Cardiovascular Risk Factors in Childhood and Adulthood and Cardiovascular Disease in Middle Age.

Importance: Recent evidence suggests that childhood levels of serum lipids, blood pressure, body mass index (BMI), and smoking contribute to adult risk of cardiovascular disease (CVD). Evidence is lacking on whether this is independent of adult risk levels. Objective: To quantify direct and indirect effects of childhood risk factors on adult CVD via adulthood risk factors using mediation analysis, and to quantify their relative importance during different life-course stages using a life-course approach. Design, Setting, and Participants: This prospective cohort study followed participants from the US, Finland, and Australia from childhood (1970s-1990s) until 2019, with data on CVD risk factors in childhood and adulthood. Longitudinal childhood and adulthood risk factors were summarized to describe BMI, lipids, and blood pressure cumulatively. Childhood and adulthood smoking were assessed with questionnaires. Data analysis was performed May 2022 to August 2023. Main Outcomes and Measures: The primary outcomes were fatal and nonfatal cardiovascular events in adulthood. Mediation analysis was used to estimate the direct and indirect effects of the childhood risk factors with CVD events, reported as incidence rate ratios (RRs) and 95% CIs. Results: A total of 10 634 participants (4506 male participants [42.4%]; mean [SD] age at childhood visit, 13.3 [3.0] years; mean [SD] age at adulthood visit, 32.3 [6.0] years) were included in the cohort. The mean (SD) age at CVD event or censoring was 49.2 (7.0) years. The median (IQR) follow-up time was 23.6 (18.7-30.2) years. Childhood risk factors, (low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC], triglycerides, systolic blood pressure [SBP], smoking, BMI, and a combined score of these) were associated with CVD. BMI (direct effect for incidence RR per 1 SD unit, 1.18; 95% CI, 1.05-1.34) and LDL-C (direct effect incidence RR, 1.16; 95% CI, 1.01-1.34) in particular were found to play an important role via direct pathways, whereas the indirect effects were larger for TC, triglycerides, SBP, and the combined score. Childhood smoking only affected CVD via adulthood smoking. Life-course models confirmed that for the risk of CVD, childhood BMI plays nearly as important role as adulthood BMI, whereas for the other risk factors and the combined score, adulthood was the more important period. Conclusions and Relevance: In this cohort study of 10 634 participants, childhood risk factors were found to be associated both directly and indirectly to adult CVD, with the largest direct effect seen for BMI and LDL-C. These findings suggest that intervention for childhood risk factors, in particular BMI, is warranted to reduce incidence of adult CVD as it cannot be fully mitigated by risk factor management in adulthood.

Association of common maternal infections with birth outcomes: a multinational cohort study.

PURPOSE: It is unclear whether common maternal infections during pregnancy are risk factors for adverse birth outcomes. We assessed the association between self-reported infections during pregnancy with preterm birth and small-for-gestational-age (SGA) in an international cohort consortium. METHODS: Data on 120,507 pregnant women were obtained from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA. Self-reported common infections during pregnancy included influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections, cystitis, urinary tract infection, and the symptoms fever and diarrhoea. Birth outcomes included preterm birth, low birth weight and SGA. Associations between maternal infections and birth outcomes were first assessed using Poisson regression in each cohort and then pooled using random-effect meta-analysis. Risk ratios (RR) and 95% confidence intervals (CI) were calculated, adjusted for potential confounders. RESULTS: Vaginal infections (pooled RR, 1.10; 95% CI, 1.02-1.20) and urinary tract infections (pooled RR, 1.17; 95% CI, 1.09-1.26) during pregnancy were associated with higher risk of preterm birth. Similar associations with low birth weight were also observed for these two infections. Fever during pregnancy was associated with higher risk of SGA (pooled RR, 1.07; 95% CI, 1.02-1.12). No other significant associations were observed between maternal infections/symptoms and birth outcomes. CONCLUSION: Vaginal infections and urinary infections during pregnancy were associated with a small increased risk of preterm birth and low birth weight, whereas fever was associated with SGA. These findings require confirmation in future studies with laboratory-confirmed infection diagnosis.

Association of Ideal Cardiovascular Health in Youth with Cancer Risk in Adulthood: A Cardiovascular Risk in Young Finns Study.

BACKGROUND: Lifestyle factors may affect cancer risk. This study aimed to identify whether the American Heart Association ideal cardiovascular health (ICH) score and its individual variables in youth are associated with subsequent cancer incidence. METHODS: This study comprised participants of the Cardiovascular Risk in Young Finns Study free of cancer at the analysis baseline in 1986 (n = 1,873). The baseline age was 12 to 24 years, and the follow-up occurred between 1986 and 2018. RESULTS: Among 1,873 participants (mean age 17.3 ± 4.1 years; 53.4% females at baseline), 72 incident cancer cases occurred during the follow-up (mean follow-up time 31.4 ± 3.4 years). Baseline ICH score was not associated with future cancer risk (HR, 0.96; 95% confidence interval, 0.78-1.12 per 1-point increment). Of individual ICH score variables, ideal physical activity (PA) was inversely associated with cancer incidence [age- and sex-adjusted HR, 0.45 (0.23-0.88) per 1-category change (nonideal/ideal)] and remained significant in the multivariable-adjusted model, including body mass index, smoking, diet, and socioeconomic status. A continuous PA index at ages 9 to 24 years and moderate-to-vigorous PA in youth were also related to decreased cancer incidence (P < 0.05). Body mass index, smoking, diet, total cholesterol, glucose, and blood pressure were not related to cancer risk. Of the dietary components, meat consumption was associated with cancer incidence (P = 0.023). CONCLUSIONS: These findings indicate that higher PA levels in youth are associated with a reduced subsequent cancer incidence, whereas the American Heart Association's ICH score in youth does not. IMPACT: This finding supports efforts to promote a healthy lifestyle and encourages PA during childhood, yielding a subsequent healthier life.

Non-High-Density Lipoprotein Cholesterol Levels From Childhood to Adulthood and Cardiovascular Disease Events.

Importance: Elevated non-high-density lipoprotein cholesterol (non-HDL-C; a recommended measure of lipid-related cardiovascular risk) is common in children and increases risk of adult cardiovascular disease (CVD). Whether resolution of elevated childhood non-HDL-C levels by adulthood is associated with reduced risk of clinical CVD events is unknown. Objective: To examine the associations of non-HDL-C status between childhood and adulthood with incident CVD events. Design, Setting, and Participants: Individual participant data from 6 prospective cohorts of children (mean age at baseline, 10.7 years) in the US and Finland. Recruitment took place between 1970 and 1996, with a final follow-up in 2019. Exposures: Child (age 3-19 years) and adult (age 20-40 years) non-HDL-C age- and sex-specific z scores and categories according to clinical guideline-recommended cutoffs for dyslipidemia. Main Outcomes and Measures: Incident fatal and nonfatal CVD events adjudicated by medical records. Results: Over a mean length of follow-up of 8.9 years after age 40 years, 147 CVD events occurred among 5121 participants (60% women; 15% Black). Both childhood and adult non-HDL-C levels were associated with increased risk of CVD events (hazard ratio [HR], 1.42 [95% CI, 1.18-1.70] and HR, 1.50 [95% CI, 1.26-1.78] for a 1-unit increase in z score, respectively), but the association for childhood non-HDL-C was reduced when adjusted for adult levels (HR, 1.12 [95% CI, 0.89-1.41]). A complementary analysis showed that both childhood non-HDL-C levels and the change between childhood and adulthood were independently associated with the outcome, suggesting that from a preventive perspective, both childhood non-HDL-C levels and the change into adulthood are informative. Compared with those whose non-HDL-C levels remained within the guideline-recommended range in childhood and adulthood, participants who had incident non-HDL-C dyslipidemia from childhood to adulthood and those with persistent dyslipidemia had increased risks of CVD events (HR, 2.17 [95% CI, 1.00-4.69] and HR, 5.17 [95% CI, 2.80-9.56], respectively). Individuals who had dyslipidemic non-HDL-C in childhood but whose non-HDL-C levels were within the guideline-recommended range in adulthood did not have a significantly increased risk (HR, 1.13 [95% CI, 0.50-2.56]). Conclusions and Relevance: Individuals with persistent non-HDL-C dyslipidemia from childhood to adulthood had an increased risk of CVD events, but those in whom dyslipidemic non-HDL-C levels resolve by adulthood have similar risk to individuals who were never dyslipidemic. These findings suggest that interventions to prevent and reduce elevated childhood non-HDL-C levels may help prevent premature CVD.

A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation.

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P < 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.

Childhood Non-HDL Cholesterol and LDL Cholesterol and Adult Atherosclerotic Cardiovascular Events.

BACKGROUND: Although low-density lipoprotein cholesterol (LDL-C) remains the primary cholesterol target in clinical practice in children and adults, non-high-density lipoprotein cholesterol (non-HDL-C) has been suggested as a more accurate measure of atherosclerotic cardiovascular disease (ASCVD) risk. We examined the associations of childhood non-HDL-C and LDL-C levels with adult ASCVD events and determined whether non-HDL-C has better utility than LDL-C in predicting adult ASCVD events. METHODS: This prospective cohort study included 21 126 participants from the i3C Consortium (International Childhood Cardiovascular Cohorts). Proportional hazards regressions were used to estimate the risk for incident fatal and fatal/nonfatal ASCVD events associated with childhood non-HDL-C and LDL-C levels (age- and sex-specific z scores; concordant/discordant categories defined by guideline-recommended cutoffs), adjusted for sex, Black race, cohort, age at and calendar year of child measurement, body mass index, and systolic blood pressure. Predictive utility was determined by the C index. RESULTS: After an average follow-up of 35 years, 153 fatal ASCVD events occurred in 21 126 participants (mean age at childhood visits, 11.9 years), and 352 fatal/nonfatal ASCVD events occurred in a subset of 11 296 participants who could be evaluated for this outcome. Childhood non-HDL-C and LDL-C levels were each associated with higher risk of fatal and fatal/nonfatal ASCVD events (hazard ratio ranged from 1.27 [95% CI, 1.14-1.41] to 1.35 [95% CI, 1.13-1.60] per unit increase in the risk factor z score). Non-HDL-C had better discriminative utility than LDL-C (difference in C index, 0.0054 [95% CI, 0.0006-0.0102] and 0.0038 [95% CI, 0.0008-0.0068] for fatal and fatal/nonfatal events, respectively). The discordant group with elevated non-HDL-C and normal LDL-C had a higher risk of ASCVD events compared with the concordant group with normal non-HDL-C and LDL-C (fatal events: hazard ratio, 1.90 [95% CI, 0.98-3.70]; fatal/nonfatal events: hazard ratio, 1.94 [95% CI, 1.23-3.06]). CONCLUSIONS: Childhood non-HDL-C and LDL-C levels are associated with ASCVD events in midlife. Non-HDL-C is better than LDL-C in predicting adult ASCVD events, particularly among individuals who had normal LDL-C but elevated non-HDL-C. These findings suggest that both non-HDL-C and LDL-C are useful in identifying children at higher risk of ASCVD events, but non-HDL-C may provide added prognostic information when it is discordantly higher than the corresponding LDL-C and has the practical advantage of being determined without a fasting sample.

Modelling the replacement of red and processed meat with plant-based alternatives and the estimated effect on insulin sensitivity in a cohort of Australian adults.

Dietary guidelines are increasingly promoting mostly plant-based diets, limits on red meat consumption, and plant-based sources of protein for health and environmental reasons. It is unclear how the resulting food substitutions associate with insulin resistance, a risk factor for type 2 diabetes. We modelled the replacement of red and processed meat with plant-based alternatives and the estimated effect on insulin sensitivity. We included 783 participants (55 % female) from the Childhood Determinants of Adult Health study, a population-based cohort of Australians. In adulthood, diet was assessed at three time points using FFQ: 2004­2006, 2009­2011 and 2017­2019. We calculated the average daily intake of each food group in standard serves. Insulin sensitivity was estimated from fasting glucose and insulin concentrations in 2017­2019 (aged 39­49 years) using homoeostasis model assessment. Replacing red meat with a combination of plant-based alternatives was associated with higher insulin sensitivity (ß = 10·5 percentage points, 95 % CI (4·1, 17·4)). Adjustment for waist circumference attenuated this association by 61·7 %. Replacing red meat with either legumes, nuts/seeds or wholegrains was likewise associated with higher insulin sensitivity. Point estimates were similar but less precise when replacing processed meat with plant-based alternatives. Our modelling suggests that regularly replacing red meat, and possibly processed meat, with plant-based alternatives may associate with higher insulin sensitivity. Further, abdominal adiposity may be an important mediator in this relationship. Our findings support advice to prioritise plant-based sources of protein at the expense of red meat consumption.

Tracking of Cardiorespiratory Fitness from Childhood to Mid-adulthood.

High cardiorespiratory fitness (CRF) in adulthood is important for survival from major chronic diseases and preserving good health. We examined how childhood CRF tracks, or persists, into adulthood. Among a cohort of 748 school children followed over 34 years, we found child CRF correlated with young- (r = 0.30) and mid-adulthood (r = 0.16) CRF.

Determining pathways of effect between correlates and outcomes of transport-related physical activity at differing timepoints across the lifecourse: A structural equation modelling approach.

Transport-related physical activity levels differ across the lifecourse; however, the nature of these differences is poorly understood. This study examined the relationship between correlates of transport-related physical activity and how they differ in strength, pathway, and direction across the lifecourse. Structural Equation Modelling assessed relationships between correlates (e.g., age, smoking, education) and transport-related physical activity (assessed via the International Physical Activity Questionnaire) at four timepoints of the Australian Childhood Determinants of Adult Health study: childhood (7-15y; n = 6302), early-adulthood (26-36y; n = 2700), early/mid-adulthood (31-41y; n = 1649), and mid-adulthood (36-49y; n = 1794). Several pathways were consistent across the lifecourse. Self-rated health directly associated with transport-related physical activity across all timepoints. During adulthood greater body mass index and smoking frequency were indirectly associated with lower levels of transport-related physical activity via self-rated health; similarly, lower educated adults, who smoked more frequently, and had poorer health, had lower transport-related physical activity. Urban residence was directly associated with greater transport-related physical activity in childhood and early-adulthood; having more children in early/mid- and mid-adulthood was directly associated with less transport-related physical activity. This is the first study to report pathways of direct and indirect association between correlates and transport-related physical activity at key lifecourse stages. The pathways highlighted can inform policy and practice to aid in the development of age-specific lifecourse interventions.

Association of body mass index from childhood to mid-adulthood with health-related quality of life in mid-adulthood.

PURPOSE: Most studies regarding the association of obesity with health-related quality of life (HRQoL) have assessed obesity at only one or two time points. We aimed to examine the associations of life course body mass index (BMI) from childhood with health-related quality of life (HRQoL) in mid-adulthood. METHODS: Data were from a cohort study of Australian children (n = 2254, mean baseline age 12.0 (2.0) years in 1985, 46.8% male). Weight and height were measured at baseline and measured or self-reported on average 20, 25, and 30 years later. Age and sex-standardised BMI-z score was calculated at each time point. Physical and mental HRQoL and health state utilities (HSUs) were measured by SF-12 and SF-6D at the last adult follow-up. Linear regression was used to examine the associations adjusting for age, sex, and childhood health status. RESULTS: Higher BMI-z score in childhood (ßadjusted - 1.39, 95% CI - 1.73 to - 1.05) and increasing BMI-z score from childhood to young adulthood (ßadjusted - 1.82, 95% CI - 2.17 to - 1.46) and from young to mid-adulthood (ßadjusted - 1.77, 95% CI - 2.28 to - 1.26) were associated with lower physical HRQoL in mid-adulthood. Similar results were found for mid-adulthood HSUs (ßadjusted ranged - 0.006 to - 0.014, all P < 0.05). Only increasing BMI-z score from young to mid-adulthood significantly related to poorer mental HRQoL (ßadjusted - 0.74, 95% CI - 1.29 to - 0.19) in mid-adulthood. CONCLUSION: High BMI from childhood to mid-adulthood had only modest associations with HRQoL and HSUs, with effects on physical HRQoL most apparent.

Exploring the direct and indirect effects of cardiovascular disease risk factors on exercise blood pressure.

OBJECTIVE: Exaggerated exercise blood pressure (BP) is independently associated with cardiovascular disease (CVD) outcomes. However, it is unknown how individual CVD risk factors may interact with one another to influence exercise BP. The aim of this study was to quantify direct and indirect associations between CVD risk factors and exercise BP, to determine what CVD risk factor/s most-strongly relate to exercise BP. METHODS: In a cross-sectional design, 660 participants (44 ± 2.6 years, 54% male) from the population-based Childhood Determinants of Adult Health Study had BP measured during low-intensity fixed-workload cycling. CVD risk factors were measured, including body composition, clinic (rest) BP, blood biomarkers, and cardiorespiratory fitness. Associations between CVD risk factors and exercise BP were assessed using linear regression, with direct and indirect pathways of association assessed via structural equation model. RESULTS: Sex, waist-to-hip ratio, fitness, and clinic BP were independently associated with exercise systolic BP (SBP), and along with age, had direct associations with exercise SBP (p < 0.05 all). Most CVD risk factors were indirectly associated with exercise SBP via a relation with clinic BP (p < 0.05 all). Clinic BP, waist-to-hip ratio, and fitness were most-strongly associated (direct and indirect association) with exercise SBP (ß[95% CI]: 9.35 [8.04, 10.67], 4.91 [2.56, 7.26], and -2.88 [-4.25, -1.51] mm Hg/SD, respectively). CONCLUSION: Many CVD risk factors are associated with exercise BP, mostly with indirect effects via clinic BP. Clinic BP, body composition, and fitness were most-strongly associated with exercise BP. These results may elucidate how lifestyle modification could be a primary strategy to decrease exaggerated exercise BP-related CVD risk.

Tracking handgrip strength asymmetry from childhood to mid-life.

AIM: Determine if asymmetric handgrip strength exists in childhood and adulthood and quantify the degree of tracking of handgrip strength asymmetry over time. METHODS: Participants from the Childhood Determinants of Adult Health Study had their right and left handgrip strength measured using handgrip dynamometry in childhood (1985: 9-15 y), young adulthood (2004-06: 26-36 y) and/or mid-adulthood (2014-19: 36-49 y). Handgrip strength asymmetry was calculated as: strongest handgrip strength/strongest handgrip strength on the other hand. Participants were categorised based on the degree of their asymmetry (0.0%-10.0%, 10.1%-20.0%, 20.1%-30.0%, >30.0%). Tracking was quantified using Spearman's correlations and log binomial regression. RESULTS: Handgrip strength asymmetry was present in childhood and adulthood (>30.0% asymmetry: childhood = 6%, young adulthood = 3%, mid-adulthood = 4%). Handgrip strength asymmetry did not track between childhood and young- (r = 0.06, 95% CI = -0.02, 0.12) and mid-adulthood (r = 0.01, 95% CI = -0.09, 0.10). Tracking was more apparent between young- and mid-adulthood (r = 0.16, 95% CI = 0.09, 0.22). Participants with >30.0% asymmetry were at greater risk to maintain this status between childhood and young- (RR = 3.53, 95% CI = 1.15, 10.87) and mid-adulthood (RR = 2.14, 95% CI = 0.45, 10.20). CONCLUSION: Although handgrip strength asymmetry tracked relatively poorly, asymmetric handgrip strength was apparent in children and adults. Handgrip strength asymmetry does not exclusively affect older adults and should be considered in protocols to better understand its role across the life course.

Metabolic Syndrome and Inflammation from Young to Mid-Adulthood and Subclinical Kidney Damage in Middle-Aged Australians.

Background: Relationships between metabolic syndrome (MetS), inflammation, and chronic kidney disease (CKD) have been reported, but long-term follow-up studies are limited. This study aimed to investigate whether MetS and C-reactive protein (CRP) from young adulthood associated with the risk of subclinical kidney damage (SKD), a surrogate measure for CKD, in mid-adulthood. Materials and Methods: One thousand fifteen participants from the Childhood Determinants of Adult Health study aged 26-36 years at baseline (2004-2006) were followed up at age 36-49 (2014-2019). Log-binomial regression was used to determine whether MetS and high CRP in young adulthood and from young to mid-adulthood predicted the risk of SKD (an estimated glomerular filtration rate [eGFR] of 30-60 mL/min/1.73 m2 or an eGFR >60 mL/min/1.73 m2 with a urine albumin-creatinine ratio ≥2.5 mg/mmol [males] or ≥3.5 mg/mmol [females]) in midlife. Results: Having MetS in young adulthood was associated with an increased risk of SKD in midlife (adjusted relative risk [aRR] = 2.67, 95% confidence interval [CI]: 1.24-5.76). Participants with MetS and high CRP as young adults had a greater risk of having SKD in midlife (aRR = 4.27, 95% CI: 1.61-11.30) compared with those without MetS and high CRP. Furthermore, for participants with persistent MetS, the aRR of SKD in midlife was 4.08 (95% CI: 1.84-9.05) compared with those without MetS from young to mid-adulthood. No significant associations were found between CRP in young adulthood, or change in CRP from young to mid-adulthood, and SKD in midlife. Conclusions: MetS in young adulthood, with and without high CRP, and persistent MetS were associated with an increased risk of SKD in middle midlife.

Sex differences in the association between stroke risk factors and pre-clinical predictors of stroke in the childhood determinants of Adult Health study.

BACKGROUND AND AIMS: It is unclear why blood pressure (BP), metabolic markers and smoking increase stroke incidence in women more than men. We examined these associations with carotid artery structure and function in a prospective cohort study. METHODS: Participants in the Australian Childhood Determinants of Adult Health study at ages 26-36 years (2004-06) were followed-up at 39-49 years (2014-19). Baseline risk factors included smoking, fasting glucose, insulin, systolic and diastolic BP. Carotid artery plaques, intima-media thickness [IMT], lumen diameter and carotid distensibility [CD] were assessed at follow up. Log binomial and linear regression with risk factor × sex interactions predicted carotid measures. Sex-stratified models adjusting for confounders were fitted when significant interactions were identified. RESULTS: Among 779 participants (50% women), there were significant risk factor × sex interactions with baseline smoking, systolic BP and glucose associated with carotid measures in women only. Current smoking was associated with incidence of plaques (RRunadjusted 1.97 95% CI 1.4, 3.39), which reduced when adjusted for sociodemographics, depression, and diet (RRadjusted 1.82 95% CI 0.90, 3.66). Greater systolic BP was associated with lower CD adjusted for sociodemographics (ßadjusted -0.166 95% CI -0.233, -0.098) and hypertension with greater lumen diameter (ßunadjusted 0.131 95% CI 0.037, 0.225), which decreased when adjusted for sociodemographics, body composition and insulin (ßadjusted 0.063 95% CI -0.052, 0.178). Greater glucose (ßunadjusted -0.212 95% CI -0.397, -0.028) was associated with lower CD, which decreased when adjusted for sociodemographics, BP, depression and polycystic ovary syndrome (ßadjusted -0.023 95% CI -0.249, 0.201). CONCLUSIONS: Smoking, SBP and glucose affect carotid structure and function more in women than men with some of this risk due to co-occurring risk factors.

Sex-Specific Associations of MDM2 and MDM4 Variants with Risk of Multiple Primary Melanomas and Melanoma Survival in Non-Hispanic Whites.

MDM2-SNP309 (rs2279744), a common genetic modifier of cancer incidence in Li-Fraumeni syndrome, modifies risk, age of onset, or prognosis in a variety of cancers. Melanoma incidence and outcomes vary by sex, and although SNP309 exerts an effect on the estrogen receptor, no consensus exists on its effect on melanoma. MDM2 and MDM4 restrain p53-mediated tumor suppression, independently or together. We investigated SNP309, an a priori MDM4-rs4245739, and two coinherited variants, in a population-based cohort of 3663 primary incident melanomas. Per-allele and per-haplotype (MDM2_SNP309-SNP285; MDM4_rs4245739-rs1563828) odds ratios (OR) for multiple-melanoma were estimated with logistic regression models. Hazard ratios (HR) for melanoma death were estimated with Cox proportional hazards models. In analyses adjusted for covariates, females carrying MDM4-rs4245739*C were more likely to develop multiple melanomas (ORper-allele = 1.25, 95% CI 1.03-1.51, and Ptrend = 0.03), while MDM2-rs2279744*G was inversely associated with melanoma-death (HRper-allele = 0.63, 95% CI 0.42-0.95, and Ptrend = 0.03). We identified 16 coinherited expression quantitative loci that control the expression of MDM2, MDM4, and other genes in the skin, brain, and lungs. Our results suggest that MDM4/MDM2 variants are associated with the development of subsequent primaries and with the death of melanoma in a sex-dependent manner. Further investigations of the complex MDM2/MDM4 motif, and its contribution to the tumor microenvironment and observed associations, are warranted.

Distinct patterns of adult transport-related physical activity (TRPA) behaviour exist independent of the TRPA behaviours of childhood: the childhood determinants of adult health study.

BACKGROUND: Transport-related physical activity (TRPA) is recognised as a potential means of increasing total physical activity participation that may yield substantial health benefits. Public health campaigns focusing on promoting TRPA from a young age aim to develop life-long healthy habits. However, few studies have examined how TRPA changes across the lifecourse and whether childhood TRPA levels influence those observed later in life. METHODS: Using the Australian Childhood Determinants of Adult Health study (baseline, 1985), latent class growth mixture modelling with adjustment for time-varying covariates was performed using four timepoints (ranging from 7 to 49 years) to assess behavioural patterns and retention of TRPA across the lifecourse. As child and adult adjusted TRPA measures could not be harmonised, trajectories of adult TRPA (n = 702) were instead identified, and log-binomial regression analysis was performed to determine whether childhood levels of TRPA (high/medium/low) influenced these trajectories. RESULTS: Two stable groups of adult TRPA trajectories were identified: persistently low (n = 520; 74.2%), and increasingly high TRPA (n = 181; 25.8%). There was no significant relationship between childhood TRPA levels and patterns in adulthood (relative risk of high childhood TRPA yielding high adult TRPA trajectory membership = 1.06; 95% confidence interval = 0.95-1.09). CONCLUSION: This study found childhood TRPA levels were not associated with TRPA patterns in adulthood. These findings suggest that while TRPA in childhood may have health, social, and environmental benefits, it does not appear to impact adult TRPA directly. Therefore, further intervention is required beyond childhood to promote the implementation of healthy TRPA behaviours into adulthood.

A Healthful Plant-Based Eating Pattern Is Longitudinally Associated with Higher Insulin Sensitivity in Australian Adults.

BACKGROUND: A healthful plant-based eating pattern is associated with lower type 2 diabetes risk; however, the association with its preceding state, impaired insulin sensitivity, is less well established, particularly in younger populations with repeated measures of diet over time. OBJECTIVE: We aimed to examine the longitudinal relationship between a healthful plant-based eating pattern and insulin sensitivity in young to middle-aged adults. METHODS: We included 667 participants from the Childhood Determinants of Adult Health (CDAH) study, a population-based cohort in Australia. Healthful plant-based diet index (hPDI) scores were derived from food frequency questionnaire data. Plant foods considered "healthful" were scored positively (e.g., whole grains, fruit, vegetables), with all remaining foods scored reversely (e.g., refined grains, soft drinks, meat). Updated homeostatic model assessment (HOMA2) estimated insulin sensitivity from fasting insulin and glucose concentrations. We used linear mixed-effects regression to analyze data from 2 time points: CDAH-1 (2004-2006, 26-36 y of age) and CDAH-3 (2017-2019, 36-49 y of age). hPDI scores were modeled as between- and within-person effects (i.e., a participant's overall mean and their deviation from said mean at each time point, respectively). RESULTS: The median follow-up duration was 13 y. In our primary analysis, each 10-unit difference in hPDI score was associated with higher log-HOMA2 insulin sensitivity [95% confidence interval], with between-person (ß = 0.11 [0.05, 0.17], P < 0.001) and within-person effects (ß = 0.10 [0.04, 0.16], P = 0.001). The within-person effect persisted despite accounting for compliance with dietary guidelines. Adjustment for waist circumference attenuated the between-person effect by 70% (P = 0.26) and the within-person effect by 40% (P = 0.04). CONCLUSIONS: In young to middle-aged Australian adults, a healthful plant-based eating pattern (determined using hPDI scores) was longitudinally associated with higher insulin sensitivity, and therefore, potentially lower type 2 diabetes risk later in life.

Association Between Risk Factors in Childhood and Sex Differences in Prevalence of Carotid Artery Plaques and Intima-Media Thickness in Mid-Adulthood in the Childhood Determinants of Adult Health Study.

Background The origins of sex differences in cardiovascular diseases are not well understood. We examined the contribution of childhood risk factors to sex differences in adult carotid artery plaques and intima-media thickness (carotid IMT). Methods and Results Children in the 1985 Australian Schools Health and Fitness Survey were followed up when they were aged 36 to 49 years (2014-19, n=1085-1281). Log binomial and linear regression examined sex differences in adult carotid plaques (n=1089) or carotid IMT (n=1283). Childhood sociodemographic, psychosocial, and biomedical risk factors that might contribute to sex differences in carotid IMT/plaques were examined using purposeful model building with additional adjustment for equivalent adult risk factors in sensitivity analyses. Women less often had carotid plaques (10%) than men (17%). The sex difference in the prevalence of plaques (relative risk [RR] unadjusted 0.59 [95% CI, 0.43 to 0.80]) was reduced by adjustment for childhood school achievement and systolic blood pressure (RR adjusted 0.65 [95% CI, 0.47 to 0.90]). Additional adjustment for adult education and systolic blood pressure further reduced sex difference (RR adjusted 0.72 [95% CI, 0.49 to 1.06]). Women (mean±SD 0.61±0.07) had thinner carotid IMT than men (mean±SD 0.66±0.09). The sex difference in carotid IMT (ß unadjusted -0.051 [95% CI, -0.061 to -0.042]) reduced with adjustment for childhood waist circumference and systolic blood pressure (ß adjusted -0.047 [95% CI, -0.057 to -0.037]) and further reduced with adjustment for adult waist circumference and systolic blood pressure (ß adjusted -0.034 [95% CI, -0.048 to -0.019]). Conclusions Some childhood factors contributed to adult sex differences in plaques and carotid IMT. Prevention strategies across the life course are important to reduce adult sex differences in cardiovascular diseases.

Use of clinical scores in young Australian adults for prediction of atherosclerosis in middle age.

We sought to apply a simple cardiovascular health tool not requiring laboratory tests (the Fuster-BEWAT score, FBS) to predict subclinical atherosclerosis. This study included 2657 young adults (< 40 years of age). In the prognostic group (n = 894, followed for 13 years until aged 40-50 years at follow-up), the primary outcome was presence of carotid plaque measured by carotid ultrasound at follow-up. Of these 894 participants, 86 (9.6%) had unilateral, and 23 participants (2.6%) had bilateral, carotid plaques at follow-up. The baseline FBS was predictive of carotid plaque at follow-up [odds ratio OR = 0.86 (95% CI 0.77-0.96) per 1-SD increase in FBS], similar to prediction from Pooled Cohort Equation [PCE, OR = 0.72 (0.61-0.85) per 1-SD decrease in PCE]. Risk scores at baseline predicted outcomes more strongly than those at follow-up, and did so independently of any changes over 13 years of follow-up. Similar discrimination for predicting carotid plaque after 13 years was found for both baseline FBS [C-statistic = 0.68 (95% CI 0.62-0.74)] and PCE [C-statistic = 0.69 (95% CI 0.63-0.75)]. Application of this FBS prognostic information to a contemporary cohort of 1763 young adults anticipates the future development of plaque in 305 (17.3%), especially in the 1494 participants (85%) with ≤ 2 metrics of ideal health. In conclusions, FBS measured in young adulthood predicted atherosclerosis 13 years later in middle age, independent of score changes over the follow-up period, emphasizing the importance of early damage to vascular health. FBS may be a simple and feasible risk score for engaging low-risk young people with reduction of future cardiovascular risk.

Evaluation of Maternal Infection During Pregnancy and Childhood Leukemia Among Offspring in Denmark.

Importance: Maternal infection is common during pregnancy and is an important potential cause of fetal genetic and immunological abnormalities. Maternal infection has been reported to be associated with childhood leukemia in previous case-control or small cohort studies. Objective: To evaluate the association of maternal infection during pregnancy with childhood leukemia among offspring in a large study. Design, Setting, and Participants: This population-based cohort study used data from 7 Danish national registries (including the Danish Medical Birth Register, the Danish National Patient Registry, the Danish National Cancer Registry, and others) for all live births in Denmark between 1978 and 2015. Swedish registry data for all live births between 1988 and 2014 were used to validate the findings for the Danish cohort. Data were analyzed from December 2019 to December 2021. Exposures: Maternal infection during pregnancy categorized by anatomic locations identified from the Danish National Patient Registry. Main Outcomes and Measures: The primary outcome was any leukemia; secondary outcomes were acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML). Offspring childhood leukemia was identified in the Danish National Cancer Registry. Associations were first assessed in the whole cohort using Cox proportional hazards regression models, adjusted for potential confounders. A sibling analysis was performed to account for unmeasured familial confounding. Results: This study included 2 222 797 children, 51.3% of whom were boys. During the approximately 27 million person-years of follow-up (mean [SD], 12.0 [4.6] years per person), 1307 children were diagnosed with leukemia (ALL, 1050; AML, 165; or other, 92). Children born to mothers with infection during pregnancy had a 35% increased risk of leukemia (adjusted hazard ratio [HR], 1.35 [95% CI, 1.04-1.77]) compared with offspring of mothers without infection. Maternal genital and urinary tract infections were associated with a 142% and 65% increased risk of childhood leukemia, with HRs of 2.42 (95% CI, 1.50-3.92) and 1.65 (95% CI, 1.15-2.36), respectively. No association was observed for respiratory tract, digestive, or other infections. The sibling analysis showed comparable estimates to the whole-cohort analysis. The association patterns for ALL and AML were similar to that for any leukemia. No association was observed for maternal infection and brain tumors, lymphoma, or other childhood cancers. Conclusions and Relevance: In this cohort study of approximately 2.2 million children, maternal genitourinary tract infection during pregnancy was associated with childhood leukemia among offspring. If confirmed in future studies, our findings may have implications for understanding the etiology and developing preventive measures for childhood leukemia.