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Background Women's reproductive factors have been associated with the risk of dementia; however, these findings remain uncertain. This study aimed to examine the risk of incident all-cause dementia associated with reproductive factors in women and the number of children in both sexes and whether the associations vary by age, socioeconomic status (SES), smoking status, and body mass index (BMI) in the UK Biobank. Methods and findings A total of 273,240 women and 228,957 men without prevalent dementia from the UK Biobank were included in the analyses. Cox proportional hazard regressions estimated hazard ratios (HRs) for reproductive factors with incident all-cause dementia. Multiple adjusted models included age at study entry, SES, ethnicity, smoking status, systolic blood pressure, BMI, history of diabetes mellitus, total cholesterol, antihypertensive drugs, and lipid-lowering drugs. Over a median of 11.8 years follow-up, 1,866 dementia cases were recorded in women and 2,202 in men. Multiple adjusted HRs ((95% confidence intervals (CIs)), p-value) for dementia were 1.20 (1.08, 1.34) (p = 0.016) for menarche 14 years compared to 13 years; 0.85 (0.74, 0.98) (p = 0.026) for ever been pregnant; 1.43 (1.26, 1.62) (p < 0.001) for age at first live birth Conclusions In this study, we observed that some reproductive events related to shorter cumulative endogenous estrogen exposure in women were associated with higher dementia risk, and there was a similar association between the number of children and dementia risk between women and men., Author(s): Jessica Gong 1,*, Katie Harris 1, Sanne A. E. Peters 1,2,3, Mark Woodward 1,2 Introduction The dementia epidemic confronts the world as a major challenge, with extensive impact on [...]

Background Sex differences in cardiometabolic disease risk are commonly observed across the life course but are poorly understood and may be due to different associations of adiposity with cardiometabolic risk in females and males. We examined whether adiposity is differently associated with cardiometabolic trait levels in females and males at 3 different life stages. Methods and findings Data were from 2 generations (offspring, Generation 1 [G1] born in 1991/1992 and their parents, Generation 0 [G0]) of a United Kingdom population-based birth cohort study, the Avon Longitudinal Study of Parents and Children (ALSPAC). Follow-up continues on the cohort; data up to 25 y after recruitment to the study are included in this analysis. Body mass index (BMI) and total fat mass from dual-energy X-ray absorptiometry (DXA) were measured at mean age 9 y, 15 y, and 18 y in G1. Waist circumference was measured at 9 y and 15 y in G1. Concentrations of 148 cardiometabolic traits quantified using nuclear magnetic resonance spectroscopy were measured at 15 y, 18 y, and 25 y in G1. In G0, all 3 adiposity measures and the same 148 traits were available at 50 y. Using linear regression models, sex-specific associations of adiposity measures at each time point (9 y, 15 y, and 18 y) with cardiometabolic traits 3 to 6 y later were examined in G1. In G0, sex-specific associations of adiposity measures and cardiometabolic traits were examined cross-sectionally at 50 y. A total of 3,081 G1 and 4,887 G0 participants contributed to analyses. BMI was more strongly associated with key atherogenic traits in males compared with females at younger ages (15 y to 25 y), and associations were more similar between the sexes or stronger in females at 50 y, particularly for apolipoprotein B-containing lipoprotein particles and lipid concentrations. For example, a 1 standard deviation (SD) (3.8 kg/m.sup.2) higher BMI at 18 y was associated with 0.36 SD (95% confidence interval [CI] = 0.20, 0.52) higher concentrations of extremely large very-low-density lipoprotein (VLDL) particles at 25 y in males compared with 0.15 SD (95% CI = 0.09, 0.21) in females, P value for sex difference = 0.02. By contrast, at 50 y, a 1 SD (4.8 kg/m.sup.2) higher BMI was associated with 0.33 SD (95% CI = 0.25, 0.42) and 0.30 SD (95% CI = 0.26, 0.33) higher concentrations of extremely large VLDL particles in males and females, respectively, P value for sex difference = 0.42. Sex-specific associations of DXA-measured fat mass and waist circumference with cardiometabolic traits were similar to findings for BMI and cardiometabolic traits at each age. The main limitation of this work is its observational nature, and replication in independent cohorts using methods that can infer causality is required. Conclusions The results of this study suggest that associations of adiposity with adverse cardiometabolic risk begin earlier in the life course among males compared with females and are stronger until midlife, particularly for key atherogenic lipids. Adolescent and young adult males may therefore be high priority targets for obesity prevention efforts., Author(s): Linda M. O'Keeffe 1,2,3,*, Joshua A. Bell 2,3, Kate N. O'Neill 1, Matthew A. Lee 2,3, Mark Woodward 4,5, Sanne A. E. Peters 4,5,6, George Davey Smith 2,3, Patricia [...]

Author(s): Rema Ramakrishnan, Aiden Doherty, Karl Smith-Byrne, Kazem Rahimi, Derrick Bennett, Mark Woodward, Rosemary Walmsley, Terence Dwyer In subsequent data analyses associated with this article, the authors became aware of [...]

Background Over a million adolescents die globally each year from preventable or treatable causes, with injuries (intentional and unintentional) being the leading cause of these deaths. To inform strategies to prevent these injuries, we aimed to assess psychosocial factors associated with serious injury occurrence, type, and mechanism in adolescents. Methods and findings We conducted a secondary analysis of cross-sectional survey data collected from the Global School-based Student Health Survey between 2009 and 2015. We used logistic regression to estimate associations between prevalence of serious injuries, injury type (effects of injury), and injury mechanism (cause of injury) and psychosocial factors (factors that relate to individuals socially, or their thoughts or behaviour, or the interrelation between these variables). Psychosocial factors were categorised, based on review of the literature, author knowledge, and discussion amongst authors. The categories were markers of risky behaviour (smoking, alcohol use, drug use, and physical activity), contextual factors (hunger, bullying, and loneliness), protective factors (number of friends and having a supportive family), and markers of poor mental health (planned or attempted suicide and being too worried to sleep). Models were adjusted for country factors (geographical area and income status, both using World Bank classification), demographic factors (age and sex), and factors to explain the survey design. A total of 87,269 adolescents living in 26 countries were included. The weighted majority were 14-15 years old (45.88%), male (50.70%), from a lower-middle-income country (81.93%), and from East Asia and the Pacific (66.83%). The weighted prevalence of a serious injury in the last 12 months was 36.33%, with the rate being higher in low-income countries compared to other countries (48.74% versus 36.14%) and amongst males compared to females (42.62% versus 29.87%). Psychosocial factors most strongly associated with serious injury were being bullied (odds ratio [OR] 2.45, 95% CI 1.93 to 3.13, p < 0.001), drug use (OR 2.08, 95% CI 1.73 to 2.49, p < 0.001), attempting suicide (OR 1.78, CI 1.55 to 2.04, p < 0.001), being too worried to sleep (OR 1.80, 95% CI 1.54 to 2.10, p < 0.001), feeling lonely (OR 1.61, 95% CI 1.37 to 1.89, p < 0.001), and going hungry (OR 1.61, 95% CI 1.30 to 2.01, p < 0.001). Factors hypothesised to be protective were not associated with reduced odds of serious injury: Number of close friends was associated with an increased odds of injury (OR 1.23, 95% CI 1.06 to 1.43, p = 0.007), as was having understanding parents or guardians (OR 1.13, 95% CI 1.01 to 1.26, p = 0.036). Being bullied, using drugs, and attempting suicide were associated with most types of injury, and being bullied or too worried to sleep were associated with most mechanisms of injury; other psychosocial factors were variably associated with injury type and mechanism. Limitations include the cross-sectional study design, making it not possible to determine the directionality of the associations found, and the survey not capturing children who did not go to school. Conclusions We observed strong associations between serious injury and psychosocial factors, but we note the relationships are likely to be complex and our findings do not inform causality. Nevertheless, our findings suggest that multifactorial programmes to target psychosocial factors might reduce the number of serious injuries in adolescents, in particular programmes concentrating on reducing bullying and drug use and improving mental health., Author(s): Samiha Ismail 1,2,3, Maria Lisa Odland 3, Amman Malik 4, Misghina Weldegiorgis 5,6, Karen Newbigging 7, Margaret Peden 5, Mark Woodward 5,6, Justine Davies 3,8,9,* Introduction The World Health [...]

Background Randomised evidence on the efficacy of blood pressure (BP)-lowering treatment to reduce cardiovascular risk in patients with atrial fibrillation (AF) is limited. Therefore, this study aimed to compare the effects of BP-lowering drugs in patients with and without AF at baseline. Methods and findings The study was based on the resource provided by the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), in which individual participant data (IPD) were extracted from trials with over 1,000 patient-years of follow-up in each arm, and that had randomly assigned patients to different classes of BP-lowering drugs, BP-lowering drugs versus placebo, or more versus less intensive BP-lowering regimens. For this study, only trials that had collected information on AF status at baseline were included. The effects of BP-lowering treatment on a composite endpoint of major cardiovascular events (stroke, ischaemic heart disease or heart failure) according to AF status at baseline were estimated using fixed-effect one-stage IPD meta-analyses based on Cox proportional hazards models stratified by trial. Furthermore, to assess whether the associations between the intensity of BP reduction and cardiovascular outcomes are similar in those with and without AF at baseline, we used a meta-regression. From the full BPLTTC database, 28 trials (145,653 participants) were excluded because AF status at baseline was uncertain or unavailable. A total of 22 trials were included with 188,570 patients, of whom 13,266 (7%) had AF at baseline. Risk of bias assessment showed that 20 trials were at low risk of bias and 2 trials at moderate risk. Meta-regression showed that relative risk reductions were proportional to trial-level intensity of BP lowering in patients with and without AF at baseline. Over 4.5 years of median follow-up, a 5-mm Hg systolic BP (SBP) reduction lowered the risk of major cardiovascular events both in patients with AF (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.83 to 1.00) and in patients without AF at baseline (HR 0.91, 95% CI 0.88 to 0.93), with no difference between subgroups. There was no evidence for heterogeneity of treatment effects by baseline SBP or drug class in patients with AF at baseline. The findings of this study need to be interpreted in light of its potential limitations, such as the limited number of trials, limitation in ascertaining AF cases due to the nature of the arrhythmia and measuring BP in patients with AF. Conclusions In this meta-analysis, we found that BP-lowering treatment reduces the risk of major cardiovascular events similarly in individuals with and without AF. Pharmacological BP lowering for prevention of cardiovascular events should be recommended in patients with AF., Author(s): Ana-Catarina Pinho-Gomes 1, Luis Azevedo 2, Emma Copland 3, Dexter Canoy 3,4, Milad Nazarzadeh 3, Rema Ramakrishnan 3, Eivind Berge 5,6, Johan Sundström 7, Dipak Kotecha 8, Mark Woodward [...]

Background Clinical practice guidelines have traditionally recommended blood pressure treatment based primarily on blood pressure thresholds. In contrast, using predicted cardiovascular risk has been advocated as a more effective strategy to guide treatment decisions for cardiovascular disease (CVD) prevention. We aimed to compare outcomes from a blood pressure-lowering treatment strategy based on predicted cardiovascular risk with one based on systolic blood pressure (SBP) level. Methods and findings We used individual participant data from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) from 1995 to 2013. Trials randomly assigned participants to either blood pressure-lowering drugs versus placebo or more intensive versus less intensive blood pressure-lowering regimens. We estimated 5-y risk of CVD events using a multivariable Weibull model previously developed in this dataset. We compared the two strategies at specific SBP thresholds and across the spectrum of risk and blood pressure levels studied in BPLTTC trials. The primary outcome was number of CVD events avoided per persons treated. We included data from 11 trials (47,872 participants). During a median of 4.0 y of follow-up, 3,566 participants (7.5%) experienced a major cardiovascular event. Areas under the curve comparing the two treatment strategies throughout the range of possible thresholds for CVD risk and SBP demonstrated that, on average, a greater number of CVD events would be avoided for a given number of persons treated with the CVD risk strategy compared with the SBP strategy (area under the curve 0.71 [95% confidence interval (CI) 0.70-0.72] for the CVD risk strategy versus 0.54 [95% CI 0.53-0.55] for the SBP strategy). Compared with treating everyone with SBP [greater than or equal to] 150 mmHg, a CVD risk strategy would require treatment of 29% (95% CI 26%-31%) fewer persons to prevent the same number of events or would prevent 16% (95% CI 14%-18%) more events for the same number of persons treated. Compared with treating everyone with SBP [greater than or equal to] 140 mmHg, a CVD risk strategy would require treatment of 3.8% (95% CI 12.5% fewer to 7.2% more) fewer persons to prevent the same number of events or would prevent 3.1% (95% CI 1.5%-5.0%) more events for the same number of persons treated, although the former estimate was not statistically significant. In subgroup analyses, the CVD risk strategy did not appear to be more beneficial than the SBP strategy in patients with diabetes mellitus or established CVD. Conclusions A blood pressure-lowering treatment strategy based on predicted cardiovascular risk is more effective than one based on blood pressure levels alone across a range of thresholds. These results support using cardiovascular risk assessment to guide blood pressure treatment decision-making in moderate- to high-risk individuals, particularly for primary prevention., Author(s): Kunal N. Karmali 1, Donald M. Lloyd-Jones 1, Joep van der Leeuw 2, David C. Goff 3, Salim Yusuf 4, Alberto Zanchetti 5, Paul Glasziou 6, Rodney Jackson 7, [...]

Background Mitral regurgitation in people without prior cardiac disease is considered a degenerative disease with no established risk factors for its prevention. We aimed to test the hypothesis that elevated systolic blood pressure (SBP) across its usual spectrum is associated with higher risk of mitral regurgitation. Methods and findings We used linked electronic health records from the United Kingdom Clinical Practice Research Datalink (CPRD) from 1 January 1990 to 31 December 2015. CPRD covers approximately 7% of the current UK population and is broadly representative of the population by age, sex, and ethnicity. About 5.5 million UK patients with no known cardiovascular or valve disease at baseline were included in this cohort study. We investigated the relationship between blood pressure (BP) and risk of mitral regurgitation using Cox regression models. Our primary exposure variable was SBP and our primary outcome was incident reports of mitral regurgitation, which were identified from hospital discharge reports or primary care records. Of the 5,553,984 patients in the CPRD that met our inclusion criteria, during the 10-year follow-up period, 28,655 (0.52%) were diagnosed with mitral regurgitation and a further 1,262 (0.02%) were diagnosed with mitral stenosis. SBP was continuously related to the risk of mitral regurgitation with no evidence of a nadir down to 115 mmHg (p < 0.001). Each 20 mmHg increment in SBP was associated with a 26% higher risk of mitral regurgitation (hazard ratio [HR] 1.26; CI 1.23, 1.29). The observed association was partially mediated by diseases affecting the left ventricle during follow-up (myocardial infarction [MI], ischaemic heart disease [IHD], cardiomyopathy, and heart failure). However, the percentage of excess risk mediated (PERM) by these proximate causes of secondary mitral regurgitation was only 13% (CI 6.1%, 20%), and accounting for them had little effect on the long-term association between SBP and mitral regurgitation (mediator-adjusted HR 1.22; CI 1.20, 1.25; p < 0.001). Associations were similar for each 10 mmHg increment in diastolic blood pressure (DBP) (p < 0.001) or each 15 mmHg increment in pulse pressure (PP) (p < 0.001). By contrast, there was no association between SBP and risk of mitral stenosis (HR per 20 mmHg higher SBP 1.03; CI 0.93, 1.14; p = 0.58). These analyses are based on routinely collected data from health records which may be sensitive to measurement errors, and the observed associations may not be generalizable to less severe and subclinical cases of mitral regurgitation. Conclusions Long-term exposure to elevated BP across its whole spectrum is associated with an increased risk of primary and secondary mitral regurgitation. These findings suggest that BP control may be of importance in the prevention of mitral regurgitation., Author(s): Kazem Rahimi 1,2,*, Hamid Mohseni 1, Catherine M. Otto 3, Nathalie Conrad 1, Jenny Tran 1, Milad Nazarzadeh 4,5, Mark Woodward 1,6,7, Terence Dwyer 1, Stephen MacMahon 1,6 Introduction [...]

Background: Heart failure places a significant burden on patients and health systems in high-income countries. However, information about its burden in low- and middle-income countries (LMICs) is scant. We thus set out to review both published and unpublished information on the presentation, causes, management, and outcomes of heart failure in LMICs. Methods and Findings: Medline, Embase, Global Health Database, and World Health Organization regional databases were searched for studies from LMICs published between 1 January 1995 and 30 March 2014. Additional unpublished data were requested from investigators and international heart failure experts. We identified 42 studies that provided relevant information on acute hospital care (25 LMICs; 232,550 patients) and 11 studies on the management of chronic heart failure in primary care or outpatient settings (14 LMICs; 5,358 patients). The mean age of patients studied ranged from 42 y in Cameroon and Ghana to 75 y in Argentina, and mean age in studies largely correlated with the human development index of the country in which they were conducted (r = 0.71, p < 0.001). Overall, ischaemic heart disease was the main reported cause of heart failure in all regions except Africa and the Americas, where hypertension was predominant. Taking both those managed acutely in hospital and those in nonacute outpatient or community settings together, 57% (95% confidence interval [CI]: 49%-64%) of patients were treated with angiotensin-converting enzyme inhibitors, 34% (95% CI: 28%-41%) with beta-blockers, and 32% (95% CI: 25%-39%) with mineralocorticoid receptor antagonists. Mean inpatient stay was 10 d, ranging from 3 d in India to 23 d in China. Acute heart failure accounted for 2.2% (range: 0.3%-7.7%) of total hospital admissions, and mean in-hospital mortality was 8% (95% CI: 6%- 10%). There was substantial variation between studies (p < 0.001 across all variables), and most data were from urban tertiary referral centres. Only one population-based study assessing incidence and/or prevalence of heart failure was identified. Conclusions: The presentation, underlying causes, management, and outcomes of heart failure vary substantially across LMICs. On average, the use of evidence-based medications tends to be suboptimal. Better strategies for heart failure surveillance and management in LMICs are needed. Please see later in the article for the Editors' Summary., Introduction In high-income countries (HICs), heart failure is a well-recognized public health problem representing a significant burden for patients and healthcare systems [1,2]. For example, in the UK and US, [...]

Background: Guidelines recommend intensive blood pressure (BP) lowering in patients at high risk. While placebo-controlled trials have demonstrated 22% reductions in coronary heart disease (CHD) and stroke associated with a 10-mmHg difference in systolic BP, it is unclear if more intensive BP lowering strategies are associated with greater reductions in risk of CHD and stroke. We did a systematic review to assess the effects of intensive BP lowering on vascular, eye, and renal outcomes. Methods and Findings: We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and July 2011. We included trials that randomly assigned individuals to different target BP levels. We identified 15 trials including a total of 37,348 participants. On average there was a 7.5/4.5-mmHg BP difference. Intensive BP lowering achieved relative risk (RR) reductions of 11% for major cardiovascular events (95% CI 1%-21%), 13% for myocardial infarction (0%-25%), 24% for stroke (8%-37%), and 11% for end stage kidney disease (3%-18%). Intensive BP lowering regimens also produced a 10% reduction in the risk of albuminuria (4%-16%), and a trend towards benefit for retinopathy (19%, 0%-34%, p = 0.051) in patients with diabetes. There was no clear effect on cardiovascular or noncardiovascular death. Intensive BP lowering was well tolerated; with serious adverse events uncommon and not significantly increased, except for hypotension (RR 4.16, 95% CI 2.25 to 7.70), which occurred infrequently (0.4% per 100 person-years). Conclusions: Intensive BP lowering regimens provided greater vascular protection than standard regimens that was proportional to the achieved difference in systolic BP, but did not have any clear impact on the risk of death or serious adverse events. Further trials are required to more clearly define the risks and benefits of BP targets below those currently recommended, given the benefits suggested by the currently available data. Please see later in the article for the Editors' Summary., Introduction Cohort studies show continuous positive associations of blood pressure (BP) with cardiovascular risk with no evidence of a threshold at BP levels down to 110/70 mmHg [1-3]. Large-scale placebo-controlled [...]

Background: Diabetes imposes a substantial burden globally in terms of premature mortality, morbidity, and health care costs. Estimates of economic outcomes associated with diabetes are essential inputs to policy analyses aimed at prevention and treatment of diabetes. Our objective was to estimate and compare event rates, hospital utilization, and costs associated with major diabetes-related complications in high-, middle-, and low-income countries. Methods and Findings: Incidence and history of diabetes-related complications, hospital admissions, and length of stay were recorded in 11,140 patients with type 2 diabetes participating in the Action in Diabetes and Vascular Disease (ADVANCE) study (mean age at entry 66 y). The probability of hospital utilization and number of days in hospital for major events associated with coronary disease, cerebrovascular disease, congestive heart failure, peripheral vascular disease, and nephropathy were estimated for three regions (Asia, Eastern Europe, and Established Market Economies) using multiple regression analysis. The resulting estimates of days spent in hospital were multiplied by regional estimates of the costs per hospital bed-day from the World Health Organization to compute annual acute and long-term costs associated with the different types of complications. To assist, comparability, costs are reported in international dollars (Int$), which represent a hypothetical currency that allows for the same quantities of goods or services to be purchased regardless of country, standardized on purchasing power in the United States. A cost calculator accompanying this paper enables the estimation of costs for individual countries and translation of these costs into local currency units. The probability of attending a hospital following an event was highest for heart failure (93%-96% across regions) and lowest for nephropathy (15%-26%). The average numbers of days in hospital given at least one admission were greatest for stroke (17-32 d across region) and heart failure (16-31 d) and lowest for nephropathy (12-23 d). Considering regional differences, probabilities of hospitalization were lowest in Asia and highest in Established Market Economies; on the other hand, lengths of stay were highest in Asia and lowest in Established Market Economies. Overall estimated annual hospital costs for patients with none of the specified events or event histories ranged from Int$76 in Asia to Int$296 in Established Market Economies. All complications included in this analysis led to significant increases in hospital costs; coronary events, cerebrovascular events, and heart failure were the most costly, at more than Int$1,800, Int$3,000, and Int$4,000 in Asia, Eastern Europe, and Established Market Economies, respectively. Conclusions: Major complications of diabetes significantly increase hospital use and costs across various settings and are likely to impose a high economic burden on health care systems. Please see later in the article for the Editors' Summary., Introduction The prevalence of diabetes worldwide was estimated to be 2.8% in 2000 and projected to rise to 4.4% by 2030, with more than three-quarters of people with diabetes living [...]

Background: Guidelines recommend intensive blood pressure (BP) lowering in patients at high risk. While placebocontrolled trials have demonstrated 22% reductions in coronary heart disease (CHD) and stroke associated with a 10-mmHg difference in systolic BP, it is unclear if more intensive BP lowering strategies are associated with greater reductions in risk of CHD and stroke. We did a systematic review to assess the effects of intensive BP lowering on vascular, eye, and renal outcomes. Methods and Findings: We systematically searched Medline, Embase, and the Cochrane Library for trials published between 1950 and July 2011. We included trials that randomly assigned individuals to different target BP levels. We identified 15 trials including a total of 37,348 participants. On average there was a 7.5/4.5-mmHg BP difference. Intensive BP lowering achieved relative risk (RR) reductions of 11% for major cardiovascular events (95% CI 1%-21%), 13% for myocardial infarction (0%-25%), 24% for stroke (8%-37%), and 11% for end stage kidney disease (3%-18%). Intensive BP lowering regimens also produced a 10% reduction in the risk of albuminuria (4%-16%), and a trend towards benefit for retinopathy (19%, 0%-34%, p = 0.051) in patients with diabetes. There was no clear effect on cardiovascular or noncardiovascular death. Intensive BP lowering was well tolerated; with serious adverse events uncommon and not significantly increased, except for hypotension (RR 4.16, 95% CI 2.25 to 7.70), which occurred infrequently (0.4% per 100 person-years). Conclusions: Intensive BP lowering regimens provided greater vascular protection than standard regimens that was proportional to the achieved difference in systolic BP, but did not have any clear impact on the risk of death or serious adverse events. Further trials are required to more clearly define the risks and benefits of BP targets below those currently recommended, given the benefits suggested by the currently available data. [ABSTRACT FROM AUTHOR]