Impact of Distinct Anti-Androgen Exposures on the Plasma Metabolome in Feminizing Gender-Affirming Hormone Therapy.

CONTEXT: The plasma metabolome is a functional readout of metabolic activity and is associated with phenotypes exhibiting sexual dimorphism, such as cardiovascular disease. Sex hormones are thought to play a key role in driving sexual dimorphism. OBJECTIVE: Gender-affirming hormone therapy (GAHT) is a cornerstone of transgender care, but longitudinal changes in the plasma metabolome with feminizing GAHT have not been described. METHODS: Blood samples were collected at baseline and after three and six months of GAHT from transgender women (n = 53). Participants were randomized to different anti-androgens, cyproterone acetate or spironolactone. NMR-based metabolomics was used to measure 249 metabolic biomarkers in plasma. Additionally, we used metabolic biomarker data from an unrelated cohort of children and their parents (n = 3,748) to identify sex- and age-related metabolite patterns. RESULTS: We identified 43 metabolic biomarkers altered after six months in both anti-androgen groups, most belonging to the very low- or low-density lipoprotein subclasses, with all but one showing a decrease. We observed a cyproterone acetate-specific decrease in glutamine, glycine, and alanine levels. Notably, of the metabolic biomarkers exhibiting the most abundant 'sex- and age-related' pattern (higher in assigned female children and lower in assigned female adults, relative to assigned males), 80% were significantly lowered after GAHT, reflecting a shift toward the adult female profile. CONCLUSION: Our results suggest an anti-atherogenic signature in the plasma metabolome after the first six months of feminizing GAHT, with cyproterone acetate also reducing specific plasma amino acids. This study provides novel insight into the metabolic changes occurring across feminizing GAHT.

Prevalence of Eating Disorder Symptoms in Transgender and Gender Diverse Adolescents Presenting for Gender-Affirming Care.

PURPOSE: To describe the prevalence of eating disorder symptoms among adolescents seeking gender-affirming care. METHODS: Cross-sectional study of 660 gender-diverse adolescents who completed the Branched Eating Disorder Test to measure anorexia and bulimia symptoms. RESULTS: 23.9% (95% CI 20.7-27.4) reported both anorexia symptoms, namely overvaluation of weight and fear of (or recurrent interference with) weight gain. 0.9% (95% CI 0.3-2.0) reported all bulimia symptoms, namely overvaluation of weight, recurrent binge eating, and recurrent compensatory behaviors (e.g., weekly purging). For all symptoms, prevalence was higher among i) adolescents assigned female at birth compared to those assigned male at birth, and ii) adolescents who felt unsure about their gender identity compared to those who identified as trans or nonbinary. DISCUSSION: Clinicians should monitor eating disorder symptoms among adolescents presenting for gender-affirming care, especially among those assigned female at birth or who are unsure about their gender identity.

Polygenic Risk Scores and the Risk of Childhood Overweight/Obesity in Association With the Consumption of Sweetened Beverages: A Population-Based Cohort Study.

Background: Sugar-sweetened beverage (SSB) and non-nutritive sweetened beverage (NNSB) consumption is associated with obesity and are targets for population-level dietary interventions. In children (<16 years), we evaluate whether SSB or NNSB consumption is associated with subsequent (2 years later) overweight and/or obesity, and the effect of consumption on subsequent overweight/obesity differs by BMI polygenic risk score (BMI-PRS). Methods: The nationally representative Longitudinal-Study-of-Australian-Children had biennial data collection from birth (n = 5107) until age 14/15 years (n = 3127). At age 11/12 years, a comprehensive biomedical assessment, including PRS assessment, was undertaken (n = 1422). Parent- or self-reported beverage consumption (SSBs: soft drinks, energy drinks, and/or juice; NNSBs: diet drinks) was measured as any/none over previous 24 hours. BMI-PRS was derived using published results (high PRS ≥75th percentile). At ages 4/5-14/15 children were classified as having obesity, overweight/obesity, or not having overweight/obesity using BMI z-score (CDC cut points). Results: SSB consumption had limited association with subsequent overweight/obesity. NNSB consumption was associated with ∼8% more children with subsequent overweight/obesity at most ages. In older children with high BMI-PRS, associations between NNSB consumption and subsequent overweight/obesity strengthened with age [at age 14-15 for high BMI-PRS, difference in proportion with overweight/obesity among NNSB consumers vs. nonconsumers = 0.38 (95% confidence interval: 0.22 to 0.55, p ≤ 0.001)]. There was limited association between SSB consumption and BMI-PRS. Conclusion: NNSB consumption was associated with increased risk of overweight/obesity for children with greater genetic risk at older ages (12-15 years). Focused intervention among children with high genetic risk could target NNSB consumption; however, reverse causality (children with genetic risk and/or high BMI consume more NNSBs) cannot be excluded.

Intervention targets for reducing mortality between mid-adolescence and mid-adulthood: a protocol for a machine-learning facilitated systematic umbrella review.

INTRODUCTION: A rise in premature mortality-defined here as death during the most productive years of life, between adolescence and middle adulthood (15-60 years)-is contributing to stalling life expectancy in high-income countries. Causes of mortality vary, but often include substance misuse, suicide, unintentional injury and non-communicable disease. The development of evidence-informed policy frameworks to guide new approaches to prevention require knowledge of early targets for intervention, and interactions between higher level drivers. Here, we aim to: (1) identify systematic reviews with or without meta-analyses focused on intervention targets for premature mortality (in which intervention targets are causes of mortality that can, at least hypothetically, be modified to reduce risk); (2) evaluate the review quality and risk of bias; (3) compare and evaluate each review's, and their relevant primary studies, findings to identify existing evidence gaps. METHODS AND ANALYSIS: In May 2023, we searched electronic databases (MEDLINE, PubMed, Embase, Cochrane Library) for peer-reviewed papers published in the English language in the 12 years from 2012 to 2023 that examined intervention targets for mortality. Screening will narrow these papers to focus on systematic reviews with or without meta-analyses, and their primary papers. Our outcome is death between ages 15 and 60 years; with potential intervention targets measured prior to death. A MeaSurement Tool to Assess systematic Reviews (AMSTAR 2) will be used to assess quality and risk of bias within included systematic reviews. Results will be synthesised narratively due to anticipated heterogeneity between reviews and between primary studies contained within included reviews. ETHICS AND DISSEMINATION: This review will synthesise findings from published systematic reviews and meta-analyses, and their primary reviewed studies, meaning ethics committee approval is not required. Our findings will inform cross-cohort consortium development, be published in a peer-reviewed journal, and be presented at national and international conferences. PROSPERO REGISTRATION NUMBER: CRD42022355861.

Cardiometabolic Risk Markers for Aboriginal and Torres Strait Islander Children and Youths: A Systematic Review of Data Quality and Population Prevalence.

Cardiovascular disease and type 2 diabetes mellitus are leading contributors to the health inequity experienced by Aboriginal and Torres Strait Islander peoples, and their antecedents can be identified from early childhood. We aimed to establish the quality of available data and the prevalence of cardiometabolic risk markers among Aboriginal and Torres Strait Islander children and youths (0-24-year-olds) to inform public health approaches. A systematic review of the peer-reviewed and grey literature was conducted between 1 January 2000-28 February 2021. Included studies reported population prevalence of cardiometabolic risks, including elevated blood pressure, obesity, central adiposity, dyslipidaemia, hyperglycaemia, and 'metabolic syndrome' for Aboriginal and Torres Strait Islander people aged 0-24 years. Fifteen studies provided population estimates. Data quality was limited by low response rates (10/15 studies) and suboptimal outcome measurements. Obesity is the most reported risk (13/15 studies). Aboriginal and Torres Strait Islander children have an excess risk of obesity from early childhood and prevalence increases with age: 32.1% of Aboriginal and Torres Strait Islander 18-24-year-olds had obesity and 50.8% had central adiposity. In a cohort of 486 9-14-year-olds in Darwin, 70% had ≥1 component of metabolic syndrome; 14% met the full criteria for the syndrome. The prevalence of cardiometabolic risk in Aboriginal and Torres Strait Islander young people is difficult to estimate due to limitations in measurement quality and sampling representativeness. Available data suggest that cardiometabolic risk markers are evident from early childhood. The establishment of national and state-level datasets and a core outcome set for cardiometabolic screening would provide opportunities for preventative action.

Weight status and weight-control exercise in adolescents: A longitudinal population-based study.

OBJECTIVE: Exercise is a transdiagnostic clinical feature of eating disorders, but consensus is lacking as to what constitutes, and gives rise to, excessive exercise motivated by weight control. Using a longitudinal cohort study, we aimed to describe population-level prevalence rates of varying levels of weight-control exercise and examine gender and weight status (overweight or obesity; OVOB) as cross-sectional determinants of weight-control exercise in 14-15-year-old adolescents. We then evaluated the association of OVOB at 10-11 years with weight-control exercise at 14-15 years. METHODS: The sample comprised 6329 adolescents from the Longitudinal Study of Australian Children (LSAC). Weight and height were measured in early adolescence (aged 10-11) and in mid-adolescence (aged 14-15). Participants reported weight-control exercise using the Branched Eating Disorders Test at 14-15 years. RESULTS: In mid-adolescence, the estimated population prevalence for any weight-control exercise was 49 % (55 % in females). For girls, moderate levels of exercise were most prevalent, and low levels for boys. For all levels except for the very lowest, boys with (vs. without) OVOB history (10-11 years) had about twice the odds of endorsing every level of weight-control exercise. Patterns among girls were similar, though lower in magnitude (∼1.5 times). CONCLUSIONS: For both girls and boys, across most exercise levels, rates of weight-control exercise were greatest for those with OVOB; for the highest exercise level, effects were strongest for boys with OVOB. To accurately identify at-risk adolescents, our results provide preliminary support for a fluid definition of excessive weight-control exercise, dependent on gender and weight status.

Socioeconomic disadvantage and polygenic risk for high BMI magnify obesity risk across childhood: a longitudinal, population, cohort study.

BACKGROUND: Across the life course, socioeconomic disadvantage disproportionately afflicts those with genetic predispositions to inflammatory diseases. We describe how socioeconomic disadvantage and polygenic risk for high BMI magnify the risk of obesity across childhood, and using causal analyses, explore the hypothetical impact of intervening on socioeconomic disadvantage to reduce adolescent obesity. METHODS: Data were drawn from a nationally representative Australian birth cohort, with biennial data collection between 2004 and 2018 (research and ethics committee approved). We generated a polygenic risk score for BMI using published genome-wide association studies. We measured early-childhood disadvantage (age 2-3 years) with a neighbourhood census-based measure and a family-level composite of parent income, occupation, and education. We used generalised linear regression (Poisson-log link) to estimate the risk of overweight or obesity (BMI ≥85th percentile) at age 14-15 years for children with early-childhood disadvantage (quintiles 4-5) versus average (quintile 3) and least disadvantage (quintiles 1-2), for those with high and low polygenic risk separately. FINDINGS: For 1607 children (n=796 female, n=811 male; 31% of the original cohort [N=5107]), polygenic risk and disadvantage were both associated with overweight or obesity; effects of disadvantage were more marked as polygenic risk increased. Of children with polygenic risk higher than the median (n=805), 37% of children living in disadvantage at age 2-3 years had an overweight or obese BMI by adolescence, compared with 26% of those with least disadvantage. For genetically vulnerable children, causal analyses indicated that early neighbourhood intervention to lessen disadvantage (to quintile 1-2) would reduce risk of adolescent overweight or obesity by 23% (risk ratio 0·77; 95% CI 0·57-1·04); estimates for improving family environments were similar (0·59; 0·43-0·80). INTERPRETATION: Actions addressing socioeconomic disadvantage could mitigate polygenic risk for developing obesity. This study benefits from population-representative longitudinal data but is limited by sample size. FUNDING: Australian National Health and Medical Research Council.

Greenness modifies the association between ambient air pollution and cognitive function in Australian adolescents, but not in mid-life adults.

Exposure to ambient air pollution has been associated with reduced cognitive function in childhood and later life, with too few mid-life studies to draw conclusions. In contrast, residential greenness has been associated with enhanced cognitive function throughout the lifecourse. Here we examine the extent to which (1) ambient air pollution and residential greenness predict later cognitive function in adolescence and mid-life, and (2) greenness modifies air pollution-cognitive function associations. PARTICIPANTS: 6220 adolescents (51% male) and 2623 mid-life adults (96% mothers) from the Longitudinal Study of Australian Children. MEASURES: Exposures: Annual average particulate matter <2.5 µm (PM2.5), nitrogen dioxide (NO2) and greenness (Normalised Difference Vegetation Index) for residential addresses from validated land-use regression models over a 10-13-year period. OUTCOMES: Cognitive function from CogState tests of attention, working memory and executive function, dichotomised into poorer (worst quartile) versus not poor. ANALYSES: Adjusted mixed-effects generalised linear models with residential greenness assessed as an effect modifier (high vs. low divided at median). The annual mean for PM2.5 and NO2 across exposure windows was 6.3-6.8 µg/m3, and 5.5-7.1 ppb, respectively. For adolescents, an IQR increment of NO2 was associated with 19-24% increased odds of having poorer executive function across all time windows, while associations weren't observed between air pollution and other outcomes. For adults, high NO2 predicted poorer cognitive function across all outcomes, while high PM2.5 predicted poorer attention only. There was little evidence of associations between greenness and cognitive function in adjusted models for both generations. Interactions were found between residential greenness, air pollutants and cognitive function in adolescents, but not adults. The magnitude of effects was similar across generations and exposure windows. Findings highlight the potential benefits of cognitive health associated with the regulation of air pollution and urban planning strategies for increasing green spaces and vegetation.

The effect of adverse and positive experiences on inflammatory markers in Australian and UK children.

Background: The relationship between childhood adversity and inflammation is well-established. Examination of positive experiences can provide a more complete understanding of intervention opportunities. We investigated associations of adverse and positive experiences, and their intersection, with inflammation in children and adolescents. Methods: Data sources: Longitudinal Study of Australian Children (LSAC; N = 1237) and Avon Longitudinal Study of Parents and Children (ALSPAC; N = 3488). Exposures: Adverse and positive experiences assessed repeatedly (LSAC: 0-11 years; ALSPAC: 0-15 years). Outcomes: Inflammation quantified by high sensitivity C-reactive protein (hsCRP) and glycoprotein acetyls (GlycA) (LSAC: 11-12 years; ALSPAC: 15.5 years). Analyses: Linear regression on the log-transformed outcomes estimated the relative difference in inflammatory markers with adverse/positive experiences, adjusting for socio-demographics and concurrent positive/adverse experiences, respectively. Results: Most associations were in the expected direction but differed in magnitude by exposure, outcome and cohort. Across both cohorts, adverse experiences were associated with up to 7.3% higher hsCRP (95% CI: -18.6%, 33.2%) and up to 2.0% higher GlycA (95% CI: 0.5%, 3.5%); while positive experiences were associated with up to 22.1% lower hsCRP (95% CI: -49.0%, 4.7%) and 1.3% lower GlycA (95% CI: -2.7%, 0.2%). In LSAC, the beneficial effect of positive experiences on inflammation was more pronounced among those with fewer concurrent adverse experiences. Conclusion: Across two cohorts, we found small but directionally consistent associations between adverse experiences and higher inflammation, and positive experiences and lower inflammation, particularly for GlycA. Future research should give further consideration to positive experiences to complement the current focus on adversity and inform the design and evaluation of early life interventions.

Stress, eating and weight change in first year students: the moderating role of self-compassion.

OBJECTIVE: The current study sought to examine the drivers of weight change in first-year university students. The study examined the moderating role of self-compassion in the relationship between stress, eating and weight change. Specifically, we expected that students low in self-compassion would respond to stress with unhealthy eating resulting in weight gain. We expected students high in self-compassion to be buffered from the negative effects of stress (moderated mediation model). METHODS: First-year university students in New Zealand (N = 136) completed measures of healthy and unhealthy food intake and BMI at the beginning and end of the academic year. Self-compassion was measured at baseline only, and perceived stress was averaged over four time points across the year. RESULTS: Students gained a significant 1.45 kg (SD 3.67 kg) of body weight. Self-compassion moderated the relationship between stress and changes in: (a) unhealthy (but not healthy) food intake, and (b) body weight. For those with low self-compassion, perceived stress was significantly related to an increase in BMI and, unexpectedly, to a decrease in unhealthy food intake. Changes in food intake did not explain changes in BMI. CONCLUSION: Wellbeing interventions for university students to reduce negative effects of stress should incorporate concurrent training in self-compassion.

Can adult polygenic scores improve prediction of body mass index in childhood?

BACKGROUND/OBJECTIVES: Modelling genetic pre-disposition may identify children at risk of obesity. However, most polygenic scores (PGSs) have been derived in adults, and lack validation during childhood. This study compared the utility of existing large-scale adult-derived PGSs to predict common anthropometric traits (body mass index (BMI), waist circumference, and body fat) in children and adults, and examined whether childhood BMI prediction could be improved by combining PGSs and non-genetic factors (maternal and earlier child BMI). SUBJECTS/METHODS: Participants (n = 1365 children, and n = 2094 adults made up of their parents) were drawn from the Longitudinal Study of Australian Children. Children were weighed and measured every two years from 0-1 to 12-13 years, and adults were measured or self-reported measurements were obtained concurrently (average analysed). Participants were genotyped from blood or oral samples, and PGSs were derived based on published genome-wide association studies. We used linear regression to compare the relative utility of these PGSs to predict their respective traits at different ages. RESULTS: BMI PGSs explained up to 12% of child BMI z-score variance in 10-13 year olds, compared with up to 15% in adults. PGSs for waist circumference and body fat explained less variance (up to 8%). An interaction between BMI PGSs and puberty (p = 0.001-0.002) suggests the effect of some variants may differ across the life course. Individual BMI measures across childhood predicted 10-60% of the variance in BMI at 12-13 years, and maternal BMI and BMI PGS each added 1-9% above this. CONCLUSION: Adult-derived PGSs for BMI, particularly those derived by modelling between-variant interactions, may be useful for predicting BMI during adolescence with similar accuracy to that obtained in adulthood. The level of precision presented here to predict BMI during childhood may be relevant to public health, but is likely to be less useful for individual clinical purposes.

Does an inflammatory diet affect mental well-being in late childhood and mid-life? A cross-sectional study.

Inflammatory diets are increasingly recognised as a modifiable determinant of mental illness. However, there is a dearth of studies in early life and across the full mental well-being spectrum (mental illness to positive well-being) at the population level. This is a critical gap given that inflammatory diet patterns and mental well-being trajectories typically establish by adolescence. We examined the associations of inflammatory diet scores with mental well-being in 11-12-year-olds and mid-life adults. Throughout Australia, 1759 11-12-year-olds (49 % girls) and 1812 parents (88 % mothers) contributed cross-sectional population-based data. Alternate inflammatory diet scores were calculated from a twenty-six-item FFQ, based on the prior literature and prediction of inflammatory markers. Participants reported negatively and positively framed mental well-being via psychosocial health, quality of life and life satisfaction surveys. We used causal inference modelling techniques via generalised linear regression models (mean differences and risk ratios (RR)) to examine how inflammatory diets might influence mental well-being. In children and adults, respectively, a 1 sd higher literature-derived inflammatory diet score conferred between a 44 % (RR 95 % CI 1·2, 1·8) to 57 % (RR 95 % CI 1·3, 2·0) and 54 % (95 % CI 1·2, 2·0) to 86 % (RR 95 % CI 1·4, 2·4) higher risk of being in the worst mental well-being category (i.e. <16th percentile) across outcome measures. Results for inflammation-derived scores were similar. BMI mediated effects (21-39 %) in adults. Inflammatory diet patterns were cross-sectionally associated with mental well-being at age 11-12 years, with similar effects observed in mid-adulthood. Reducing inflammatory dietary components in childhood could improve population-level mental well-being across the life course.

Takeaway food, sugar-sweetened beverages and preclinical cardiometabolic phenotypes in children and adults.

AIMS: To investigate relationships between takeaway food and sugar-sweetened beverage (SSB) consumption with cardiometabolic phenotypes during childhood and mid-adulthood. METHOD: Design: Cross-sectional Child Health CheckPoint within the national population-representative Longitudinal Study of Australian Children. Participants: 1838 children (mean age 11.5 years; 49.1% female) and 1846 adults (mean age 43.7 years; 87.6% female). Exposures: Self-reported takeaway food and SSB consumption ('frequent': ≥ weekly). Outcomes: Functional (pulse wave velocity (PWV), blood pressure (BP)) and structural (carotid intima-media thickness, retinal microvascular calibre) preclinical cardiovascular phenotypes; lipids (total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides). Analysis: Linear regression (exposure: takeaway or SSB consumption, individually or together) adjusted for age, sex and socio-economic position; and mediation analysis for body mass index (BMI). RESULTS: Associations were small among children (standardized mean difference (SMD) ≤0.15). In adults, associations were stronger with functional, but not structural, cardiovascular phenotypes and lipids, particularly for frequent takeaway food consumption (e.g. PWV (0.20 m/s; 95% confidence interval (CI) 0.03 to 0.37); systolic (3.3 mmHg; 95% CI 1.3 to 5.3) and diastolic BP (1.4 mmHg; 95% CI 0.2 to 2.6); LDL (0.10 mmol/L; 95% CI 0.02 to 0.18); HDL (-0.14 mmol/L; 95% CI -0.19 to -0.10) and triglycerides (0.30 mmol/L; 95% CI 0.12 to 0.48)]. BMI mediated associations between takeaway food consumption and PWV, BP, HDL and TG (proportion of mediation 34% to 75%), while mediation effects were smaller for SSB consumption. CONCLUSIONS: Frequent takeaway food consumption in adults was associated with adverse blood lipids and vascular function (mainly via BMI). Lack of strong associations in children highlights opportunities for prevention.

Backyard benefits? A cross-sectional study of yard size and greenness and children's physical activity and outdoor play.

BACKGROUND: The home environment is the most important location in young children's lives, yet few studies have examined the relationship between the outdoor home environment and child physical activity levels, and even fewer have used objectively measured exposures and outcomes. This study examined relationships between objectively assessed home yard size and greenness, and child physical activity and outdoor play. METHODS: Data were drawn from the HealthNuts study, a longitudinal study of 5276 children in Melbourne, Australia. We used cross-sectional data from a sample at Wave 3 (2013-2016) when participants were aged 6 years (n = 1648). A sub-sample of 391 children had valid accelerometer data collected from Tri-axial GENEActive accelerometers worn on their non-dominant wrist for 8 consecutive days. Yard area and greenness were calculated using geographic information systems. Objective outcome measures were minutes/day in sedentary, light, and moderate-vigorous physical activity (weekday and weekend separately). Parent-reported outcome measures were minutes/day playing outdoors (weekend and weekday combined). Multi-level regression models (adjusted for child's sex, mother's age at the birth of child, neighbourhood socioeconomic index, maternal education, and maternal ethnicity) estimated effects of yard size and greenness on physical activity. RESULTS: Data were available on outdoor play for 1648 children and usable accelerometer data for 391. Associations between yard size/greenness and components of physical activity were minimal. For example, during weekdays, yard size was not associated with daily minutes in sedentary behaviour (ß: 2.4, 95% CI: - 6.2, 11.0), light physical activity (ß: 1.4, 95% CI: - 5.7, 8.5) or MVPA (ß: -2.4, 95% CI: - 6.5, 1.7), with similar patterns at weekends. There was no relationship between median annual yard greenness and physical activity or play. CONCLUSION: In our study of young children residing in higher socio-economic areas of Melbourne yard characteristics did not appear to have a major impact on children's physical activity. Larger studies with greater variation in yard characteristics and identification of activity location are needed to better understand the importance of home outdoor spaces and guide sustainable city planning.

Diet quality trajectories and cardiovascular phenotypes/metabolic syndrome risk by 11-12 years.

OBJECTIVE: To investigate associations between early-life diet trajectories and preclinical cardiovascular phenotypes and metabolic risk by age 12 years. METHODS: Participants were 1861 children (51% male) from the Longitudinal Study of Australian Children. At five biennial waves from 2-3 to 10-11 years: Every 2 years from 2006 to 2014, diet quality scores were collected from brief 24-h parent/self-reported dietary recalls and then classified using group-based trajectory modeling as 'never healthy' (7%), 'becoming less healthy' (17%), 'moderately healthy' (21%), and 'always healthy' (56%). At 11-12 years: During children's physical health Child Health CheckPoint (2015-2016), we measured cardiovascular functional (resting heart rate, blood pressure, pulse wave velocity, carotid elasticity/distensibility) and structural (carotid intima-media thickness, retinal microvasculature) phenotypes, and metabolic risk score (composite of body mass index z-score, systolic blood pressure, high-density lipoproteins cholesterol, triglycerides, and glucose). Associations were estimated using linear regression models (n = 1100-1800) adjusted for age, sex, and socioeconomic position. RESULTS: Compared to 'always healthy', the 'never healthy' trajectory had higher resting heart rate (2.6 bpm, 95% CI 0.4, 4.7) and metabolic risk score (0.23, 95% CI 0.01, 0.45), and lower arterial elasticity (-0.3% per 10 mmHg, 95% CI -0.6, -0.1) and distensibility (-1.2%, 95% CI -1.9, -0.5) (all effect sizes 0.3-0.4). Heart rate, distensibility, and diastolic blood pressure were progressively poorer for less healthy diet trajectories (linear trends p ≤ 0.02). Effects for systolic blood pressure, pulse wave velocity, and structural phenotypes were less evident. CONCLUSIONS: Children following the least healthy diet trajectory had poorer functional cardiovascular phenotypes and metabolic syndrome risk, including higher resting heart rate, one of the strongest precursors of all-cause mortality. Structural phenotypes were not associated with diet trajectories, suggesting the window to prevent permanent changes remains open to at least late childhood.

Sleep and cardiometabolic health in children and adults: examining sleep as a component of the 24-h day.

STUDY OBJECTIVES: Sleep, physical activity and sedentary time are all known to play a role in cardiometabolic health. Compositional data analysis (CoDA) enables us to examine associations between 24-h use of time and health outcomes. METHODS: Data were collected in the Child Health CheckPoint study, a one-off national population-cohort study conducted between February 2015 and March 2016. Wrist-worn actigraphy monitors (GENEActiv Original, Cambs, UK) were used to measure activity behaviours (sleep, physical activity and sedentary time) and sleep characteristics (sleep variability, midsleep, efficiency). CoDA was applied to determine the association between 24-h use of time and cardiometabolic risk markers (blood pressure; body mass index; apolipoprotein B/A1; glycoprotein acetyls; and composite metabolic syndrome score). Substitution modelling (one-for-remaining and one-for-one) examined the associations of reallocating sleep time with other activity behaviours. RESULTS: Data were available for 1073 Australian children aged 11-12 years (50% male) and 1337 adults (13% male). Strong association was found between 24-h use of time and all cardiometabolic health outcomes. Longer sleep was associated with more favourable cardiovascular health. Sleep characteristics other than duration (efficiency, timing, variability) were weakly and inconsistently associated with outcomes. Reallocating time from sleep to moderate-vigorous physical activity (MVPA) had favourable associations with cardiometabolic health, but reallocating from sleep to sedentary time was associated with less favourable cardiometabolic health. CONCLUSION: The 24-h activity composition is strongly associated with cardiometabolic health in children and adults. Days with more sleep and MVPA are associated with improved cardiometabolic health.

Trimethylamine N-oxide (TMAO) Is not Associated with Cardiometabolic Phenotypes and Inflammatory Markers in Children and Adults.

BACKGROUND: Trimethylamine N-oxide (TMAO) is a diet- and microbiome-derived metabolite and a proposed biomarker of adverse cardiometabolic outcomes. TMAO studies have mainly been conducted in individuals with cardiometabolic disease, and studies in population-derived samples are limited. OBJECTIVE: We aimed to investigate the associations between plasma TMAO concentrations and its precursors [carnitine, choline, betaine, and dimethylglycine (DMG)] with metabolic syndrome (MetS) scores, preclinical cardiovascular phenotypes, and inflammatory biomarkers (i.e. high-sensitivity C-reactive protein and serum glycoprotein acetyls) in a population-derived cohort of children and their parents. METHODS: The concentrations of TMAO and its precursors were quantified using UHPLC coupled with tandem MS (UHPLC/MS-MS) in 1166 children (mean age 11 y ± 0.5 y, 51% female) and 1324 adults (44 y ± 5.1 y, 87% female) participating in The Growing Up in Australia's Child Health CheckPoint Study. We developed multivariable fractional polynomial models to analyze associations between TMAO, its precursors, MetS (adjusted for sex and age), and cardiovascular phenotypes (adjusted for sex, age, BMI, household income, and the urinary albumin to creatinine ratio). Pearson's correlations were computed to identify associations between TMAO, its precursors, and inflammatory biomarkers. RESULTS: The concentrations of TMAO precursors, but not TMAO itself, were associated with MetS, cardiovascular phenotypes, and inflammatory biomarkers in children and adults. CONCLUSIONS: TMAO precursors, but not TMAO itself, were associated with adverse cardiometabolic and inflammatory phenotypes in children and adults. TMAO precursor concentrations may better reflect cardiovascular health and inflammatory status within the wider population. Replication in other population settings and mechanistic studies are warranted.

Plasma Trimethylamine N-Oxide and Its Precursors: Population Epidemiology, Parent-Child Concordance, and Associations with Reported Dietary Intake in 11- to 12-Year-Old Children and Their Parents.

BACKGROUND: Trimethylamine N-oxide (TMAO) is a microbiome- and diet-derived metabolite implicated in adverse cardiovascular outcomes. To date, studies of plasma TMAO concentrations have largely focused on individuals with metabolic disease. As such, data on TMAO concentrations in population settings and parent-child dyads are lacking. OBJECTIVES: This study aimed to investigate parent-child concordance, age, and sex effects on plasma concentrations of TMAO and its precursors [l-carnitine, choline, betaine, and dimethylglycine (DMG)]. Associations between concentrations of TMAO and its precursors and self-reported dietary intakes of animal protein (i.e., red meat, meat products, chicken, fish, milk products, and cheese) and fast-food meals were also investigated. METHODS: A total of 1166 children (mean ± SD age: 11 ± 0.5 y, 51% female) and 1324 parents (mean ± SD age: 44 ± 5.1 y, 87% female) had a biomedical assessment as part of Growing Up in Australia's Child Health Checkpoint. Plasma TMAO and precursor concentrations were quantified using ultra-high-pressure LC coupled with tandem MS. RESULTS: Familial dyads significantly contributed to plasma TMAO and precursor concentrations (P < 0.0001), explaining 37% of variance for TMAO concentrations. Least-square mean ± SE plasma TMAO was lower in children (0.79 ± 0.02 µM on the log-scale) than in adults (1.22 ± 0.02 µM). By contrast, children's betaine (40.30 ± 0.34 µM) and DMG concentrations (1.02 ± 0.01 µM on the log-scale) were higher than adults' betaine (37.50 ± 0.32 µM) and DMG concentrations (0.80 ± 0.01 µM) (P < 0.0001). Mean values of all metabolites, except adult TMAO, were higher in males than in females (P < 0.001). Greater reported intake of red meat and fish was associated with higher TMAO concentrations in both children [estimates (95% CIs) for red meat: 0.06 (0.01, 0.10); fish: 0.11 (0.06, 0.17)] and adults [red meat: 0.13 (0.08, 0.17); meat products: 0.07 (0.03, 0.12); and fish: 0.09 (0.04, 0.14)]. CONCLUSIONS: Age, sex, and shared family factors, including diet, contribute to variation in plasma concentrations of TMAO and its precursors.