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Background Adversity experiences (AEs) are major risk factors for psychiatric illness, and ample evidence suggests that adversity‐related changes in brain structure enhance this vulnerability. To achieve greater understanding of the underlying biological pathways, increased convergence among findings is needed. Suggested future directions may benefit from the use of large population samples which may contribute to achieving this goal. We addressed mechanistic pathways by investigating the associations between multiple brain phenotypes and retrospectively reported AEs in early life (child adversity) and adulthood (partner abuse) in a large population sample, using a cross‐sectional approach. Methods The UK Biobank resource was used to access imaging‐derived phenotypes (IDPs) from 6,751 participants (aged: M = 62.1, SD = 7.2, range = 45‐80), together with selected reports of childhood AEs and adult partner abuse. Principal component analysis was used to reduce the dimensionality of the data prior to multivariate tests. Results The data showed that participants who reported experiences of childhood emotional abuse (‘felt hated by family member as a child’) had smaller cerebellar and ventral striatum volumes. This result was also depicted in a random subset of participants; however, we note small effect sizes (urn:x-wiley:00219630:media:jcpp13298:jcpp13298-math-0001 < .01), suggestive of modest biological changes. Conclusions Using a large population cohort, this study demonstrates the value of big datasets in the study of adversity and using automatically preprocessed neuroimaging phenotypes. While retrospective and cross‐sectional characteristics limit interpretation, this study demonstrates that self‐perceived adversity reports, however nonspecific, may still expose neural consequences, identifiable with increased statistical power.

Background: Both physical and psychological health outcomes have been associated with exposure to environmental noise. It is not known whether all individuals are equally susceptible to these effects. Noise sensitivity has chiefly been examined in studies of annoyance where it has been shown to moderate the annoyance responses to transport-related noise. Noise sensitivity could have the same moderating effect on physical and psychological health outcomes related to environmental noise exposure but this has been little tested. Noise sensitivity which is also associated with sensitivity to chemicals, light and odours could be an indicator of a more pervasive susceptibility to ill-health related to environmental sources. Methods: A cohort of 2398 men between 45 and 59 years, the longitudinal Caerphilly Collaborative Heart Disease study, was established in 1984/88 and followed into the mid-1990s. Road traffic noise maps were assessed at baseline. Baseline psychological ill-health measures were measured in phase 2 in 1984/88, at phase 3 follow up 1989/93 and phase 4 follow up in 1993/6.Ischaemic heart disease and risk factors were measured in clinic and by questionnaire at baseline and through hospital records and administrative records of deaths during follow up. This study aimed to test if noise sensitivity and noise annoyance have moderating effects on road traffic noise and psychological ill-health and secondly if noise sensitivity and noise annoyance predict physical and psychological ill-health and mortality, irrespective of exposure to road traffic noise. Results: Road traffic noise was associated with Phase 4 psychological ill-health but only among those exposed to 56-60dBA (OR= 1.98 95%CI 1.21, 3.24). High noise sensitivity was associated with lower mortality risk (HR=0.71, 95%CI 0.54-0.94). High noise sensitivity was associated longitudinally with psychological ill-health at phase 3 (OR=1.82 95%CI1.30, 2.56) and phase 4 (OR=1.78 95%CI 1.26, 2.52). There was weak evidence that noise sensitivity moderated the association of road traffic noise exposure with psychological ill-health. Noise annoyance predicted psychological ill-health at phase 4 in the sample in which baseline cases of psychological ill-health were included (OR= 2.08 95%CI 1.00, 4.31). Neither noise sensitivity nor noise annoyance moderated the effects of road traffic noise on ischaemic heart disease morbidity or mortality. Noise annoyance did not moderate the effects of road traffic noise on psychological ill-health.Conclusions: Noise sensitivity is a specific predictor of psychological ill-health and may be an indicator of current psychological ill-health as part of a wider construct of environmental susceptibility. It may increase the risk of psychological ill-health when exposed to road traffic noise.

Background Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks. Methods Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality. Findings Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically-predicted 25(OH)D with coronary heart disease, stroke, or all-cause mortality. However, for the participants with vitamin D deficiency (25[OH]D concentration Interpretation Stratified Mendelian randomisation analyses suggest a causal relationship between 25(OH)D concentrations and mortality for individuals with low vitamin D status. Our findings have implications for the design of vitamin D supplementation trials, and potential disease prevention strategies. Funding British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.

BackgroundConceptualising comorbidity is complex and the term is used variously. Here, it is the coexistence of two or more diagnoses which might be defined as ‘chronic’ and, although they may be pathologically related, they may also act independently. Of interest here is the comorbidity of common psychiatric disorders and impaired cognition.ObjectivesTo examine whether anxiety and/or depression are/is important longitudinal predictors of cognitive change.MethodsUK Biobank participants used at three time points (n=502 664): baseline, first follow-up (n=20 257) and first imaging study (n=40 199). Participants with no missing data were 1175 participants aged 40–70 years, 41% women. Machine learning was applied and the main outcome measure of reaction time intraindividual variability (cognition) was used.FindingsUsing the area under the receiver operating characteristic curve, the anxiety model achieves the best performance with an area under the curve (AUC) of 0.68, followed by the depression model with an AUC of 0.63. The cardiovascular and diabetes model, and the covariates model have weaker performance in predicting cognition, with an AUC of 0.60 and 0.56, respectively.ConclusionsOutcomes suggest that psychiatric disorders are more important comorbidities of long-term cognitive change than diabetes and cardiovascular disease, and demographic factors. Findings suggest that psychiatric disorders (anxiety and depression) may have a deleterious effect on long-term cognition and should be considered as an important comorbid disorder of cognitive decline.Clinical implicationsImportant predictive effects of poor mental health on longitudinal cognitive decline should be considered in secondary and also primary care.

Summary: Background: Rapid urbanisation and associated socioeconomic transformations have modified current lifestyles, shifting dietary preferences towards ready-to-eat, calorie-dense food of poor nutritional quality. The effect of ready-to-eat food environments that sell food for instant consumption on the risk of type 2 diabetes has received scant attention. We therefore aimed to examine the association between exposure to ready-to-eat food environments and type 2 diabetes in a large and diverse population sample. Methods: We conducted a cross-sectional study of adult male and female participants from the baseline phase of the UK Biobank cohort. Participants in this cohort were aged 37–73 years and resided in one of 21 cities in the UK. Ready-to-eat food environments, which we determined from a modelled and linked built environment database, were objectively measured within 1-km catchment areas of the residential streets of participants and were expressed as metrics of density and proximity to the participants' homes. We used logistic regression models to examine the associations between exposure to ready-to-eat food environments and the odds of type 2 diabetes, adjusting for individual covariates such as physical activity. As sensitivity analyses, we investigated the associations between the street distance to the nearest ready-to-eat food outlet and type 2 diabetes. We also tested post hoc for effect modification by sex, income, body-mass index, and location of the UK Biobank collection centre. Findings: Of 502 635 UK Biobank participants enrolled between March 13, 2006, and Oct 1, 2010, the sample analysed included 347 551 (69·1%) participants. The density of ready-to-eat food environments within a 1-km catchment area was associated with higher odds of type 2 diabetes for participants in the groups with highest exposure to restaurants and cafeterias (odss ratio 1·129, 95% CI 1·05–1·21; p=0·0007) and a composite measure of ready-to-eat outlet density (1·112, 1·02–1·21; p=0·0134) compared with those with no exposure. Exposure to hot and cold takeaways was only significantly associated with higher odds of type 2 diabetes at the second highest exposure category that we examined (1·076, 1·01–1·14; p=0·0171), representing a density of 0·75–2·15 units per km2. A protective effect with distance decay was observed: participants in the highest quintile of street distance to nearest ready-to-eat food outlet reported lower odds of type 2 diabetes than those in the lowest quintile (0·842, 0·78–0·91; p

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose–response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th–95th percentile 1·04–13·5]) from 71 011 participants from 37 studies.FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10–1·17), coronary disease excluding myocardial infarction (1·06, 1·00–1·11), heart failure (1·09, 1·03–1·15), fatal hypertensive disease (1·24, 1·15–1·33); and fatal aortic aneurysm (1·15, 1·03–1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91–0·97). In comparison to those who reported drinking >0–≤100 g per week, those who reported drinking >100–≤200 g per week, >200–≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1–2 years, or 4–5 years, respectively.INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

ObjectiveTo help determine whether midlife obesity is a cause of dementia and whether low body mass index (BMI), low caloric intake, and physical inactivity are causes or merely consequences of the gradual onset of dementia by recording these factors early in a large 20-year prospective study and relating them to dementia detection rates separately during follow-up periods of MethodsA total of 1,136,846 UK women, mean age 56 (SD 5) years, were recruited in 1996 to 2001 and asked about height, weight, caloric intake, and inactivity. They were followed up until 2017 by electronic linkage to National Health Service records, detecting hospital admissions with mention of dementia. Cox regression yielded adjusted rate ratios (RRs) for first dementia detection during particular follow-up periods.ResultsFifteen years after the baseline survey, only 1% were lost to follow-up, and 89% remained alive with no detected dementia, of whom 18,695 had dementia detected later, at a mean age of 77 (SD 4) years. Dementia detection during years 15+ was associated with baseline obesity (BMI 30+ vs 20–24 kg/m2: RR 1.21, 95% confidence interval 1.16–1.26,p< 0.0001) but not clearly with low BMI, low caloric intake, or inactivity at baseline. The latter 3 factors were associated with increased dementia rates during the first decade, but these associations weakened substantially over time, approaching null after 15 years.ConclusionsMidlife obesity may well be a cause of dementia. In contrast, behavioral changes due to preclinical disease could largely or wholly account for associations of low BMI, low caloric intake, and inactivity with dementia detection during the first decade of follow-up.

Summary Background The role of environmental exposures in chronic obstructive pulmonary disease (COPD) remains inconclusive. We examined the association between environmental exposures (PM2·5, greenness, and urbanicity) and COPD prevalence using the UK Biobank cohort data to identify key built environment correlates of COPD. Methods In this cross-sectional, observational study we used baseline data for UK Biobank participants. Included participants were aged 39 years and older, white, had available spirometry data, and had complete data for phenotypes and exposures. COPD was defined by spirometry with the 2017 Global Initiative for Chronic Obstructive Lung Disease criteria. Environmental exposures were PM2·5 derived from monitoring data and interpolated using land-use regression at the participants' geocoded residential addresses. Built environment metrics of residential greenness were modelled in terms of normalised difference vegetation index from remotely sensed colour infrared data within a 500 m residential catchment, and an urbanicity index derived from spatial analyses and measured with a 1 km buffer around each participant's residential address. Logistic regression models examined the associations between environmental exposures and COPD prevalence adjusting for a range of confounders. Subgroup analyses by urbanicity and effect modification by white blood cell count as an inflammatory marker were also done. Findings We assessed 96 779 participants recruited between April 4, 2006, and Oct 1, 2010, of which 5391 participants had COPD with a prevalence of 5·6%. Each 10 μg/m3 increment in ambient PM2·5 exposure at a participant's residential location was associated with higher odds of COPD (odds ratio 1·55, 95% CI 1·14–2·10). Among the built environment metrics, urbanicity was associated with higher odds of COPD (1·05, 1·01–1·08 per interquartile increment), whereas residential greenness was protective, being associated with lower odds of COPD (0·89, 0·84–0·93 for each interquartile increment in greenness). The results remained consistent in models of COPD defined as per lower limit of normal criteria. The highest quartile of white blood cell count was associated with lower lung function and higher COPD risk with a significant interaction between PM2·5 and white blood cell count only in the model of lung function (p=0·0003). Interpretation In this study of the built environment and COPD, to our knowledge the largest done in the UK, we found that exposure to ambient PM2·5 and urbanicity were associated with a higher risk of COPD. Residing in greener areas, as measured by normalised difference vegetation index, was associated with lower odds of COPD, suggesting the potential value of urban planning and design in minimising or offsetting environmental risks for the prevention and management of COPD. Funding University of Hong Kong, UK Biobank, and UK Economic & Social Research Council.

BackgroundThis study investigated differences in cognitive performance between middle-aged adults with and without a lifetime history of mood disorder features, adjusting for a range of potential confounders.MethodsCross-sectional analysis of baseline data from the UK Biobank cohort. Adults aged 40–69 (n = 143,828) were assessed using measures of reasoning, reaction time and memory. Self-reported data on lifetime features of major depression and bipolar disorder were used to construct groups for comparison against controls. Regression models examined the association between mood disorder classification and cognitive performance, adjusting for sociodemographic, lifestyle and clinical confounders.ResultsInverse associations between lifetime history of bipolar or severe recurrent depression features and cognitive performance were attenuated or reversed after adjusting for confounders, including psychotropic medication use and current depressive symptoms. Participants with a lifetime history of single episode or moderate recurrent depression features outperformed controls to a small (but statistically significant) degree, independent of adjustment for confounders. There was a significant interaction between use of psychotropic medication and lifetime mood disorder features, with reduced cognitive performance observed in participants taking psychotropic medication.ConclusionsIn this general population sample of adults in middle age, lifetime features of recurrent depression or bipolar disorder were only associated with cognitive impairment within unadjusted analyses. These findings underscore the importance of adjusting for potential confounders when investigating mood disorder-related cognitive function.

Introduction: Prospective studies reporting associations between cognitive performance and subsequent incident dementia have been subject to attrition bias. Furthermore, the extent to which established risk factors account for such associations requires further elucidation. Methods: We used UK Biobank baseline cognitive data (n ≤ 488,130) and electronically linked hospital inpatient and death records during three‐ to eight‐year follow‐up, to estimate risk of total dementia (n = 1051), Alzheimer's disease (n = 352), and vascular dementia (n = 169) according to four brief cognitive tasks, with/without adjustment for constitutional and modifiable risk factors. Results: We found associations of cognitive task performance with all‐cause and cause‐specific dementia (P < .01); these were not accounted for by established risk factors. Cognitive data added up to 5% to the discriminative accuracy of receiver operating characteristic curve models; areas under the curve ranged from 82% to 86%. Discussion: This study offers robust evidence that brief cognitive testing could be a valuable addition to dementia prediction models.

The association between dietary patterns (DP) and prevalence of hearing loss in men enrolled in the Caerphilly Prospective Study was investigated. During 1979–1983, the study recruited 2512 men aged 45–59 years. At baseline, dietary data were collected using a semi-quantitative FFQ, and a 7-d weighed food intake (WI) in a 30 % subsample. Five years later, pure-tone unaided audiometric threshold was assessed at 0·5, 1, 2 and 4 kHz. Principal component analysis (PCA) identified three DP and multiple logistic and ordinal logistic regression models examined the association with hearing loss (defined as pure-tone average of frequencies 0·5, 1, 2 and 4 kHz >25 dB). Traditional, healthy and high-sugar/low-alcohol DP were found with both FFQ and WI data. With the FFQ data, fully adjusted models demonstrated significant inverse association between the healthy DP and hearing loss both as a dichotomous variable (OR=0·83; 95 % CI 0·77, 0·90; PPPP=0·02) and as an ordinal variable (OR=1·17; 95 % CI 1·03, 1·33; P=0·02). A healthy DP was significantly and inversely associated with hearing loss in older men. The role of diet in age-related hearing loss warrants further investigation.

Background With an estimated one billion hypertension cases worldwide, the role of the built environment in its prevention and control is still uncertain. The present study aims to examine the associations between neighbourhood walkability and hypertension in a large and diverse population-based cohort. Materials and methods We examined the association between neighbourhood walkability and blood pressure outcomes for N=429,334 participants drawn from the UK Biobank and aged 38–73 years. Neighbourhood walkability was objectively modelled from detailed building footprint-level data within multi-scale functional neighbourhoods (1.0-, 1.5- and 2.0-kilometer street catchments of geocoded dwelling). A series of linear and modified Poisson regression models were employed to examine the association between walkability and outcomes of diastolic blood pressure (DBP in mmHg), systolic blood pressure (SBP in mmHg) and prevalent hypertension adjusting for socio-demographic, lifestyle and related physical environmental covariates. We also examined the relationship between walkability and change in blood pressure for a sub-sample of participants with follow-up data and tested for interaction effects of age, sex, employment status, neighbourhood SES, residential density and green exposure Results Neighbourhood walkability within one-kilometer street catchment was beneficially associated with all the three blood pressure outcomes, independent of all other factors. Each interquartile increment in walkability was associated with the lower blood pressure outcomes of DBP (β=−0.358, 95% CI: −0.42, −0.29mmHg), SBP (β=−0.833, 95% CI: −0.95, −0.72mmHg) as well as reduced hypertension risk (RR=0.970, 95% CI: 0.96, 0.98). The results remained consistent across spatial and temporal scales and were sensitive to sub-groups, with pronounced protective effects among female participants, those aged between 50 and 60 years, in employment, residing in deprived, high density and greener areas. Conclusion This large population-based cohort found evidence of protective association between neighbourhood walkability and blood pressure outcomes. Given the enduring public health impact of community design on individual behaviour and lifestyle, of particular interest, are the targetted upstream-level interventions in city design aimed at optimizing walkability. Further long term studies are required to assess its sustained effects upon hypertension prevention and control.

Summary Background Increased urbanisation and the associated reduced contact of individuals with natural environments have led to a rise in mental disorders, including depression. Residential greenness, a fundamental component of urban design, has been shown to reduce the public health burden of mental disorders. The present study investigates the association between residential green exposure and prevalence of major depressive disorders using a large and diverse cross-sectional dataset from the UK Biobank. Methods In this cross-sectional, observational, associational study, we used baseline data from the UK Biobank cohort of participants aged 37–73 years from across the UK. Environmental exposure data were derived from a modelled and linked built environment database. Residential greenness was assessed with a 0·5 m resolution Normalised Difference Vegetation Index, which is derived from spectral reflectance measurements in remotely sensed colour infrared data and measured within geocoded dwelling catchments. Other environment metrics included street-level movement density, terrain, and fine particulate exposures. A series of logistic models examined associations between residential greenness and odds of major depressive disorder after adjusting for activity-influencing environments and individual covariates. Findings Of 122 993 participants with data on major depressive disorder, the study analytical sample comprised 94 879 (77·1%) participants recruited across ten UK Biobank assessment centres between April 29, 2009, and Oct 1, 2010. A protective effect of greenness on depression was consistently observed, with 4·0% lower odds of major depressive disorder per interquartile increment in Normalised Difference Vegetation Index greenness (odds ratio 0·960, 95% CI 0·93–0·99; p=0·0044). Interaction analyses indicated that the beneficial effects of greenness were more pronounced among women, participants younger than 60 years, and participants residing in areas with low neighbourhood socioeconomic status or high urbanicity. Interpretation The results point to the benefits of well designed green environments on mental health. Further longitudinal studies are needed to decipher causal pathways. In the UK, policies aimed at optimising allocation and design of green spaces might help preserve psychological ecosystem services, thereby, improving the mental wellbeing of populations and enhancing the mental capital of cities. Funding University of Hong Kong, UK Biobank, and the UK Economic & Social Research Council.

Background Evidence suggests that facilitating empathy could improve individuals’ well-being. Loving-kindness meditation (LKM) could be a facilitator, and online delivery a cost-effective format. Methods We conducted an internet-based randomised controlled trial recruiting 809 adults to test whether an LKM course improves well-being through evoking pleasant emotions, psychological resources, and altruism compared to a light physical exercise course (LE). Participants in both arms followed video-based instructions, completed post-intervention questionnaires, and used online diaries and forums. To measure altruism 10 GBP/10 USD were offered to participants with a choice of donating all/half to charity. Thematic analysis was applied to diary/forum entries. Results Both courses increased well-being without significant differences. LKM participants were less anxious than LE participants (ß = -0.22, 95% confidence interval (CI) [-0.43, -0.02], p = .03), and more likely to donate 5 GBP/5 USD (Relative Risk = 3.57, 95%CI [0.82, 15.50], p = .09). Attrition was high (82%). Participants engaged in diary/forum usage. LKM was an emotionally intense experience, generating deep reflections and increased connectedness but difficult for some to process. LE led to gentle increases in relaxation, generating a sense of achievement. Conclusion Future research needs to confirm findings and devise ways of delivering online LKM effectively to diverse populations.

Background Using UK Biobank data, this study sought to explain the causal relationship between alcohol intake and cognitive decline in middle and older aged populations. Methods Data from 13,342 men and women, aged between 40 and 73 years were used in regression analysis that tested the functional relationship and impact of alcohol on cognitive performance. Performance was measured using mean reaction time and intra-individual variation in reaction time, collected in response to a perceptual matching task. Covariates included body mass index, physical activity, tobacco use, socioeconomic status, education and baseline cognitive function. Results A restricted cubic spline regression with three knots showed how the linear (β1=-0.048, 95% CI -0.105 to -0.030) and non-linear effects (β2=0.035, 95% CI 0.007 to 0.059) of alcohol use on mean reaction time and intra-individual variation in reaction time (β1=-0.055, 95% CI -0.125 to -0.034; β2=0.034, 95% CI 0.002 to 0.064) were significant adjusting for covariates. Cognitive function declined as alcohol use increased beyond 10g/day. Decline was more apparent as age increased. Conclusions The relationship between alcohol use and cognitive function is non-linear. Consuming more than one UK standard unit of alcohol per day is detrimental to cognitive performance and is more pronounced in older populations.

The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is associated with worse physical performance. Data from six adult cohorts (ages 50-92 years) were included in a two stage meta-analysis of individual participant data. We analysed each study separately using linear and logistic regression models and then used meta-analytic methods to pool the results. Physical performance outcome measures were walking speed, balance time, chair rise time and grip strength. Exposure measures were morning (serum and salivary) and evening (salivary) cortisol. Total sample sizes in meta-analyses ranged from N=2,146 for associations between morning Cortisol Awakening Response and balance to N=8,448 for associations between morning cortisol and walking speed. A larger diurnal drop was associated with faster walking speed (standardised coefficient per SD increase 0.054, 95% confidence interval (CI) 0.029, 0.081, p

There exist no long term longitudinal studies assessing BMI trends of older adults in relation to the built environment. We employed cohort data from the Caerphilly Prospective Study (CaPS) to analyze the long term independent associations between a broad set of built environmental factors and change in BMI measured at three time points over a 12-year period. Built environment morphological metrics (morphometrics) used include measures of land use accessibility and space syntax modelled street network accessibility. A multilevel modelling framework was adopted wherein measurement occasions were nested within individuals and individuals were nested within LSOA census areas. BMI was observed to be significantly (p

Activated partial thromboplastin time (aPTT) and prothrombin time (PT) are clinical tests commonly used to screen for coagulation-factor deficiencies. One genome-wide association study (GWAS) has been reported previously for aPTT, but no GWAS has been reported for PT. We conducted a GWAS and meta-analysis to identify genetic loci for aPTT and PT. The GWAS for aPTT was conducted in 9,240 individuals of European ancestry from the Atherosclerosis Risk in Communities (ARIC) study, and the GWAS for PT was conducted in 2,583 participants from the Genetic Study of Three Population Microisolates in South Tyrol (MICROS) and the Lothian Birth Cohorts (LBC) of 1921 and 1936. Replication was assessed in 1,041 to 3,467 individuals. For aPTT, previously reported associations with KNG1, HRG, F11, F12, and ABO were confirmed. A second independent association in ABO was identified and replicated (rs8176704, p = 4.26 × 10(-24)). Pooling the ARIC and replication data yielded two additional loci in F5 (rs6028, p = 3.22 × 10(-9)) and AGBL1 (rs2469184, p = 3.61 × 10(-8)). For PT, significant associations were identified and confirmed in F7 (rs561241, p = 3.71 × 10(-56)) and PROCR/EDEM2 (rs2295888, p = 5.25 × 10(-13)). Assessment of existing gene expression and coronary artery disease (CAD) databases identified associations of five of the GWAS loci with altered gene expression and two with CAD. In summary, eight genetic loci that account for ∼29% of the variance in aPTT and two loci that account for ∼14% of the variance in PT were detected and supported by functional data.

To examine the hypothesis that caloric intake in mid-life is associated with later dementia or cognitive impairment not dementia (CIND). A prospective cohort study was conducted in Caerphilly, South Wales, United Kingdom. Men aged 45-59 years were identified from the electoral roll and general practice. 2,512 men were examined between July 1979 until September 1983. Four follow-up examinations were conducted every 4-5 years until 2004. Participants were categorized on the basis of their average daily caloric intake over each of the first three phases. Outcomes were CIND and dementia ascertained at phase five (2004). 192 men (15% of 1,248 participants at phase five) had CIND and 100 (8%) dementia. Age adjusted odds ratios demonstrated strongest associations between average energy consumption and vascular CIND or dementia (OR 1.62 95% CI 1.25-2.10). Adjustment for nutritional factors, vascular disease, diabetes, smoking, BP and BMI if anything increased the association (OR 1.64, 95% CI 1.03-2.60). After adjusting for social class, associations were attenuated and consistent with chance (OR 1.48, 95% CI 0.92-2.38). When adjusted for social class, the previously observed association between caloric intake and cognitive outcomes is modest, consistent with chance, and may be due to residual confounding.

Context The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated. Objective To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A(2) to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction. Design, Setting, and Participants Individual records were available for 165 544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15 126 incident fatal or nonfatal CVD outcomes (10 132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years). Main Outcome Measures Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low ( = 20%) risk. Results The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A(2) mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100 000 adults aged 40 years or older, 15 436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A(2) mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines. Conclusion In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A(2) mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction. JAMA. 2012; 307(23):2499-2506 www.jama.com

Background: The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. Methods: We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies. Results: For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Conclusion: Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved.

BackgroundBenzodiazepine use is widespread in older people, although its benefit is uncertain.AimTo investigate the long-term effect of benzodiazepine use upon dementia risk.MethodsA prospective cohort of men seen on five occasions over 22 years with full medication histories, repeat measures of cognitive function and a clinical diagnosis of dementia.ResultsOf 1134 men with complete data, 103 (9.1%) had been taking benzodiazepines regularly at one or more phases. These men showed a marked increased incidence of dementia (OR=3.50, 95% CI 1.57 to 7.79, p=0.002), which persisted despite adjustment for psychological distress and other covariates. Men exposed in earlier phases showed a greater association than more recent exposure, counter to what one would expect if this was due to reverse causation, though we failed to demonstrate a dose–response effect with drug duration.ConclusionThe taking of benzodiazepines is associated with an increased risk of dementia.

Background Cross-sectional studies have suggested that elevated cortisol is associated with worse physical performance, a surrogate of ageing. We examined the relationship between repeat cortisol measures over 20 years and physical performance in later life. Methods Middle-aged men (45–59 years) were recruited between 1979 and 1983 (Phase 1) from the Caerphilly Prospective Study (CaPS) and re-examined 20 years later at 65–83 years of age (Phase 5). Participants included 750 and 898 subjects with either Phase 1 and/or Phase 5 data on exposure and outcomes. Outcome measures were walking speed and balance time and exposures included morning fasting serum cortisol (Phase 1) and four salivary samples on 2 consecutive days (Phase 5). Results Faster walking speed was associated with higher morning cortisol at Phase 1 [coefficient per standard deviation (SD) increase 0.68, 95% confidence interval (95% CI) 0.09–1.27; P = 0.02] though this was attenuated after adjustment for covariates (coefficient per SD increase 0.45; 95% CI –0.16 to 1.07; P = 0.15). Higher night-time cortisol at Phase 5 was associated with slower speed (coefficient per SD increase –1.06; 95% CI –1.60 to –0.52; P

Objective— Hemostasis and inflammation have been implicated in dementia. This study investigates the role of specific hemostatic and inflammatory pathways with incident vascular and nonvascular dementia. Methods and Results— This was a prospective study of a population sample of men aged 65 to 84 years, with baseline assessment of hemostatic and inflammatory factors and cognition measured 17 years later. The sample included 865 men (59 had dementia and 112 had cognitive impairment, not dementia), free of vascular disease at baseline and for whom hemostatic and inflammatory marker data were available and cognitive status was known. A total of 15 hemostatic and 6 inflammatory markers were assessed. Factor analysis was used to identify hemostatic subsystems. The National Institute of Neurological Disorders and Stroke–Association Internationale pour la Recherche et l’Enseignement en Neurologie criteria were used to identify vascular dementia. By using standardized ( z ) scores for hemostatic and inflammatory markers, and after adjustment for age and risk factors, vascular dementia was associated with fibrinogen (hazard ratio [HR], 1.68; 95% confidence interval [CI], 1.02–2.76), factor VIII (HR, 1.79; 95% CI, 1.09–3.00), and plasminogen activator inhibitor 1 (HR, 3.13; 95% CI, 1.73–5.70). For vascular dementia, the HR risk from high levels of all three hemostatic variables (fibrinogen, factor VIII, and plasminogen activator inhibitor 1) was 2.97 ( P Conclusion— The associations of these hemostatic markers with vascular dementia may implicate clot formation as the primary mechanism and are consistent with a microinfarct model of vascular dementia.

Objective Low thyroid function has been associated with depression in clinical populations. We have examined whether thyroid function in the normal range is associated with minor psychiatric morbidity. Design Prospective cohort study of 2269 middle aged men (45–59 years) with thyroid function (total T 4 only, TSH unavailable) measured between 1979 and 1983 and with repeat measures of minor psychiatric morbidity (GHQ-30) over a mean of 12·3 years follow-up. We also undertook a systematic review and meta-analysis of population-based studies examining thyroid function and mood. Results There was a positive association between total T 4 and chronic psychiatric morbidity (odds ratio 1·21, 95% CI 1·02–1·43, P = 0·03), but this was consistent with chance after adjusting for social class, alcohol and smoking behaviours. The association with incident and recovery from psychiatric morbidity was weaker and consistent with chance. We identified seven eligible studies, from our systematic review and included six studies, including our own, in a meta-analysis. The pooled estimate showed a positive association (odds ratio 1·12, 95% CI 1·02–1·22, P -value = 0·01) between depression and T 4 and an inverse association with TSH (odds ratio 0·92, 95% CI 0·88–0·97, P = 0·0007) with no evidence of heterogeneity or publication bias. Conclusion The results from CaPS and our meta-analysis are consistent and suggest that, if anything, higher levels of thyroxine in the normal range are associated with increased risk of depression.The effects of thyroid hormone on mood may differ in normal populations and patients with clinical thyroid dysfunction.

We investigated the associations of circulating C-reactive protein (CRP) and interleukin-6 (IL-6) with cancer risk. We examined the associations of CRP and IL-6 with incident cancer in two prospective cohorts, the British Women’s Heart and Health Study (4,286 women aged 60–80) and the Caerphilly Cohort (2,398 men aged 45–59) using Cox regression and pooled our findings with previous prospective studies’ in fixed and random effects meta-analyses. CRP and IL-6 were associated with some incident cancers in our cohorts, but the numbers of cancer cases were small. In our meta-analyses elevated CRP was associated with an increased overall risk of cancer (random effects estimate (RE): 1.10, 95% CI: 1.02, 1.18) and lung cancer (RE: 1.32, 95% CI: 1.08, 1.61). Its associations with colorectal (RE: 1.09, 95% CI: 0.98, 1.21) and breast cancer risks (RE: 1.10, 95% CI: 0.97, 1.26) were weaker. CRP appeared unrelated to prostate cancer risk (RE: 1.00 0.88, 1.13). IL-6 was associated with increased lung and breast cancer risks and decreased prostate cancer risk, and was unrelated to colorectal cancer risk. Our findings suggest an etiological role for CRP and IL-6 in some cancers. Further large prospective and genetic studies would help to better understand this role.

Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular-metabolic, neuropsychiatric, physiological-anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample (N=112?151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.Molecular Psychiatry advance online publication, 26 January 2016; doi:10.1038/mp.2015.225.

BackgroundStudies have found associations between psychological distress (PD) and increased risk of myocardial infarction (MI). However, it is not clear whether the relationship reflects the subtle influence of pre-existing illness on both PD and MI. This study examines the association between PD and MI in a prospective epidemiological study of 1864 middle-aged men to examine if the association is explained by existing illness.MethodThis study was a prospective cohort study modelling the association between PD, measured using the 30-item General Health Questionnaire (GHQ) and non-fatal myocardial infarction (NFMI) and fatal/non-fatal myocardial infarction (FNFMI).The relationship was modelled in a series of logistic regression models adjusted for age, then cigarette smoking, then social position, and finally for all sociodemographic characteristics, coronary heart disease (CHD) risk factors, and baseline CHD.ResultsPD was associated with a 70% and 68% increased risk of NFMI and FNFMI in fully adjusted analysis. However, PD was not associated with an increased risk of NFMI and FNFMI in analyses excluding those with baseline CHD. Further, being psychologically distressed and physically ill was associated with a greater than twofold risk of NFMI and FNFMI, 2·37 (95% CI 1·33–4·20) and 2·33 (95% CI 1·32–4·12) respectively.ConclusionsThis study suggests that PD is a moderator of the increased risk of MI associated with existing physical illness. PD in men who are physically ill is a marker of an underlying chronic physical illness. The prospective association of PD with MI is not independent of baseline physical illness.

The authors examined associations between leisure-time and occupational physical activity and common mental disorder (CMD), defined as anxiety and depression, using data from a cohort of middle-aged men in Caerphilly, South Wales, United Kingdom, who were followed for 5 years (1989-1993) and 10 years (1993-1997). CMD was measured using the General Health Questionnaire. Total leisure-time activity and percentage of time spent in heavy-intensity activity were estimated from self-reports (Minnesota Leisure Time Physical Activity Questionnaire). Men were classified into four classes of occupational activity. Among 1,158 men with complete data, those who participated in any heavy-intensity leisure-time activity had reduced odds of CMD 5 years later (below median vs. none: adjusted odds ratio (OR(adj)) = 0.61, 95% confidence interval (CI): 0.40, 0.93); median or above vs. none: OR(adj) = 0.54, 95% CI: 0.35, 0.83). Analyses using multiple imputation to deal with missing data found weaker evidence for an association (OR(adj) = 0.79 (95% CI: 0.54, 1.15) and OR(adj) = 0.73 (95% CI: 0.49, 1.09), respectively). There was little evidence that men in the most physically demanding jobs had reduced odds of CMD after 5 years, and there was no association between physical activity and CMD 10 years later. Among these men, heavy-intensity leisure-time physical activity was associated with a small reduction in CMD over 5 years.

Although dietary intake over a single 24-h period may be atypical of an individual’s habitual pattern, multiple 24-h dietary assessments can be representative of habitual intake and help in assessing seasonal variation. Web-based questionnaires are convenient for the participant and result in automatic data capture for study investigators. This study reports on the acceptability of repeated web-based administration of the Oxford WebQ – a 24-h recall of frequency from a set food list suitable for self-completion from which energy and nutrient values can be automatically generated. As part of the UK Biobank study, four invitations to complete the Oxford WebQ were sent by email over a 16-month period. Overall, 176 012 (53 % of those invited) participants completed the online version of the Oxford WebQ at least once and 66 % completed it more than once, although only 16 % completed it on all four occasions. The response rate for any one round of invitations varied between 34 and 26 %. On most occasions, the Oxford WebQ was completed on the same day that they received the invitation, although this was less likely if sent on a weekend. Participants who completed the Oxford WebQ tended to be white, female, slightly older, less deprived and more educated, which is typical of health-conscious volunteer-based studies. These findings provide preliminary evidence to suggest that repeated 24-h dietary assessment via the Internet is acceptable to the public and a feasible strategy for large population-based studies.

Importance Visual impairment due to myopia is an important public health issue. A prior analysis of population-based cohorts aged 15 to 22 years recruited from the United Kingdom and Israel suggested myopia and high myopia were approximately 10% more common in first-born compared with later-born children. Objective To examine whether myopia was associated with birth order in an earlier generation than studied previously and, if so, whether the association was attenuated after adjusting for education exposure, as predicted by the hypothesis that the education of children with later birth orders is less intense. Design, Setting, and Participants Cross-sectional study of UK Biobank participants recruited from 2006 to 2010. Analysis was restricted to participants aged 40 to 69 years who had a vision assessment, self-reported white ethnicity, and no history of eye disorders (N = 89 120). Myopia and high myopia were defined as autorefraction of −0.75 diopters (D) or less and −6.00 D or less, respectively. Exposures Birth order and information on potential confounders including highest educational qualification ascertained using a structured questionnaire. Main Outcomes and Measures Odds ratios (ORs) for myopia and high myopia by birth order, using logistic regression and adjusting for age and sex (model 1) or age, sex, and highest educational qualification (model 2). Results In model 1 (no adjustment for education), birth order was associated with both myopia and high myopia (eg, comparing first- vs second-born individuals; OR, 1.12; 95% CI, 1.08-1.16; P = 1.40E-11 and OR, 1.21; 95% CI, 1.11-1.30; P = 3.60E-06 for myopia and high myopia, respectively). The risk for myopia became progressively lower for later birth orders, suggesting a dose response. In model 2 (after adjusting for education), the effect sizes were attenuated by approximately 25% (OR, 1.09; 95% CI, 1.05-1.12; P = 1.30E-06 and OR, 1.15; 95% CI, 1.06-1.25; P = 4.60E-04 for myopia and high myopia, respectively) and the apparent dose response was abolished. Conclusions and Relevance These data suggest that the association between birth order and myopia is not due to a new environmental pressure in the last 30 to 40 years. The attenuated effect size after adjusting for educational exposure supports a role for reduced parental investment in education of children with later birth orders in their relative protection from myopia.

An association between blood markers of thrombosis and haemostasis and cognitive decline has been described. These results may be confounded by lifestyle and environmental factors. We used a Mendelian randomisation approach to describe the association between thrombosis/haemostasis genotypes and cognition. We studied the genetic variants (single nucleotide polymorphisms) of circulating markers of thrombosis and haemostasis. Our chosen blood factors and associated polymorphisms were D-dimer [rs12029080], fibrinogen [rs1800789], plasminogen activator inhibitor [rs2227631], and von Willebrand factor [rs1063857]. We described association with multidomain cognitive test scores using data from the Scottish Family Health Study. Cognitive data were analysed for individual tests and combined to give a general cognitive factor. In 20,288 subjects, we found no evidence of association between cognitive function (individual tests and combined scores) and any of the above-mentioned single nucleotide polymorphisms. Lower scores on cognitive measures were associated with increasing age, socioeconomic deprivation, blood pressure, waist-hip ratio, smoking, and vascular comorbidity (all p < 0.001). In a post hoc sensitivity analysis restricted to those aged over 50 years, there was still no signal of association. Our data add to our understanding of determinants of cognition but are not definitive; the variation in blood levels explained by SNPs was modest and our sample size may have been insufficient to detect a modest association.

Background Diagnosis of dementia often requires specialist referral and detailed, time-consuming assessments. Aim To investigate the utility of simple clinical items that non-specialist clinicians could use, in addition to routine practice, to diagnose all-cause dementia syndrome. Design and setting Cross-sectional diagnostic test accuracy study. Participants were identified from the electoral roll and general practice lists in Caerphilly and adjoining villages in South Wales, UK. Method Participants (1225 men aged 45–59 years) were screened for cognitive impairment using the Cambridge Cognitive Examination, CAMCOG, at phase 5 of the Caerphilly Prospective Study (CaPS). Index tests were a standardised clinical evaluation, neurological examination, and individual items on the Informant Questionnaire for Cognitive Disorders in the Elderly (IQCODE). Results Two-hundred and five men who screened positive (68%) and 45 (4.8%) who screened negative were seen, with 59 diagnosed with dementia. The model comprising problems with personal finance and planning had an area under the curve (AUC) of 0.92 (95% confidence interval [CI] = 0.86 to 0.97), positive likelihood ratio (LR+) of 23.7 (95% CI = 5.88 to 95.6), negative likelihood ratio (LR−) of 0.41 (95% CI = 0.27 to 0.62). The best single item for ruling out was no problems learning to use new gadgets (LR− of 0.22, 95% CI = 0.11 to 0.43). Conclusion This study found that three simple questions have high utility for diagnosing dementia in men who are cognitively screened. If confirmed, this could lead to less burdensome assessment where clinical assessment suggests possible dementia.

BackgroundMajor depressive disorder and subthreshold depression have been associated with premature mortality. We investigated the association between depressive symptoms and mortality across the full continuum of severity.MethodWe used Cox proportional hazards models to examine the association between depressive symptom severity, assessed using the eight-item Center for Epidemiological Studies Depression Scale (CES-D; range 0–8), and the risk of all-cause mortality over a 9-year follow-up, in 11 104 members of the English Longitudinal Study of Ageing.ResultsDuring follow-up, one fifth of study members died (N = 2267). Depressive symptoms were associated with increased mortality across the full range of severity (ptrend < 0.001). Relative to study members with no symptoms, an increased risk of mortality was found in people with depressive symptoms of a low [hazard ratio (HR) for a score of 2 was 1.59, 95% confidence interval (CI) 1.40–1.82], moderate (score of 4: HR 1.80, 95% CI 1.52–2.13) and high (score of 8: HR 2.27, 95% CI 1.69–3.04) severity, suggesting risk emerges at low levels but plateaus thereafter. A third of participants (36.4%, 95% CI 35.5–37.3) reported depressive symptoms associated with an increased mortality risk. Adjustment for physical activity, physical illnesses, and impairments in physical and cognitive functioning attenuated this association (ptrend = 0.25).ConclusionsDepressive symptoms are associated with an increased mortality risk even at low levels of symptom severity. This association is explained by physical activity, physical illnesses, and impairments in physical and cognitive functioning.

The challenge of understanding the determinants of common life-threatening and disabling conditions is substantial. These conditions are typically caused by a combination of lifestyle, environmental, and genomic factors, with individually modest effects and complex interactions, the detection and quantification of which require studies with large numbers of disease cases. While retrospective case-control studies of particular diseases [1] or existing prospective studies of particular risk factors can help to address this challenge [2,3], a complementary approach is to establish large prospective cohorts designed to study a much wider range of known and novel risk factors for a wide range of diseases [4]. Prospective studies can assess exposures before the onset and treatment of disease, diseases that are not readily investigated by retrospective studies, and both the adverse and beneficial effects of a specific exposure on the lifetime risks of different diseases.\ud \ud UK (United Kingdom) Biobank is a very large, population-based prospective study, established to allow detailed investigations of the genetic and nongenetic determinants of the diseases of middle and old age [5,6]. It aims to combine extensive and precise assessment of exposures with comprehensive follow-up and characterisation of many different health-related outcomes, as well as to promote innovative science by maximising access to the resource. Recruitment of 500,000 participants and the collection of an unprecedented wealth of baseline data and samples were completed in 2010. Activity is now focused on further phenotyping of participants and their health outcomes and on providing access to researchers from around the world.

Study objective: There is evidence suggesting that artificial feeding is associated with a reduction in cognitive function in infants and children, in contrast with breast feeding, but the available evidence suffers from confounding by social and educational factors. An opportunity arose in the Caerphilly cohort study to examine relations between cognitive function in older men and their feeding as infants, when breast feeding was usual. Design: A prospective cohort study. Setting: Caerphilly, South Wales, UK, was a deprived coal mining community when the men had been born in 1920–35. Most had been breast fed as infants. Participants: 779 men aged 60–74 years when tested. The men had earlier been asked to obtain from their mothers their birth weight, and how they had been fed as infants. Results: Complete data were obtained for 779 men. In those whose birth weight had been at or above the median, the adjusted mean cognitive function was only slightly and non-significantly lower in those who had been artificially fed. In the men whose birth weight had been below the median, having been artificially fed was associated with significantly lower results in both a test of reasoning (the AH4) and word power (the national adult reading test (NART)). Two standard deviations below the median birth weight, artificial feeding was associated with a reduction of six points (70% of a SD) on word power (the NART). Conclusions: In men whose birth weight had been low, having been artificially fed is associated with poorer cognitive function in late adult life.

Aims: Traffic noise is a psychosocial stressor. Epidemiological studies suggest chronic noise stress to be a risk factor for cardiovascular disorders. Methods: In a prospective cohort study, the association between annoyance and disturbances due to road traffic noise and the incidence of ischaemic heart disease (IHD) was studied in 3950 middle aged men. Results: Depending on the questionnaire item, non-significant odds ratios for IHD incidence ranging from 0.9 to 1.4 were found for the highly noise annoyed/disturbed subjects when compared with the less annoyed/disturbed subjects, over the six year follow up period. However, this relation was strongly modified by the prevalence of pre-existing chronic diseases. In subjects free of any chronic disease at the beginning of the follow up, significant odds ratios between 1.7 and 3.0 were seen. In the subgroup with chronic diseases no such noise effects were seen. This surprising result of no effect in the group of people with a potential risk, due to pre-existing health problems, may be because of the dilution of the true effect due to recall bias. Conclusions: Annoyance and disturbance due to road traffic noise is associated with a higher incidence of IHD. Prevalence of disease can be an important effect modifier of the relation between noise annoyance and health outcomes.

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689 300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128 843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499 808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

OBJECTIVES: Stroke can impair cognitive function, but the associations between other manifestations of vascular disease and cognitive function have not been adequately studied in representative population samples of subjects. We report the associations between cardiac and peripheral vascular disease and cognitive function for a large representative sample of men in Caerphilly, South Wales, UK. DESIGN: The Caerphilly cohort is the basis of on-going studies of vascular disease, of cognitive function and of predictors of these. We have made intensive attempts to identify all cases of vascular disease: myocardial infarction, angina, ECG ischaemia, peripheral vascular disease (intermittent claudication) and stroke. Here we present data on associations between vascular disease and cognitive function. SETTING: The study is based upon a representative population sample of over 1,500 men in South Wales, aged 55-69 years when cognitive function was measured. The men, and hospital and GP notes relating to them, had been repeatedly examined for evidence of vascular disease during the previous ten years. MAIN OUTCOME MEASURES: Standard tests of cognitive function: the AH4, CAMCOG, MMSE and choice reaction time. RESULTS: After the omission of men who had had a stroke, we detected significant associations between cognitive function and the presence of angina, ECG ischaemia, past myocardial infarction and intermittent claudication. The strength of the associations between cognitive function and the various manifestations of vascular disease were similar, and the various cognitive function tests showed effects of similar size. Overall, cardiac and peripheral vascular disease is associated with a significant reduction in cognitive function equivalent to about one sixth of the standard deviation of a number of tests of cognitive function. The size of this effect is roughly equivalent to the decline in cognitive performance over five years of ageing. CONCLUSIONS: Subjects with evidence of cardiac or peripheral vascular disease have on average a significant reduction in cognitive function equivalent to about four or five years of additional age. The effect of long-term, low-dose aspirin on cognitive decline should now be tested.

BackgroundThe relative contribution of demographic, lifestyle and medication factors to the association between affective disorders and cardiometabolic diseases is poorly understood.AimsTo assess the relationship between cardiometabolic disease and features of depresion and bipolar disorder within a large population sample.MethodCross-sectional study of 145 991 UK Biobank participants: multivariate analyses of associations between features of depression or bipolar disorder and five cardiometabolic outcomes, adjusting for confounding factors.ResultsThere were significant associations between mood disorder features and ‘any cardiovascular disease’ (depression odds ratio (OR) = 1.15, 95% CI 1.12–1.19; bipolar OR = 1.28, 95% CI 1.14–1.43) and with hypertension (depression OR = 1.15, 95% CI 1.13–1.18; bipolar OR = 1.26, 95% CI 1.12–1.42). Individuals with features of mood disorder taking psychotropic medication were significantly more likely than controls not on psychotropics to report myocardial infarction (depression OR = 1.47, 95% CI 1.24–1.73; bipolar OR = 2.23, 95% CI 1.53–3.57) and stroke (depression OR = 2.46, 95% CI 2.10–2.80; bipolar OR = 2.31, 95% CI 1.39–3.85).ConclusionsAssociations between features of depression or bipolar disorder and cardiovascular disease outcomes were statistically independent of demographic, lifestyle and medication confounders. Psychotropic medication may also be a risk factor for cardiometabolic disease in individuals without a clear history of mood disorder.

Background. Haptoglobin acts as an antioxidant by limiting peroxidative tissue damage by free hemoglobin. The haptoglobin gene allele Hp2 comprises a 1.7 kb partial duplication. Relative to allele Hp1, Hp2 carriers form protein multimers, suboptimal for hemoglobin scavenging. Objective. To examine the association of haptoglobin genotype with a range of phenotypes, with emphasis on vitamin C and hemoglobin levels. Methods. We applied a quantitative PCR assay for the duplication junction to two population cohorts including 2747 British women and 1198 British men. We examined the association of haptoglobin duplicon copy number with hemoglobin and vitamin C and used the copy number to complete a phenome scan. Results. Hemoglobin concentrations were greater in those with Hp2,2 genotype, in women only (Hp1,1 13.45 g/dL, Hp1,2 13.49 g/dL, Hp2,2 13.61 g/dL; P = 0.002), though statistically there was no evidence of a difference between the sexes (z value = 1.2, P = 0.24). Haptoglobin genotype was not associated with vitamin C or any other phenotype in either cohort. Conclusions. Our results do not support association of haptoglobin genotype with vitamin C or with other phenotypes measured in two population cohorts. The apparent association between haptoglobin genotype and hemoglobin in the women's cohort merits further investigation.

Background: The increasing incidence of cognitive impairment and dementia in an aging population poses a significant burden on healthcare. Consequently, identifying modifiable physiological factors which may influence the onset of cognitive decline are becoming increasingly important. Previous studies have suggested an association between levels of insulin-like growth factors and cognitive function. Objective: To investigate whether low IGF-I, IGF-II, and IGF molar ratio is associated with greater cognitive decline and increased risk of dementia. Methods: We examined prospective associations between IGF-I, IGF-II, and IGFBP-3 and cognitive function in the Caerphilly Prospective Study (CaPS) (n = 746 men) from samples obtained around 1986, with assessment in around 2003 for clinical diagnosis of cognitive impairment but no dementia (CIND) or dementia, as well as with CAMCOG scores at three phases. Results: A one standard deviation increase in IGF-II was associated with a reduced odds ratio for CIND (0.76, 95% CI 0.60, 0.96) which hardly altered after further adjustment for confounders. A one standard deviation increase in IGFBP-3 among participants without dementia or CIND was associated with greater decline in cognition (p = 0.002) equivalent to 2.4 years difference in age. All the associations between IGF-I and our outcomes were consistent with chance. Conclusion: In this study of men, we found that both IGF-II and IGFBP-3 are associated with normal age-related cognitive decline and clinical pathology associated with CIND, but we failed to replicate previous associations with IGF-I. Assuming these findings are replicated, they may provide new insights into potential biological mechanisms that underlie age-related cognitive changes and development of dementia.

Objectives UK Biobank is a landmark cohort of over 500,000 participants which will be used to investigate genetic and non-genetic risk factors for a wide range of adverse health outcomes. This is the first study to systematically assess the prevalence and validity of proposed criteria for probable mood disorders within the cohort (major depression and bipolar disorder).\ud \ud Methods This was a descriptive epidemiological study of 172,751 individuals assessed for a lifetime history of mood disorder in relation to a range of demographic, social, lifestyle, personality and health-related factors. The main outcomes were prevalence of a probable lifetime (single) episode of major depression, probable recurrent major depressive disorder (moderate), probable recurrent major depressive disorder (severe), probable bipolar disorder and no history of mood disorder (comparison group). Outcomes were compared on age, gender, ethnicity, socioeconomic status, educational attainment, functioning, self-reported health status, current depressive symptoms, neuroticism score, smoking status and alcohol use.\ud \ud Results Prevalence rates for probable single lifetime episode of major depression (6.4%), probable recurrent major depression (moderate) (12.2%), probable recurrent major depression (severe) (7.2%) and probable bipolar disorder (1.3%) were comparable to those found in other population studies. The proposed diagnostic criteria have promising validity, with a gradient in evidence from no mood disorder through major depression and probable bipolar disorder in terms of gender distribution, socioeconomic status, self-reported health rating, current depressive symptoms and smoking.\ud \ud Significance The validity of our proposed criteria for probable major depression and probable bipolar disorder within this cohort are supported by these cross-sectional analyses. Our findings are likely to prove useful as a framework for a wide range of future genetic and non-genetic studies.

Objective measures of physical capability are being used in a growing number of studies as biomarkers of healthy ageing. However, very little research has been done to assess the impact of physical capability on subsequent positive mental wellbeing, the maintenance of which is widely considered to be an essential component of healthy ageing. We aimed to test the associations of grip strength and walking, timed get up and go and chair rise speeds (assessed at ages 53 to 82 years) with positive mental wellbeing assessed using the Warwick–Edinburgh Mental Wellbeing Scale (WEMWBS) 5 to 10 years later. Data were drawn from five British cohorts participating in the Healthy Ageing across the Life Course research collaboration. Data from each study were analysed separately and then combined using random-effects meta-analyses. Higher levels of physical capability were consistently associated with higher subsequent levels of wellbeing; for example, a 1SD increase in grip strength was associated with an age and sex-adjusted mean difference in WEMWBS score of 0.81 (0.25, 1.37), equivalent to 10 % of a standard deviation (three studies, N = 3,096). When adjusted for body size, health status, living alone, socioeconomic position and neuroticism the associations remained albeit attenuated. The finding of these consistent modest associations across five studies, spanning early and later old age, highlights the importance of maintaining physical capability in later life and provides additional justification for using objective measures of physical capability as markers of healthy ageing. Electronic supplementary material The online version of this article (doi:10.1007/s11357-013-9553-8) contains supplementary material, which is available to authorized users.

BackgroundGene-environment interaction studies offer the prospect of robust causal inference through both gene identification and instrumental variable approaches. As such they are a major and much needed development. However, conducting these studies using traditional methods, which require direct participant contact, is resource intensive. The ability to conduct gene-environment interaction studies remotely would reduce costs and increase capacity.AimTo develop a platform for the remote conduct of gene-environment interaction studies.MethodsA random sample of 15,000 men and women aged 50+ years and living in Cardiff, South Wales, of whom 6,012 were estimated to have internet connectivity, were mailed inviting them to visit a web-site to join a study of successful ageing. Online consent was obtained for questionnaire completion, cognitive testing, re-contact, record linkage and genotyping. Cognitive testing was conducted using the Cardiff Cognitive Battery. Bio-sampling was randomised to blood spot, buccal cell or no request.ResultsA heterogeneous sample of 663 (4.5% of mailed sample and 11% of internet connected sample) men and women (47% female) aged 50-87 years (median=61 yrs) from diverse backgrounds (representing the full range of deprivation scores) was recruited. Bio-samples were donated by 70% of those agreeing to do so. Self report questionnaires and cognitive tests showed comparable distributions to those collected using face-to-face methods. Record linkage was achieved for 99.9% of participants.ConclusionThis study has demonstrated that remote methods are suitable for the conduct of gene-environment interaction studies. Up-scaling these methods provides the opportunity to increase capacity for large-scale gene-environment interaction studies.

People with high intake of fish have lower reported rates of depression and a small trial in psychiatric patients suggested that fish oil supplements reduced episodes of depression and mania. As part of a factorial trial of interventions to reduce mortality in angina 452 men were randomised to advice to eat more fatty fish or no fish advice. Maxepa fish oil capsules were supplied to men who found the fish unpalatable. Fish intake and mood were assessed at baseline and six months. Most men (83%) had mood assessed using the Derogatis Stress Profile at baseline and follow-up. Self reported intake of fish was higher in the fish advice group at six months. There was, however, no difference in depression or anxiety in those allocated to receive fish advice. After controlling for baseline mood, the difference in depression score between those randomised to fish advice and those not was 1.29 (95% CI -0.29 to 2.88) and the difference in anxiety was 0.82 (95% CI -0.57 to 2.22) with positive differences indicating more depression or anxiety in those allocated to the fish arm. This trial provides no evidence that increased fatty fish intake in people without depressive symptoms has any substantial effect on mood.

Previous studies suggest that physical activity may be protective for dementia and cognitive impairment. We report findings comparing leisure-time and work-related physical activity from the Caerphilly Prospective study (CaPS) with dementia and cognitive impairment not dementia (CIND) after around 16 years of follow-up. We synthesized our results with a meta-analysis specifically testing if length of follow-up was associated with the size of any association. Age-adjusted models found no real association with dementia, and if anything increased risk for CIND (odds ratio (OR) highest versus lowest tertile 2.61, 95% CI 1.58 to 4.31), though this was attenuated after adjustment for other confounders (OR highest versus lowest tertile 1.38, 95% CI 0.78 to 2.44). There was no evidence that this differed by type (vascular versus non-vascular) of cognitive disease. Meta-analysis of other published effect estimates showed a protective effect of physical activity on cognitive impairment (OR 0.66, 95% CI 0.52 to 0.85) but with significant heterogeneity which was partially explained by length of follow up (p = 0.03). A protective association was also seen for dementia (OR 0.78, 95% CI 0.65, 0.94), which did not appear to be related to follow-up length but there was evidence of small study bias (p = 0.002) suggesting an absence of small null studies. The apparent protective effects of physical activity on cognitive health may partially reflect reverse causation and current estimates may be overly optimistic in terms of cognitive benefits.

Background: studies have shown that milk and dairy consumption in adulthood have beneficial effects on health. Methods: we examined the impact of childhood and adult diet on physical performance at age 63–86 years. The Boyd Orr cohort (n = 405) is a 65-year prospective study of children who took part in a 1930's survey; the Caerphilly Prospective Study (CaPS; n = 1,195) provides data from mid-life to old age. We hypothesised that higher intakes of childhood and adult milk, calcium, protein, fat and energy would be associated with a better performance. Results: in fully adjusted models, a standard deviation (SD) increase in natural log-transformed childhood milk intake was associated with 5% faster walking times from the get-up and go test in Boyd Orr (95% CI: 1 to 9) and 25% lower odds of poor balance (OR: 0.75; 0.55 to 1.02). Childhood calcium intake was positively associated with walking times (4% faster per SD; 0 to 8) and a higher protein intake was associated with lower odds of poor balance (OR: 0.71; 0.54 to 0.92). In adulthood, protein intake was positively associated with walking times (2% faster per SD; 1 to 3; Boyd Orr and CaPS pooled data). Conclusion: this is the first study to show positive associations of childhood milk intake with physical performance in old age.

The 'Age Well Feel Good' programme is a cohort study of older people in Wales. There is a gap in knowledge on how older people in Wales perceive health and social care services. Research is necessary to help address this gap and to provide an evidence base that informs policy making and service delivery.A representative sample of 15 000 men and women aged 50 years and over, living in Cardiff, the Welsh capital, were invited to participate in a web-based study of successful ageing. A wide range of data were collected in the study. These included psychological and cognitive assessments, self-reported health, financial status and deprivation measures.Based on over 500 responses, information on health and social care service perceptions was analysed. Overall, the perception of service availability was rated as good, yet there was widespread dissatisfaction. Furthermore, only 14% of older people were aware of a major health and social care programme in Wales, the National Service Framework for Older People.The main observation is the difference between service availability and satisfaction that views are sought. In the main, health service availability is good, yet there is widespread dissatisfaction. This raises some questions about the services provided. The evidence provided in this article is a further contribution to the policy-making process. Further work is needed.

Objective\ud \ud Insulin and the insulin-like growth factor (IGF) system regulate growth and are involved in determining muscle mass, strength and body composition. We hypothesised that IGF-I and IGF-II are associated with improved, and insulin with worse, physical performance in old age.\ud Methods\ud \ud Physical performance was measured using the get-up and go timed walk and flamingo balance test at 63–86 years. We examined prospective associations of insulin, IGF-I, IGF-II and IGFBP-3 with physical performance in the UK-based Caerphilly Prospective Study (CaPS; n = 739 men); and cross-sectional insulin, IGF-I, IGF-II, IGFBP-2 and IGFBP-3 in the Boyd Orr cohort (n = 182 men, 223 women).\ud Results\ud \ud In confounder-adjusted models, there was some evidence in CaPS that a standard deviation (SD) increase in IGF-I was associated with 1.5% faster get-up and go test times (95% CI: −0.2%, 3.2%; p = 0.08), but little association with poor balance, 19 years later. Coefficients in Boyd Orr were in the same direction as CaPS, but consistent with chance. Higher levels of insulin were weakly associated with worse physical performance (CaPS and Boyd Orr combined: get-up and go time = 1.3% slower per SD log-transformed insulin; 95% CI: 0.0%, 2.7%; p = 0.07; OR poor balance 1.13; 95% CI; 0.98, 1.29; p = 0.08), although associations were attenuated after controlling for body mass index (BMI) and co-morbidities. In Boyd Orr, a one SD increase in IGFBP-2 was associated with 2.6% slower get-up and go times (95% CI: 0.4%, 4.8% slower; p = 0.02), but this was only seen when controlling for BMI and co-morbidities. There was no consistent evidence of associations of IGF-II, or IGFBP-3 with physical performance.\ud Conclusions\ud \ud There was some evidence that high IGF-I and low insulin levels in middle-age were associated with improved physical performance in old age, but estimates were imprecise. Larger cohorts are required to confirm or refute the findings.