BACKGROUND:Increasing knowledge about stroke may reduce its burden. We examined the effect of the Stroke RiskometerTM mobile phone application (the App) on stroke knowledge in a randomized controlled trial (RCT). METHODS:This was a pre-specified secondary outcome analysis in a phase III, prospective, participant and outcome assessor-blinded, two-arm RCT in Australia and New Zealand. Participants were recruited between 2021 and 2023, aged 35-75 years, with ⩾2 stroke risk factors and no cardiovascular disease history. Participants were randomized after assessment of stroke risk factors and knowledge to the intervention group (IG-received risk factor assessment by email and links to the App), and the usual care group (UCG-received risk factor assessment with links to generic information by email). Stroke knowledge was measured at baseline, 3, 6, and 12 months using six validated questions (total score 0 (low knowledge) to 19 (high knowledge)). We used linear and logistic mixed-effects modeling to assess differences in the level of overall stroke knowledge and domains (description, warning signs, risk factors, management) between IG and UCG at each time point. Effect modification of the intervention with age, sex, level of education, ethnicity, socioeconomic status (SES), and country was assessed. RESULTS:There were 862 participants (mean age: 58.1 years (standard deviation (SD): 10.8), 63.0% female, 61.6% tertiary educated, 73.3% European, and 14.7% most disadvantaged area-level SES) randomized to IG (n = 429) and UCG (n = 433). Dropouts (IG/UCG) were as follows: 7.9%/4.8% at 3 months, 3.0%/1.8% at 6 months, and 13.5%/9.0% at 12 months. The time-IG interaction showed a statistically significantly increased overall stroke knowledge (β = 0.50, 95% confidence interval (CI) = 0.02, 0.97) compared with UCG at 6 months only. The intervention effect was stronger in tertiary educated, non-European, and non-Indigenous ethnic groups, and the least disadvantaged SES group. For domains, IG was more likely to correctly identify stroke risk factors (odds ratio (OR) = 1.92, 95% CI = 1.09, 3.39) at 3 months, compared with UCG. CONCLUSION:The Stroke RiskometerTM App modestly improved stroke knowledge compared with UCG at 6 months but lacks evidence for retaining knowledge at 12 months. As knowledge can drive behavior change, the App may be a tool to enhance primary stroke prevention. TRIAL REGISTRATION:ACTRN12621000211864.

Background and ObjectivesAccording to region-specific hospital-based studies, the location of ruptured intracranial aneurysm (RIA) influences the case fatality rate (CFR) of aneurysmal subarachnoid hemorrhage (SAH). However, little is known about whether CFRs vary by RIA location in population-based studies that include prehospital SAH deaths. We assessed whether CFRs and CFR-trends differ by RIA location using whole population data from Finland and New Zealand.MethodsWe used externally validated administrative databases to identify all nonhospitalized and hospitalized SAH cases in Finland and New Zealand from 2001 to 2017. Using the ICD-10, we categorized RIAs into anterior communicating artery (Acom) (ICD-10 I60.2), internal carotid artery (ICA) (I60.0/I60.3), middle cerebral artery (MCA) (I60.1), and vertebrobasilar artery (VBA) (I60.4/I60.5) locations. To validate the location-specific SAH diagnoses, we used external hospital- and population-based datasets and autopsy data. We calculated sudden death rates (those occurring before admission to a ward) and overall 30-day CFRs, and computed age-, sex, and country-adjusted risk ratios using a Poisson regression model with 95% CIs.ResultsAmong 13,470 SAH cases (5,056 from New Zealand; median age 58 years; 61.3% women), 26.6% had Acom, 18.4% ICA, 29.5% MCA, 11.5% VBA, and 14.0% other/unspecified RIAs. The overall 30-day CFRs were the greatest for VBA (54.1%), followed by MCA (40.5%), Acom (29.1%), and ICA (28.5%) RIAs. Location-specific sudden death rates were 33.0%, 21.6%, 11.9%, and 9.9%, respectively. Between 2001-2003 and 2015-2017, overall 30-day CFRs declined significantly for VBA (24%, 95% CI 13%-34%) and MCA (15%, 95% CI 5%-24%) RIAs. Location-specific differences in CFRs were similar between countries, but temporal decreases were observed only in Finland. Between 2001-2003 and 2014-2017, the proportion of VBA RIAs increased by 35.9% (from 10.3% to 14.0%).DiscussionSAH CFRs vary significantly by RIA location, with VBA and MCA RIAs having the greatest CFRs, mainly due to high sudden death rates. It is unclear whether aneurysms with these high-risk locations could benefit from improved primary/secondary prevention or prehospital management strategies. These findings cannot be directly applied to the preventive treatment of unruptured intracranial aneurysms.

Despite recent advances in prevention and treatment, cardiovascular disease (CVD) remains a leading cause of premature death and disability globally, with a rising burden in many low- and middle-income countries. Several modifiable determinants of CVD are well-established (eg, smoking, hypertension, obesity, dyslipidaemia), but they do not fully explain temporal trends and large variations in disease rates between different populations. Moreover, the causal relevance of certain CVD risk factors and/or their associated biological mechanisms is still incompletely understood. High-throughput affinity-based proteomic assays now enable quantification of several thousand protein markers in the blood, and their application in large epidemiological and clinical studies will facilitate the development of precision cardiovascular medicine. This review describes recent findings from large population-based studies to illustrate the value of proteomics in cardiology for improved risk prediction, diagnosis and patient stratification; better understanding of disease aetiology and pathophysiology; and identification of repurposing and novel therapeutic targets. To overcome the current limitations, future studies should aim to further increase the sample size, number of proteins measured reliably (eg, via multiple assay platforms) and longitudinally, and ancestry population diversity, to expedite clinical translation of key research findings that will help to transform development of precision medicine in cardiology globally.

BACKGROUND AND OBJECTIVES:According to region-specific hospital-based studies, the location of ruptured intracranial aneurysm (RIA) influences the case fatality rate (CFR) of aneurysmal subarachnoid hemorrhage (SAH). However, little is known about whether CFRs vary by RIA location in population-based studies that include prehospital SAH deaths. We assessed whether CFRs and CFR-trends differ by RIA location using whole population data from Finland and New Zealand. METHODS:We used externally validated administrative databases to identify all nonhospitalized and hospitalized SAH cases in Finland and New Zealand from 2001 to 2017. Using the ICD-10, we categorized RIAs into anterior communicating artery (Acom) (ICD-10 I60.2), internal carotid artery (ICA) (I60.0/I60.3), middle cerebral artery (MCA) (I60.1), and vertebrobasilar artery (VBA) (I60.4/I60.5) locations. To validate the location-specific SAH diagnoses, we used external hospital- and population-based datasets and autopsy data. We calculated sudden death rates (those occurring before admission to a ward) and overall 30-day CFRs, and computed age-, sex, and country-adjusted risk ratios using a Poisson regression model with 95% CIs. RESULTS:Among 13,470 SAH cases (5,056 from New Zealand; median age 58 years; 61.3% women), 26.6% had Acom, 18.4% ICA, 29.5% MCA, 11.5% VBA, and 14.0% other/unspecified RIAs. The overall 30-day CFRs were the greatest for VBA (54.1%), followed by MCA (40.5%), Acom (29.1%), and ICA (28.5%) RIAs. Location-specific sudden death rates were 33.0%, 21.6%, 11.9%, and 9.9%, respectively. Between 2001-2003 and 2015-2017, overall 30-day CFRs declined significantly for VBA (24%, 95% CI 13%-34%) and MCA (15%, 95% CI 5%-24%) RIAs. Location-specific differences in CFRs were similar between countries, but temporal decreases were observed only in Finland. Between 2001-2003 and 2014-2017, the proportion of VBA RIAs increased by 35.9% (from 10.3% to 14.0%). DISCUSSION:SAH CFRs vary significantly by RIA location, with VBA and MCA RIAs having the greatest CFRs, mainly due to high sudden death rates. It is unclear whether aneurysms with these high-risk locations could benefit from improved primary/secondary prevention or prehospital management strategies. These findings cannot be directly applied to the preventive treatment of unruptured intracranial aneurysms.

BACKGROUND:Previous studies on the reproducibility of 7-day accelerometer measurements have been limited by small sample sizes and short follow-up periods. We aimed to assess the long-term reproducibility of accelerometer-derived physical activity and sleep, and to illustrate the impact of regression dilution bias on the association between daily step count and coronary heart disease (CHD) in UK Biobank. METHODS:We analysed data from 3138 UK Biobank participants in the main accelerometry sub-study with up to four repeat accelerometer measurements after 3-4 years. Nine physical activity and sleep phenotypes were extracted to capture different movement behaviours. Reproducibility was assessed by using intraclass correlation coefficients (ICCs). The impact on disease associations was illustrated by considering daily step count and incident CHD using Cox regression (87 038 participants; 3879 CHD events), before and after correction for regression dilution. RESULTS:Among the 3138 participants, 51% were women and the mean (SD) age was 63.1 (9.4) years. Reproducibility was good for overall activity, with an ICC (95% confidence interval) of 0.75 (0.74-0.76), and moderate for other phenotypes, with ICCs ranging from 0.58 (0.56-0.59) for sleep efficiency to 0.69 (0.68-0.70) for sedentary behaviour. In our example, the inverse association between daily step count and CHD showed a 20% lower risk of CHD per usual 4000 steps after correcting for regression dilution compared with 13% before correction. CONCLUSION:Accelerometer measurements are moderately reproducible and comparable to measures such as blood pressure. Correction for regression dilution bias is crucial to quantify associations of usual physical activity and sleep with disease risk.

BACKGROUND:We evaluated the efficacy of the Stroke Riskometer mobile phone application to change the Life's Simple 7 risk factor score in a primary prevention population at 6 months postrandomization. METHODS:This phase III, prospective, outcome assessor-blinded, 2-arm randomized controlled trial in Australia and New Zealand recruited participants from August 2021 to January 2024. Inclusion criteria: age ≥35 and ≤75 years; ≥2 risk factors; smartphone ownership; and no cardiovascular disease history. The intervention group was given access to the application; the usual care group received one email with generic risk factor information. The primary outcome was the mean between-group difference in Life's Simple 7 (score 0 [poor] to 14 [ideal], comprising blood pressure, cholesterol, glucose, body mass index, smoking, and physical activity and diet) from baseline to 6 months postrandomization. Secondary outcomes were between-group changes in individual Life's Simple 7 items. Analyses were performed using intention-to-treat principles with ANCOVA and linear mixed models to examine differences between groups, with prespecified per-protocol and subgroup analyses. RESULTS:We randomized 862 participants (mean±SD age, 58±11 years; 63% women; 74% White). At 6 months postrandomization in intention-to-treat analyses, the mean difference between usual care (n=433) and intervention (n=429) groups in the change in Life's Simple 7 score from baseline was 0.03 ([95% CI, -0.19 to 0.25]; P=0.788). Per-protocol analyses (n=320 usual care; n=276 intervention) were similar (mean difference in change, 0.20 [95% CI, -0.04 to 0.43]; P=0.106). Compared with usual care in intention-to-treat analyses, the intervention group had a nonsignificant increase in metabolic equivalent of task (metabolic equivalent of task) minutes per week of physical activity (313.42 [95% CI, -2.80 to 629.65]; P=0.052), with no differences in other Life's Simple 7 items. CONCLUSIONS:Among a general population aged 35 years to 75 years with ≥2 stroke risk factors, there was no evidence that having access to the application changed overall Life's Simple 7 scores at 6-month follow-up. Participants in the intervention group did have a nonsignificant increase in physical activity, compared with the usual care group, after 6 months, but not in other individual risk factors. REGISTRATION:URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12621000211864.

The use of statistical methods in medical research has long been a concern and careful review of these methods is required to ensure that published papers are of sufficient statistical quality. However, there is a shortage of statistical reviewers for medical journals and there is a dearth of training for those with little or no experience. An online workshop on statistical reviewing for medical journals was convened by the Improving Statistical Literacy and Early Career Development streams of the National Institute for Health and Care Research (NIHR) Statistics Group to address this gap. This article summarizes the key learnings from this workshop and provides some practical advice for those potentially interested in undertaking statistical reviews for a medical journal.

Abstract Copy-number variants (CNVs) represent an important source of genetic variation that can influence complex traits and disease risk by altering gene dosage, disrupting coding sequence, or modifying regulatory elements. Existing CNV association studies have been limited in scale and have largely focused on European-ancestry populations. We present a CNV genome-wide association study of 13 anthropometric and cardiometabolic traits in 94,730 adults from the China Kadoorie Biobank, a large East Asian study. We identify 19 independent locus-phenotype associations across 15 unique loci. Novel associations include random plasma glucose at 8p23.1 (β = -0.29 SD, P = 5.40×10⁻) and 14q11.2 (β = +0.43 SD, P = 8.41×10⁻), diastolic blood pressure at 7p21.1 (β = +0.75 SD, P = 5.25×10⁻), and duplication-associated reductions in body fat percentage at 12p12.1 (β = -0.74 SD, P = 8.11×10⁻) and 17q12 (β = -0.56 SD, P = 7.36×10⁻). We also replicated established dosage-sensitive regions, most prominently at two distinct intervals within 16p11.2 (BP2-BP3 and BP4-BP5), where CNVs show large bidirectional dosage effects across 5 adiposity traits including body mass index (β = -0.84 SD per copy, P = 1.77×10⁻). These findings identify structural variants contributing to cardiometabolic and anthropometric trait variation in Chinese adults and expand the ancestry diversity of CNV association studies.

BACKGROUND:Adiposity is associated with increased risk of breast cancer in post-menopausal women, while the association appears to be the inverse among premenopausal women in Western populations, but is unclear for Chinese women. METHODS:Using data on 284 538 women with no history of cancer, hysterectomy, oophorectomy, or breast surgery at baseline in 2004-8 from the China Kadoorie Biobank (a prospective cohort study), Cox regression was used to estimate adjusted hazard ratios (HRs) for breast cancer and its subtypes by measured body mass index (BMI) and other adiposity measures (waist circumference, fat percentage, waist-hip ratio, fat mass) and by self-reported BMI at age 25 years. RESULTS:Mean BMI was 23.8 (3.5 SD) kg/m2 at baseline (mean age 51.4 years) and 21.9 (2.7 SD) kg/m2 at age 25 years. During 10 years of follow-up, there were 2379 incident breast cancer cases. Higher BMI was associated with a higher risk of breast cancer in women who were post-menopausal [HR = 1.35, 95% confidence interval (CI) 1.24-1.47] and premenopausal (HR = 1.13, 95% CI 1.03-1.24) at baseline, but not when censoring at age 50 years to capture mainly premenopausal cancers. Among post-menopausal women, BMI was associated with oestrogen-receptor positive (ER ) (HR = 1.47, 95% CI 1.24-1.74), but not with oestrogen-receptor negative (ER-) breast cancer (HR = 1.02, 95% CI 0.75-1.37). Waist circumference and fat percentage were associated with a higher risk of breast cancer. CONCLUSION:In this cohort of Chinese women, higher levels of general and central adiposity were associated with a higher risk of breast cancer, in both women who were premenopausal and women who were post-menopausal at baseline. Among post-menopausal women, adiposity was associated with ER   but not ER - breast cancer.

BACKGROUND:The role of physical activity in the risk of amyotrophic lateral sclerosis (ALS) is debated. It is also unclear whether the association differs in people at high genetic risk of ALS. METHODS:The strength and shape of the association between self-reported and device-measured physical activity and incident diagnosis of ALS in the UK Biobank cohort was analysed using Cox regression, adjusting for potential confounders. Cubic splines were used to assess non-linearity. Analyses were performed in the entire cohort and restricted to those with increased genetic risk due to C9ORF72 expansion carriage or C-allele homozygosity at rs12608932 in UNC13A. RESULTS:Among 384 836 participants with valid questionnaire data, the median age at recruitment was 57.0 years (IQR 50.0-63.0) and median follow-up was for 14.0 years (IQR 13.3-14.6), with 541 incident diagnoses of ALS. Higher self-reported physical activity was associated with a lower risk of ALS (HRhigh vs low=0.77, 95% CI 0.61 to 0.96). The relationship was non-linear, with lowest risk in those in the mid-range self-reported activity. Higher overall device-measured activity was also associated with a lower risk of ALS (HRper 1SD = 0.75, 95% CI 0.58 to 0.97, n=96 570, 98 ALS events) but with a linear dose-response relationship. The association of physical activity with ALS was similar in individuals with C-allele homozygosity at rs12608932 in UNC13A and directionally consistent but not statistically significant in C9ORF72-HRE carriers (n=535, 56 ALS events). CONCLUSION:Higher self-reported and device-measured overall physical activity were associated with a lower risk of ALS overall, but with a potentially non-linear dose-response relationship.

Abstract Background and aims The role of mHealth in the primary prevention of cardiovascular diseases is uncertain. We evaluated the effectiveness of Stroke Riskometer™ App (App) in improving cardiovascular behavioral risk factors. Methods This secondary analysis of a 2-arm RCT in Australia and New Zealand recruited people aged 35-75 years, with ≥2 stroke modifiable risk factors, no history of stroke, myocardial infarction, or cognitive impairment between August 2021 and November 2023. Participants were randomized to the intervention group (IG—App access) or usual care group (UCG—links to generic information). Cardiovascular behavioral risk factors (diet, physical activity and smoking) were measured at baseline, 3, 6, and 12 months using validated questionnaires and classified as “ideal” or “non-ideal” using Life’s Simple 7® criteria. Mixed-effects logistic regression assessed changes in individual and combined (categorized as “3 ideal risk factors” and “<3 ideal risk factors”) between groups over time. Results Of 862 participants randomized (mean age 58.1 [SD 11] years, 63.0% female), there were no significant differences between IG (n = 429) and UCG (n = 429) on individual ideal risk factors at any time point (Table 1). For combined ideal risk factors, there were no significant differences at 3 and 6 months; however, at 12 months, IG more often achieved all ideal risk factors (8%, adjusted odds ratio 2.71, 95% CI 1.04, 7.09) compared to UCG (5%). Conclusions While few achieved ideal risk factor levels, the App supports an overall change in risk profile and should be considered as an important adjunct to managing risk factors. Conflict of interest Disclosures: The Stroke Riskometer™ App was developed by Auckland University of Technology including authors Valery Feigin and Rita Krishnamurthi. Declaration of interests: Valery Feigin is a shareholder and serves as Chief Scientific Adviser for PreventS-MD Ltd, a spin-off company of AUT Ventures Ltd (Auckland University of Technology). AUT Ventures Ltd and PreventS-MD Ltd jointly hold the copyright for the free-to-use Stroke Riskometer app. Funding: This study was funded by Synergies to Prevent Stroke (STOPstroke), an NHMRC Synergy Grant (GNT1182071). Declaration of conflicting interest: The author(s) declared no potential conflicts of interest with respect to this work. Table 1 - belongs to Results

Background:Cardiovascular and metabolic diseases account for an increasing share of morbidity and mortality globally. Folic acid supplementation has been linked to a lowered risk of stroke and some metabolic indicators due to its involvement in homocysteine and one-carbon metabolism and its role in the production of nitric oxide; however, the evidence on these associations is inconclusive. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations of folate (dietary intake, supplementation, or blood concentrations) with any cardiometabolic outcome. We performed screening, data abstraction, and risk of bias assessment in duplicate, and assessed the credibility of the evidence using predefined criteria. Results:We identified 113 unique associations from 49 reviews. The included syntheses mostly had low risk of bias of and provided pooled risk estimates from intervention trials or prospective cohorts. A larger volume of evidence was available for composite cardiovascular outcomes, coronary heart disease, and stroke compared to other outcomes. No association reached a convincing or highly suggestive level of credibility. Six directional associations and five null associations met the criteria for a suggestive level of credibility. Three dose-response relationships, all at suggestive levels of credibility, supported an association between higher dietary folate intake and a reduced risk of coronary heart disease and stroke. Conclusion:The available evidence on the association between folate status and cardiometabolic outcomes primarily focuses on secondary prevention of cardiometabolic diseases and substantially underrepresents low- and middle-income countries. More large-scale studies are warranted to validate a relationship between folate status and cardiometabolic events or indicators. Overall, the evidence landscape around folate and cardiometabolic diseases appears to be limited both in volume and scope. Registration:PROSPERO: CRD42021265041.

BACKGROUND:Protein-based ageing clocks can be used to help identify individuals at high risk of death or morbidity. There is a lack of evidence in non-European populations on clocks derived from combining different proteomic platforms and their relationship with age-related traits, diseases and genetic architecture. METHODS:The prospective China Kadoorie Biobank assayed proteins via Olink and SomaScan in ∼4000 individuals with a mean age of 58 years. We used organ-enriched plasma proteins identified from the Genotype-Tissue Expression Project and trained Light Gradient Boosting models on chronological age (ChronAge) to derive protein organ age and age gaps (ProtAgeGap) for 18 organs. We then investigated their relationship with age-related traits and incident diseases after adjustment for multiple testing. Moreover, we conducted genome-wide association studies to identify genetic variants for overall and organ-specific ProtAgeGaps. FINDINGS:The overall proteomic and organ-specific ageing clocks for each platform combined for all participants were strongly related with ChronAge. The organ-specific and overall proteomic age were associated with age-related traits and a range of incident diseases independent of ChronAge. In particular, the kidney organ-specific ageing clock was associated with higher risk of stroke (1.03; 1.02-1.05), chronic liver disease (CLD, 1.11; 1.05-1.18); chronic kidney disease (CKD, 1.19; 1.11-1.27) per 1-year higher ProtAgeGap. GWAS of overall proteomic age identified AFF3 and IL1RAPL1 as associated with biological ageing. INTERPRETATION:Advanced proteomic ageing, in particular kidney organ ageing, was associated with age-related traits and diseases and, pending further validation, may have utility as a potential biomarker for clinical trials. FUNDING:British Heart Foundation.

Abstract Rationale Up to 90% of strokes are preventable through the modification and control of lifestyle risk factors. Health and Wellness (HWC) coaching is an established psychological intervention that may address multiple risk factors, including high blood pressure to reduce the risk of stroke. Aims To determine the effectiveness of HWC in the management of blood pressure and stroke-related modifiable risk factors in reducing the risk of stroke. Methods This Phase III, open-label, single-blinded, two-arm randomised controlled trial recruited adults with first-ever or recurrent minor stroke or transient ischaemic attack from hospitals in Auckland and Hamilton, New Zealand. Eligible participants were ≥18 years, independent in activities of daily living, had at least two modifiable cardiovascular risk factors, elevated or treated systolic blood pressure, were English-speaking, and had no history of major stroke, myocardial infarction, significant cognitive or mood disorders, or terminal illness. Longitudinal outcomes will be analysed using linear mixed-effects models under an intention-to-treat framework, with time-to-event outcomes analysed using competing-risk methods and missing data handled using multiple imputation with pooling based on Rubin’s rules. Study outcomes The primary outcome is difference in the mean change from baseline systolic blood pressure (SBP) to 6-months post-randomisation between control (Usual Care, UC) and HWC groups. The study (n=360) is powered 85% (two sided α=0.05) to detect a mean difference in change of SBP 6 mm Hg (SD ± 20 mm Hg) between HWC and UC groups at 6-months post-randomisation, accounting for a 20% attrition rate. A revised sample size calculation due to a lower attrition rate (9%) provided a required sample size of 320. Secondary outcomes include cardiovascular health score using the Life’s Simple 7; stroke awareness; quality of life; satisfaction with life: cognition; mood; medication adherence; adverse cardiovascular events; health and service costs and productivity status. Discussion HWC has the potential to modify lifestyle risk factors for stroke. This trial will be the first to test the effectiveness of HWC to modify lifestyle risk factors for secondary stroke prevention. Ethical approval The trial was approved by the New Zealand Health and Disability Ethics Committee (#2022 EXP 124562022), and The Auckland University of Technology Ethics Committee (#22/206). Trial registration ACTRN12622000939796 (registered 01/07/2022)

INTRODUCTION:The CHA2DS2 VASc score is widely used for stroke risk stratification in atrial fibrillation (AF). Efforts to improve prediction using demographic refinements have uncertain incremental value, particularly in multi-ethnic populations. We evaluated whether demographic modification or AF type provides additional discriminatory value. METHODS:We conducted a retrospective nested case-control study of patients with AF diagnosed prior to the fifth Auckland Regional Community Stroke Study (September 2020-August 2021). Cases with ischaemic stroke or transient ischaemic attack were identified from this population-based registry with central adjudication. Controls were randomly selected from the National Minimum Dataset, stratified by ethnicity. Predictors included CHA2DS2 VASc components, demographic refinements (alternative age transformations, ethnicity, and exclusion of sex), and AF type. The primary baseline model was a multivariable logistic regression model using standard CHA2DS2 VASc predictors as covariates. The traditional point-based CHA2DS2 VASc score was evaluated separately for comparison. Discrimination was assessed using the area under the receiver operating characteristic curve (AUC). RESULTS:The study included 1,908 patients (300 cases). A logistic regression model using standard CHA2DS2 VASc predictors demonstrated moderate discrimination {AUC 0.68 (95% confidence interval [CI]: 0.65-0.71)}. The traditional point-based CHA2DS2 VASc score showed lower discrimination (AUC 0.63 [95% CI: 0.60-0.66]; ΔAUC +0.05; p = 0.0003). Demographic refinements did not improve discrimination (ΔAUC ≤ 0.01). Addition of AF type modestly increased discrimination (AUC 0.71; ΔAUC +0.03; p = 0.015), with greater improvement in non-anticoagulated patients (ΔAUC +0.05). CONCLUSION:Demographic refinements, including ethnicity, provide limited incremental value beyond CHA2DS2 VASc, whereas AF type offers a modest discriminatory signal. This finding is hypothesis-generating and requires external validation before clinical implementation is considered.

BACKGROUND:Understanding the short-term effects of temperature on physical activity and sedentary behavior, as well as adaptation patterns under extreme temperatures, will help China and other countries with similar climatic conditions implement targeted interventions to promote physical activity and enhance public health. METHODS:During 2020 and 2021, 22,511 China Kadoorie Biobank participants in the 3rd resurvey consented to wear an Axivity AX3 wrist-worn triaxial accelerometer for 7 consecutive days to assess their movement behaviors. To investigate the short-term effects of daytime temperature on physical activity and sedentary behavior, we used distributed lag nonlinear models combined with generalized estimating equations. The final analysis included 110,553 days of acceleration data from 19,977 participants from 10 Chinese cities. RESULTS:Temperature exhibited an inverted U-shaped association with overall activity and moderate-to-vigorous intensity physical activity (MVPA), with a peak at 26°C. In contrast, light-intensity physical activity (LIPA) showed an inverted N-shaped relationship with temperature, while sedentary behavior gradually increased. The maximum change in overall activity was a decrease of 13.33% (95% CI: 11.54% to 14.93%, cumulative lag 0 days) and 4.50% (95% CI: 2.65% to 6.32%, cumulative lag 4 days) under extremely low and high temperatures, respectively. Males and manual workers exhibited greater variability in both overall activity and MVPA across the temperature range. CONCLUSIONS:Our findings highlight the need for targeted interventions to mitigate the adverse effects of temperature on physical activity, with strategies tailored to specific groups, particularly sex and occupation.

Background:Folate has been examined extensively in relation to carcinogenesis due to its role in one-carbon metabolism impacting the synthesis of DNA and RNA, methylation processes, and genomic integrity. Current evidence on the relationship between folate status and the risk of cancer is equivocal: low or deficient folate status may contribute to an increased risk of cancers, while high-dose folic acid supplementation may have adverse effects on carcinogenesis. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects up to February 2024 for systematic reviews and meta-analyses investigating the associations of folate (measured as dietary intake, supplementation, or blood concentrations) with any specific cancer outcome. Screening, data extraction, and risk of bias assessment were performed in duplicate. We assessed the credibility of the evidence using predefined criteria. Results:We found 67 syntheses, of which 57 provided meta-analyses. Over half of the syntheses had a high risk of bias. We identified 168 unique associations (unique exposure - unique outcome - unique setting) across 10 cancer types, 3 system cancers, and total cancer. Of these, we assessed 15 directional associations (colorectal, oesophageal, and total cancers) to be at a highly suggestive level of credibility, and 17 directional and 10 null associations to be at a suggestive level of credibility. Conclusions:The available evidence for each category of unique association was generally limited. Highly suggestive associations were found for oesophageal, colorectal, childhood brain and spinal tumours and total cancers. More robust primary studies are warranted to follow-up the signal of a positive relationship reported for prostate cancer warranting further research. Evidence was weak for all but colorectal and oesophageal cancers, or the central nervous system cancers in children. Registration:PROSPERO: CRD42021265041.

Background:Folate is essential for normal growth and in human health throughout the lifecycle. Clinical deficiency of folate impairs DNA synthesis and results in megaloblastic anaemia, while suboptimal folate status before and in early pregnancy results in an elevated risk of neural tube defects (NTD). The evidence on the association of folate status with other health outcomes is largely fragmented and understudied. We conducted a series of umbrella reviews examining the association between folate and multiple health outcomes in various populations and settings. Methods:We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and DARE from inception to February 2024 for systematic reviews with or without meta-analyses examining an association between folate intake/status and any health outcome. We performed screening and data extraction in duplicate and assessed the risk of bias using the ROBIS tool. Evidence was then characterised into unique associations (unique exposure measure - unique outcome measure - unique setting). For each category of unique associations, we identified the evidence based on the statistical power, recency of publication and the potential risk of bias. All unique associations were evaluated for credibility using predefined criteria. Results:We retrieved 3565 records and included 283 in the final synthesis. The evidence on anaemia consisted of four intervention trials demonstrating effectiveness of folic acid supplementation during pregnancy in reducing the risk of megaloblastic anaemia (relative risk (RR) = 0.21; 95% CI = 0.11, 0.38; I2 = 15%). Maternal folic acid use was also significantly inversely related to the prevention of NTD at birth (RR = 0.31; 95% CI = 0.16, 0.60; I2 = 0%) and NTD recurrence (RR = 0.30; 95% CI = 0.14, 0.65; I2 = 0%). This relationship was supported by the inverse association reported between low maternal blood folate concentrations and the increased risk of NTD. Further evidence showed that fortification of food with folic acid was associated with the lower prevalence of NTD on a population-level. Conclusion:In NTDs and anaemia, we identified strong evidence supporting the protective role of folate status based on intervention trials and observational studies. More recent reviews examining the role of folate in other less well understood health conditions will be presented in the subsequent reports. Registration:PROSPERO: CRD42021265041.

Background Autoimmune diseases and bone density loss (osteopenia and osteoporosis) are chronic conditions of complex aetiology that affect diverse populations. Folate may be associated with a higher risk of these disorders due to its essential role in one-carbon metabolism required for nucleotide synthesis, homocysteine metabolism, and methylation processes. However, the evidence on this association is inconclusive. Methods We searched MEDLINE, Embase, CINAHL, the Cochrane Library, and the Database of Abstracts of Reviews of Effects from inception to February 2024 for systematic reviews and meta-analyses investigating the associations between folate exposure (dietary intake, supplementation, or blood concentrations) and any autoimmune diseases or skeletal outcomes. Pairs of researchers screened the retrieved syntheses, extracted the relevant data, assessed their risk of bias using the ROBIS tool, and evaluated the credibility of the evidence using predefined criteria. Results We found 19 reviews reporting 25 unique associations: 15 on autoimmune diseases (multiple sclerosis, inflammatory bowel disease, psoriasis, human immunodeficiency virus, vitiligo, and systemic lupus erythematosus) and 10 on skeletal outcomes (fractures and bone mineral density loss). Most of the syntheses consisted of small-scale case-control studies. The risk of bias in the included syntheses was high. Owing to the small sample sizes, all the unique associations were assessed to be at a weak level of credibility. Conclusions The evidence on the relationship between folate status and autoimmune diseases or skeletal outcomes was limited in breadth and depth. Most of the 25 unique associations were reported by a single synthesis comprising small-scale studies. Subgroup analyses or dose-response analyses were severely limited or unavailable. More well-powered, prospective studies investigating the relationships between folate and autoimmune and skeletal conditions are warranted. Registration PROSPERO: CRD42021265041.