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.

Prior nonmelanoma skin cancer is associated with fewer fractures, more vitamin D sufficiency, greater bone mineral density and improved bone microarchitecture in older adults.

INTRODUCTION: Prior nonmelanoma skin cancer (NMSC), a biomarker of cumulative lifetime sun exposure, is associated with reduced fracture risk later in life. The mechanism is unknown. METHODS: Prospective cohort analysis of 1,099 community-dwelling adults aged 50-80 years with baseline and 10 year follow up assessments. Histopathologically-confirmed NMSC diagnosis was established by linkage with the Tasmanian Cancer Registry. Bone mineral density (BMD) and vertebral deformity were quantified by DXA, 25(OH)D by radioimmunoassay, bone microarchitecture by high resolution peripheral quantitative CT, melanin density by spectrophotometry and skin photosensitivity and clinical fracture by questionnaire. 25(OH)D <50 nmol/L was considered deficient. RESULTS: Participants with a NMSC reported prior to baseline were less likely to sustain an incident vertebral deformity over 10 years (RR=0.74, p=0.036). There were similar reductions for other fracture types but these did not reach significance. Prior NMSC was associated with baseline (RR=1.23, p=0.005) and 10 year longitudinal (RR=5.9, p=0.014) vitamin D sufficiency and greater total body BMD (ß=0.021g/cm2, p=0.034), but not falls risk or muscle strength. The relationship between prior NMSC and bone microarchitecture was age dependent (pinteraction<0.05). In the oldest age tertile, prior NMSC was associated with greater volumetric BMD (ß=57.8-62.6, p=0.002-0.01) and less porosity (ß= -4.6 - -5.2, p=0.002-0.009) at cortical, compact cortical and outer transitional zones. CONCLUSION: Prior NMSC was associated with fewer incident fractures in community-dwelling older adults. This protective association is most likely mediated by modifiable fracture risk factors associated with an outdoor lifestyle, including 25(OH)D, BMD and bone microarchitecture.

Health System and Individual Barriers to Supporting Healthy Gestational Weight Gain and Nutrition: A Qualitative Study of the Experiences of Midwives and Obstetricians in Publicly Funded Antenatal Care in Tasmania, Australia.

Individual and health system barriers can impede clinicians from supporting weight-related behaviour change for pregnant women, particularly in publicly funded antenatal care accessed by women from diverse socioeconomic backgrounds. The aim was to understand clinicians' experiences of supporting healthy gestational weight gain for pregnant women in a publicly funded antenatal setting. The work was undertaken to guide the implementation of systems changes, resource development, and workforce capacity building related to nutrition, physical activity, and gestational weight gain in the service. The qualitative descriptive study used purposive sampling and semi-structured interviews conducted between October 2019 and February 2020. Nine midwives and five obstetricians from a publicly funded hospital antenatal service in Tasmania, Australia participated. Interview transcripts were analysed using inductive thematic analysis. The three dominant themes were prioritising immediate needs, continuity of care support weight-related conversations, and limited service capacity for weight- and nutrition-related support. The subthemes were different practices for women according to weight and the need for appropriately tailored resources. Improving access to continuity of care and clinician training, and providing resources that appropriately consider women's socioeconomic circumstances and health literacy would enhance the ability and opportunities for clinicians to better support all women.

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.

Keratinocyte carcinomas, area-level socioeconomic status and geographic remoteness in Tasmania: cross-sectional associations and temporal trends.

OBJECTIVE: This article aims to examine cross-sectional associations and assess temporal trends in keratinocyte carcinoma (KC) incidence by area-level socioeconomic status (SES) and geographic remoteness in Tasmania, Australia. METHODS: KCs - basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) - registered by the Tasmanian Cancer Registry were assigned to area-level SES and remoteness area. Incidence rate ratios (2014-2018) were estimated using Poisson regression. Average annual percentage changes (2001-2018) were estimated using the Joinpoint Regression Program. RESULTS: BCC incidence increased with increasing area-level advantage (p-value for trend <0.001), but no trend was found for SCC. SCC incidence was higher in rural than urban areas (p-value <0.001), and BCC incidence was slightly higher in rural than urban areas for females (p-value = 0.009), but not for males (p-value = 0.373). BCC and SCC incidence increased between 2001 and the mid-2010s, when it peaked across most areas. CONCLUSIONS: Associations were found between BCC and higher area-level SES, and between SCC and geographic remoteness. The findings suggest differences in sun exposure behaviours, skin cancer awareness and access to services, or ascertainment bias. IMPLICATIONS FOR PUBLIC HEALTH: Efforts to control and deliver KC services in Tasmania should consider targeting populations with specific area-level characteristics.

The effect of three years of vitamin D supplementation on erectile dysfunction: Results from the randomized placebo-controlled D-Health Trial.

BACKGROUND & AIMS: Erectile dysfunction is common among older men and has been associated with low serum 25-hydroxy vitamin D concentration. However, this association may be due to uncontrolled confounding, and there is a paucity of evidence from interventional studies. We aimed to examine the effect of vitamin D supplementation on the prevalence of erectile dysfunction, in an exploratory analysis using data from a large randomized controlled trial. METHODS: The D-Health Trial recruited Australians aged 60-84 years between January 2014 and May 2015 and randomly assigned them to supplementation with 60,000 IU of vitamin D or placebo per month for up to 5 years. Blood samples were collected annually from randomly selected participants (total N = 3943). We assessed erectile dysfunction at the end of the third year of follow-up. We used log-binomial regression to examine the effect of vitamin D on the prevalence of erectile dysfunction overall, and within sub-groups. RESULTS: Of the 11,530 men enrolled, 8920 (77.4 %) completed the erectile dysfunction question and were included in the analysis. After three years of supplementation, the mean serum 25-hydroxy vitamin D concentration was 76 nmol/L (standard deviation (SD) 24.94) in the placebo group and 106 nmol/L (SD 26.76) in the vitamin D group (p < 0.0001). The prevalence of erectile dysfunction was 58.8 % and 59.0 % in the vitamin D and placebo groups, respectively (prevalence ratio 1.00, 95 % CI 0.97, 1.03); there was no evidence of an effect of vitamin D in any subgroup analyses. CONCLUSION: Supplementing older men with vitamin D is unlikely to prevent or improve erectile dysfunction. CLINICAL TRIALS REGISTRY: (ACTRN12613000743763).

Evaluation of prescription medication changes following sleeve gastrectomy surgery.

Objective: The increasing global prevalence of obesity, coupled with its association with chronic health conditions and rising healthcare costs, highlights the need for effective interventions; however, despite the availability of treatment options, the ongoing success of primary interventions in maintaining long-term weight loss remains limited. This study examined the prescription medication dispensing changes following sleeve gastrectomy in Australians aged 45 years and over. Methods: In a retrospective analysis of 847 bariatric surgery patients from the New South Wales 45 and Up Study, the assessment of medication patterns categorizing into three groups: gastrointestinal, metabolic, cardiorespiratory, musculoskeletal, and nervous systems was conducted. Each drug class was analyzed, focusing on patients with dispensing records within the 12 months before surgery. This study employed interrupted time-series analysis to compare pre- and post-surgery medication usage. Results: With a predominantly female population (76.9%) and an average age of 57.2 (standard deviation 5.71), there were statistically significant reductions in both unique medications (12.5% decrease, p = 0.004) and total medications dispensed (15.9% decrease, p = 0.003) from 12 months before surgery to 13-24 months after bariatric surgery. All medication categories, except opioids, showed reductions. Notably, the most significant reductions were observed in diabetes (38.6%), agents acting on the renin-angiotensin system (40.4%), lipid modifying agents (26.5%), anti-inflammatory products (46.3%), and obstructive airway diseases (53.3%) medications during this time frame. Conclusion: These findings suggest that sleeve gastrectomy provides an effective therapeutic intervention for patients with comorbidities requiring multiple medications, especially for obesity-related diseases such as diabetes, cardiovascular, respiratory and musculoskeletal disorders.

Association between knee magnetic resonance imaging markers and knee symptoms over 6-9 years in young adults.

OBJECTIVES: To describe associations between MRI markers with knee symptoms in young adults. METHODS: Knee symptoms were assessed using the WOMAC scale during the Childhood Determinants of Adult Health Knee Cartilage study (CDAH-knee; 2008-2010) and at the 6- to 9-year follow-up (CDAH-3; 2014-2019). Knee MRI scans obtained at baseline were assessed for morphological markers (cartilage volume, cartilage thickness, subchondral bone area) and structural abnormalities [cartilage defects and bone marrow lesions (BMLs)]. Univariable and multivariable (age, sex, BMI adjusted) zero-inflated Poisson (ZIP) regression models were used for analysis. RESULTS: The participants' mean age in CDAH-knee and CDAH-3 were 34.95 (s.d. 2.72) and 43.27 (s.d. 3.28) years, with 49% and 48% females, respectively. Cross-sectionally, there was a weak but significant negative association between medial femorotibial compartment (MFTC) [ratio of the mean (RoM) 0.99971084 (95% CI 0.9995525, 0.99986921), P < 0.001], lateral femorotibial compartment (LFTC) [RoM 0.99982602 (95% CI 0.99969915, 0.9999529), P = 0.007] and patellar cartilage volume [RoM 0.99981722 (95% CI 0.99965326, 0.9999811), P = 0.029] with knee symptoms. Similarly, there was a negative association between patellar cartilage volume [RoM 0.99975523 (95% CI 0.99961427, 0.99989621), P = 0.014], MFTC cartilage thickness [RoM 0.72090775 (95% CI 0.59481806, 0.87372596), P = 0.001] and knee symptoms assessed after 6-9 years. The total bone area was negatively associated with knee symptoms at baseline [RoM 0.9210485 (95% CI 0.8939677, 0.9489496), P < 0.001] and 6-9 years [RoM 0.9588811 (95% CI 0.9313379, 0.9872388), P = 0.005]. The cartilage defects and BMLs were associated with greater knee symptoms at baseline and 6-9 years. CONCLUSION: BMLs and cartilage defects were positively associated with knee symptoms, whereas cartilage volume and thickness at MFTC and total bone area were weakly and negatively associated with knee symptoms. These results suggest that the quantitative and semiquantitative MRI markers can be explored as a marker of clinical progression of OA in young adults.

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.

Trajectory of metabolic syndrome and its association with knee pain in middle-aged adults.

OBJECTIVE: Metabolic syndrome (MetS) is characterised by the clustering of central obesity with metabolic abnormalities. We aimed to describe the association of MetS and trajectories of MetS over 10-13 years with knee symptoms in general population-based middle-aged adults. METHODS: Fasting blood biochemistry, waist circumference and blood pressure measures were collected during Childhood Determinants of Adult Health (CDAH)-1 study (year:2004-6; n = 2447; mean age:31.48 ± 2.60) and after 10-13 year at CDAH-3 (year:2014-2019; n = 1549; mean age:44 ± 2.90). Participants were defined as having MetS as per International Diabetes Federation (IDF) definition. Knee symptoms were assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scale at CDAH-3 (mid-adulthood). RESULTS: The prevalence of MetS increased from 8 % at young adulthood (female:52.06 %) to 13 % in mid-adulthood (female:53.78 %) over 10-13 years. Presence of MetS at mid-adulthood was associated with knee symptoms at mid-adulthood [ratio of means (RoM): 1.33; 95%CI:1.27,1.39]. Four MetS trajectories were identified-'No MetS' (85.01 %); 'Improved MetS' (2.14 %), 'Incident MetS' (8.81 %), and 'Persistent MetS, (4.04 %). Compared to 'No MetS', 'Persistent MetS' [RoM:1.15; 95%CI:1.06,1.25], 'Incident MetS' [RoM:1.56; 95%CI:1.48,1.65], and 'Improved MetS' [RoM:1.22; 95%CI:1.05,1.41] was associated with higher knee symptoms. Notably, 'Incident MetS' was strongly associated with knee symptoms [RoM: 1.56; 95%CI:1.48,1.65] and pain [RoM:1.52; 95%CI:1.37,1.70] at mid-adulthood. CONCLUSION: In this sample of middle-aged adults, there was a significant positive association between MetS and knee symptoms. Relative to those without MetS at either life stage, the elevation in mean knee pain scores was more pronounced for those who developed MetS after young adulthood than for those who had MetS in young adulthood.

Contrasting Health Outcomes following a Severe Smoke Episode and Ambient Air Pollution in Early Life: Findings from an Australian Data Linkage Cohort Study of Hospital Utilization.

BACKGROUND: Episodic spikes in air pollution due to landscape fires are increasing, and their potential for longer term health impacts is uncertain. OBJECTIVE: Our objective is to evaluate associations between exposure in utero and in infancy to severe pollution from a mine fire, background ambient air pollution, and subsequent hospital care. METHODS: We linked health records of births, emergency department (ED) visits, and hospitalizations of children born in the Latrobe Valley, Australia, 2012-2015, which included a severe pollution episode from a mine fire (9 February 2014 to 25 March 2014). We assigned modeled exposure estimates for fire-related and ambient particulate matter with an aerodynamic diameter of 2.5µm (PM2.5) to residential address. We used logistic regression to estimate associations with hospital visits for any cause and groupings of infectious, allergic, and respiratory conditions. Outcomes were assessed for the first year of life in the in utero cohort and the year following the fire in the infant cohort. We estimated exposure-response for both fire-related and ambient PM2.5 and also employed inverse probability weighting using the propensity score to compare exposed and not/minimally exposed children. RESULTS: Prenatal exposure to fire-related PM2.5 was associated with ED presentations for allergies/skin rash [odds ratio (OR)=1.34, 95% confidence interval (CI): 1.01, 1.76 per 240 µg/m3 increase]. Exposure in utero to ambient PM2.5 was associated with overall presentations (OR=1.18, 95% CI: 1.05, 1.33 per 1.4 µg/m3) and visits for infections (ED: OR=1.13, 95% CI: 0.98, 1.29; hospitalizations: OR=1.23, 95% CI: 1.00, 1.52). Exposure in infancy to fire-related PM2.5 compared to no/minimal exposure, was associated with ED presentations for respiratory (OR=1.37, 95% CI: 1.05, 1.80) and infectious conditions (any: OR=1.21, 95% CI: 0.98, 1.49; respiratory-related: OR=1.39, 95% CI: 1.05, 1.83). Early life exposure to ambient PM2.5 was associated with overall ED visits (OR=1.17, 95% CI: 1.05, 1.30 per 1.4 µg/m3 increase). DISCUSSION: Higher episodic and lower ambient concentrations of PM2.5 in early life were associated with visits for allergic, respiratory, and infectious conditions. Our findings also indicated differences in associations at the two developmental stages. https://doi.org/10.1289/EHP12238.

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.

The Effect of Vitamin D Supplementation on Hypothyroidism in the Randomized Controlled D-Health Trial.

Background: Hypothyroidism is common, and in iodine-sufficient areas, it is primarily caused by autoimmune destruction of the thyroid gland. Observational studies have consistently shown an inverse association between serum 25-hydroxyvitamin D concentration and autoimmune diseases; however, there is a lack of evidence from randomized controlled trials to support a benefit of vitamin D supplementation, particularly for autoimmune thyroid diseases. We, therefore, aimed to assess the effect of vitamin D supplementation on the incidence of hypothyroidism. Methods: We analyzed data from the D-Health Trial (n = 21,315), a randomized double-blind placebo-controlled trial of 60,000 international units per month of supplemental vitamin D3 among Australians aged 60 years and over. Hypothyroidism, a tertiary outcome of the D-Health Trial, was defined by treatment with levothyroxine, ascertained through linkage with the Australian Pharmaceutical Benefits Scheme. The outcome was time to first prescription of levothyroxine. We began follow-up at 12 months after randomization; people who had died or who had been dispensed levothyroxine during the first year were excluded. Flexible parametric survival models were used to assess the effect of vitamin D supplementation on hypothyroidism, overall and within strata defined by age, sex, body mass index, and predicted baseline vitamin D status. Results: We included 17,851 participants in the main analysis (vitamin D = 8939; placebo = 8912). During a median follow-up of 4.1 years (interquartile range 4.1-4.1), 293 participants developed hypothyroidism (vitamin D = 138 [1.5%]; placebo = 155 [1.7%]). Vitamin D supplementation did not significantly reduce the incidence of hypothyroidism (overall hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.71-1.12). There was some suggestion of an effect in females (overall HR 0.78; CI 0.58-1.06) but not in males (overall HR 1.06; CI 0.74-1.50; p interaction 0.20). Conclusions: Vitamin D supplementation did not reduce the incidence of hypothyroidism overall; however, the possible beneficial effect observed in females warrants further investigation. Clinical Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12613000743763.

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.

Vitamin D supplementation and major cardiovascular events: D-Health randomised controlled trial.

OBJECTIVE: To investigate whether supplementing older adults with monthly doses of vitamin D alters the incidence of major cardiovascular events. DESIGN: Randomised, double blind, placebo controlled trial of monthly vitamin D (the D-Health Trial). Computer generated permuted block randomisation was used to allocate treatments. SETTING: Australia from 2014 to 2020. PARTICIPANTS: 21 315 participants aged 60-84 years at enrolment. Exclusion criteria were self-reported hypercalcaemia, hyperparathyroidism, kidney stones, osteomalacia, sarcoidosis, taking >500 IU/day supplemental vitamin D, or unable to give consent because of language or cognitive impairment. INTERVENTION: 60 000 IU/month vitamin D3 (n=10 662) or placebo (n=10 653) taken orally for up to five years. 16 882 participants completed the intervention period: placebo 8270 (77.6%); vitamin D 8552 (80.2%). MAIN OUTCOME MEASURES: The main outcome for this analysis was the occurrence of a major cardiovascular event, including myocardial infarction, stroke, and coronary revascularisation, determined through linkage with administrative datasets. Each event was analysed separately as secondary outcomes. Flexible parametric survival models were used to estimate hazard ratios and 95% confidence intervals. RESULTS: 21 302 people were included in the analysis. The median intervention period was five years. 1336 participants experienced a major cardiovascular event (placebo 699 (6.6%); vitamin D 637 (6.0%)). The rate of major cardiovascular events was lower in the vitamin D group than in the placebo group (hazard ratio 0.91, 95% confidence interval 0.81 to 1.01), especially among those who were taking cardiovascular drugs at baseline (0.84, 0.74 to 0.97; P for interaction=0.12), although the P value for interaction was not significant (<0.05). Overall, the difference in standardised cause specific cumulative incidence at five years was -5.8 events per 1000 participants (95% confidence interval -12.2 to 0.5 per 1000 participants), resulting in a number needed to treat to avoid one major cardiovascular event of 172. The rate of myocardial infarction (hazard ratio 0.81, 95% confidence interval 0.67 to 0.98) and coronary revascularisation (0.89, 0.78 to 1.01) was lower in the vitamin D group, but there was no difference in the rate of stroke (0.99, 0.80 to 1.23). CONCLUSIONS: Vitamin D supplementation might reduce the incidence of major cardiovascular events, although the absolute risk difference was small and the confidence interval was consistent with a null finding. These findings could prompt further evaluation of the role of vitamin D supplementation, particularly in people taking drugs for prevention or treatment of cardiovascular disease. TRIAL REGISTRATION: ACTRN12613000743763.