of women. Methods We used data from the cognitive cohort of the Women’s Health Study, a U.S.-based cohort of predominantly White women currently or formerly employed in health professions. Our analyses included 6,362 women aged ≥65 years at baseline who underwent cognitive assessments. The exposure was residency in the Stroke Belt. Cognitive change was assessed as the primary outcome using repeated measures of a global cognitive composite score. Linear mixed-effects models were applied, adjusted for age, education, and lifestyle factors, measured by Life’s Simple 7 score with random effects for each of the participating women (fully adjusted model). Secondary analyses used logistic regression to examine the association between Stroke Belt residency and the odds of belonging to the first quintile or first decile of the cognitive change distribution (secondary outcome), representing women with the greatest cognitive decline. Results Of the participating women, 1,131 (17.8%) resided within the Stroke Belt. Compared to women residing outside the Stroke Belt, women residing in the Stroke Belt did not have significantly different rates of cognitive decline. The fully adjusted difference in change in the global cognitive composite score from the first to the last assessment between women living inside and outside the Stroke Belt was β = -0.03, SE = 0.02, p = 0.233. Women residing in the Stroke Belt had higher odds of being in the first quintile (adjusted odds ratio (OR) 1.20, 95% confidence interval (CI) 1.00–1.42) and in the first decile (adjusted OR 1.43, 95% CI 1.14–1.78) of the cognitive change distribution. Discussion Residence in the U.S. Stroke Belt was not associated with overall differences in cognitive decline trajectories, although secondary analyses suggested a possible increase in more pronounced decline among women living in the region. Trial Registration Information ClinicalTrials.gov Identifier: NCT00000479; retrospectively submitted: October 27, 1999.

BACKGROUND:Multivitamin-multimineral (MVM) supplements have been associated with lower blood pressure (BP) in several small trials. We investigated the effects of a MVM on incident hypertension and BP in a secondary analysis of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). METHODS:COSMOS is a 2×2 factorial, double-blinded RCT testing effects of cocoa extract and MVM supplementation among women aged ≥65 years and men aged ≥60 years. Among 8905 COSMOS participants free from hypertension, effects of MVM supplementation on incident hypertension were investigated. Hypertension diagnosis was ascertained through self-reports. Additionally, in two substudies with BP measurements (N = 529 at clinic by research staff and 994 at home by technician), we evaluated the effects on 2-year BP changes. RESULTS:Incident hypertension was observed in N = 1034 (22.9%) in MVM arm and N = 1039 (23.6%) in placebo arm over a median of 3.4 years (IQR: 3.0, 3.9) of follow-up, with hazard ratio (HR) 0.98 [95% CI: 0.90, 1.06]. Effects differed according to baseline diet quality, with HRs of incident hypertension 0.81 [0.70, 0.95] and 1.14 [1.01, 1.28] among participants with lower and higher Alternate Mediterranean Diet score, respectively (P-interaction = .001). There was no effect of MVM on 2-year changes in systolic BP (4.4 mmHg in MVM; 4.5 mmHg in placebo), while pronounced effects were observed for baseline normal BP (P-interaction = .004). CONCLUSIONS:MVM supplementation versus placebo did not reduce hypertension incidence or lower BP overall. Exploratory analyses showed greater reduction in hypertension risk and BP changes among those with lower dietary quality and normal BP at baseline, respectively. CLINICAL TRIAL REGISTRATION:NCT02422745.

BACKGROUND:Adequate intake of carotenoids and vitamin E supports healthy aging, yet evidence is limited on whether multivitamin-multimineral (MVM) supplementation changes serum concentrations over time. OBJECTIVE:The aim of this investigation was to evaluate the effect of daily MVM supplementation among older adults on serum carotenoid and vitamin E concentrations over a 2-year period. DESIGN:The COcoa Supplement and Multivitamin Outcomes Study is a large-scale, randomized, placebo-controlled, 2 × 2 factorial trial, designed to test the effects of daily MVM and cocoa extract supplementation for chronic disease prevention. Participants completed semiannual questionnaires and provided optional biospecimen samples at baseline, 1-year, and 2-year follow-up. PARTICIPANTS AND SETTING:Between 2015 and 2020, US adults (women aged 65 years and older, men aged 60 years and older) without major cardiovascular disease or recent cancer were enrolled in the COcoa Supplement and Multivitamin Outcomes Study. This analysis included biospecimen substudy participants with blood samples provided at baseline and ≥1 follow-up timepoint (n = 400; 1 excluded due to unusable sample; final N = 399). INTERVENTION:Participants were randomized to receive daily MVM supplementation or a placebo, with or without cocoa extract. MAIN OUTCOME MEASURES:Changes in serum carotenoids and α-tocopherol concentrations were evaluated over the 2-year follow-up. STATISTICAL ANALYSES:Multivariable linear mixed models estimated changes in serum biomarker concentrations, comparing MVM with placebo, adjusting for covariates (age, sex, and cocoa extract intervention). RESULTS:Increases in serum carotenoids and α-tocopherol levels with MVM supplementation emerged at year 1 and persisted through year 2. MVM supplementation led to significantly higher serum concentrations of total carotenoids (percent change: 15.5%; 95% CI, 8.72 to 22.70), lutein (percent change: 17.17%; 95% CI, 7.53 to 27.66), beta carotene (percent change: 46.96%; 95% CI, 35.10 to 59.85), and α-tocopherol (percent change: 29.50%; 95% CI, 22.88 to 36.47) over 2 years compared with placebo. No significant differences were observed for lycopene, β-cryptoxanthin, zeaxanthin, or α-carotene. Cocoa extract supplementation did not modify the effect of MVM on serum carotenoid and vitamin E levels (P ≥ .05). CONCLUSIONS:Daily MVM supplementation increased specific serum carotenoids and α-tocopherol concentrations over 2 years. These findings suggest regular MVM use may support nutritional status in older adults; future research is needed to examine links with aging-related outcomes.

Abstract Background Impaired cognitive function has been linked to an elevated risk of stroke. However, the effect of cognitive change, conceptualized as a dynamic process, has received limited attention. We therefore aimed to estimate the effect of cognitive decline on the risk of stroke in older women. Methods Our analyses were based on data from the cognitive cohort of the Women’s Health Study composed of 6,377 US female health professionals aged 65 years and older at baseline. We included women without a history of stroke who had complete information on global cognitive performance change. Women were categorized into quintiles based on their 4-year global cognitive performance change and followed for self-reported incident stroke confirmed by a physician Endpoints Committee through December 31, 2022. We used multivariable-adjusted Cox proportional hazards regression models to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of the association between cognitive change and stroke. Secondary analyses assessed the risk for stroke subtypes, lowest 10% and 20% of the cognitive change distribution, and changes in verbal memory. Results 5,093 women with a mean age of 66 years (SD = 3.93) were analyzed. The mean follow-up time was 11.6 years per person during which 302 incident stroke cases were reported. Compared to the 5th quintile (greatest improvement), the adjusted HR for stroke was 0.76 (95%CI [0.53–1.10]) for the 4th, 0.91 (95%CI [0.64–1.29]) for the 3rd, 0.95 (95%CI [0.67–1.34]) for the 2nd, and 1.02 (95%CI [0.72–1.45]) for the 1st quintile characterized by the greatest decline. Similar patterns were observed in secondary analyses. Women in the lowest 10% of global cognitive change exhibited a non-significant increase in the risk of stroke compared to the rest of the distribution (HRadj = 1.25 (95%CI [0.86–1.82]). Conclusions Large declines in cognitive performance were not strongly associated with stroke risk in this cohort of older female health professionals. However, future studies should further explore whether cognitive trajectories may influence risk of stroke and assess the generalizability of our findings, particularly to men.

Epidemiological and experimental studies suggest cocoa flavanols and multivitamin-multimineral (MVM) supplements may confer arterial vascular benefits. However, their effects on clinical venous thromboembolic events have been infrequently examined. To evaluate whether cocoa extract (CE) or MVM supplementation reduces the risk of venous thromboembolism (VTE) among older adults. We conducted an ancillary study analysis of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS), a completed randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of CE and MVM supplementation for the prevention of cardiovascular disease and cancer among 21,442 older US adults. Our primary outcome was self-reported incident VTE, defined as the first reported deep vein thrombosis (DVT) or pulmonary embolism (PE) event after randomization; secondary outcomes were the individual components. Over a median follow-up of 3.5 years, 379 participants reported an incident VTE event (including 277 DVT and 165 PE). In intention-to-treat analyses, neither CE (HR: 0.88; 95% CI: 0.72, 1.08) nor MVM (HR: 0.89; 95% CI: 0.73, 1.09) significantly reduced VTE risk, with similar findings for DVT and PE. Exploratory latency and per-protocol analyses suggested potential patterns of benefit that merit further evaluation. In this large trial of older adults, neither CE nor MVM supplementation significantly reduced the risk of VTE or its component parts in intention-to-treat analyses. Additional research may help clarify whether these supplements influence VTE risk in other contexts or populations.

Background Persistent post-surgical pain, a chronic pain syndrome with few effective treatments, has spiked in recent years due to the increase in life expectancy and the number of surgical procedures performed. Studies have shown that non-pharmacological interventions, such as yoga, may help manage chronic pain, reducing pain severity and interference. Despite emerging evidence of the efficacy of yoga in managing chronic pain symptoms, rigorous studies evaluating its use in patients with persistent post-surgical pain have not been conducted. This study describes protocols used in Persistent Relief, an ongoing pilot randomized controlled trial comparing yoga to chronic pain health education. Results from a modified Delphi validation process used to adapt a yoga program for chronic low back pain to the unique needs of this patient population are also included. Methods/Design Fifty patients aged ≥18 with persistent post-surgical pain for at least 3 months and a mean pain severity of 4/10 on the Brief Pain Inventory are randomized to a 12-week yoga program (12, 75-minute sessions) or a chronic pain health education program (12, 15-30-minute sessions), followed by a 12-week follow-up period. Results of an iterative Delphi validation process led by an interdisciplinary expert panel indicated strong endorsement of the Yoga Program (across 7 experts and 9 questions; mean=6.7 [SD=0.64] on a 7-point Likert scale). Primary outcomes include pre-specified feasibility and acceptability metrics. Secondary outcomes include a battery of biopsychosocial measures, with the Brief Pain Inventory as the primary clinical outcome for a future fully powered trial. Discussion Results will provide preliminary data to inform modifications for a future fully powered study evaluating the efficacy of yoga integrated into the management of persistent post-surgical pain. Findings will also inform the design of future studies examining the biological mechanisms underlying the integrative use of yoga to prevent or resolve chronic pain syndromes. Clinicaltrials.gov identifier NCT06949007.

BACKGROUND:The effect of long-term daily multivitamin-mineral (MVM) supplementation on Coronavirus Disease 2019 (COVID-19) prevention and symptom severity remains unclear. OBJECTIVES:We tested the hypothesis that a daily MVM reduced COVID-19 incidence or symptom severity among generally healthy older adults. METHODS:We conducted a secondary analysis in the COcoa Supplement and Multivitamin Outcomes Study, a randomized, double-blinded, placebo-controlled trial (June 2015 to December 2020), evaluating daily MVM and cocoa extract supplementation for the prevention of cardiovascular disease and cancer among 21,442 United States adults. The primary outcome was incident COVID-19 between 1 January, 2020 and 31 December, 2020, defined as the first occurrence of a self-reported positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, a physician's diagnosis, hospitalization, or death due to COVID-19. The prespecified secondary outcomes were symptomatic COVID-19 and symptom count among nonfatal cases through 31 August, 2020, when detailed symptoms were collected. We conducted intention-to-treat (primary) and per-protocol (secondary) analyses among consistently adherent participants. RESULTS:The final year of the COcoa Supplement and Multivitamin Outcomes Study intervention phase from January 2020 to December 2020 coincided with the start of the COVID-19 pandemic. Of the 18,205 participants who remained in the trial and were adherent to study pills as of 1 January, 2020, 382 were randomly assigned to MVM and 404 to MVM placebo (no MVM) and reported a COVID-19 infection through 31 December, 2020. In intention-to-treat analysis, the hazard ratio for MVM compared with placebo was 0.93 for COVID-19 incidence [95% confidence interval (CI): 0.81, 1.07]. Among the 338 cases with detailed symptom data, the odds ratio for symptomatic COVID-19 comparing MVM with placebo was 0.70 (95% CI: 0.44, 1.11). In per-protocol analyses, among participants compliant with study pills during 2020, the odds ratio for symptomatic COVID-19 was 0.60 (95% CI: 0.37, 0.99). CONCLUSIONS:A daily MVM supplement, compared with placebo, does not significantly reduce COVID-19 incidence among older adults but shows a promising signal lowering the odds of symptomatic COVID-19 illness. The Cocoa Supplement and Multivitamin Outcomes Study was registered at clinicaltrials.gov as NCT02422745.

Rigorous integration of external controls in large-scale cardiovascular prevention randomized controlled trials (RCTs) is under-explored. The Cocoa Supplement and Multivitamin Outcomes Study (COSMOS), a primary prevention RCT of cocoa extract supplementation, initially showed a statistically non-significant effect on total cardiovascular disease (CVD). We aimed to obtain more robust estimates of cocoa extract effects by integrating external control data from The VITamin D and OmegA-3 TriaL (VITAL), a similarly designed large-scale RCT. We analyzed 21,442 COSMOS participants (median 3.6-year follow-up) and used the VITAL omega-3 placebo arm as an external control. Outcomes included the original COSMOS primary CVD endpoint (a composite of myocardial infarction [MI], stroke, cardiovascular death, and coronary revascularization) and major adverse cardiovascular events (MACE; MI, stroke, and cardiovascular death). Two statistical approaches were used: a propensity score-based inverse probability weighting (IPW)-weighted Cox proportional hazard model and a doubly robust method to estimate 4-year risk ratios (RRs) and 95% confidence intervals (CIs) via bootstrapping. IPW-weighted VITAL-placebo data showed similar covariate distributions and 4-year event rates to COSMOS-placebo. While COSMOS data alone showed non-significant RRs (CVD: 0.91 [95% CI 0.79, 1.04]; MACE: 0.84 [0.70, 1.00]), incorporating VITAL-placebo showed protective effects of cocoa extract for cardiovascular endpoints ; RRs were 0.87 [0.76, 0.98] for CVD and 0.80 [0.68, 0.93] for MACE in Cox models; and those were 0.84 [0.74, 0.95] for CVD and 0.77 [0.67, 0.89] for MACE in the doubly robust method. E-values and sensitivity analyses indicated robustness. The present results suggest that original non-significant results of COSMOS could be due to type 2 error. While additional assumptions are needed, external control integration offers a feasible approach to strengthen interpretations of large-scale prevention trials.

Abstract Background With global population aging and an increasing prevalence of cognitive decline, the association between cognitive change as a dynamic process and all-cause mortality remains insufficiently investigated. We therefore aimed to assess the association of cognitive decline on all-cause mortality in older women. Methods We analyzed data originating from the cognitive cohort of the Women’s Health Study established in 1998. 6,377 US-based women aged ≥ 65 years and currently or formerly employed in health-related professions were enrolled at baseline. Women with complete information on 4-year global cognitive performance change were eligible for our analysis and assigned to quintiles according to change in global cognitive performance. Follow-up for all-cause mortality was administered until December 31, 2022. Multivariable adjusted Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of the effect of cognitive change on the risk of all-cause mortality. Secondary analyses evaluated the risk in the lowest 20% and 10% of the cognitive change distribution, and according to verbal memory changes. Results 5,214 women with a mean age of 66.1 years (SD 4.0) were included in the analyses. Women were followed for an average of 13.4 person years and 3,333 deaths were observed. When compared to the 5th quintile with the greatest improvement, the adjusted HR for all-cause mortality was 0.96 (95%CI [0.86–1.08]) for the 4th, 1.04 (95%CI [0.93–1.16]) for the 3rd, 1.15 (95%CI [1.04–1.29]) for the 2nd, and 1.37 (95%CI [1.23–1.52]) for the 1st quintile characterized by the greatest decline. Similar patterns were observed for verbal memory change. Risk was further elevated when comparing the worst 20% (HR: 1.32 (95%CI [1.21–1.43])) and 10% (HR: 1.44 (95%CI [1.29–1.60])) to all other participants. Conclusion Cognitive decline over four years was associated with an increased risk of mortality among older women. Further studies should explore whether declines earlier in life or among men are also associated with an increased risk of mortality.

Cocoa flavanols may reduce cardiovascular disease (CVD) risk, yet large randomized trials remain inconclusive. The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) suggested a modest, nonsignificant benefit using Cox models, which do not account for event severity in composite outcomes. To address this, we applied generalized pairwise comparison (GPC), or “win ratio” (WR), to assess cocoa flavanols versus placebo on hierarchical CVD outcomes among healthy older US adults. This secondary analysis of COSMOS, a randomized, placebo-controlled, 2 × 2 factorial trial of cocoa extract and multivitamins for preventing CVD and cancer, included 21,442 adults (women ≥ 65, men ≥ 60 years) followed for a median of 3.6 years. The primary outcome was a hierarchical composite of total CVD, prioritizing: fatal CVD, non-fatal myocardial infarction (MI), non-fatal stroke, coronary revascularization, carotid surgery, peripheral artery surgery, and hospitalized unstable angina. Analyses followed the intention-to-treat principle. GPC estimated WRs and net treatment benefits (NTBs) for cocoa flavanols versus placebo. GPC analyses showed cocoa flavanol wins of 3.41

Despite widespread use in the USA, little is known about the impact of multivitamin-multimineral (MVM) supplementation on metabolomic profiles and how this may translate to biological aging and long-term risk of age-related chronic diseases. The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a 2 × 2 factorial, placebo-controlled, double-blinded, randomized clinical trial testing daily MVM (Centrum Silver®) in US older adults. In 399 participants with metabolomics profiles quantified using the Nightingale Health nuclear magnetic resonance platform at baseline, year 1, and year 2 (70.3 ± 5.7 years; 50.1

Large-scale randomized trials have found that multivitamin-multimineral (MVM) supplements and cocoa flavanols may benefit several age-related chronic conditions among older adults, but it remains unclear whether these two supplements directly slow the biological aging process. This prespecified ancillary study evaluated the 2-year effect of a daily MVM (Centrum Silver) and cocoa extract (500 mg cocoa flavanols per day, including 80 mg (-)-epicatechin) on five DNA methylation measures of biological aging (PCHannum, PCHorvath, PCPhenoAge, PCGrimAge and DunedinPACE) among 958 participants (482 women and 476 men) in the COcoa Supplement and Multivitamin Outcomes Study (COSMOS). Compared with placebo, daily MVM supplementation modestly reduced the rate of increase of second-generation epigenetic clocks, with a between-group difference in yearly change of -0.113 years (95% confidence interval (CI) -0.205 to -0.020; P = 0.017) for PCGrimAge and -0.214 years (-0.410 to -0.019; P = 0.032) for PCPhenoAge. MVM had a stronger effect on PCGrimAge among those with accelerated biological aging at baseline (-0.236 [-0.380 to -0.091]) compared with those with normal or decelerated biological aging (-0.013 [-0.130 to 0.104]; P = 0.018 for interaction). Cocoa extract did not have an effect on the five epigenetic clocks tested. Although the statistically significant but small effects of daily MVM supplementation on slowing biological aging are encouraging, additional studies are needed to determine the clinical relevance of daily MVM supplementation on epigenetic clocks and whether such effects can help explain the beneficial effects of MVM supplementation on aging-related chronic conditions.

Background As interest in non-pharmacologic treatments for migraine prevention increases, there is an urgent need to evaluate these treatments in well-designed randomized trials. However, designing a “control” for non-pharmacologic treatments is complex. One possible solution is to design credible educational programs to use as comparators which partially control for natural history, patient engagement, attention and positive expectancy. Objective To develop and validate through a modified Delphi process a “Headache Health Education” (HHE) program to be used as the control arm in a pilot study of multimodal chiropractic care for episodic migraine. Methods Leveraging existing patient educational materials, we drafted an initial HHE program with 14 modules, each covering a different migraine-related topic. Designed to be delivered by research personnel in a one-on-one video conference, each module provides education using a slide deck and guided conversation that is grounded in adult learning theory. Furthermore, to engage participants, the script-based sessions are informed by the psychological implications of polyvagal theory and motivational interviewing. The program was validated using a modified Delphi process. Modifications were made to the program based on the ratings and feedback, and a second round of review was then performed. Results Initial endorsement of the HHE program was generally supportive but included considerable variability. After program refinement, endorsement improved with much lower score variability. Key improvements included the addition of 2 topics, selection of new videos, and training for research assistants/associates in how to use conversational style and specific prompts to engage participants. Conclusion Initial development and validation of an HHE program to use as a comparator in trials of a non-pharmacological treatment for migraine has been completed. Future analysis will examine the fidelity and acceptability of the HHE program when used as a comparator in a randomized controlled trial of multimodal care for migraine.

Backgrounds: Cocoa flavanols have potential blood pressure (BP)-lowering effects in shorter-term, smaller-scale randomized clinical trials (RCTs), but its effect on incident hypertension has not been examined in a large-scale RCT. The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) evaluated whether longer-term cocoa extract supplementation had an effect on incident hypertension in older adults. Methods: COSMOS is a 2x2 factorial, double-blind, placebo-controlled RCT testing cocoa extract (including 500 mg/day cocoa flavanols, with 80 mg/day (-)-epicatechin) and a multivitamin among 21,442 women aged ≥65y and men aged ≥60y. In 8,905 COSMOS participants free from baseline self-reported hypertension, we investigated the effect of cocoa extract on incident hypertension using Cox proportional hazards models. Incident hypertension was defined as self-reported first-time physician diagnosis, initiation of anti-hypertensive medications, or self-reported elevated systolic BP (SBP) ≥ 140 mmHg or diastolic BP (DBP) ≥ 90 mmHg. Results: Mean age at baseline was 71.1 years (SD: 6.2) and 58.8% of the participants were women. 48.6% had baseline SBP < 120 mmHg, corresponding to the normal range. Baseline characteristics were balanced between the cocoa extract and placebo groups. Over a median follow-up of 3.4 years, in intention-to-treat analyses cocoa extract supplementation had no significant effect on incident hypertension, with the incidence rates (IRs) of 71.2 and 73.8 per 1000 person-years in cocoa and placebo groups, respectively (hazard ratio [HR]: 0.96 [95% confidence interval: 0.88, 1.05]). A significant interaction was observed between treatment assignment and baseline SBP (p=0.002). Cocoa extract supplementation reduced the incidence of hypertension among participants with baseline SBP < 120 mmHg (IR: 38.2 vs. 50.3 per 1000 person-years; HR: 0.76 [0.64, 0.90]), but not among those with SBP of 120-139 mmHg (IR: 101.4 vs. 96.8 per 1000 person-years; HR: 1.05 [0.93, 1.18]; Figure ). Consistent results were obtained in sensitivity analyses using different definitions of hypertension: physician diagnosis, initiation of anti-hypertensive medications, or elevated BP alone. Per-protocol analysis using inverse probability weighting to account for non-adherence also supported the effect in SBP < 120 mmHg. Conclusion: In older adults, years-long supplementation of cocoa extract may reduce the risk of incident hypertension among those with normal BP levels.

BACKGROUND:Cocoa flavanols have potential blood pressure (BP)-lowering effects in shorter-term, smaller-scale randomized clinical trials, but their effect on incident hypertension has not been examined in a large-scale and long-term randomized clinical trial. METHODS:The COSMOS (Cocoa Supplement and Multivitamin Outcomes Study) is a 2×2 factorial, double-blind, placebo-controlled randomized clinical trial testing cocoa extract (including 500 mg/d cocoa flavanols, with 80 mg/d [-]-epicatechin) and a multivitamin among 21 442 women aged ≥65 years and men aged ≥60 years. Placebos did not include any bioactive compounds. In 8905 COSMOS participants free from baseline hypertension, we investigated the effect of cocoa extract on incident hypertension using Cox proportional hazards models. Incident hypertension was defined as self-reported first-time physician diagnosis, initiation of antihypertensive medications, or elevated BP. RESULTS:Mean age at baseline was 71.1 years (SD, 6.2), and 59% were women. Over a median follow-up of 3.4 years, cocoa extract supplementation had no significant effect on incident hypertension in an intention-to-treat analysis, with incidence rates of 7.1 and 7.4 per 100 person-years in cocoa and placebo groups, respectively (hazard ratio, 0.96 [95% CI, 0.88-1.05]). In subgroup analyses, cocoa extract supplementation reduced the incidence of hypertension among participants with baseline systolic BP <120 mm Hg (hazard ratio, 0.76 [0.64-0.90]), but not among those with systolic BP of 120 to 139 mm Hg (hazard ratio, 1.05 [0.93-1.18]; P-interaction=0.002). The effect among baseline systolic BP <120 mm Hg became evident at year 2 after randomization. CONCLUSIONS:In older adults, long-term cocoa extract supplementation did not reduce the overall risk of self-reported incident hypertension. However, among those with normal systolic BP at baseline, cocoa extract reduced hypertension risk by 24%.

BACKGROUND AND OBJECTIVES:In the United States, stroke is the third leading cause of death among women, with 1 in 5 women aged 55 to 75 years expected to experience a stroke. The Brain Care Score (BCS) is an evidence-based tool designed to motivate lifestyle changes, with higher scores associated with reduced risk of stroke, dementia, and depression. We aim to measure the association of the BCS and incident cerebrovascular events (CVEs), including stroke and transient ischemic attack (TIA), in the Women's Health Study (WHS). METHODS:The WHS comprises women health professionals aged 45 and older in the United States. Participants without history of CVE and complete data available to calculate a BCS and covariates 5 years after enrollment were included. Higher BCS reflects better risk factor control, with the minimum score being 0 and the maximum score being 20. Cox proportional hazard models examined the association between BCS and incident CVE adjusted for potential confounders. RESULTS:A total of 21,271 women were eligible with a median age of 57.9 years (interquartile range: 53.9-63.8) and median BCS of 15 (interquartile range [IQR]:13-16). There were 1,294 incident CVE cases (6.1%) during a median follow-up of 22.4 (IQR: 15.9-23.5) years. A five-point higher baseline BCS was associated with a 37% decrease in the risk of incident CVE after adjusting for age, menopausal status, use of hormonal replacement therapy, and other known cardiovascular disease risk factors (hazard ratio [HR] 0.63, 95% CI 0.56-0.71). This association remained significant after adjusting for race, educational attainment, and income (HR 0.64, 95% CI 0.57-0.72). There was a 28% decreased risk of incident CVE among those with a BCS equal to or above the median compared with those with a BCS below the median, in a fully adjusted model (HR 0.72, 95% CI 0.64-0.80). DISCUSSION:Higher baseline BCS was associated with a decreased risk of incident CVE in the WHS. Future studies are needed to study the BCS in more diverse populations and to investigate how changes in BCS across the lifespan affect risk of CVE.

BACKGROUND:Little is known about the longitudinal trajectories of novel neurodegenerative biomarkers including neurofilament light (NfL), tau, and glial fibrillary acidic protein (GFAP). OBJECTIVES:We aimed to investigate the short- and long-term natural history of these biomarkers measured longitudinally among healthy adults. METHODS:In this cohort study from the Physicians' Health Study (PHS), VITamin D and OmegA-3 TriaL (VITAL), and COcoa Supplement and Multivitamin Outcomes Study (COSMOS), we included 1299 adults with bloods collected 2 years (VITAL and COSMOS) or 14 years (PHS) apart and without diagnosed neurodegenerative diseases before baseline or during follow-up through two years after the final blood collection. Associations between baseline characteristics and changes in NfL, tau, and GFAP were evaluated. RESULTS:Mean (SD) age at baseline was 49.8 (6.8), 67.5 (6.2), and 70.3 (5.7) in PHS, VITAL, and COSMOS, respectively. PHS enrolled only men while ∼50% of the VITAL and COSMOS populations in this study were men. Median percent changes (IQR) of NfL were 40.6% (2.4, 58.2) increase over 14 years (PHS) and 8.5% (-6.6, 28.6) over 2 years (VITAL and COSMOS); increases in tau were 101% (10.7, 285) over 14 years and 11.8% (-35.2, 106) over 2 years; and increases in GFAP were 25.1% (-1.7, 23.8) over 14 years and 5.6% (-12.8, 28.6) over 2 years. In multivariable models, age was most strongly and robustly associated with 14-year changes in NfL and GFAP (adjusted p<0.001), and increases in levels accelerated at older ages. No baseline variables were associated with changes in tau. CONCLUSION:Increases in NfL and GFAP accelerated with age, highlighting the need to improve our understanding of the clinical relevance of short- and long-term changes in these neurodegenerative biomarkers in large-scale, long-term cohorts.