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Background: Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk., Methods: LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years., Conclusion: The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter., Trial Registration: ClinicalTrials.gov NCT05757869., Competing Interests: Disclosures SSJ reports consulting fees from Bristol Myers Squibb, ARTIS Ventures, and Broadview Ventures outside of the submitted work. KWM’s financial disclosures can be reviewed at http://med.stanford.edu/profiles/kenneth-mahaffey. KSP is a member of The Thrombosis Research Institute which has received institutional research grant support from Anthos Therapeutics and Bayer Pharmaceuticals. She has received honoraria from Element Science and Artivion, Inc. WS has received honoraria (>10K USD) from Daiichi Sankyo, Nippon Boehringer Ingelheim, and Pfizer Japan, and research grants (>50K USD) from Daiichi Sankyo and Nippon Boehringer Ingelheim. CTR reports Research Grants through Institution from: Athos, AstraZeneca, Daiichi Sankyo, Janssen and Novartis. Honoraria for scientific ad boards and consulting from: Anthos, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Janssen and Pfizer. He is a member of The TIMI Study Group which has received institutional research grant support through Brigham and Women's Hospital from: Abbott, Abiomed, Inc, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Inc, Janssen Research & Development, LLC, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc, Roche, Saghmos Therapeutics, Inc, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, Verve Therapeutics, Inc, Zora Biosciences. PRK reports consultancy from Anthos, J&J, BMS and Bayer. GS has received research grants from Amarin, AstraZeneca, and Sanofi; has participated in clinical trials, consulting, or speaking for Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Idorsia, Janssen, Novartis, Novo Nordisk, PhaseBio, Pfizer, and Sanofi; is a Senior Associate Editor at Circulation; and serves as the CMO for Bioquantis. RM reports institutional research payments from: Abbott, Affluent Medical, Alleviant Medical, Amgen, AstraZeneca, BAIM, Beth Israel Deaconess Medical Center, Boston Scientific, Bristol-Myers Squibb, CardiaWave, CERC, Chiesi, Concept Medical, Daiichi Sankyo, Duke, Faraday, Idorsia, Janssen, MedAlliance, Medscape, Mediasphere, Medtelligence, Medtronic, Novartis, OrbusNeich, Pi-Cardia, Protembis, RM Global Bioaccess Fund Management, Sanofi; consultant to Affluent Medical, Boehringer Ingelheim, Chiesi USA, Cordis, Esperion Science/Innovative Biopharma, Gaffney Events, Educational Trust, Global Clinical Trial Partners, Ltd., IQVIA, Medscape/WebMD Global, NovoNordisk, PeerView Institute for Medical Education, TERUMO Europe N.V., Radcliffe and honoararia from AMA and ACC. SCJ has received research support from Jansen, BMS, and AstraZeneca. GJH reports personal honoraria outside the submitted work from the American Heart Association (Associate Editor, Circulation), Bristol Myers Squibb (Steering Committee, AXIOMATIC-SSP trial of milvexian [factor XIa inhibitor] for secondary stroke prevention) and Janssen (Co-chair, Executive Committee, Librexia Stroke trial of milvexian for secondary stroke prevention). RAH has received research grants/contracts from NHLBI (ISCHEMIA), Duke/PCORI (ADAPTABLE), Janssen (Factor Xia inhibitor), CSL (HDL), Baim Institute, UColorado, Harvard (BWH), and Merck; has served as a consultant/advisor for NHLBI (COVID/CONNECTS), Atropos Health, Bitterroot Bio, Bristol Myers Squibb, Bridge Bio, Chiesi, CSL Behring, Edwards Lifesciences Corp, Element Science, Foresight, Merck, and WebMD; and serves on the Board of Directors for AHA and Cytokinetics. CSPL is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has Received research support from Novo Nordisk and Roche Diagnostics; has Served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Biopeutics, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, CardioRenal, CPC Clinical Research, Eli Lilly, Hanmi, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Quidel Corporation, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as Co-founder and nonexecutive director of Us2.ai. The remaining authors report no relevant disclosures or competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Stroke is a leading global cause of death and disability. Daily tea/coffee intake is consumed by > 50% of populations and may represent an important population-level exposure. Therefore, it is first essential that we better understand the associations between the tea/coffee intake and stroke., Aims: This research aims to generate hypotheses about the global associations between tea and coffee intake and stroke. These insights will identify interventions for stroke prevention that can be further explored using alternative study designs., Methods: INTERSTROKE is a large international matched case-control study of first stroke from 32 countries. Participants were asked "how many cups do you drink each day?" of coffee, green tea, black tea, and other tea. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between intake and stroke., Results: We included 13,462 cases and 13,488 controls from INTERSTROKE; mean age was 61.7 (13.4) years and 59.6% (n = 16,010) were male. Overall, 19.4% (n = 5239) did not consume tea/coffee, 47.0% (n = 12,666) consumed tea only, 14.9% (n = 4024) consumed coffee alone, and 18.6% (n = 5021) consumed both, with significant regional variations. After multivariable adjustment, there was no association between low/moderate coffee intake and stroke, but high consumption (> 4/day) was associated with higher odds of all stroke (OR = 1.37 (95% CI = 1.06-1.77)) or ischemic stroke (OR = 1.32 (95% CI = 1.00-1.74)). Tea consumption was associated with lower odds of all (OR = 0.81 (95% CI = 0.69-0.94) for highest intake) or ischemic stroke (OR = 0.81 (95% CI = 0.68-0.98) for highest intake)., Conclusions: High coffee consumption was associated with higher odds of all or ischemic stroke; low-moderate coffee had no association with stroke. In contrast, tea consumption was associated with lower odds of stroke. These associations suggest that individuals consider avoiding high coffee consumption (⩾ five cups/day) to impact future stroke risk., Data Access Statement: The design and rationale of INTERSTROKE was published previously. Individual participant data, or other documents are not available., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Purpose: Cold beverage intake (carbonated drinks, fruit juice/drinks, and water) may be important population-level exposures relevant to stroke risk and prevention. We sought to explore the association between intake of these beverages and stroke., Methods: INTERSTROKE is an international matched case-control study of first stroke. Participants reported beverage intake using food frequency questionnaires or were asked "How many cups do you drink each day of water?" Multivariable conditional logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations with stroke., Results: We include 13,462 cases and 13,488 controls; mean age was 61.7±13.4 years and 59.6% (n=16,010) were male. After multivariable adjustment, carbonated beverages were linearly associated with ischemic stroke (OR 2.39 [95% CI 1.64-3.49]); only consumption once/day was associated with intracerebral hemorrhage (ICH) (OR 1.58 [95% CI 1.23-2.03]). There was no association between fruit juice/drinks and ischemic stroke, but increased odds of ICH for once/day (OR 1.37 [95% CI 1.08-1.75)] or twice/day (OR 3.18 [95% CI 1.69-5.97]). High water intake (>7 cups/day) was associated ischemic stroke (OR 0.82 [95% CI 0.68-0.99]) but not ICH. Associations differed by Eugeographical region-increased odds for carbonated beverages in some regions only; opposing directions of association of fruit juices/drinks with stroke in selected regions., Conclusion: Carbonated beverages were associated with increased odds of ischemic stroke and ICH, fruit juice/drinks were associated with increased odds of ICH, and high water consumption was associated with reduced odds of ischemic stroke, with important regional differences. Our findings suggest optimizing water intake, minimizing fruit juice/drinks, and avoiding carbonated beverages.

Background and Objectives: Acute stroke is associated with a spectrum of functional deficits. The objective of this analysis was to explore whether the importance of individual risk factors differ by stroke severity, which may be of relevance to public health strategies to reduce disability., Methods: INTERSTROKE is an international case-control study of risk factors of first acute stroke (recruitment 2007-August 2015) in 32 countries. Stroke severity was measured using the modified Rankin Scale (mRS) score within 72 hours of admission to hospital. Severe stroke is defined as mRS scores of 4-6 (and non-severe stroke, score of 0-3). We used multinomial logistic regression to estimate comparative odds ratios (ORs; 95% CIs) for severe and non-severe stroke and tested for heterogeneity ( p heterogeneity ). We also conducted a matched case-case analysis (matched for age, sex, country, and primary stroke subtype) to determine whether the prevalence of risk factors differed significantly between severe and non-severe stroke. A significant difference in the association of a risk factor of severe stroke compared with non-severe stroke was defined as p < 0.05 for both p heterogeneity and p case-case ., Results: Of patients with acute stroke (n = 13,460), 64.0% (n = 8,612) were reported to have mRS scores of 0-3 and 36.0% (n = 4,848) scores of 4-6. The mean age was 61.7 years for patients with non-severe stroke and 62.9 years for patients with severe stroke ( p = 0.72). 38.1% (n = 3,278) of patients with non-severe stroke and 44.6% (n = 2,162) of patients with severe stroke were female. Hypertension (OR 3.21; 95% CI 2.97-3.47 for severe stroke, OR 2.87; 95% CI 2.69-3.05 for non-severe stroke; p heterogeneity = 0.03; p case-case < 0.001), atrial fibrillation (OR 4.70; 95% CI 4.05-5.45 for severe stroke, OR 3.61; 95% CI 3.16-4.13 for non-severe stroke; p heterogeneity = 0.009; p case-case < 0.001), and smoking (OR 1.87; 95% CI 1.72-2.03 for severe stroke, OR 1.65; 95% CI 1.54-1.77 for non-severe stroke; p heterogeneity = 0.02; p case-case < 0.001) had a stronger association with severe stroke, compared with non-severe stroke. The waist-to-hip ratio had a stronger association with non-severe stroke compared with severe stroke ( p heterogeneity < 0.001; p case-case < 0.001)., Discussion: Hypertension, atrial fibrillation, and smoking had a stronger magnitude of association with severe stroke (compared with non-severe stroke) while the increased waist-to-hip ratio had a stronger magnitude of association with non-severe stroke.

Background and Purpose: Blood pressure variability, in acute stroke, may be an important modifiable determinant of functional outcome after stroke. In a large international cohort of participants with acute stroke, it was sought to determine the association of blood pressure variability (in the early period of admission) and functional outcomes, and to explore risk factors for increased blood pressure variability., Patients and Methods: INTERSTROKE is an international case-control study of risk factors for first acute stroke. Blood pressure was recorded at the time of admission, the morning after admission and the time of interview in cases (median time from admission 36.7 h). Multivariable ordinal regression analysis was employed to determine the association of blood pressure variability (standard deviation [SD] and coefficient of variance) with modified Rankin score at 1-month follow-up, and logistic regression was used to identify risk factors for blood pressure variability., Results: Amongst 13,206 participants, the mean age was 62.19 ± 13.58 years. When measured by SD, both systolic blood pressure variability (odds ratio 1.13; 95% confidence interval 1.03-1.24 for SD ≥20 mmHg) and diastolic blood pressure variability (odds ratio 1.15; 95% confidence interval 1.04-1.26 for SD ≥10 mmHg) were associated with a significant increase in the odds of poor functional outcome. The highest coefficient of variance category was not associated with a significant increase in risk of higher modified Rankin score at 1 month. Increasing age, female sex, high body mass index, history of hypertension, alcohol use, and high urinary potassium and low urinary sodium excretion were associated with increased blood pressure variability., Conclusion: Increased blood pressure variability in acute stroke, measured by SD, is associated with an increased risk of poor functional outcome at 1 month. Potentially modifiable risk factors for increased blood pressure variability include low urinary sodium excretion., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Periodontal disease may be an important modifiable risk factor for stroke., Aims: To determine the contribution of markers of periodontal disease to stroke risk globally, within subpopulations, and by stroke subtypes., Methods: INTERSTROKE is the largest international case-control study of risk factors for first acute stroke. All participants were asked a standardised set of questions about the presence or absence of painful teeth, painful gums or lost teeth, as markers of periodontal disease, within the previous year. The total number of reported variables was calculated per participant. Multivariable conditional logistic regression examined the association of these variables with acute stroke., Results: In 26901 participants, across 32 countries, there was a significant multivariable association between lost teeth and stroke (OR 1.11, 95 % CI 1.01 - 1.22), but not painful teeth (OR 1.00, 95 % CI 0.91-1.10) or painful gums (OR 1.01, 95 % CI 0.89 - 1.14). When these symptoms were considered together there was a graded increased odds of stroke, with the largest magnitude of association seen if a patient reported all three of painful teeth, painful gums and lost teeth (OR 1.34, 95 % CI 1.00 - 1.79)., Conclusions: Our findings suggest that features of severe periodontal disease are a risk factor for acute stroke. Periodontal disease should be considered as a potentially modifiable risk factor for stroke., Competing Interests: Declaration of competing interest Regarding Manuscript: Markers of Periodontal Disease and risk of stroke: INTERSTROKE case-control study, (Copyright © 2024. Published by Elsevier Inc.)

Background: Three large randomized controlled trials of fluoxetine for stroke recovery have been performed. We performed an individual patient data meta-analysis (IPDM) on the combined data., Methods: Fixed effects meta-analyses were performed on the combined data set, for the primary outcome (modified Rankin scale (mRS) at 6 months), and secondary outcomes common to the individual trials. As a sensitivity analysis, summary statistics from each trial were created and combined., Findings: The three trials recruited a combined total of 5907 people (mean age 69.5 years (SD 12.3), 2256 (38%) females, 2-15 days post-stroke) from Australia, New Zealand, United Kingdom, Sweden, and Vietnam; and randomized them to fluoxetine 20 mg daily or matching placebo for 6 months. Data on 5833 (98.75%) were available at 6 months. The adjusted ordinal comparison of mRS was similar in the two groups (common OR 0.96, 95% CI 0.87 to 1.05, p = 0.37). There were no statistically significant interactions between the minimization variables (baseline probability of being alive and independent at 6 months, time to treatment, motor deficit, or aphasia) and pre-specified subgroups (including age, pathological type, inability to assess mood, proxy or patient consent, baseline depression, country). Fluoxetine increased seizure risk (2.64% vs 1.8%, p = 0.03), falls with injury (6.26% vs 4.51%, p = 0.03), fractures (3.15% vs 1.39%, p < 0.0001) and hyponatremia (1.22% vs 0.61%, p = 0.01) but reduced new depression (10.05% vs 13.42%, p < 0.0001). At 12 months, there was no difference in adjusted mRS (n = 5760; common OR 0.98, 95% CI 0.89 to 1.07). Sensitivity analyses gave the same results., Interpretation: Fluoxetine 20 mg daily for 6 months did not improve functional recovery. It increased seizures, falls with injury, and bone fractures but reduced depression frequency at 6 months., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The traditional Chinese medicine (TCM) herbal compound FYTF-919 (Zhong Feng Xing Nao prescription) may improve outcome from acute intracerebral hemorrhage (ICH) by reducing brain edema, hematoma absorption, and enhancement of the immune system. We outline the statistical analysis plan (SAP) for the Chinese Herbal medicine in Acute INtracerebral haemorrhage (CHAIN) study., Design: CHAIN is a multicenter, prospective, randomized, double-blind, placebo-controlled trial being undertaken at 20-30 hospitals in China. After the completion of eligibility checks, patients are randomly allocated to FYTF-919 (100 mL per day, oral) or matching placebo over 28 days. A sample size of 1504 patients is estimated to provide 90% power (α 0.05) for a 0.06 absolute improvement in the primary outcome of utility-weighted modified Rankin scale scores at 90 days, analyzed by general linear regression., Methods: The statistical analysis plan was developed by the study statistician, principal investigators, international experts, and the study project manager. The plan provides details for analyzing baseline characteristics, patient management, and outcomes. It includes provisions for covariate adjustments, subgroup analysis, the handling missing data, and in the conduct of sensitivity analyzes., Results: A predefined statistical analysis plan was established for CHAIN, facilitating transparent and verifiable analysis., Conclusions: The CHAIN statistical analysis plan was prospectively developed with a focus on maintaining high-quality standards of internal validity to minimise potential analysis biases., Trial Registration: ClinicalTrials.gov (NCT05066620)., (S. Karger AG, Basel.)

Objectives: To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3)., Design: Multicentre, double blind, randomised, placebo controlled trial., Setting: 244 hospitals in China between 11 August 2022 and 13 April 2023., Participants: 8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled., Interventions: Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days., Main Outcome Measures: The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat., Results: 4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83)., Conclusions: The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L., Trial Registration: ClinicalTrials.gov, NCT05439356., Competing Interests: Declaration of interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from National Key R&D Program of China, the National Natural Science Foundation of China, the Capital's Funds for Health Improvement and Research, and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We examined the associations between 25-hydroxy vitamin D (25(OH)D 3 ) concentration and the diagnosis and growth of abdominal aortic aneurysm (AAA)., Methods: AAA cases and healthy controls were recruited from vascular centers or the community. A subset of participants with AAA were monitored by repeat ultrasound examination to assess AAA growth. Serum 25(OH)D 3 concentration was measured using a validated mass spectrometry method and categorized into guideline-recommended cut-points after deseasonalization. The associations between deseasonalized 25(OH)D 3 concentration and AAA diagnosis and growth were examined using logistic regression and linear mixed effects modeling., Results: A total of 4673 participants consisting of 873 (455 controls and 418 cases) from Queensland and 3800 (3588 controls and 212 cases) from Western Australia were recruited. For every 1 standard deviation increase in 25(OH)D 3 concentration, odds of AAA diagnosis was significantly reduced in both Queensland (adjusted odds ratio: 0.81; 95% confidence interval [CI]: 0.69-0.95; P  = .009) and Western Australia (adjusted odds ratio: 0.80; 95% CI: 0.68-0.94; P  = .005) cohorts. A subset of 310 eligible participants with small AAA from both regions were followed for a median of 4.2 (interquartile range: 2.0-5.8) years. Compared with vitamin D sufficient participants (50 to ˂75 nmol/L), annual mean AAA growth was significantly greater in those with higher vitamin D (≥75 nmol/L) (adjusted mean difference: 0.1 mm/y, 95% CI: 0.1-0.2; P  < .001)., Conclusions: High 25(OH)D 3 concentration was paradoxically associated with a lower likelihood of AAA diagnosis and faster AAA growth. Further research is needed to resolve these conflicting findings., Competing Interests: None., (© 2024 The Author(s).)

Background: Days alive out of hospital (DAOH) is an objective and patient-centered net benefit end point. There are no assessments of DAOH in clinical trials of interventions for atrial fibrillation (AF), and it is not known whether this end point is of clinical utility in these populations., Methods and Results: ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) was an international double-blind, double-dummy randomized clinical trial that compared rivaroxaban with warfarin in patients with atrial fibrillation at increased risk for stroke. We assessed DAOH using investigator-reported event data for up to 12 months after randomization in ROCKET AF. We assessed DAOH overall, by treatment group, and by subgroup, including age, sex, and comorbidities, using Poisson regression. The mean±SD number of days dead was 7.3±41.2, days hospitalized was 1.2±7.2, and mean DAOH was 350.7±56.2, with notable left skew. Patients with comorbidities had fewer DAOH overall. There were no differences in DAOH by treatment arm, with mean DAOH of 350.6±56.5 for those randomized to rivaroxaban and 350.7±55.8 for those randomized to warfarin ( P =0.86). A sensitivity analysis found no difference in DAOH not disabled with rivaroxaban versus warfarin (DAOH not disabled, 349.2±59.5 days and 349.1 days±59.3 days, respectively, P =0.88)., Conclusions: DAOH did not identify a treatment difference between patients randomized to rivaroxaban versus warfarin. This may be driven in part by the low overall event rates in atrial fibrillation anticoagulation trials, which leads to substantial left skew in measures of DAOH.

Background: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial., Purpose: To clarify associations of sex hormones with these outcomes., Data Sources: Systematic literature review to July 2019, with bridge searches to March 2024., Study Selection: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up., Data Extraction: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use., Data Synthesis: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates ( n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events., Limitations: Observational study design, heterogeneity among studies, and imputation of missing data., Conclusion: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality., Primary Funding Source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668)., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-2781.

Background and Purpose: Whilst sleep disturbances are associated with stroke, their association with stroke severity is less certain. In the INTERSTROKE study, the association of pre-morbid sleep disturbance with stroke severity and functional outcome following stroke was evaluated., Methods: INTERSTROKE is an international case-control study of first acute stroke. This analysis included cases who completed a standardized questionnaire concerning nine symptoms of sleep disturbance (sleep onset latency, duration, quality, nocturnal awakening, napping duration, whether a nap was planned, snoring, snorting and breathing cessation) in the month prior to stroke (n = 2361). Two indices were derived representing sleep disturbance (range 0-9) and obstructive sleep apnoea (range 0-3) symptoms. Logistic regression was used to estimate the magnitude of association between symptoms and stroke severity defined by the modified Rankin Score., Results: The mean age of participants was 62.9 years, and 42% were female. On multivariable analysis, there was a graded association between increasing number of sleep disturbance symptoms and initially severe stroke (2-3, odds ratio [OR] 1.44, 95% confidence interval [CI] 1.07-1.94; 4-5, OR 1.66, 95% CI 1.23-2.25; >5, OR 2.58, 95% CI 1.83-3.66). Having >5 sleep disturbance symptoms was associated with significantly increased odds of functional deterioration at 1 month (OR 1.54, 95% CI 1.01-2.34). A higher obstructive sleep apnoea score was also associated with significantly increased odds of initially severe stroke (2-3, OR 1.48; 95% CI 1.20-1.83) but not functional deterioration at 1 month (OR 1.19, 95% CI 0.93-1.52)., Conclusions: Sleep disturbance symptoms were common and associated with an increased odds of severe stroke and functional deterioration. Interventions to modify sleep disturbance may help prevent disabling stroke/improve functional outcomes and should be the subject of future research., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: The contribution of atrial fibrillation (AF) to the etiology and burden of stroke may vary by country income level., Aims: We examined differences in the prevalence of AF and described variations in the magnitude of the association between AF and ischemic stroke by country income level., Methods: In the INTERSTROKE case-control study, participants with acute first ischemic stroke were recruited across 32 countries. We included 10,363 ischemic stroke cases and 10,333 community or hospital controls who were matched for age, sex, and center. Participants were grouped into high-income (HIC), upper-middle-income (subdivided into two groups-UMIC-1 and UMIC-2), and lower-middle-income (LMIC) countries, based on gross national income. We evaluated the risk factors for AF overall and by country income level, and evaluated the association of AF with ischemic stroke., Results: AF was documented in 11.9% (n = 1235) of cases and 3.2% (n = 328) of controls. Compared to HIC, the prevalence of AF was significantly lower in UMIC-2 (aOR 0.35, 95% CI 0.29-0.41) and LMIC (aOR 0.50, 95% CI 0.41-0.60) on multivariable analysis. Hypertension, female sex, valvular heart disease, and alcohol intake were stronger risk factors for AF in lower-income countries, and obesity a stronger risk factor in higher-income countries. The magnitude of association between AF and ischemic stroke was significantly higher in lower-income countries compared to higher-income countries. The population attributable fraction for AF and stroke varied by region and was 15.7% (95% CI 13.7-17.8) in HIC, 14.6% (95% CI 12.3-17.1) in UMIC-1, 5.7% (95% CI 4.9-6.7) in UMIC-2, and 6.3% (95% CI 5.3-7.3) in LMIC., Conclusion: Risk factors for AF vary by country income level. AF contributes to stroke burden to a greater extent in higher-income countries than in lower-income countries, due to a higher prevalence and despite a lower magnitude of odds ratio., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Pre-treatment re-bleeding following aneurysmal subarachnoid hemorrhage (aSAH) affects up to 7.2% of patients even with ultra-early treatment within 24 hours. We retrospectively compared the utility of three published re-bleed prediction models and individual predictors between cases who re-bled matched to controls using size and parent vessel location from a cohort of patients treated in an ultra-early, 'endovascular first' manner., Methods: On retrospective analysis of our 9-year cohort of 707 patients suffering 710 episodes of aSAH, there were 53 episodes of pre-treatment re-bleeding (7.5%). Forty-seven cases who had a single culprit aneurysm were matched to 141 controls. Demographic, clinical and radiological data were extracted and predictive scores calculated. Univariate, multivariate, area under the receiver operator characteristic curve (AUROCC) and Kaplan-Meier (KM) survival curve analyses were performed., Results: The majority of patients (84%) were treated using endovascular techniques at a median 14.5 hours post-diagnosis. On AUROCC analysis the score of Liu et al. had minimal utility (C-statistic 0.553, 95% confidence interval (CI) 0.463 to 0.643) while the risk score of Oppong et al. (C-statistic 0.645 95% CI 0.558 to 0.732) and the ARISE-extended score of van Lieshout et al. (C-statistic 0.53 95% CI 0.562 to 0.744) had moderate utility. On multivariate modeling, the World Federation of Neurosurgical Societies (WFNS) grade was the most parsimonious predictor of re-bleeding (C-statistic 0.740, 95% CI 0.664 to 0.816)., Conclusions: For aSAH patients treated in an ultra-early timeframe matched on size and parent vessel location, WFNS grade was superior to three published models for re-bleed prediction. Future re-bleed prediction models should incorporate the WFNS grade., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Smoking is a major risk factor for the global burden of stroke. We have previously reported a global population attributable risk (PAR) of stroke of 12.4% associated with current smoking. In this study we aimed to explore the association of current tobacco use with different types of tobacco exposure and environmental tobacco smoke (ETS) exposure on the risk of stroke and stroke subtypes, and by regions and country income levels., Methods: The INTERSTROKE study is a case-control study of acute first stroke and was undertaken with 13,462 stroke cases and 13,488 controls recruited between January 11, 2007 and August 8, 2015 in 32 countries worldwide. Association of risk of tobacco use and ETS exposure were analysed with overall stroke, ischemic and intracerebral hemorrhage (ICH), and with TOAST etiological stroke subtypes (large vessel, small vessel, cardioembolism, and undetermined)., Findings: Current smoking was associated with an increased risk of all stroke (odds ratio [OR] 1.64, 95% CI 1.46-1.84), and had a stronger association with ischemic stroke (OR 1.85, 95% CI 1.61-2.11) than ICH (OR 1.19 95% CI 1.00-1.41). The OR and PAR of stroke among current smokers varied significantly between regions and income levels with high income countries (HIC) having the highest odds (OR 3.02 95% CI 2.24-4.10) and PAR (18.6%, 15.1-22.8%). Among etiological subtypes of ischemic stroke, the strongest association of current smoking was seen for large vessel stroke (OR 2.16, 95% CI 1.63-2.87) and undetermined cause (OR 1.97, 95% CI 1.55-2.50). Both filtered (OR 1.73, 95% CI 1.50-1.99) and non-filtered (OR 2.59, 95% CI 1.79-3.77) cigarettes were associated with stroke risk. ETS exposure increased the risk of stroke in a dose-dependent manner, exposure for more than 10 h per week increased risk for all stroke (OR 1.95, 95% CI 1.69-2.27), ischemic stroke (OR 1.89, 95% CI 1.59-2.24) and ICH (OR 2.00, 95% CI 1.60-2.50)., Interpretation: There are significant variations in the magnitude of risk and PAR of stroke according to the types of tobacco used, active and ETS exposure, and countries with different income levels. Specific strategies to discourage tobacco use by any form and to build a smoke free environment should be implemented to ease the global burden of stroke., Funding: The Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Stroke Network, Swedish Research Council, Swedish Heart and Lung Foundation, The Health & Medical Care Committee of the Regional Executive Board, Region Västra Götaland, and through unrestricted grants from several pharmaceutical companies with major contributions from Astra Zeneca, Boehringer Ingelheim (Canada), Pfizer (Canada), MERCK, Sharp and Dohme, Swedish Heart and Lung Foundation, UK Chest, and UK Heart and Stroke., Competing Interests: We declare no competing interests. Dr. Hans-Christoph Diener has reported receiving fees from Pfizer, Abbott, and Daiichi Sankyo. Dr. Denis Xavier reported receiving grants from Population Health Research Institute, Hamilton Health Science, Boehringer Ingelheim, Bristol Myers Squibb, Coco cola India, Indian Council of Medical Research, Pfizer, United Kingdom Medical Research Council and Welcome Trust., (© 2024 The Authors.)

Background and Purpose: Early this century, the high risk strategy of primary stroke and cardiovascular disease (CVD) prevention for individuals shifted away from identifying (and treating, as appropriate) all at-risk individuals towards identifying and treating individuals who exceed arbitrary thresholds of absolute CVD risk. The public health impact of this strategy is uncertain., Methods: In our systematic scoping review, the electronic databases (Scopus, MEDLINE, Embase, Google Scholar, Cochrane Library) were searched to identify and appraise publications related to primary CVD/stroke prevention strategies and their effectiveness published in any language from January 1990 to August 2023., Results: No published randomized controlled trial was found on the effectiveness of the high CVD risk strategy for primary stroke/CVD prevention. Targeting high CVD risk individuals excludes a large proportion of the population from effective blood-pressure-lowering and lipid-lowering treatment and effective CVD prevention. There is also evidence that blood pressure lowering and lipid lowering are beneficial irrespective of blood pressure and cholesterol levels and irrespective of absolute CVD risk and that risk-stratified pharmacological management of blood pressure and lipids to only high CVD risk individuals leads to significant underuse of blood-pressure-lowering and lipid-lowering medications in individuals otherwise eligible for such treatment., Conclusions: Primary stroke and CVD prevention needs to be done in all individuals with increased risk of CVD/stroke. Pharmacological management of blood pressure and blood cholesterol should not be solely based on the high CVD risk treatment thresholds. International guidelines and global strategies for primary CVD/stroke prevention need to be revised., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Objective: Prevalence of subclinical thyroid disease increases with age, but optimal detection and surveillance strategies remain unclear particularly for older men. We aimed to assess thyroid stimulating hormone (TSH) and free thyroxine (FT4) concentrations and their longitudinal changes, to determine the prevalence and incidence of subclinical thyroid dysfunction in older men., Design, Participants and Measurements: Longitudinal study of 994 community-dwelling men aged ≥70 years without known or current thyroid disease, with TSH and FT4 concentrations assessed at baseline and follow-up (after 8.7 ± 0.9 years). Factors associated with incident subclinical thyroid dysfunction were examined by logistic regression and receiver operating characteristic analyses., Results: At baseline, 85 men (8.6%) had subclinical hypothyroidism and 10 (1.0%) subclinical hyperthyroidism. Among 899 men euthyroid at baseline (mean age 75.0 ± 3.0 years), 713 (79.3%) remained euthyroid, 180 (20.0%) developed subclinical/overt hypothyroidism, and 6 (0.7%) subclinical/overt hyperthyroidism. Change in TSH correlated with baseline TSH (r = .16, p < .05). Change in FT4 correlated inversely with baseline FT4 (r = -0.35, p < .05). Only higher age and baseline TSH predicted progression from euthyroid to subclinical/overt hypothyroidism (fully-adjusted odds ratio [OR] per year=1.09, 95% confidence interval [CI] = 1.02-1.17, p = .006; per 2.7-fold increase in TSH OR = 65.4, CI = 31.9-134, p < .001). Baseline TSH concentration ≥2.34 mIU/L had 76% sensitivity and 77% specificity for predicting development of subclinical/overt hypothyroidism., Conclusions: In older men TSH concentration increased over time, while FT4 concentration showed little change. Subclinical or overt hypothyroidism evolved in one fifth of initially euthyroid men, age and higher baseline TSH predicted this outcome. Increased surveillance for thyroid dysfunction may be justified in older men, especially those with high-normal TSH., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Background: Improving physical activity levels and diet quality are important for secondary stroke prevention., Aim: To test the feasibility and safety of 6-month, co-designed telehealth-delivered interventions to increase physical activity and improve diet quality., Methods: A 2 × 2 factorial trial (physical activity (PA); diet (DIET); PA + DIET; control) randomized, open-label, blinded endpoint trial. Primary outcomes were feasibility and safety. Secondary outcomes included stroke risk factors (blood pressure, self-report PA (International Physical Activity Questionnaire (IPAQ)) and diet quality (Australian Recommended Food Score (ARFS)), and quality of life. Between-group differences were analyzed using linear-mixed models., Results: Over 23 months, 99 people were screened for participation and 40 (40%) randomized (3 months to 10 years post-stroke, mean age 59 (16) years). Six participants withdrew, and an additional five were lost to follow-up. Fifteen serious adverse events were reported, but none were deemed definitely or probably related to the intervention. Median attendance was 32 (of 36) PA sessions and 9 (of 10) DIET sessions. The proportion of missing primary outcome data (blood pressure) was 3% at 3 months, 11% at 6 months, and 14% at 12 months. Between-group 95% confidence intervals showed promising, clinically relevant differences in support of the interventions across the range of PA, diet quality, and blood pressure outcomes., Conclusion: Our telehealth PA and diet interventions were safe and feasible and may have led to significant behavior change., Trial Registration: ACTRN12620000189921., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid β, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed., Competing Interests: The authors declare that while some of their CAA research projects have been supported by commercial funding from Biogen Inc. and Alnylam Pharmaceuticals, this specific manuscript did not receive any funding and the funders of our research were not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Savar, Ma, Hone, Jahan, Markovic, Pedrini, Shemehsavar, Easwaran, Taddei, Gardener, Chhatwal, van Etten, van Osch, Clarke, Gnjec, van Buchem, Wermer, Hankey, Greenberg, Martins and Sohrabi.)

Background: Most strokes and cardiovascular diseases (CVDs) are potentially preventable if their risk factors are identified and well controlled. Digital platforms, such as the PreventS-MD web app (PreventS-MD) may aid health care professionals (HCPs) in assessing and managing risk factors and promoting lifestyle changes for their patients., Methods: This is a mixed-methods cross-sectional two-phase survey using a largely positivist (quantitative and qualitative) framework. During Phase 1, a prototype of PreventS-MD was tested internationally by 59 of 69 consenting HCPs of different backgrounds, age, sex, working experience, and specialties using hypothetical data. Collected comments/suggestions from the study HCPs in Phase 1 were reviewed and implemented. In Phase 2, a near-final version of PreventS-MD was developed and tested by 58 of 72 consenting HCPs using both hypothetical and real patient (n = 10) data. Qualitative semi-structured interviews with real patients (n = 10) were conducted, and 1 month adherence to the preventive recommendations was assessed by self-reporting. The four System Usability Scale (SUS) groups of scores (0-50 unacceptable; 51-68 poor; 68-80.3 good; >80.3 excellent) were used to determine usability of PreventS-MD., Findings: Ninety-nine HCPs from 27 countries (45% from low- to middle-income countries) participated in the study, and out of them, 10 HCPs were involved in the development of PreventS before the study, and therefore were not involved in the survey. Of the remaining 89 HCPs, 69 consented to the first phase of the survey, and 59 of them completed the first phase of the survey (response rate 86%), and 58 completed the second phase of the survey (response rate 84%). The SUS scores supported good usability of the prototype (mean score = 80.2; 95% CI [77.0-84.0]) and excellent usability of the final version of PreventS-MD (mean score = 81.7; 95% CI [79.1-84.3]) in the field. Scores were not affected by the age, sex, working experience, or specialty of the HCPs. One-month follow-up of the patients confirmed the high level of satisfaction/acceptability of PreventS-MD and (100%) adherence to the recommendations., Interpretation: The PreventS-MD web app has a high level of usability, feasibility, and satisfaction by HCPs and individuals at risk of stroke/CVD. Individuals at risk of stroke/CVD demonstrated a high level of confidence and motivation in following and adhering to preventive recommendations generated by PreventS-MD., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: V.L.F., R.K., B.N., S.J.-M., A.M., and M.K. declare that the PreventS-MD web app and the free Stroke Riskometer app are owned and copyrighted by Auckland University of Technology (AUT) Ventures Ltd, New Zealand. Other co-authors reported no conflict of interest.

Introduction: Diet quality is a marker of how closely eating patterns reflect dietary guidelines. The highest tertile for diet quality scores is associated with 40% lower odds of first stroke compared with the lowest tertile. Little is known about the diet of stroke survivors. We aimed to assess dietary intake and quality of Australian stroke survivors., Methods: Stroke survivors enrolled in the ENAbLE pilot trial (2019/ETH11533, ACTRN12620000189921) and Food Choices after Stroke study (2020ETH/02264) completed the Australian Eating Survey Food Frequency Questionnaire (AES), a 120-item, semiquantitative questionnaire of habitual food intake over the previous 3-6 months. Diet quality was determined by calculating the Australian Recommended Food Score (ARFS): a higher score indicates higher diet quality., Results: Eighty-nine adult, stroke survivors (female: n = 45, 51%) of mean age 59.5 years (±9.9) had a mean ARFS of 30.5 (±9.9) (low diet quality). Mean energy intake was similar to the Australian population: 34.1% from noncore (energy-dense/nutrient-poor) and 65.9% from core (healthy) foods. However, participants in the lowest tertile for diet quality (n = 31) had significantly lower intake of core (60.0%) and higher intake from noncore foods (40.0%). Most participants did not meet daily requirements for fiber, potassium, or omega 3 fatty acids (2%, 15%, and 18%), nutrients important to reduce stroke risk., Conclusion: The diet quality of stroke survivors was poor, with inadequate intake of nutrients important for reducing recurrent stroke risk. Further research is needed to develop effective interventions to improve diet quality., (© 2023 S. Karger AG, Basel.)

Background: Pre-treatment rebleeding following aneurysmal subarachnoid hemorrhage (aSAH) increases the risk of death and a poor neurological outcome. Current guidelines recommend aneurysm treatment "as early as feasible after presentation, preferably within 24 h of onset" to mitigate this risk, a practice termed ultra-early treatment. However, ongoing debate regarding whether ultra-early treatment is independently associated with reduced re-bleeding risk, together with the recognition that re-bleeding occurs even in centres practicing ultra-early treatment due to the presence of other risk-factors has resulted in a renewed need for patient-specific re-bleed risk prediction. Here, we systematically review models which seek to provide patient specific predictions of pre-treatment rebleeding risk., Methods: Following registration on the International prospective register of systematic reviews (PROSPERO) CRD 42023421235; Ovid Medline (Pubmed), Embase and Googlescholar were searched for English language studies between 1st May 2002 and 1st June 2023 describing pre-treatment rebleed prediction models following aSAH in adults ≥18 years. Of 763 unique records, 17 full texts were scrutinised with 5 publications describing 4 models reviewed. We used the semi-automated template of Fernandez-Felix et al. incorporating the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) checklist and the Prediction model Risk Of Bias ASsessment Tool (PROBAST) for data extraction, risk of bias and clinical applicability assessment. To further standardize risk of bias and clinical applicability assessment, we also used the published explanatory notes for the PROBAST tool and compared the aneurysm treatment practices each prediction model's formulation cohort experienced to a prespecified benchmark representative of contemporary aneurysm treatment practices as outlined in recent evidence-based guidelines and published practice pattern reports from four developed countries., Results: Reported model discriminative performance varied between 0.77 and 0.939, however, no single model demonstrated a consistently low risk of bias and low concern for clinical applicability in all domains. Only the score of Darkwah Oppong et al. was formulated using a patient cohort in which the majority of patients were managed in accordance with contemporary, evidence-based aneurysm treatment practices defined by ultra-early and predominantly endovascular treatment. However, this model did not undergo calibration or clinical utility analysis and when applied to an external cohort, its discriminative performance was substantially lower that reported at formulation., Conclusions: No existing prediction model can be recommended for clinical use in centers practicing contemporary, evidence-based aneurysm treatment. There is a pressing need for improved prediction models to estimate and minimize pre-treatment re-bleeding risk., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: People with factor XI deficiency have lower rates of ischaemic stroke than the general population and infrequent spontaneous bleeding, suggesting that factor XI has a more important role in thrombosis than in haemostasis. Milvexian, an oral small-molecule inhibitor of activated factor XI, added to standard antiplatelet therapy, might reduce the risk of non-cardioembolic ischaemic stroke without increasing the risk of bleeding. We aimed to estimate the dose-response of milvexian for recurrent ischaemic cerebral events and major bleeding in patients with recent ischaemic stroke or transient ischaemic attack (TIA)., Methods: AXIOMATIC-SSP was a phase 2, randomised, double-blind, placebo-controlled, dose-finding trial done at 367 hospitals in 27 countries. Eligible participants aged 40 years or older, with acute (<48 h) ischaemic stroke or high-risk TIA, were randomly assigned by a web-based interactive response system in a 1:1:1:1:1:2 ratio to receive one of five doses of milvexian (25 mg once daily, 25 mg twice daily, 50 mg twice daily, 100 mg twice daily, or 200 mg twice daily) or matching placebo twice daily for 90 days. All participants received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg daily for the first 90 days. Investigators, site staff, and participants were masked to treatment assignment. The primary efficacy endpoint was the composite of ischaemic stroke or incident covert brain infarct on MRI at 90 days, assessed in all participants allocated to treatment who completed a follow-up MRI brain scan, and the primary analysis assessed the dose-response relationship with Multiple Comparison Procedure-Modelling (MCP-MOD). The main safety outcome was major bleeding at 90 days, assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov (NCT03766581) and the EU Clinical Trials Register (2017-005029-19)., Findings: Between Jan 27, 2019, and Dec 24, 2021, 2366 participants were randomly allocated to placebo (n=691); milvexian 25 mg once daily (n=328); or twice-daily doses of milvexian 25 mg (n=318), 50 mg (n=328), 100 mg (n=310), or 200 mg (n=351). The median age of participants was 71 (IQR 62-77) years and 859 (36%) were female. At 90 days, the estimates of the percentage of participants with either symptomatic ischaemic stroke or covert brain infarcts were 16·8 (90·2% CI 14·5-19·1) for placebo, 16·7 (14·8-18·6) for 25 mg milvexian once daily, 16·6 (14·8-18·3) for 25 mg twice daily, 15·6 (13·9-17·5) for 50 mg twice daily, 15·4 (13·4-17·6) for 100 mg twice daily, and 15·3 (12·8-19·7) for 200 mg twice daily. No significant dose-response was observed among the five milvexian doses for the primary composite efficacy outcome. Model-based estimates of the relative risk with milvexian compared with placebo were 0·99 (90·2% CI 0·91-1·05) for 25 mg once daily, 0·99 (0·87-1·11) for 25 mg twice daily, 0·93 (0·78-1·11) for 50 mg twice daily, 0·92 (0·75-1·13) for 100 mg twice daily, and 0·91 (0·72-1·26) for 200 mg twice daily. No apparent dose-response was observed for major bleeding (four [1%] of 682 participants with placebo, two [1%] of 325 with milvexian 25 mg once daily, two [1%] of 313 with 25 mg twice daily, five [2%] of 325 with 50 mg twice daily, five [2%] of 306 with 100 mg twice daily, and five [1%] of 344 with 200 mg twice daily). Five treatment-emergent deaths occurred, four of which were considered unrelated to the study drug by the investigator., Interpretation: Factor XIa inhibition with milvexian, added to dual antiplatelet therapy, did not substantially reduce the composite outcome of symptomatic ischaemic stroke or covert brain infarction and did not meaningfully increase the risk of major bleeding. Findings from our study have informed the design of a phase 3 trial of milvexian for the prevention of ischaemic stroke in patients with acute ischaemic stroke or TIA., Funding: Bristol Myers Squibb and Janssen Research & Development., Competing Interests: Declaration of interests MS has received consulting fees from Janssen, HLS Therapeutics, and Bayer; and has served in a leadership or fiduciary role for the Canadian Stroke Consortium. CAM has received honoraria from Bristol Myers Squibb and Boehringer Ingelheim. KT has received honoraria from Bayer, Daiichi Sankyo, Bristol Myers Squibb, Otsuka, Novartis, and Abbott Medical. DB has received consulting fees from Bristol Myers Squibb, Bayer, Ipsen, and Boehringer Ingelheim; and has received honoraria from Novo Nordisk, HUMAN BioPlazma, and Parexel. SEK has received grants or contracts from Bristol Myers Squibb; and has received consulting fees from Bristol Myers Squibb. HL has received consulting fees from Bristol Myers Squibb; has participated on steering committees or advisory boards for Bristol Myers Squibb, the US National Institute of Neurological Disorders and Stroke, and Coherex Medical; and is on the Editorial Board for Medscape Neurology. GT has received consulting fees from Bristol Myers Squibb. GN has received financial support from Bristol Myers Squibb. AC has participated on a steering committee for Bristol Myers Squibb; has received grants or contracts from Bristol Myers Squibb; and has previously served as the President of the Cerebrovascular Section of Polish Neurological Society, honorary president of the Polish Neurological Society, and in a leadership role for the Angels Initiative— Poland. PA has participated on a steering committee for Bristol Myers Squibb and Janssen; has received grants or contracts from Sanofi, Bristol Myers Squibb, AstraZeneca, Pfizer, Merck, AltheraPharm, and the French Government; has received consulting fees from Bayer, Novartis, and Novo Nordisk; has received honoraria from Viatris and Sanofi; and has participated in an advisory board for Novartis. ME has received grants or contracts from Bayer; has received consulting fees from Bayer; has received honoraria from Abbott, Boehringer Ingelheim, Pfizer, Amgen, GSK, Sanofi, and Novartis; has participated on data safety monitoring boards or advisory boards for Bristol Myers Squibb, Bayer, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Amgen, and Covidien; has served in a leadership or fiduciary role for the European Academy of Neurology, German Neurological Society (DGN), International Society for Cerebral Blood Flow and Metabolism, American Heart Association/American Stroke Association, European Stroke Organisation, World Stroke Organization, German Center for Cardiovascular Research (DZHK), and German Center for Neurodegenerative Diseases (DZNE); and has been a recipient of materials from Amgen. DTa has received consulting fees from QuantaIX Neuroscience, Babylink, and Pi-cardia, and for being a national leader in a randomised controlled trial. DTo has received honoraria from Abbott, Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, and Pfizer. LY has participated in steering committees for Bristol Myers Squibb and Janssen Research & Development; has received honoraria from Bayer, Bristol Myers Squibb, Pfizer, Boehringer Ingelheim, and Daiichi Sankyo; and has received support for attendance at the World Stroke Congress from the World Stroke Organization Future Stroke Leaders Program. PvWM has received contracts and support for attending an investigator meeting from Bristol Myers Squibb; and has served as a national leader and member of a steering committee for Bristol Myers Squibb. GSS has received support from and participated on a steering committee for Bristol Myers Squibb; has received grants or contracts from Boehringer Ingelheim; has received consulting fees from Bristol Myers Squibb and Boehringer Ingelheim; and has participated in an advisory board for Bristol Myers Squibb. AAv has received grants and honoraria from Bayer. JD has received support from Bristol Myers Squibb; has received grants from Pfizer; and has received honoraria from Pfizer, Daiichi Sankyo, and AstraZeneca. DS has received contracts, support for attending a steering committee meeting, and materials and drugs for performing the trial from Bristol Myers Squibb. TT has received grants from the University of Gothenburg, Sahlgrenska University Hospital, and Wennerstrom's Foundation; and has received consulting fees from Bayer, Inventiva Pharma, Bristol Myers Squibb, and Portola Pharmaceuticals. JE has received travel support from Bristol Myers Squibb for attending steering committee meetings. SFA has received grants from Bayer and Boehringer Ingelheim; and has received honoraria from Novo Nordisk and Abbott. JRW has served as President Elect of the Austrian Society of Neurology. ECS has received honoraria from Bristol Myers Squibb, Daiichi Sankyo, and Boston Scientific. NGP has served as the President of the Russian National Society of Preventive Cardiology. PML has received grants from Bristol Myers Squibb and Janssen; has received honoraria from Boehringer Ingelheim and Pfizer; has received support for attending the Global Stroke Alliance; has participated on a data safety monitoring board or advisory board for RapidAI; and has served as the President of the Chilean Stroke Association. DG has received grants or contracts, or both, from the US National Heart, Lung and Blood Institute and the US National Institutes of Health; has received consulting fees from Bristol Myers Squibb, Ionis, Janssen, and Anthos Therapeutics; and has participated on a steering committee for Bristol Myers Squibb. HCD has received support from Bristol Myers Squibb; has received grants from Boehringer Ingelheim and AstraZeneca; has received honoraria from Boehringer Ingelheim, Pfizer, Sanofi, and Bristol Myers Squibb; has received support for attending meetings or travel, or both, from Boehringer Ingelheim; and has participated on data safety monitoring boards or advisory boards for Actelion, the German Research Council, and the ELAN Study. RAB has received consulting fees from and has participated on a steering committee for Bristol Myers Squibb. CC has received honoraria from Bristol Myers Squibb and Amgen; and has participated on data safety monitoring boards or advisory boards for AstraZeneca and Biogen. GA, MD, and CP are employees and shareholders of Bristol Myers Squibb. AK and DL are employees and shareholders of Bristol Myers Squibb; and have a pending patent application related to this study. GJH has received consulting fees from Bristol Myers Squibb, Janssen Research & Development, and Bayer; has received honoraria from Janssen Medical Affairs; has received honoraria for participating on a data safety monitoring board for AC Immune; and has received honoraria from the American Heart Association for serving as an Associate Editor for Circulation. SIB, AS, BWY, and AAr declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: To determine the prevalence of common mental disorders among older Australians included in the Health In Men Data Linkage Study and compare those with the results of the 2020-2021 National Study of Mental Health and Wellbeing (NSMHW)., Method: We used longitudinal record linkage to estimate the prevalence of mental disorders from age 65 years in a random sample of 38173 Australian men aged 65-85 years living in the Perth metropolitan region. Outcome was the proportion of participants affected by depressive episodes or dysthymia, bipolar disorder, anxiety disorder, psychotic disorder and alcohol use disorder., Results: Prevalence estimates for participants aged 65-69, 70-74, 75-79, 80-84 and ≥85 years were 0.9%, 2.0%, 3.6%, 5.8% and 12.6% for depressive, 0.2%, 0.3%, 0.4%, 0.4% and 0.7% for bipolar, 0.1%, 0.5%, 1.3%, 2.2%, 6.9% for anxiety, 0.2%, 0.4%, 0.5%, 0.4% and 0.6% for psychotic and 1.2%, 1.7%, 2.1%, 2.2% and 4.2% for alcohol use disorders., Conclusions: In contrast to the NSMHW, our data indicate that the prevalence of depressive and anxiety disorders increases with age, particularly among the older old. We conclude that the NSMHW should not be relied upon to guide planning or policies to address the mental health needs of older Australians.

Objectives: As people age, rates of morbidity and mortality are heterogenous. Balance and strength performance may contribute to this, offering modifiable risk factors for mortality. We aimed to compare relationships of balance and strength performance with all-cause and cause-specific mortality., Design: The Health in Men Study, a cohort study, using wave 4 as baseline for analyses (2011-2013)., Setting and Participants: 1335 older men (>65 years old), initially recruited April 1996-January 1999 in Western Australia, were included., Methods: Physical tests included a strength (knee extension test) and balance measure (modified Balance Outcome Measure for Elder Rehabilitation (mBOOMER) Score), derived from baseline physical assessments. Outcome measures included all-cause, cardiovascular, and cancer mortality, ascertained via the WADLS death registry. Data were analyzed using Cox proportional hazards regression models (age as analysis time, adjusted for sociodemographic data, health behaviors, and conditions)., Results: Four hundred seventy-three participants died before the end of follow-up (December 17, 2017). Better performance on both the mBOOMER score and knee extension test was associated with lower likelihood of all-cause [hazard ratio (HR) 0.83, 95% CI 0.80-0.87, and HR 0.96, 95% CI 0.95-0.98, respectively] and cardiovascular mortality (HR 0.82, 95% CI 0.77-0.87, and HR 0.96, 95% CI 0.94-0.98, respectively). Better mBOOMER score performance was associated with lower likelihood of cancer mortality (HR 0.90, 95% CI 0.83-0.98) only when including participants with prior cancer., Conclusions and Implications: In summary, this study demonstrates an association of poorer performance in both strength and balance with future all-cause and cardiovascular mortality. Notably, these results clarify the relationship of balance with cause-specific mortality, with balance equaling strength as a modifiable risk factor for mortality., (Copyright © 2023 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Background: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT 4 ) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT 4 based on the risk of cardiovascular disease and mortality., Methods: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT 4 , and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT 4 , thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576., Findings: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 cohorts agreed to participate. We included IPD on 134 346 participants with a median age of 59 years (range 18-106) at baseline. There was a J-shaped association of FT 4 with the composite outcome and secondary outcomes, with the 20th (median 13·5 pmol/L [IQR 11·2-13·9]) to 40th percentiles (median 14·8 pmol/L [12·3-15·0]) conveying the lowest risk. Compared with the 20-40th percentiles, the age-adjusted and sex-adjusted hazard ratio (HR) for FT 4 in the 80-100th percentiles was 1·20 (95% CI 1·11-1·31) for the composite outcome, 1·34 (1·20-1·49) for all-cause mortality, 1·57 (1·31-1·89) for cardiovascular disease mortality, and 1·22 (1·11-1·33) for cardiovascular disease events. In individuals aged 70 years and older, the 10-year absolute risk of composite outcome increased over 5% for women with FT 4 greater than the 85th percentile (median 17·6 pmol/L [IQR 15·0-18·3]), and men with FT 4 greater than the 75th percentile (16·7 pmol/L [14·0-17·4]). Non-linear associations were identified for TSH, with the 60th (median 1·90 mIU/L [IQR 1·68-2·25]) to 80th percentiles (2·90 mIU/L [2·41-3·32]) associated with the lowest risk of cardiovascular disease and mortality. Compared with the 60-80th percentiles, the age-adjusted and sex-adjusted HR of TSH in the 0-20th percentiles was 1·07 (95% CI 1·02-1·12) for the composite outcome, 1·09 (1·05-1·14) for all-cause mortality, and 1·07 (0·99-1·16) for cardiovascular disease mortality., Interpretation: There was a J-shaped association of FT 4 with cardiovascular disease and mortality. Low concentrations of TSH were associated with a higher risk of all-cause mortality and cardiovascular disease mortality. The 20-40th percentiles of FT 4 and the 60-80th percentiles of TSH could represent the optimal healthy ranges of thyroid function based on the risk of cardiovascular disease and mortality, with more than 5% increase of 10-year composite risk identified for FT 4 greater than the 85th percentile in women and men older than 70 years. We propose a feasible approach to establish the optimal healthy ranges of thyroid function, allowing for better identification of individuals with a higher risk of thyroid-related outcomes., Funding: None., Competing Interests: Declaration of interests TIMK reports personal fees from IBSA, Meck, Berlin-Chemie, and Quidel; is an unpaid co-chair of the American Thyroid Association guidelines on thyroid and pregnancy. BBY reports grants from National Health and Medical Research Council, Fremantle Hospital Medical Research Foundation, and Ada Bartholomew Medical Research Trust. NR reports a grant from the Swiss National Science Foundation. SR reports a grant for an investigator-initiated trial by Merck; manufacturer of levothyroxine and speaker fees from Merck, Abbott Pharmaceuticals, IBSA (makers of levothyroxine). JWJ reports research grants from or was a speaker (with or without lecture fees) at (Continuing Medical Education accredited) meetings sponsored or supported by Abbott, Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Edwards Lifesciences, GE Healthcare, Johnson and Johnson, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, the Netherlands Heart Foundation, CardioVascular Research the Netherlands, the Netherlands Heart Institute, and the European Community Framework KP7 Programme. DCB reports research grants from the National institutes of Health. DF reports a research grant from DFG SFB TR 296 LOCOTACT. RGJW reports a research grant from the Novo Nordisk Foundation Challenge Programme (NNF17OC0027812). All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Air pollution is a cause of lung cancer and is associated with bladder cancer. However, the relationship between air pollution and these cancers in regions of low pollution is unclear. We investigated associations between fine particulate matter (PM 2.5 ), nitrogen dioxide, and black carbon (BC), and both these cancers in a low-pollution city., Methods: A cohort of 11,679 men ≥65 years old in Perth (Western Australia) were followed from 1996-1999 until 2018. Pollutant concentrations, as a time-varying variable, were estimated at participants' residential addresses using land use regression models. Incident lung and bladder cancer were identified through the Western Australian Cancer Registry. Risks were estimated using Cox proportional-hazard models (age as the timescale), adjusting for smoking, socioeconomic status, and co-pollutants., Results: Lung cancer was associated with PM 2.5 and BC in the adjusted single-pollutant models. A weak positive association was observed between ambient air pollution and squamous cell lung carcinoma but not lung adenocarcinoma. Positive associations were observed with bladder cancer, although these were not statistically significant. Associations were attenuated in two-pollutant models., Conclusion: Low-level ambient air pollution is associated with lung, and possibly bladder, cancer among older men, suggesting there is no known safe level for air pollution as a carcinogen., (© 2023. The Author(s).)

Competing Interests: GJH reports personal honoraria outside the submitted work from the American Heart Association (as an Associate Editor for Circulation), AC Immune (as a member of the data safety monitoring committee for the ACI-35–1802 trial of immune therapies for Alzheimer's disease), Bristol Myers Squibb (as a member of the steering committee for the AXIOMATIC-SSP trial of milvexian [factor XIa inhibitor] for secondary stroke prevention), and Janssen (as Co-chair of the executive committee for the Librexia Stroke trial of milvexian for secondary stroke prevention).

Background: Various factors modulate circulating testosterone in men, affecting interpretation of testosterone measurements., Purpose: To clarify factors associated with variations in sex hormone concentrations., Data Sources: Systematic literature searches (to July 2019)., Study Selection: Prospective cohort studies of community-dwelling men with total testosterone measured using mass spectrometry., Data Extraction: Individual participant data (IPD) (9 studies; n  = 21 074) and aggregate data (2 studies; n  = 4075). Sociodemographic, lifestyle, and health factors and concentrations of total testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone, and estradiol were extracted., Data Synthesis: Two-stage random-effects IPD meta-analyses found a nonlinear association of testosterone with age, with negligible change among men aged 17 to 70 years (change per SD increase about the midpoint, -0.27 nmol/L [-7.8 ng/dL] [CI, -0.71 to 0.18 nmol/L {-20.5 to 5.2 ng/dL}]) and decreasing testosterone levels with age for men older than 70 years (-1.55 nmol/L [-44.7 ng/dL] [CI, -2.05 to -1.06 nmol/L {-59.1 to -30.6 ng/dL}]). Testosterone was inversely associated with body mass index (BMI) (change per SD increase, -2.42 nmol/L [-69.7 ng/dL] [CI, -2.70 to -2.13 nmol/L {-77.8 to -61.4 ng/dL}]). Testosterone concentrations were lower for men who were married (mean difference, -0.57 nmol/L [-16.4 ng/dL] [CI, -0.89 to -0.26 nmol/L {-25.6 to -7.5 ng/dL}]); undertook at most 75 minutes of vigorous physical activity per week (-0.51 nmol/L [-14.7 ng/dL] [CI, -0.90 to -0.13 nmol/L {-25.9 to -3.7 ng/dL}]); were former smokers (-0.34 nmol/L [-9.8 ng/dL] [CI, -0.55 to -0.12 nmol/L {-15.9 to -3.5 ng/dL}]); or had hypertension (-0.53 nmol/L [-15.3 ng/dL] [CI, -0.82 to -0.24 nmol/L {-23.6 to -6.9 ng/dL}]), cardiovascular disease (-0.35 nmol/L [-10.1 ng/dL] [CI, -0.55 to -0.15 nmol/L {-15.9 to -4.3 ng/dL}]), cancer (-1.39 nmol/L [-40.1 ng/dL] [CI, -1.79 to -0.99 nmol/L {-51.6 to -28.5 ng/dL}]), or diabetes (-1.43 nmol/L [-41.2 ng/dL] [CI, -1.65 to -1.22 nmol/L {-47.6 to -35.2 ng/dL}]). Sex hormone-binding globulin was directly associated with age and inversely associated with BMI. Luteinizing hormone was directly associated with age in men older than 70 years., Limitation: Cross-sectional analysis, heterogeneity between studies and in timing of blood sampling, and imputation for missing data., Conclusion: Multiple factors are associated with variation in male testosterone, SHBG, and LH concentrations. Reduced testosterone and increased LH concentrations may indicate impaired testicular function after age 70 years. Interpretation of individual testosterone measurements should account particularly for age older than 70 years, obesity, diabetes, and cancer., Primary Funding Source: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668)., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-0342.

Background: Anti-inflammatory therapy using colchicine has reduced recurrent vascular events in patients with coronary heart disease., Design: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3) is a randomized, double-blind, placebo-controlled multicenter trial, in which 8,238 patients with acute minor-to-moderate ischemic stroke (NIHSS ⩽ 5) or high-risk transient ischemic attack (TIA) (ABCD 2 score ⩾4) and a high-sensitivity CRP (hsCRP) level of ⩾2 mg/L will be randomly assigned within 24 h of symptom onset to colchicine (1 mg daily on days 1-3, followed by 0.5 mg daily for a total of 90 days) or matching placebo, on a background of optimal medical therapy. The study will have 90% power to detect a 25% reduction in the primary efficacy outcome of any stroke within 3 months of randomization. Adverse events potentially related to the use of colchicine will also be analyzed. The primary analysis will be by intention to treat., Trial Registry Name: Colchicine in High-risk Patients with Acute Minor-to-moderate Ischemic Stroke or Transient Ischemic Attack (CHANCE-3); URL: https://clinicaltrials.gov/ct2/show/NCT05439356?cond=CHANCE-3&draw=2&rank=1; Registration number : NCT05439356.

Objective: Older people are more prone to vitamin D deficiency than younger populations. Individual lifestyle factors have been associated with vitamin D status. We examined the influence of a combination of lifestyle factors on vitamin D status in older men., Participants and Measurements: In a population-based cohort study of older men (age ≥65 years), a lifestyle score was calculated from eight prudent health-related behaviours (smoking, exercise, alcohol, fish and meat consumption, adding salt, milk choices and obesity) collected via questionnaire at baseline. Blood samples were collected 5 years afterwards to measure plasma 25-hydroxyvitamin D (25OHD) levels. Associations between lifestyles and the likelihood of having plasma 25OHD levels of ≥75 versus <75 nmol/L and ≥50 versus <50 nmol/L were tested using logistic regression models., Results: Of the 2717 men analysed, mean plasma 25OHD was 69.0 ± 23.5 nmol/L, with 20.7% having plasma 25OHD <50 nmol/L. Men engaging in ≥4 healthy lifestyle behaviours had 20% higher odds of plasma 25OHD ≥75 nmol/L (adjusted OR = 1.20, 95% CI: 1.01-1.45) compared to those with <4 healthy behaviours. No association was found for 25OHD ≥50 nmol/L. Higher physical activity was the only individual component significantly associated with vitamin D sufficiency (highest vs. lowest quintiles of physical activity, adjusted OR = 2.01, 95% CI: 1.47-2.74 for 25OHD ≥50 nmol/L, adjusted OR = 2.35, 95% CI: 1.81-3.06 for 25OHD ≥75 nmol/L)., Conclusion: Multiple healthy lifestyle behaviours are associated with better vitamin D status in older men. Further work is needed to determine the effects of promoting healthy lifestyle behaviours, including physical activity, on vitamin D sufficiency., (© 2023 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.)

Exposure to particulate matter with an aerodynamic diameter less than or equal to 2.5 μm (PM 2.5 ) is associated with increased risk of heart disease, but less is known about the relationship at low concentrations. This study aimed to determine the dose-response relationship between long-term PM 2.5 exposure and risk of incident ischemic heart disease (IHD), incident heart failure (HF), and incident atrial fibrillation (AF) in older men living in a region with relatively low ambient air pollution., Methods: PM 2.5 exposure was estimated for 11,249 older adult males who resided in Perth, Western Australia and were recruited from 1996 to 1999. Participants were followed until 2018 for the HF and AF outcomes, and until 2017 for IHD. Cox-proportional hazards models, using age as the analysis time, and adjusting for demographic and lifestyle factors were used. PM 2.5 was entered as a restricted cubic spline to model nonlinearity., Results: We observed a mean PM 2.5 concentration of 4.95 μg/m 3 (SD 1.68 μg/m 3 ) in the first year of recruitment. After excluding participants with preexisting disease and adjusting for demographic and lifestyle factors, PM 2.5 exposure was associated with a trend toward increased incidence of IHD, HF, and AF, but none were statistically significant. At a PM 2.5 concentration of 7 μg/m 3 the hazard ratio for incident IHD was 1.04 (95% confidence interval [CI] = 0.86, 1.25) compared with the reference category of 1 μg/m 3 ., Conclusions: We did not observe a significant association between long-term exposure to low-concentration PM 2.5 air pollution and IHD, HF, or AF., Competing Interests: J.S.J. is a recipient of the Lawrence Scholarly Plus Award in Stroke Research. L.N. is funded by a National Heart Foundation Future Leader Fellowship. J.G. is supported by grants from the Queensland government, Medical Research Future Fund, National Health and Medical Research Council, Heart Foundation and Townsville Hospital and Health Services. The other authors declare that they have no conflicts of interest with regard to the content of this report. The Health in Men Study (HIMS) is supported by competitive projects grants from the National Health and Medical Research Council of Australia (NHMRC; 1128083, 1003589). Air pollution data that support the findings of this study are held by the Centre for Air pollution, energy and health Research (https://www.car-cre.org.au/cardatplatform) and are available from the corresponding author on reasonable request. The data derived from the Health in Men Study cannot be made publicly available due to confidentiality restrictions. Access to these data can be sought via application to the Health in Men Study investigators and will need to satisfy appropriate ethical requirements. The funding sources had no role in the design of the study, nor the collection, management, analysis or interpretation of data, nor had any input into the preparation of this manuscript., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Background: Restoring hemostasis in patients on oral anticoagulants presenting with major hemorrhage (MH) or before surgical intervention has changed, with the replacement of vitamin K antagonist (VKA) with direct oral anticoagulants (DOACs)., Objectives: To observe the difference in urgent hemostatic management between patients on VKA and those on DOACs., Methods: A multicenter observational study evaluated the variation in laboratory testing, hemostatic management, mortality, and hospital length of stay (LOS) in patients on VKA or DOACs presenting with MH or urgent hemostatic restoration., Results: Of the 1194 patients analyzed, 783 had MH (61% VKA) and 411 required urgent hemostatic restoration before surgery (56% VKA). Compared to the international normalized ratio (97.6%), plasma DOAC levels were measured less frequently (<45%), and the time taken from admission for the coagulation sample to reach the laboratory varied widely (median, 52.3 minutes; IQR, 24.8-206.7). No significant plasma DOAC level (<50 ng/mL) was found in up to 19% of patients. There was a poor relationship between plasma DOAC level and the usage of a hemostatic agent. When compared with patients receiving VKA (96.5%) or dabigatran (93.7%), fewer patients prescribed a factor Xa inhibitor (75.5%) received a prohemostatic reversal agent. The overall 30-day mortality for MH (mean: 17.8%) and length of stay (LOS) (median: 8.7 days) was similar between VKA and DOAC patients., Conclusion: In DOAC patients, when compared to those receiving VKA, plasma DOAC levels were measured less frequently than the international normalized ratio and had a poor relationship with administering a hemostatic reversal agent. In addition, following MH, mortality and LOS were similar between VKA and DOAC patients., (© 2023 The Authors.)

Background and Objectives: Symptoms of sleep disturbance are common and may represent important modifiable risk factors of stroke. We evaluated the association between a spectrum of sleep disturbance symptoms and the risk of acute stroke in an international setting., Methods: The INTERSTROKE study is an international case-control study of patients presenting with first acute stroke and controls matched by age (±5 years) and sex. Sleep symptoms in the previous month were assessed through a questionnaire. Conditional logistic regression estimated the association between sleep disturbance symptoms and acute stroke, expressed as odds ratios (ORs) and 95% CIs. The primary model adjusted for age, occupation, marital status, and modified Rankin scale at baseline, with subsequent models adjusting for potential mediators (behavioral/disease risk factors)., Results: Overall, 4,496 matched participants were included, with 1,799 of them having experienced an ischemic stroke and 439 an intracerebral hemorrhage. Short sleep (<5 hours: OR 3.15, 95% CI 2.09-4.76), long sleep (>9 hours: OR 2.67, 95% CI 1.89-3.78), impaired quality (OR 1.52, 95% CI 1.32-1.75), difficulty getting to sleep (OR 1.32, 95% CI 1.13-1.55) or maintaining sleep (OR 1.33, 95% CI 1.15-1.53), unplanned napping (OR 1.48, 95% CI 1.20-1.84), prolonged napping (>1 hour: OR 1.88, 95% CI 1.49-2.38), snoring (OR 1.91, 95% CI 1.62-2.24), snorting (OR 2.64, 95% CI 2.17-3.20), and breathing cessation (OR 2.87, 95% CI 2.28-3.60) were all significantly associated with an increased odds of acute stroke in the primary model. A derived obstructive sleep apnea score of 2-3 (2.67, 2.25-3.15) and cumulative sleep symptoms (>5: 5.38, 4.03-7.18 ) were also associated with a significantly increased odds of acute stroke, with the latter showing a graded association. After an extensive adjustment, significance was maintained for most of the symptoms (not difficulty getting to/maintaining sleep and unplanned napping), with similar findings for stroke subtypes., Discussion: We found that sleep disturbance symptoms were common and associated with a graded increased risk of stroke. These symptoms may be a marker of increased individual risk or represent independent risk factors. Future clinical trials are warranted to determine the efficacy of sleep interventions in stroke prevention., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: Depression has been reported to be a risk factor of acute stroke, based largely on studies in high-income countries. In the INTERSTROKE study, we explored the contribution of depressive symptoms to acute stroke risk and 1-month outcome across regions of the world, within subpopulations and by stroke type., Methods: The INTERSTROKE is an international case-control study of risk factors of first acute stroke, conducted in 32 countries. Cases were patients with CT- or MRI-confirmed incident acute hospitalized stroke, and controls were matched for age, sex, and within sites. Standardized questions asked about self-reported depressive symptoms during the previous 12 months and the use of prescribed antidepressant medications were recorded. Multivariable conditional logistic regression was used to determine the association of prestroke depressive symptoms with acute stroke risk. Adjusted ordinal logistic regression was used to explore the association of prestroke depressive symptoms with poststroke functional outcome, measured with the modified Rankin scale at 1 month after stroke., Results: Of 26,877 participants, 40.4% were women, and the mean age was 61.7 ± 13.4 years. The prevalence of depressive symptoms within the last 12 months was higher in cases compared with that in controls (18.3% vs 14.1%, p < 0.001) and differed by region ( p interaction <0.001), with lowest prevalence in China (6.9% in controls) and highest in South America (32.2% of controls). In multivariable analyses, prestroke depressive symptoms were associated with greater odds of acute stroke (odds ratio [OR] 1.46, 95% CI 1.34-1.58), which was significant for both intracerebral hemorrhage (OR 1.56, 95% CI 1.28-1.91) and ischemic stroke (OR 1.44, 95% CI 1.31-1.58). A larger magnitude of association with stroke was seen in patients with a greater burden of depressive symptoms. While preadmission depressive symptoms were not associated with a greater odds of worse baseline stroke severity (OR 1.02, 95% CI 0.94-1.10), they were associated with a greater odds of poor functional outcome at 1 month after acute stroke (OR 1.09, 95% CI 1.01-1.19)., Discussion: In this global study, we recorded that depressive symptoms are an important risk factor of acute stroke, including both ischemic and hemorrhagic stroke. Preadmission depressive symptoms were associated with poorer functional outcome, but not baseline stroke severity, suggesting an adverse role of depressive symptoms in poststroke recovery., (© 2023 American Academy of Neurology.)

Objective: Older men on an average have lower testosterone concentrations, compared with younger men, and more age-related comorbidities. Whether lower testosterone concentrations contribute to biological ageing remains unclear. Shorter telomeres are a marker for biological age. We tested the hypothesis that testosterone concentrations are associated with leucocyte telomere length (LTL), in middle- to older-aged men., Design: Cross-sectional analysis of the UK Biobank study, involving community-dwelling men aged 40-69 years., Methods: Serum testosterone and sex hormone-binding globulin (SHBG) were assayed. Free testosterone was calculated (cFT). Leucocyte telomere length was measured using polymerase chain reaction. Multivariable models were used to assess associations of hormones with standardised LTL., Results: In 167 706 men, median age 58 years, adjusting for sociodemographic, lifestyle, and medical factors, total testosterone was inversely associated with standardised LTL, which was 0.09 longer (95% confidence interval [CI], 0.08-0.10, P < .001) in men with total testosterone at median of lowest quintile [Q1] vs highest [Q5]. This relationship was attenuated after additional adjustment for SHBG (0.03 longer, CI = 0.02-0.05, P = .003). The association between cFT and LTL was similar in direction but lower in magnitude. In multivariable analysis, SHBG was inversely associated with standardised LTL, which was 0.12 longer (CI = 0.10-0.13, P < .001) for SHBG at median Q1 vs Q5. Results were similar with testosterone included in the model (0.10 longer, CI = 0.08-0.12, P < .001)., Conclusions: Total testosterone and SHBG were independently and inversely associated with LTL. Men with higher testosterone or SHBG had shorter telomeres, arguing against a role for testosterone to slow biological ageing in men., (© The Author(s) 2023. Published by Oxford University Press on behalf of (ESE) European Society of Endocrinology.)

Background: Previous studies had limited power to assess the associations of circulating insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) with clinically relevant prostate cancer as a primary endpoint, and the association of genetically predicted IGF-I with aggressive prostate cancer is not known. We aimed to investigate the associations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 concentrations with overall, aggressive and early-onset prostate cancer., Methods: Prospective analysis of biomarkers using the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset (up to 20 studies, 17 009 prostate cancer cases, including 2332 aggressive cases). Odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression. For IGF-I, two-sample Mendelian randomization (MR) analysis was undertaken using instruments identified using UK Biobank (158 444 men) and outcome data from PRACTICAL (up to 85 554 cases, including 15 167 aggressive cases). Additionally, we used colocalization to rule out confounding by linkage disequilibrium., Results: In observational analyses, IGF-I was positively associated with risks of overall (OR per 1 SD = 1.09: 95% CI 1.07, 1.11), aggressive (1.09: 1.03, 1.16) and possibly early-onset disease (1.11: 1.00, 1.24); associations were similar in MR analyses (OR per 1 SD = 1.07: 1.00, 1.15; 1.10: 1.01, 1.20; and 1.13; 0.98, 1.30, respectively). Colocalization also indicated a shared signal for IGF-I and prostate cancer (PP4: 99%). Men with higher IGF-II (1.06: 1.02, 1.11) and IGFBP-3 (1.08: 1.04, 1.11) had higher risks of overall prostate cancer, whereas higher IGFBP-1 was associated with a lower risk (0.95: 0.91, 0.99); these associations were attenuated following adjustment for IGF-I., Conclusions: These findings support the role of IGF-I in the development of prostate cancer, including for aggressive disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Background: This is an update of the Cochrane Review last published in 2017. Survivors of stroke due to intracerebral haemorrhage (ICH) are at risk of major adverse cardiovascular events (MACE). Antithrombotic (antiplatelet or anticoagulant) treatments may lower the risk of ischaemic MACE after ICH, but they may increase the risk of bleeding., Objectives: To determine the overall effectiveness and safety of antithrombotic drugs on MACE and its components for people with ICH., Search Methods: We searched the Cochrane Stroke Group Trials Register (5 October 2021). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL: the Cochrane Library 2021, Issue 10), MEDLINE Ovid (from 1948 to October 2021) and Embase Ovid (from 1980 to October 2021). The online registries of clinical trials searched were the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (5 October 2021). We screened the reference lists of included randomised controlled trials (RCTs) for additional, potentially relevant RCTs., Selection Criteria: We selected RCTs in which participants with ICH of any age were allocated to a class of antithrombotic treatment as intervention or comparator., Data Collection and Analysis: In accordance with standard methodological procedures recommended by Cochrane, two review authors assessed each selected RCT for its risk of bias and extracted data independently. The primary outcome was a composite of MACE, and secondary outcomes included death, individual components of the MACE composite, ICH growth, functional status and cognitive status. We estimated effects using the frequency of outcomes that occurred during the entire duration of follow-up and calculated a risk ratio (RR) for each RCT. We grouped RCTs separately for analysis according to 1) the class(es) of antithrombotic treatment used for the intervention and comparator, and 2) the duration of antithrombotic treatment use (short term versus long term). We pooled the intention-to-treat populations of RCTs using a fixed-effect model for meta-analysis, but used a random-effects model if RCTs differed substantially in their design or there was considerable heterogeneity (I 2 ≥ 75%) in their results. We applied GRADE to assess the certainty of the evidence., Main Results: We identified seven new completed RCTs for this update, resulting in the inclusion of a total of nine RCTs based in secondary care, comprising 1491 participants (average age ranged from 61 to 79 years and the proportion of men ranged from 44% to 67%). The proportion of included RCTs at low risk of bias, by category was: random sequence generation (67%), allocation concealment (67%), performance (22%), detection (78%), attrition (89%), and reporting (78%). For starting versus avoiding short-term prophylactic dose anticoagulation after ICH, no RCT reported MACE. The evidence is very uncertain about the effect of starting short-term prophylactic dose anticoagulation on death (RR 1.00, 95% CI 0.59 to 1.70, P = 1.00; 3 RCTs; very low-certainty evidence), venous thromboembolism (RR 0.84, 95% CI 0.51 to 1.37, P = 0.49; 4 RCTs; very low-certainty evidence), ICH (RR 0.24, 95% CI 0.04 to 1.38, P = 0.11; 2 RCTs; very low-certainty evidence), and independent functional status (RR 2.03, 95% CI 0.78 to 5.25, P = 0.15; 1 RCT; very low-certainty evidence) over 90 days. For starting versus avoiding long-term therapeutic dose oral anticoagulation for atrial fibrillation after ICH, starting long-term therapeutic dose oral anticoagulation probably reduces MACE (RR 0.61, 95% CI 0.40 to 0.94, P = 0.02; 3 RCTs; moderate-certainty evidence) and probably reduces all major occlusive vascular events (RR 0.27, 95% CI 0.14 to 0.53, P = 0.0002; 3 RCTs; moderate-certainty evidence), but probably results in little to no difference in death (RR 1.05, 95% CI 0.62 to 1.78, P = 0.86; 3 RCTs; moderate-certainty evidence), probably increases intracranial haemorrhage (RR 2.43, 95% CI 0.88 to 6.73, P = 0.09; 3 RCTs; moderate-certainty evidence), and may result in little to no difference in independent functional status (RR 0.98, 95% CI 0.78 to 1.24, P = 0.87; 2 RCTs; low-certainty evidence) over one to three years. For starting versus avoiding long-term antiplatelet therapy after ICH, the evidence is uncertain about the effects of starting long-term antiplatelet therapy on MACE (RR 0.89, 95% CI 0.64 to 1.22, P = 0.46; 1 RCT; moderate-certainty evidence), death (RR 1.08, 95% CI 0.76 to 1.53, P = 0.66; 1 RCT; moderate-certainty evidence), all major occlusive vascular events (RR 1.03, 95% CI 0.68 to 1.55, P = 0.90; 1 RCT; moderate-certainty evidence), ICH (RR 0.52, 95% CI 0.27 to 1.03, P = 0.06; 1 RCT; moderate-certainty evidence) and independent functional status (RR 0.95, 95% CI 0.77 to 1.18, P = 0.67; 1 RCT; moderate-certainty evidence) over a median follow-up of two years. For adults within 180 days of non-cardioembolic ischaemic stroke or transient ischaemic attack and a clinical history of prior ICH, there was no evidence of an effect of long-term cilostazol compared to aspirin on MACE (RR 1.33, 95% CI 0.74 to 2.40, P = 0.34; subgroup of 1 RCT; low-certainty evidence), death (RR 1.65, 95% CI 0.55 to 4.91, P = 0.37; subgroup of 1 RCT; low-certainty evidence), or ICH (RR 1.29, 95% CI 0.35 to 4.69, P = 0.70; subgroup of 1 RCT; low-certainty evidence) over a median follow-up of 1.8 years; all major occlusive vascular events and functional status were not reported., Authors' Conclusions: We did not identify beneficial or hazardous effects of short-term prophylactic dose parenteral anticoagulation and long-term oral antiplatelet therapy after ICH on important outcomes. Although there was a significant reduction in MACE and all major occlusive vascular events after long-term treatment with therapeutic dose oral anticoagulation for atrial fibrillation after ICH, the pooled estimates were imprecise, the certainty of evidence was only moderate, and effects on other important outcomes were uncertain. Large RCTs with a low risk of bias are required to resolve the ongoing dilemmas about antithrombotic treatment after ICH., (Copyright © 2023 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.)

Background and Objectives: There is uncertainty about the association between alcohol consumption and stroke, particularly for low-moderate intake. We explored these associations in a large international study., Methods: INTERSTROKE, a case-control study, is the largest international study of risk factors for acute stroke. Alcohol consumption was self-reported and categorized by drinks/week as low (1-7), moderate (7-14 for females and 7-21 for males), or high (>14 for females and >21 for males). Heavy episodic drinking (HED) was defined as >5 drinks on ≥1 day per month. Multivariable conditional logistic regression was used to determine associations., Results: We included 12,913 cases and 12,935 controls; 25.0% (n = 6,449) were current drinkers, 16.7% (n = 4,318) former drinkers, and 58.3% (n = 15,076) never drinkers. Current drinkers were younger, male, smokers, active, and with higher-paid occupations. Current drinking was associated with all stroke (OR 1.14; 95% CI 1.04-1.26) and intracerebral hemorrhage (ICH) (OR 1.50, 95% CI 1.21-1.84) but not ischemic stroke (OR 1.06; 95% CI 0.95-1.19). HED pattern was associated with all stroke (OR 1.39; 95% CI 1.21-1.59), ischemic stroke (OR 1.29; 95% CI 1.10-1.51), and ICH (OR 1.76; 95% CI 1.31-2.36). High level of alcohol intake was consistently associated with all stroke, ischemic stroke, and ICH. Moderate intake was associated with all stroke and ICH but not ischemic stroke. Low alcohol intake was not associated with stroke overall, but there were regional differences; low intake was associated with reduced odds of stroke in Western Europe/North America (OR 0.66; 95% CI 0.45-0.96) and increased odds in India (OR 2.18; 95% CI 1.42-3.36) (p-interaction 0.037). Wine consumption was associated with reduced odds of all stroke and ischemic stroke but not ICH. The magnitudes of association were greatest in those without hypertension and current smokers., Discussion: High and moderate intake were associated with increased odds of stroke, whereas low intake was not associated with stroke. However, there were important regional variations, which may relate to differences in population characteristics of alcohol consumers, types or patterns of consumption., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Cancer has been associated with lower risk of dementia, although methodological issues raise concerns about the validity of this association. We recruited 31,080 men aged 65-85 years who were free of cancer and dementia, and followed them for up to 22 years. We used health record linkage to identify incident cases of cancer and dementia, and split time span to investigate this association. 18,693 (60.1%) and 6897 (22.2%) participants developed cancer and dementia during follow-up. The hazard ratio (HR) of dementia associated with cancer was 1.13 (95% CI = 1.07, 1.20) and dropped to 0.85 (95% CI = 0.80, 0.91) when 449 participants who developed dementia within 2 years were excluded. The diagnosis of cancer seems to facilitate the early detection of dementia cases. Older participants who survive cancer for 2 or more years have lower risk of receiving the diagnosis of dementia over time. The factors that mediate this association remain unclear.

Objectives: This study is designed to determine if hearing loss is associated with increased risk of frailty in later life., Design: A prospective cohort study., Setting and Participants: We retrieved data of a community sample of men aged 70 years and above living in the metropolitan region of Perth, Western Australia. 3,285 participants who were free of frailty at the beginning of the study were followed for up to 17 years. Data were retrieved from the Health in Men Study (HIMS) and the Western Australian Data Linkage System (WADLS)., Measurements: Hearing loss was defined by self-report or by diagnosis recorded in the WADLS. Incident frailty was assessed using the Hospital Frailty Risk Score (HFRS)., Results: A total of 2,348 (71.5%) men developed frailty during follow up. The adjusted hazard ratio was 1.03 (95% CI: 0.95-1.12). The majority of the participants became frail by age 90 regardless of hearing condition. The time point where half of the group become frail was delayed by 14.4 months for men without hearing loss compared with hearing impaired men., Conclusions: Hearing loss is not associated with incident frailty in men aged 70 years or older when frailty was measured by HFRS. However, this statistically non-significant result could be due to the low sensitivity of study measures. Also, we found a trend that men with hearing loss were more likely to develop frailty compared with their normal-hearing peers, suggesting a potential association between hearing loss and frailty., Competing Interests: None declared.

Importance: Psychosocial stress is considered a modifiable risk factor for stroke. Given the prevalence of chronic and acute exposure to stress, it represents a potentially attractive target for population-health interventions., Objectives: To determine the association of psychosocial stress with the risk of acute stroke and explore factors that might modify the association of stress with risk of acute stroke in a large international population., Design, Setting, and Participants: INTERSTROKE is an international retrospective case-control study of risk factors for first acute stroke in 32 countries in Asia, North and South America, Europe, Australia, the Middle East, and Africa. A total of 13 462 patients with stroke and 13 488 matched controls were recruited between January 11, 2007, and August 8, 2015. The present analyses were performed from June 1 to 30, 2021, and included 13 350 cases and 13 462 controls with available data on psychosocial stress., Exposures: Psychosocial stress and occurrence of stressful life events within the preceding year were measured using a standardized questionnaire of self-reported stress at home and work., Main Outcomes and Measures: The association of stress with acute stroke and its subtypes was examined using multivariable conditional logistic regression and factors that might modify the association, particularly self-reported locus of control., Results: Among 26 812 participants included in the analysis, the mean (SD) age of cases was 62.2 (13.6) years; that of controls, 61.3 (13.3) years; 7960 cases (59.6%) and 8017 controls (59.6%) were men. Several periods of stress and permanent stress were reported for 2745 cases (20.5%) and 1933 controls (14.4%), with marked regional variation in prevalence, with the lowest in China (201 of 3981 [5.0%] among controls and 364 of 3980 [9.1%] among cases) and highest in South East Asia (233 of 855 [26.1%] among controls and 241 of 782 [30.8%] among cases). Increased stress at home (odds ratio [OR], 1.95 [95% CI, 1.77-2.15]) and at work (OR, 2.70 [95% CI, 2.25-3.23]) and recent stressful life events (OR, 1.31 [95% CI, 1.19-1.43]) were associated with an increased risk of acute stroke on multivariable analyses (vs no self-reported stress). Higher locus of control at home was associated with a reduced odds of all stroke (OR, 0.73 [95% CI, 0.68-0.79]), and higher locus of control both at work and at home were associated with a lower odds of acute stroke and significantly diminished the association with stress at work (OR, 2.20 [95% CI, 1.88-2.58]; P = .008 for interaction) and home (OR, 1.69 [95% CI, 1.44-1.98]; P < .001 for interaction) for acute stroke., Conclusions and Relevance: Psychosocial stress is a common risk factor for acute stroke. The findings of this case-control study suggest that higher locus of control is associated with lower risk of stroke and may be an important effect modifier of the risk associated with psychosocial stress.

Background: In areas with moderate to severe air pollution, pollutant concentrations are associated with dementia risk. It is unclear whether the same relationship is present in regions with lower ambient air pollution., Objective: To determine whether exposure to air pollution is associated with risk of incident dementia in general, and Alzheimer's disease and vascular dementia in particular, in older men living in a relatively low ambient air pollution region., Methods: The cohort comprised 11,243 men residing in Perth, Australia. Participants were aged ≥65 years and free of a dementia diagnosis at time of recruitment in 1996-1999. Incident dementia was identified from recruitment to 2018 via ICD diagnosis codes and subsequent study waves. Concentrations for three air pollutants, nitrogen dioxide (NO 2 ), fine particulate matter less than 2.5 μm in diameter (PM 2.5 ), and black carbon (BC) were estimated at participants' home addresses using land-use regression models. We used Cox proportional hazards regression models adjusting for smoking status, physical activity, BMI, education, and socio-economic status., Results: Of 3053 (27.2%) incident cases of dementia, 1670 (54.7%) and 355 (11.6%) had documented Alzheimer's disease and vascular dementia. The average concentration of NO 2 was 13.5 (SD 4.4) μg/m 3 , of PM 2.5 was 4.54 (SD 1.6) μg/m 3 and of BC was 0.97 (SD 0.29) ×10 -5  m -1 . None of the air pollutants were associated with incident dementia or Alzheimer's disease. In the unadjusted model, increased exposure to PM 2.5 was associated with an increased risk of vascular dementia (for a 5 μg/m 3 increase: HR 1.62, 95% CI 1.13, 2.31). However, this association was attenuated following adjustment for confounders (HR 1.39, 95% CI 0.93, 2.08). NO 2 and BC were not associated with vascular dementia incidence., Discussion: Exposure to air pollution is not associated with increased risk of incident dementia in older men living in a region with relatively low ambient air pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We investigated the cumulative prevalence of self-harm ideation among stroke survivors of the AFFINITY trial. We assessed these thoughts with the last item of the PHQ-9, and functional impairment with the modified Rankin Scale (mRS). Of 1221 participants (age 63.9 ± 12.3 years, 775 men), 11 reported wishing to die or self-harm at baseline. By week 52, 36 of 1159 surviving participants had reported wishing to die or self-harm. Treatment with fluoxetine for 26 weeks did not change the prevalence of these thoughts compared with placebo. Clinically significant symptoms of depression were present in 95 % of participants with recurrent self-harm thoughts. The study was registered with the Australian and New Zealand Clinical Trials Registry, ACTRN12611000774921., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Crown Copyright © 2022. Published by Elsevier B.V. All rights reserved.)

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke., Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank., Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min -1 ·1.73 m -2 , compared with those with eGFR between 60 and 105 mL·min -1 ·1.73 m -2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min -1 ·1.73 m -2 , with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min -1 ·1.73 m -2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min -1 ·1.73 m -2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD., Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

People with aphasia have been systematically excluded from stroke research or included without the necessary modifications, threatening external study validity. In this paper, we propose that 1) the inclusion of people with aphasia should be considered as standard in stroke research irrespective of discipline and that 2) modifications should be made to stroke research procedures to support people with aphasia to achieve meaningful and valid inclusion. We argue that outright exclusion of this heterogenous population from stroke research based purely on a diagnosis of aphasia is rarely required and present a rationale for deliberate inclusion of people with aphasia in stroke research. The purpose of this paper is fourfold: 1) to highlight the issue and implications of excluding people with aphasia from stroke research; 2) to acknowledge the current barriers to including people with aphasia in stroke research; 3) to provide stroke researchers with methods to enable inclusion, including recommendations, resources, and guidance; and 4) to consider research needed to develop aphasia inclusive practices in stroke research., (Copyright © 2022 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)