Mendelian Randomization analysis of the causal effect of cigarette smoking on hospital costs.

INTRODUCTION: Knowledge of the impact of smoking on healthcare costs is important for establishing the external effects of smoking and for evaluating policies intended to modify this behavior. Conventional analysis of this association is difficult because of omitted variable bias, reverse causality, and measurement error. METHODS: We approached these challenges using a Mendelian Randomization study design; genetic variants associated with smoking behaviors were used in instrumental variables models with inpatient hospital costs (calculated from electronic health records) as the outcome. We undertook genome wide association studies to identify genetic variants associated with smoking initiation and a composite smoking index (reflecting cumulative health impacts of smoking) on up to 300,045 individuals (mean age: 57 years at baseline, range 39 to 72 years) in the UK Biobank. We followed individuals up for a mean of six years. RESULTS: Genetic liability to initiate smoking (ever versus never smoking) was estimated to increase mean per-patient annual inpatient hospital costs by £477 (95% confidence interval (CI): £187 to £766). A one-unit change in genetic liability to the composite smoking index (range: 0-4.0) increased inpatient hospital costs by £204 (95% CI: £105 to £303) per unit increase in this index. There was some evidence that the composite smoking index causal models violated the instrumental variable assumptions, and all Mendelian Randomization models were estimated with considerable uncertainty. Models conditioning on risk tolerance were not robust to weak instrument bias. CONCLUSIONS: Our findings have implications for the potential cost-effectiveness of smoking interventions. IMPLICATIONS: We report the first Mendelian Randomization analysis of the causal effect of smoking on healthcare costs. Using two distinct smoking phenotypes, we identified substantial impacts of smoking on inpatient hospital costs, although the causal models were associated with considerable uncertainty. These results could be used alongside other evidence on the impact of smoking to evaluate the cost-effectiveness of anti-smoking interventions and to understand the scale of externalities associated with this behaviour.

Infection and telomere length: a systematic review protocol.

INTRODUCTION: Telomeres are a measure of cellular ageing with potential links to diseases such as cardiovascular diseases and cancer. Studies have shown that some infections may be associated with telomere shortening, but whether an association exists across all types and severities of infections and in which populations is unclear. Therefore we aim to collate available evidence to enable comparison and to inform future research in this field. METHODS AND ANALYSIS: We will search for studies involving telomere length and infection in various databases including MEDLINE (Ovid interface), EMBASE (Ovid interface), Web of Science, Scopus, Global Health and the Cochrane Library. For grey literature, the British Library of electronic theses databases (ETHOS) will be explored. We will not limit by study type, geographical location, infection type or method of outcome measurement. Two researchers will independently carry out study selection, data extraction and risk of bias assessment using the ROB2 and ROBINS-E tools. The overall quality of the studies will be determined using the Grading of Recommendations Assessment, Development and Evaluation criteria. We will also evaluate study heterogeneity with respect to study design, exposure and outcome measurement and if there is sufficient homogeneity, a meta-analysis will be conducted. Otherwise, we will provide a narrative synthesis with results grouped by exposure category and study design. ETHICS AND DISSEMINATION: The present study does not require ethical approval. Results will be disseminated via publishing in a peer-reviewed journal and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42023444854.

Educational inequality in multimorbidity: causality and causal pathways. A mendelian randomisation study in UK Biobank.

BACKGROUND: Multimorbidity, typically defined as having two or more long-term health conditions, is associated with reduced wellbeing and life expectancy. Understanding the determinants of multimorbidity, including whether they are causal, may help with the design and prioritisation of prevention interventions. This study seeks to assess the causality of education, BMI, smoking and alcohol as determinants of multimorbidity, and the degree to which BMI, smoking and alcohol mediate differences in multimorbidity by level of education. METHODS: Participants were 181,214 females and 155,677 males, mean ages 56.7 and 57.1 years respectively, from UK Biobank. We used a Mendelian randomization design; an approach that uses genetic variants as instrumental variables to interrogate causality. RESULTS: The prevalence of multimorbidity was 55.1%. Mendelian randomization suggests that lower education, higher BMI and higher levels of smoking causally increase the risk of multimorbidity. For example, one standard deviation (equivalent to 5.1 years) increase in genetically-predicted years of education decreases the risk of multimorbidity by 9.0% (95% CI: 6.5 to 11.4%). A 5 kg/m2 increase in genetically-predicted BMI increases the risk of multimorbidity by 9.2% (95% CI: 8.1 to 10.3%) and a one SD higher lifetime smoking index increases the risk of multimorbidity by 6.8% (95% CI: 3.3 to 10.4%). Evidence for a causal effect of genetically-predicted alcohol consumption on multimorbidity was less strong; an increase of 5 units of alcohol per week increases the risk of multimorbidity by 1.3% (95% CI: 0.2 to 2.5%). The proportions of the association between education and multimorbidity explained by BMI and smoking are 20.4% and 17.6% respectively. Collectively, BMI and smoking account for 31.8% of the educational inequality in multimorbidity. CONCLUSIONS: Education, BMI, smoking and alcohol consumption are intervenable causal risk factors for multimorbidity. Furthermore, BMI and lifetime smoking make a considerable contribution to the generation of educational inequalities in multimorbidity. Public health interventions that improve population-wide levels of these risk factors are likely to reduce multimorbidity and inequalities in its occurrence.

Investigating effect modification between childhood maltreatment and genetic risk for cardiovascular disease in the UK Biobank.

Cardiovascular disease (CVD) is influenced by genetic and environmental factors. Childhood maltreatment is associated with CVD and may modify genetic susceptibility to cardiovascular risk factors. We used genetic and phenotypic data from 100,833 White British UK Biobank participants (57% female; mean age = 55.9 years). We regressed nine cardiovascular risk factors/diseases (alcohol consumption, body mass index [BMI], low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes, and stroke) on their respective polygenic scores (PGS) and self-reported exposure to childhood maltreatment. Effect modification was tested on the additive and multiplicative scales by including a product term (PGS*maltreatment) in regression models. On the additive scale, childhood maltreatment accentuated the effect of genetic susceptibility to higher BMI (Peffect modification: 0.003). Individuals not exposed to childhood maltreatment had an increase in BMI of 0.12 SD (95% CI: 0.11, 0.13) per SD increase in BMI PGS, compared to 0.17 SD (95% CI: 0.14, 0.19) in those exposed to all types of childhood maltreatment. On the multiplicative scale, similar results were obtained for BMI though these did not withstand to Bonferroni correction. There was little evidence of effect modification by childhood maltreatment in relation to other outcomes, or of sex-specific effect modification. Our study suggests the effects of genetic susceptibility to a higher BMI may be moderately accentuated in individuals exposed to childhood maltreatment. However, gene*environment interactions are likely not a major contributor to the excess CVD burden experienced by childhood maltreatment victims.

Non-alcoholic fatty liver and fibrosis is associated with cardiovascular structure and function in young adults.

BACKGROUND: Non-alcoholic fatty liver disease shares many risk factors with other metabolic disorders. We sought to establish whether non-alcoholic fatty liver disease may be associated with cardiovascular health independently of other known risk factors. METHODS: In this prospective, population-based cohort of young adults, controlled attenuation parameter-defined liver steatosis, transient elastography-defined liver fibrosis, echocardiography, carotid ultrasonography, and pulse wave analysis were assessed at age 24 years. We examined associations between liver and cardiovascular measures, with and without accounting for demographics, body mass index, alcohol, smoking, blood pressure, lipidemia, glycemia, and inflammation. RESULTS: We included 2047 participants (mean age 24.4 y; 36.2% female): 212 (10.4%) had steatosis, whereas 38 (1.9%) had fibrosis. Steatosis was associated with cardiovascular measures after adjusting for demographics, but with more comprehensive adjustment, steatosis only remained associated with stroke index [ß (95% CI) of -1.85 (-3.29, -0.41) mL/m2] and heart rate [2.17 (0.58, 3.75) beats/min]. Fibrosis was associated with several measures of cardiovascular structure and function after full adjustment for risk factors, including left ventricular mass index [2.46 (0.56, 4.37) g/m2.7], E/A ratio [0.32 (0.13, 0.50)], tricuspid annular plane systolic excursion [0.14 (0.01, 0.26) cm], carotid intima-media thickness [0.024 (0.008, 0.040) mm], pulse wave velocity [0.40 (0.06, 0.75) m/s], cardiac index [-0.23 (-0.41, -0.06) L/min⋅m2], and heart rate [-7.23 (-10.16, -4.29) beats/min]. CONCLUSIONS: Steatosis was not associated with measures of cardiovascular structure and function nor with subclinical atherosclerosis after adjusting for known cardiovascular risk factors. Fibrosis, however, was associated with several cardiovascular measures, including indicators of subclinical atherosclerosis, even after full adjustment. Further follow-up will help determine whether cardiovascular health worsens later with steatosis alone.

Socioeconomic position and adverse childhood experiences as risk factors for health-related behaviour change and employment adversity during the COVID-19 pandemic: insights from a prospective cohort study in the UK.

BACKGROUND: Non-pharmaceutical interventions to reduce the spread of COVID-19 may have disproportionately affected already disadvantaged populations. METHODS: We analysed data from 2710 young adult participants of the Avon Longitudinal Study of Parents and Children. We assessed the associations of socioeconomic position (SEP) and Adverse Childhood Experiences (ACEs, e.g. abuse, neglect, measures of family dysfunction) with changes to health-related behaviours (meals, snacks, exercise, sleep, alcohol and smoking/vaping), and to financial and employment status during the first UK lockdown between March-June 2020. RESULTS: Experiencing 4+ ACEs was associated with reporting decreased sleep quantity during lockdown (OR 1.53, 95% CI: 1.07-2.18) and increased smoking and/or vaping (OR 1.85, 95% CI: 0.99-3.43); no other associations were seen between ACEs or SEP and health-related behaviour changes. Adverse financial and employment changes were more likely for people with low SEP and for people who had experienced multiple ACEs; e.g. a history of 4+ ACEs was associated with being furloughed or on other leave during lockdown (OR 1.92, 95% CI: 1.35-2.74). CONCLUSIONS: In this sample of young adults, there was little evidence that lockdown worsened inequalities in health-related behaviours. However, adverse financial and employment consequences of lockdown were more likely to be experienced by people who have already experienced socioeconomic deprivation or childhood adversity, thereby widening social inequalities and demonstrating the need for support into adulthood for those with a history of ACEs.

The UK Coronavirus Job Retention Scheme and smoking, alcohol consumption and vaping during the COVID-19 pandemic: evidence from eight longitudinal population surveys.

BACKGROUND: Employment disruptions can impact smoking and alcohol consumption. During the COVID-19 pandemic, many countries implemented furlough schemes to prevent job loss. We examine how furlough was associated with smoking, vaping and alcohol consumption in the UK. METHODS: Data from 27,841 participants in eight UK adult longitudinal surveys were analysed. Participants self-reported employment status and current smoking, current vaping and alcohol consumption (>4 days/week or 5+ drinks per typical occasion) both before and during the early stages of the pandemic (April-July 2020). Risk ratios were estimated within each study using modified Poisson regression, adjusting for a range of potential confounders, including pre-pandemic behaviour. Findings were synthesised using random effects meta-analysis. RESULTS: Compared to stable employment and after adjustment for pre-pandemic characteristics, furlough was not associated with smoking (ARR = 1.05; 95% CI: 0.95-1.16; I2: 10%), vaping (ARR = 0.89; 95% CI: 0.74-1.08; I2: 0%) or drinking (ARR = 1.03; 95% CI: 0.94-1.13; I2: 48%). There were similar findings for no longer being employed, and stable unemployment, though this varied by sex: stable unemployment was associated with smoking for women (ARR = 1.35; 95% CI: 1.00-1.82; I2: 47%) but not men (0.84; 95% CI: 0.67-1.05; I2: 0%). No longer being employed was associated with vaping among women (ARR = 2.74; 95% CI: 1.59-4.72; I2: 0%) but not men (ARR = 1.25; 95% CI: 0.83-1.87; I2: 0%). CONCLUSIONS: We found no clear evidence of furlough or unemployment having adverse impacts on smoking, vaping or drinking behaviours during the early stages of the COVID-19 pandemic in the UK. Differences in risk compared to those who remained employed were largely explained by pre-pandemic characteristics.

The UK Coronavirus Job Retention Scheme and diet, physical activity, and sleep during the COVID-19 pandemic: evidence from eight longitudinal population surveys.

BACKGROUND: In March 2020, the UK implemented the Coronavirus Job Retention Scheme (furlough) to minimise job losses. Our aim was to investigate associations between furlough and diet, physical activity, and sleep during the early stages of the COVID-19 pandemic. METHODS: We analysed data on 25,092 participants aged 16-66 years from eight UK longitudinal studies. Changes in employment, including being furloughed, were based on employment status before and during the first lockdown. Health behaviours included fruit and vegetable consumption, physical activity, and sleep. Study-specific estimates obtained using modified Poisson regression, adjusting for socio-demographic characteristics and pre-pandemic health and health behaviours, were statistically pooled using random effects meta-analysis. Associations were also stratified by sex, age, and education. RESULTS: Across studies, between 8 and 25% of participants were furloughed. Compared to those who remained working, furloughed workers were slightly less likely to be physically inactive (RR = 0.85; [95% CI 0.75-0.97]; I 2 = 59%) and did not differ overall with respect to low fruit and vegetable consumption or atypical sleep, although findings for sleep were heterogenous (I 2 = 85%). In stratified analyses, furlough was associated with lower fruit and vegetable consumption among males (RR = 1.11; [1.01-1.22]; I 2 = 0%) but not females (RR = 0.84; [0.68-1.04]; I 2 = 65%). Considering changes in quantity, furloughed workers were more likely than those who remained working to report increases in fruit and vegetable consumption, exercise, and hours of sleep. CONCLUSIONS: Those furloughed exhibited similar health behaviours to those who remained in employment during the initial stages of the pandemic. There was little evidence to suggest that adoption of such social protection policies in the post-pandemic recovery period and during future economic crises had adverse effects on population health behaviours.

Educational attainment as a modifier for the effect of polygenic scores for cardiovascular risk factors: cross-sectional and prospective analysis of UK Biobank.

BACKGROUND: Understanding the interplay between educational attainment and genetic predictors of cardiovascular risk may improve our understanding of the aetiology of educational inequalities in cardiovascular disease. METHODS: In up to 320 120 UK Biobank participants of White British ancestry (mean age = 57 years, female 54%), we created polygenic scores for nine cardiovascular risk factors or diseases: alcohol consumption, body mass index, low-density lipoprotein cholesterol, lifetime smoking behaviour, systolic blood pressure, atrial fibrillation, coronary heart disease, type 2 diabetes and stroke. We estimated whether educational attainment modified genetic susceptibility to these risk factors and diseases. RESULTS: On the additive scale, higher educational attainment reduced genetic susceptibility to higher body mass index, smoking, atrial fibrillation and type 2 diabetes, but increased genetic susceptibility to higher LDL-C and higher systolic blood pressure. On the multiplicative scale, there was evidence that higher educational attainment increased genetic susceptibility to atrial fibrillation and coronary heart disease, but little evidence of effect modification was found for all other traits considered. CONCLUSIONS: Educational attainment modifies the genetic susceptibility to some cardiovascular risk factors and diseases. The direction of this effect was mixed across traits considered and differences in associations between the effect of the polygenic score across strata of educational attainment was uniformly small. Therefore, any effect modification by education of genetic susceptibility to cardiovascular risk factors or diseases is unlikely to substantially explain the development of inequalities in cardiovascular risk.

How does childhood maltreatment influence cardiovascular disease? A sequential causal mediation analysis.

BACKGROUND: Childhood maltreatment has been consistently associated with cardiovascular disease (CVD). However, the mechanisms of this relationship are not yet fully understood. We explored the relative contribution of anxiety/depression, smoking, body mass index (BMI) and inflammation (C-reactive protein, CRP) to the association between childhood maltreatment and CVD in men and women aged 40-69 years in the UK. METHODS: We used data from 40 596 men and 59 511 women from UK Biobank. To estimate the indirect effects of childhood maltreatment (physical, sexual and emotional abuse, and emotional and physical neglect) on incident CVD via each of the mediators, we applied a sequential mediation approach. RESULTS: All forms of maltreatment were associated with increased CVD risk [hazard ratios (HRs) ranging from 1.09 to 1.27]. Together, anxiety/depression, smoking, BMI and inflammation (indexed by CRP) mediated 26-90% of the association between childhood maltreatment and CVD, and the contribution of these mediators differed by type of maltreatment and sex. Anxiety/depression mediated the largest proportion of the association of sexual abuse, emotional abuse and emotional neglect with CVD (accounting for 16-43% of the total effect), especially in women. In men, BMI contributed the most to the indirect effect of associations of physical abuse and physical neglect with CVD; in women, anxiety/depression and BMI had similar contributions. CONCLUSIONS: These findings add to the understanding of how childhood maltreatment affects CVD risk and identify modifiable mediating factors that could potentially reduce the burden of CVD in people exposed to maltreatment in early life.

Associations between Adverse Childhood Experiences and the novel inflammatory marker glycoprotein acetyls in two generations of the Avon Longitudinal Study of Parents and Children birth cohort.

BACKGROUND: Adverse childhood experiences (ACEs) are associated with increased risk of non-communicable diseases in adulthood, potentially mediated by chronic low-grade inflammation. Glycoprotein acetyls (GlycA) is a marker of chronic and cumulative inflammation. We investigated associations between ACEs and GlycA at different ages, in two generations of the population-based Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. METHODS: ALSPAC offspring's total ACE scores were generated for two age periods using prospectively collected data: 0-7y and 0-17y. GlycA was measured using high-resolution proton nuclear magnetic resonance at mean ages 8y, 18y, and 24y. Sample sizes ranged from: n = 5116 (8y) to n = 3085 (24y). ALSPAC mothers (n = 4634) retrospectively reported ACEs experienced before age 18y and GlycA was assessed at mean age 49y. We used multivariable linear regression to estimate associations between ACEs (total ACE score and individual ACEs) and subsequent GlycA in both samples, adjusting for key confounders. RESULTS: Mean GlycA levels were similar in offspring and mothers and over time. In offspring, there was no evidence that ACEs (total score or individual ACE) were associated with GlycA at age 8y or 18y, or 24y after adjustment for maternal age at birth and parity, maternal marital status, household occupational social class, maternal education, maternal smoking, own ethnicity, sex, and age in months. In mothers, there was evidence of a positive association between the total ACE score and GlycA at age 49y (adjusted mean difference 0.007 mmol/L; 95%CI: 0.003, 0.01). Emotional neglect was the only individual ACE associated with higher GlycA after adjusting for confounders and other ACEs. CONCLUSION: Results suggest the association between ACEs and GlycA may emerge in middle age. Future research should explore the extent to which inflammation in adulthood mediates well-documented associations between ACEs and adverse health outcomes in later life.

Long-term cost-effectiveness of interventions for obesity: A mendelian randomisation study.

BACKGROUND: The prevalence of obesity has increased in the United Kingdom, and reliably measuring the impact on quality of life and the total healthcare cost from obesity is key to informing the cost-effectiveness of interventions that target obesity, and determining healthcare funding. Current methods for estimating cost-effectiveness of interventions for obesity may be subject to confounding and reverse causation. The aim of this study is to apply a new approach using mendelian randomisation for estimating the cost-effectiveness of interventions that target body mass index (BMI), which may be less affected by confounding and reverse causation than previous approaches. METHODS AND FINDINGS: We estimated health-related quality-adjusted life years (QALYs) and both primary and secondary healthcare costs for 310,913 men and women of white British ancestry aged between 39 and 72 years in UK Biobank between recruitment (2006 to 2010) and 31 March 2017. We then estimated the causal effect of differences in BMI on QALYs and total healthcare costs using mendelian randomisation. For this, we used instrumental variable regression with a polygenic risk score (PRS) for BMI, derived using a genome-wide association study (GWAS) of BMI, with age, sex, recruitment centre, and 40 genetic principal components as covariables to estimate the effect of a unit increase in BMI on QALYs and total healthcare costs. Finally, we used simulations to estimate the likely effect on BMI of policy relevant interventions for BMI, then used the mendelian randomisation estimates to estimate the cost-effectiveness of these interventions. A unit increase in BMI decreased QALYs by 0.65% of a QALY (95% confidence interval [CI]: 0.49% to 0.81%) per year and increased annual total healthcare costs by £42.23 (95% CI: £32.95 to £51.51) per person. When considering only health conditions usually considered in previous cost-effectiveness modelling studies (cancer, cardiovascular disease, cerebrovascular disease, and type 2 diabetes), we estimated that a unit increase in BMI decreased QALYs by only 0.16% of a QALY (95% CI: 0.10% to 0.22%) per year. We estimated that both laparoscopic bariatric surgery among individuals with BMI greater than 35 kg/m2, and restricting volume promotions for high fat, salt, and sugar products, would increase QALYs and decrease total healthcare costs, with net monetary benefits (at £20,000 per QALY) of £13,936 (95% CI: £8,112 to £20,658) per person over 20 years, and £546 million (95% CI: £435 million to £671 million) in total per year, respectively. The main limitations of this approach are that mendelian randomisation relies on assumptions that cannot be proven, including the absence of directional pleiotropy, and that genotypes are independent of confounders. CONCLUSIONS: Mendelian randomisation can be used to estimate the impact of interventions on quality of life and healthcare costs. We observed that the effect of increasing BMI on health-related quality of life is much larger when accounting for 240 chronic health conditions, compared with only a limited selection. This means that previous cost-effectiveness studies have likely underestimated the effect of BMI on quality of life and, therefore, the potential cost-effectiveness of interventions to reduce BMI.

Cardiorespiratory fitness, fatness, and the acute blood pressure response to exercise in adolescence.

OBJECTIVE: Exaggerated exercise blood pressure (BP) is associated with cardiovascular risk factors in adolescence. Cardiorespiratory fitness and adiposity (fatness) are independent contributors to cardiovascular risk, but their interrelated associations with exercise BP are unknown. This study aimed to determine the relationships between fitness, fatness, and the acute BP response to exercise in a large birth cohort of adolescents. METHODS: 2292 adolescents from the Avon Longitudinal Study of Parents and Children (aged 17.8 ± 0.4 years, 38.5% male) completed a sub-maximal exercise step test that allowed fitness (VO2 max ) to be determined from workload and heart rate using a validated equation. Exercise BP was measured immediately on test cessation and fatness calculated as the ratio of total fat mass to total body mass measured by DXA. RESULTS: Post-exercise systolic BP decreased stepwise with tertile of fitness (146 (18); 142 (17); 141 (16) mmHg) but increased with tertile of fatness (138 (15); 142 (16); 149 (18) mmHg). In separate models, fitness and fatness were associated with post-exercise systolic BP adjusted for sex, age, height, smoking, and socioeconomic status (standardized ß: -1.80, 95%CI: -2.64, -0.95 mmHg/SD and 4.31, 95%CI: 3.49, 5.13 mmHg/SD). However, when fitness and fatness were included in the same model, only fatness remained associated with exercise BP (4.65, 95%CI: 3.69, 5.61 mmHg/SD). CONCLUSION: Both fitness and fatness are associated with the acute BP response to exercise in adolescence. The fitness-exercise BP association was not independent of fatness, implying the cardiovascular protective effects of cardiorespiratory fitness may only be realized with more favorable body composition.

Puberty timing and markers of cardiovascular structure and function at 25 years: a prospective cohort study.

BACKGROUND: Whether earlier onset of puberty is associated with higher cardiovascular risk in early adulthood is not well understood. Our objective was to examine the association between puberty timing and markers of cardiovascular structure and function at age 25 years. METHODS: We conducted a prospective birth cohort study using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). Participants were born between April 1, 1991, and December 31, 1992. Exposure of interest was age at peak height velocity (aPHV), an objective and validated growth-based measure of puberty onset. Outcome measures included cardiovascular structure and function at age 25 years: carotid intima-media thickness (CIMT), left ventricular mass index (LVMI) and relative wall thickness (RWT), pulse wave velocity (PWV) and systolic blood pressure (SBP). Multiple imputation was used to impute missing data on covariates and outcomes. Linear regression was used to examine the association between aPHV and each measure of cardiac structure and function, adjusting for maternal age, gestational age, household social class, maternal education, mother's partner's education, breastfeeding, parity, birthweight, maternal body mass index, maternal marital status, maternal prenatal smoking status and height and fat mass at age 9. All analyses were stratified by sex. RESULTS: A total of 2752-4571 participants were included in the imputed analyses. A 1-year older aPHV was not strongly associated with markers of cardiac structure and function in males and females at 25 years and most results spanned the null value. In adjusted analyses, a 1-year older aPHV was associated with 0.003 mm (95% confidence interval (CI) 0.00001, 0.006) and 0.0008 mm (95% CI - 0.002, 0.003) higher CIMT; 0.02 m/s (95% CI - 0.05, 0.09) and 0.02 m/s (95% CI - 0.04, 0.09) higher PWV; and 0.003 mmHg (95% CI - 0.60, 0.60) and 0.13 mmHg (95% CI - 0.44, 0.70) higher SBP, among males and females, respectively. A 1-year older aPHV was associated with - 0.55 g/m2.7 (95% CI - 0.03, - 1.08) and - 0.89 g/m2.7 (95% CI - 0.45, - 1.34) lower LVMI and - 0.001 (95% CI - 0.006, 0.002) and - 0.002 (95% CI - 0.006, 0.002) lower RWT among males and females. CONCLUSIONS: Earlier puberty is unlikely to have a major impact on pre-clinical cardiovascular risk in early adulthood.

Role of the Metabolic Profile in Mediating the Relationship Between Body Mass Index and Left Ventricular Mass in Adolescents: Analysis of a Prospective Cohort Study.

Background We aimed to quantify the role of the plasma metabolic profile in explaining the effect of adiposity on cardiac structure. Methods and Results Body mass index (BMI) was measured at age 11 in the Avon Longitudinal Study of Parents and Children. Left ventricular mass indexed to height2.7 (LVMI) was assessed by echocardiography at age 17. The metabolic profile was quantified via 1H-nuclear magnetic resonance spectroscopy at age 15. Multivariable confounder (maternal age, parity, highest qualification, maternal smoking, prepregnancy BMI, prepregnancy height, household social class, adolescent birthweight, adolescent smoking, fruit and vegetable consumption, and physical activity)-adjusted linear regression estimated the association of BMI with LVMI and mediation by metabolic traits. We considered 156 metabolomic traits individually and jointly as principal components explaining 95% of the variance in the nuclear magnetic resonance platform and assessed whether the principal components for the metabolic traits added to the proportion of the association explained by putative cardiovascular risk factors (systolic and diastolic blood pressures, insulin, triglycerides, low-density lipoprotein cholesterol, and glucose). A 1 kg/m2 higher BMI was associated with a 0.70 g/m2.7 (95% CI, 0.53-0.88 g/m2.7) and 0.66 g/m2.7 (95% CI, 0.53-0.79 g/m2.7) higher LVMI in males (n=437) and females (n=536), respectively. Putative risk factors explained 3% (95% CI, 2%-5%) of this association in males, increasing to 10% (95% CI, 8%-13%) when including metabolic principal components. In females, the standard risk factors explained 3% (95% CI, 2%-5%) of the association and did not increase when including the metabolic principal components. Conclusions The addition of the nuclear magnetic resonance-measured metabolic traits appears to mediate more of the association of BMI on LVMI than the putative risk factors alone in adolescent males, but not females.

Adverse childhood experiences and early life inflammation in the Avon longitudinal study of parents and children.

BACKGROUND: Adverse childhood experiences (ACEs) have been associated with poorer health across the life course. Previous studies have used cumulative risk scores (ACE scores) or individual ACEs but these two approaches have important shortcomings. ACE scores assume that each adversity is equally important for the outcome of interest and the single adversity approach assumes that ACEs do not co-occur. Latent class analysis (LCA) is an alternative approach to operationalising ACEs data, identifying groups of people co-reporting similar ACEs. Here we apply these three approaches for ACEs operationalisation with inflammation in childhood with the aim of identifying particular ACEs or ACE combinations that are particularly associated with higher inflammation in early life. METHODS: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC) we compare ACE scores, single adversities and LCA-derived ACE clusters in their relationships with Interleukin-6 at age 9 (n = 4935) and C-Reactive Protein (CRP) at age 9 (n = 4887). ACEs included were parental separation/divorce, parental alcohol problems, parental mental health problems, parental offending, inter-parental violence, parental drug misuse, and physical, emotional and sexual abuse. RESULTS: Two thirds of the sample reported at least one ACE. Mother's mental health problems was the most frequently reported ACE (32.3 %). LCA identified four ACE classes - 'Low ACEs' (81.1 %), 'Maternal mental health problems' (10.3 %), 'Maternal mental health problems and physical abuse' (6.3 %) and 'Parental conflict, mental health problems and emotional abuse' (2.4 %). Parental separation/divorce was associated with higher IL-6. Parental alcohol problems, paternal mental health problems, parental convictions and emotional abuse were associated with lower levels of IL-6. Associations for paternal mental health problems and emotional abuse were only observed for boys. ACE score and LCA-derived ACE classes were not associated with differences in IL-6. Girls in the 'Maternal mental health problems' cluster had lower CRP levels. CONCLUSIONS: Specific adversities and adversity combinations are important for differences in childhood inflammation. Some associations were only observed for girls or boys.

The causal effects of health conditions and risk factors on social and socioeconomic outcomes: Mendelian randomization in UK Biobank.

BACKGROUND: We aimed to estimate the causal effect of health conditions and risk factors on social and socioeconomic outcomes in UK Biobank. Evidence on socioeconomic impacts is important to understand because it can help governments, policy makers and decision makers allocate resources efficiently and effectively. METHODS: We used Mendelian randomization to estimate the causal effects of eight health conditions (asthma, breast cancer, coronary heart disease, depression, eczema, migraine, osteoarthritis, type 2 diabetes) and five health risk factors [alcohol intake, body mass index (BMI), cholesterol, systolic blood pressure, smoking] on 19 social and socioeconomic outcomes in 336 997 men and women of White British ancestry in UK Biobank, aged between 39 and 72 years. Outcomes included annual household income, employment, deprivation [measured by the Townsend deprivation index (TDI)], degree-level education, happiness, loneliness and 13 other social and socioeconomic outcomes. RESULTS: Results suggested that BMI, smoking and alcohol intake affect many socioeconomic outcomes. For example, smoking was estimated to reduce household income [mean difference = -£22 838, 95% confidence interval (CI): -£31 354 to -£14 321] and the chance of owning accommodation [absolute percentage change (APC) = -20.8%, 95% CI: -28.2% to -13.4%], of being satisfied with health (APC = -35.4%, 95% CI: -51.2% to -19.5%) and of obtaining a university degree (APC = -65.9%, 95% CI: -81.4% to -50.4%), while also increasing deprivation (mean difference in TDI = 1.73, 95% CI: 1.02 to 2.44, approximately 216% of a decile of TDI). There was evidence that asthma decreased household income, the chance of obtaining a university degree and the chance of cohabiting, and migraine reduced the chance of having a weekly leisure or social activity, especially in men. For other associations, estimates were null. CONCLUSIONS: Higher BMI, alcohol intake and smoking were all estimated to adversely affect multiple social and socioeconomic outcomes. Effects were not detected between health conditions and socioeconomic outcomes using Mendelian randomization, with the exceptions of depression, asthma and migraines. This may reflect true null associations, selection bias given the relative health and age of participants in UK Biobank, and/or lack of power to detect effects.

Associations of adverse childhood experiences with educational attainment and adolescent health and the role of family and socioeconomic factors: A prospective cohort study in the UK.

BACKGROUND: Experiencing multiple adverse childhood experiences (ACEs) is a risk factor for many adverse outcomes. We explore associations of ACEs with educational attainment and adolescent health and the role of family and socioeconomic factors in these associations. METHODS AND FINDINGS: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective cohort of children born in southwest England in 1991-1992, we assess associations of ACEs between birth and 16 years (sexual, physical, or emotional abuse; emotional neglect; parental substance abuse; parental mental illness or suicide attempt; violence between parents; parental separation; bullying; and parental criminal conviction, with data collected on multiple occasions between birth and age 16) with educational attainment at 16 years (n = 9,959) and health at age 17 years (depression, obesity, harmful alcohol use, smoking, and illicit drug use; n = 4,917). We explore the extent to which associations are robust to adjustment for family and socioeconomic factors (home ownership, mother and partner's highest educational qualification, household social class, parity, child's ethnicity, mother's age, mother's marital status, mother's depression score at 18 and 32 weeks gestation, and mother's partner's depression score at 18 weeks gestation) and whether associations differ according to socioeconomic factors, and we estimate the proportion of adverse educational and health outcomes attributable to ACEs or family or socioeconomic measures. Among the 9,959 participants (49.5% female) included in analysis of educational outcomes, 84% reported at least one ACE, 24% reported 4 or more ACEs, and 54.5% received 5 or more General Certificates of Secondary Education (GCSEs) at grade C or above, including English and Maths. Among the 4,917 participants (50.1% female) included in analysis of health outcomes, 7.3% were obese, 8.7% had depression, 19.5% reported smoking, 16.1% reported drug use, and 10.9% reported harmful alcohol use. There were associations of ACEs with lower educational attainment and higher risk of depression, drug use, and smoking. For example, odds ratios (ORs) for 4+ ACEs compared with no ACEs after adjustment for confounders were depression, 2.4 (1.6-3.8, p < 0.001); drug use, 3.1 (2.1-4.4, p < 0.001); and smoking, 2.3 (1.7-3.1, p < 0.001). Associations with educational attainment attenuated after adjustment but remained strong; for example, the OR after adjustment for confounders for low educational attainment comparing 4+ ACEs with no ACEs was 2.0 (1.7-2.4, p < 0.001). Associations with depression, drug use, and smoking were not altered by adjustment. Associations of ACEs with harmful alcohol use and obesity were weak. For example, ORs for 4+ ACEs compared with no ACEs after adjustment for confounders were harmful alcohol use, 1.4 (0.9-2.0, p = 0.10) and obesity, 1.4 (0.9-2.2, p = 0.13) We found no evidence that socioeconomic factors modified the associations of ACEs with educational or health outcomes. Population attributable fractions (PAFs) for the adverse educational and health outcomes range from 5%-15% for 4+ ACEs and 1%-19% for low maternal education. Using data from multiple questionnaires across a long period of time enabled us to capture a detailed picture of the cohort members' experience of ACEs; however, a limitation of our study is that this resulted in a high proportion of missing data, and our analyses assume data are missing at random. CONCLUSIONS: This study demonstrates associations between ACEs and lower educational attainment and higher risks of depression, drug use, and smoking that remain after adjustment for family and socioeconomic factors. The low PAFs for both ACEs and socioeconomic factors imply that interventions that focus solely on ACEs or solely on socioeconomic deprivation, whilst beneficial, would miss most cases of adverse educational and health outcomes. This interpretation suggests that intervention strategies should target a wide range of relevant factors, including ACEs, socioeconomic deprivation, parental substance use, and mental health.

Risk factors for intimate partner violence and abuse among adolescents and young adults: findings from a UK population-based cohort.

Background: Approximately one-third of young people in the UK have suffered intimate partner violence and abuse (IPVA) on reaching adulthood. We need interventions to prevent IPVA in this population, but there is a lack of evidence on who is at greatest risk. Methods: We analysed questionnaire data from 3,279 participants of the Avon Longitudinal Study of Parents and Children population-based birth cohort. We estimated the prevalence of IPVA victimisation and perpetration by age 21, by sex, demographic, parenting, mental health, externalising behaviour (e.g. smoking), educational, employment, and adverse childhood factors. Results: Overall, 29% of males and 41% of females reported IPVA victimisation, with 20% and 25% reporting perpetration, respectively (16% and 22% both). The most common sub-type was emotional, followed by physical, then sexual. History of self-harm, anti-social behaviour, cannabis or illicit (non-cannabis) drug use among boys and girls was associated with a two-fold increase in likelihood of IPVA (victimisation or perpetration). Males reporting risky sexual behaviour, sexual abuse (not by an intimate partner), or witnessing domestic violence, and females reporting sexual minority status in adolescence were also twice as likely to experience IPVA. Extreme parental monitoring during adolescence was associated with a reduced risk of IPVA in males and females, as was not being in education, employment, or training for young adult men. Conclusions: A range of demographic, mental health, and behavioural factors were associated with increased prevalence of IPVA victimisation or perpetration. Further study of likely complex pathways from these factors to IPVA, to inform primary prevention, is needed.

LPS-Induced Hypotension in Pregnancy: The Effect of Progesterone Supplementation.

Our previous work has shown that pregnancy exacerbates the hypotensive response to both infection and lipopolysaccharide (LPS). The high levels of progesterone (P4) associated with pregnancy have been suggested to be responsible for the pregnancy-induced changes in the cardiovascular response to infection. Here, we test the hypothesis that P4 supplementation exacerbates the hypotensive response of the maternal cardiovascular to LPS.Female CD1 mice had radiotelemetry probes implanted to measure hemodynamic function noninvasively and were time-mated. From day 14 of pregnancy, mice received either 10 mg of P4 or vehicle alone per day and on day 16, intraperitoneal LPS (10 µg of serotype 0111:B4) was injected. In two identically treated cohorts of mice, tissue and serum (for RNA, protein studies) were collected at 6 and 12 h.Administration of LPS resulted in a fall in blood pressure in vehicle treated, but not P4 supplemented mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors and in both circulating and tissue inflammatory cell numbers, but with reduced left ventricular expression of cytokines in P4-supplemented mice. However, left ventricular expression of markers of cardiac dysfunction and apoptosis were similar.This study demonstrates that P4 supplementation prevented LPS-induced hypotension in pregnant mice in association with reduced myocardial inflammatory cytokine gene expression. These observations suggest that rather than being detrimental, P4 supplementation has a protective effect on the maternal cardiovascular response to sepsis.