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BACKGROUND AND OBJECTIVES: Identifying childhood determinants of adult cardiometabolic disease would facilitate early-life interventions. There are few longitudinal data on the contribution of childhood infections. Therefore, we investigated whether hospitalization with childhood infection is associated with adult anthropometric and metabolic outcomes in a large, wellphenotyped longitudinal cohort. METHOD(S): A total of 1376 subjects from the Cardiovascular Risk in Young Finns Study, aged 3 to 9 years at baseline (1980), who had lifetime data from birth onward on infection-related hospitalization (IRH) had repeated assessments through childhood and adolescence and at least once in adulthood (age 30-45 years in 2001-2011). Early childhood (<5 years), childhood/adolescence (5-18 years), adult (>18 years), and total lifetime IRHs were related to adiposity, BMI, and metabolic syndrome in adulthood. Analyses were adjusted for childhood and adulthood risk factors and potential confounders. RESULT(S): Early-childhood IRH correlated with adverse adult but not childhood metabolic variables: increased BMI (P =.02) and metabolic syndrome (risk ratio: 1.56; 95% confidence interval: 1.03-2.35; P =.03), adjusted for age, gender, birth weight, childhood BMI and other risk factors, and family income. The age at which differences in adult BMI became persistent was related to age of IRH in childhood. The greatest increase in adult BMI occurred in those with >1 childhood IRH. CONCLUSION(S): Childhood IRH was independently associated with adverse adult metabolic variables. This finding suggests that infections and/or their treatment in childhood may contribute to causal pathways leading to adult cardiometabolic diseases.Copyright © 2015 by the American Academy of Pediatrics.

Background:The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics.Methods:Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses.Results:Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair.Conclusions:Our pooled-analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype.

BACKGROUND: The melanocortin-1-receptor (MC1R) gene regulates human pigmentation and is highly polymorphic in populations of European origins. The aims of this study were to evaluate the association between MC1R variants and the risk of non-melanoma skin cancer (NMSC), and to investigate whether risk estimates differed by phenotypic characteristics. METHODS: Data on 3527 NMSC cases and 9391 controls were gathered through the M-SKIP Project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. We calculated summary odds ratios (SOR) with random-effect models, and performed stratified analyses. RESULTS: Subjects carrying at least one MC1R variant had an increased risk of NMSC overall, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC): SOR (95%CI) were 1.48 (1.24-1.76), 1.39 (1.15-1.69) and 1.61 (1.35-1.91), respectively. All of the investigated variants showed positive associations with NMSC, with consistent significant results obtained for V60L, D84E, V92M, R151C, R160W, R163Q and D294H: SOR (95%CI) ranged from 1.42 (1.19-1.70) for V60L to 2.66 (1.06-6.65) for D84E variant. In stratified analysis, there was no consistent pattern of association between MC1R and NMSC by skin type, but we consistently observed higher SORs for subjects without red hair. CONCLUSIONS: Our pooled-analysis highlighted a role of MC1R variants in NMSC development and suggested an effect modification by red hair colour phenotype.

BACKGROUND: Evidence relating childhood cancer to high birthweight is derived primarily from registry and case-control studies. We aimed to investigate this association, exploring the potential modifying roles of age at diagnosis and maternal anthropometrics, using prospectively collected data from the International Childhood Cancer Cohort Consortium. METHODS: We pooled data on infant and parental characteristics and cancer incidence from six geographically and temporally diverse member cohorts [the Avon Longitudinal Study of Parents and Children (UK), the Collaborative Perinatal Project (USA), the Danish National Birth Cohort (Denmark), the Jerusalem Perinatal Study (Israel), the Norwegian Mother and Child Cohort Study (Norway), and the Tasmanian Infant Health Survey (Australia)]. Birthweight metrics included a continuous measure, deciles, and categories (≥ 4.0 vs. < 4.0 kilogram). Childhood cancer (377 cases diagnosed prior to age 15 years) risk was analysed by type (all sites, leukaemia, acute lymphoblastic leukaemia, and non-leukaemia) and age at diagnosis. We estimated hazard ratios (HR) and 95% confidence intervals (CI) from Cox proportional hazards models stratified by cohort. RESULTS: A linear relationship was noted for each kilogram increment in birthweight adjusted for gender and gestational age for all cancers [HR = 1.26; 95% CI 1.02, 1.54]. Similar trends were observed for leukaemia. There were no significant interactions with maternal pre-pregnancy overweight or pregnancy weight gain. Birthweight ≥ 4.0 kg was associated with non-leukaemia cancer among children diagnosed at age ≥ 3 years [HR = 1.62; 95% CI 1.06, 2.46], but not at younger ages [HR = 0.7; 95% CI 0.45, 1.24, P for difference = 0.02]. CONCLUSION: Childhood cancer incidence rises with increasing birthweight. In older children, cancers other than leukaemia are particularly related to high birthweight. Maternal adiposity, currently widespread, was not demonstrated to substantially modify these

BACKGROUND: Self-reported physical activity has been inversely associated with mortality but the effect of objectively measured step activity on mortality has never been evaluated. The objective is to determine the prospective association of daily step activity on mortality among free-living adults. METHODS AND FINDINGS: Cohort study of free-living adults residing in Tasmania, Australia between 2000 and 2005 who participated in one of three cohort studies (n = 2 576 total participants). Daily step activity by pedometer at baseline at a mean of 58.8 years of age, and for a subset, repeated monitoring was available 3.7 (SD 1.3) years later (n = 1 679). All-cause mortality (n = 219 deaths) was ascertained by record-linkage to the Australian National Death Index; 90% of participants were followed-up over ten years, until June 2011. Higher daily step count at baseline was linearly associated with lower all-cause mortality (adjusted hazard ratio AHR, 0.94; 95% CI, 0.90 to 0.98 per 1 000 steps; P = 0.004). Risk was altered little by removing deaths occurring in the first two years. Increasing baseline daily steps from sedentary to 10 000 steps a day was associated with a 46% (95% CI, 18% to 65%; P = 0.004) lower risk of mortality in the decade of follow-up. In addition, those who increased their daily steps over the monitoring period had a substantial reduction in mortality risk, after adjusting for baseline daily step count (AHR, 0.39; 95% CI, 0.22 to 0.72; P = 0.002), or other factors (AHR, 0.38; 95% CI, 0.21-0.70; P = 0.002). CONCLUSIONS: Higher daily step count was linearly associated with subsequent long term mortality among free living adults. These data are the first to quantify mortality reductions using an objective measure of physical activity in a free living population. They strongly underscore the importance of physical inactivity as a major public health problem.

Variation in the melanocortin-1receptor (MC1R) gene is associated with pigmentary phenotypes and risk of malignant melanoma. Few studies have reported on MC1R variation with respect to tumor characteristics, especially clinically important prognostic features. We examined associations between MC1R variants and histopathological melanoma characteristics. Study participants were enrolled from nine geographic regions in Australia, Canada, Italy and the United States and were genotyped for MC1R variants classified as high-risk [R] (D84E, R142H, R151C, R160W, and D294H, all nonsense and insertion/deletion) or low-risk [r] (all other nonsynonymous) variants. Tissue was available for 2,160 white participants of the Genes, Environment and Melanoma (GEM) Study with a first incident primary melanoma diagnosis, and underwent centralized pathologic review. No statistically significant associations were observed between MC1R variants and AJCC established prognostic tumor characteristics: Breslow thickness, presence of mitoses or presence of ulceration. However, MC1R was significantly associated with anatomic site of melanoma (p = 0.002) and a positive association was observed between carriage of more than one [R] variant and melanomas arising on the arms (OR = 2.39; 95% CI: 1.40, 4.09). We also observed statistically significant differences between sun-sensitive and sun-resistant individuals with respect to associations between MC1R genotype and AJCC prognostic tumor characteristics. Our results suggest inherited variation in MC1R may play an influential role in anatomic site presentation of melanomas and may differ with respect to skin pigmentation phenotype.

Objectives: Intermittent antenatal iron supplementation is an attractive alternative to daily dosing during pregnancy, however the impact of this strategy on infant outcomes remains unclear. We compared the effect of intermittent antenatal iron supplementation with daily iron supplementation on maternal and infant outcomes in rural Vietnam. Methods: This cluster randomised trial was conducted in Ha Nam province, Vietnam. 1,258 pregnant women in 104 communes were assigned to daily iron-folic acid (IFA), twice weekly IFA, or twice weekly multiple micronutrient (MMN) supplementation. Primary outcome was birth weight. Results: There was no difference in birth weights of infants of women receiving twice weekly IFA compared to daily IFA (mean difference [MD] 28 g; 95% CI -22 to 78), or twice weekly MMN compared to daily IFA (MD -36.8 g; 95% CI -82 to 8.2). At 32 wk gestation, maternal ferritin was lower in women receiving twice weekly compared to daily IFA (geometric mean ratio (GMR) 0.73; 95% CI 0.67 to 0.80), and in women receiving twice weekly MMN compared to daily IFA (GMR 0.62; 95% CI 0.57 to 0.68), with no difference in hemoglobin levels. Infants of mothers who received twice weekly IFA had higher cognitive scores at 6 mo of age compared to those who received daily IFA (MD 1.89; 95% CI 0.23 to 3.56). Conclusions: Twice-weekly antenatal IFA supplementation achieved similar mean birthweight, and improved cognitive scores in infants at 6 months of age, compared to daily IFA supplementation, and should be considered for use in settings with low anemia prevalence.

The MC1R gene is a key regulator of skin pigmentation. We aimed to evaluate the association between MC1R variants and the risk of sporadic cutaneous melanoma (CM) within the M-SKIP project, an international pooled-analysis on MC1R, skin cancer and phenotypic characteristics. Data included 5,160 cases and 12,119 controls from 17 studies. We calculated a summary odds ratio (SOR) for the association of each of the nine most studied MC1R variants and of variants combined with CM by using random-effects models. Stratified analysis by phenotypic characteristics were also performed. Melanoma risk increased with presence of any of the main MC1R variants: the SOR for each variant ranged from 1.47 (95%CI: 1.17-1.84) for V60L to 2.74 (1.53-4.89) for D84E. Carriers of any MC1R variant had a 66% higher risk of developing melanoma compared with wildtype subjects (SOR; 95%CI: 1.66; 1.41-1.96) and the risk attributable to MC1R variants was 28%. When taking into account phenotypic characteristics, we found that MC1R-associated melanoma risk increased only for darker-pigmented Caucasians: SOR (95%CI) was 3.14 (2.06-4.80) for subjects with no freckles, no red hair and skin Type III/IV. Our study documents the important role of all the main MC1R variants in sporadic CM and suggests that they have a direct effect on melanoma risk, independently on the phenotypic characteristics of carriers. This is of particular importance for assessing preventive strategies, which may be directed to darker-pigmented Caucasians with MC1R variants as well as to lightly pigmented, fairskinned subjects.

BACKGROUND: Neonatal dried blood spots (DBS) represent an inexpensive method for long-term biobanking worldwide and are considered gold mines for research for several human diseases, including those of metabolic, infectious, genetic and epigenetic origin. However, the utility of DBS is restricted by the limited amount and quality of extractable biomolecules (including DNA), especially for genome wide profiling. Degradation of DNA in DBS often occurs during storage and extraction. Moreover, amplifying small quantities of DNA often leads to a bias in subsequent data, particularly in methylome profiles. Thus it is important to develop methodologies that maximize both the yield and quality of DNA from DBS for downstream analyses. RESULTS: Using combinations of in-house-derived and modified commercial extraction kits, we developed a robust and efficient protocol, compatible with methylome studies, many of which require stringent bisulfite conversion steps. Several parameters were tested in a step-wise manner, including blood extraction, cell lysis, protein digestion, and DNA precipitation, purification and elution. DNA quality was assessed based on spectrophotometric measurements, DNA detectability by PCR, and DNA integrity by gel electrophoresis and bioanalyzer analyses. Genome scale Infinium HumanMethylation450 and locus-specific pyrosequencing data generated using the refined DBS extraction protocol were of high quality, reproducible and consistent. CONCLUSIONS: This study may prove useful to meet the increased demand for research on prenatal, particularly epigenetic, origins of human diseases and for newborn screening programs, all of which are often based on DNA extracted from DBS.

BACKGROUND: Despite growing interest in prevention of lower urinary tract symptoms (LUTS) through better understanding of modifiable risk factors, large-scale population-based evidence is limited. OBJECTIVE: To describe risk factors associated with severe LUTS in the 45 and Up Study, a large cohort study. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional analysis of questionnaire data from 106,435 men aged ≥ 45 years, living in New South Wales, Australia. OUTCOME MEASURES AND STATISTICAL ANALYSIS: LUTS were measured by a modified version of the International Prostate Symptom Score (m-IPSS). The strength of association between severe LUTS and socio-demographic, lifestyle and health-related factors was estimated, using logistic regression to calculate odds ratios, adjusted for a range of confounding factors. RESULTS: Overall, 18.3% reported moderate, and 3.6% severe, LUTS. Severe LUTS were more common among men reporting previous prostate cancer (7.6%), total prostatectomy (4.9%) or having part of the prostate removed (8.2%). After excluding men with prostate cancer or prostate surgery, the prevalence of moderate-severe LUTS in the cohort (n = 95,089) ranged from 10.6% to 35.4% for ages 45-49 to ≥ 80; the age-related increase was steeper for storage than voiding symptoms. The adjusted odds of severe LUTS decreased with increasing education (tertiary qualification versus no school certificate, odds ratio (OR = 0.78 (0.68-0.89))) and increasing physical activity (high versus low, OR = 0.83 (0.76-0.91)). Odds were elevated among current smokers versus never-smokers (OR = 1.64 (1.43-1.88)), obese versus healthy-weight men (OR = 1.27 (1.14-1.41)) and for comorbid conditions (e.g., heart disease versus no heart disease, OR = 1.36 (1.24-1.49)), and particularly for severe versus no physical functional limitation (OR = 5.17 (4.51-5.93)). CONCLUSIONS: LUTS was associated with a number of factors, including modifiable risk factors, suggesting potential targets for prevention

BACKGROUND: Antenatal anaemia, iron deficiency and common mental disorders (CMD) are prevalent in low- and middle-income countries. The aim of this study was to examine the direct and indirect effects of antenatal exposures to these risks and infant motor development. METHODS: A cohort of women who were pregnant with a single foetus and between 12 and 20 weeks pregnant in 50 randomly-selected rural communes in Ha Nam province was recruited. Participants provided data twice during pregnancy (early and late gestation) and twice after giving birth (8 weeks and 6 months postpartum). The Edinburgh Postnatal Depression Scale was used at all four data collection waves to detect CMD (score ≥ 4). Maternal anaemia (Hb < 11 g/dL) and iron deficiency (ferritin < 15 ng/mL) were evaluated at early and late gestation. Infants' motor development was assessed by the Bayley of Infant and Toddler Development Motor Scales (BSID-M) at the age of six months. Direct and indirect effects of the exposures on the outcome were examined with Path analysis. RESULTS: In total, 497 of 523 (97%) eligible pregnant women were recruited and 418 mother-infant pairs provided complete data and were included in the analyses. The prevalence of anaemia was 21.5% in early pregnancy and 24.4% in late pregnancy. There was 4.1% iron deficiency at early pregnancy and 48.2% at late pregnancy. Clinically significant symptoms of CMD were apparent among 40% women in early pregnancy and 28% in late pregnancy. There were direct adverse effects on infant BSID-M scores at 6 months of age due to antenatal anaemia in late pregnancy (an estimated mean reduction of 2.61 points, 95% Confidence Interval, CI, 0.57 to 4.65) and CMD in early pregnancy (7.13 points, 95% CI 3.13 to 11.13). Iron deficiency and anaemia in early pregnancy were indirectly related to the outcome via anaemia during late pregnancy. CONCLUSIONS: Antenatal anaemia, iron deficiency, and CMD have a negative impact on subsequent infant motor development. The

OBJECTIVES: Physical activity is negatively associated with arterial stiffness. However, the relationship between sedentary behaviour and arterial stiffness is poorly understood. In this study, we aimed to investigate the association of sedentary behaviour with arterial stiffness among young adults. DESIGN: Cross-sectional. SETTING: 34 study clinics across Australia during 2004-2006. PARTICIPANTS: 2328 participants (49.4% male) aged 26-36 years who were followed up from a nationally representative sample of Australian schoolchildren in 1985. MEASUREMENTS: Arterial stiffness was measured by carotid ultrasound. Sitting time per weekday and weekend day, and physical activity were self-reported by questionnaire. Cardiorespiratory fitness was estimated as physical work capacity at a heart rate of 170 bpm. Anthropometry, blood pressure, resting heart rate and blood biochemistry were measured. Potential confounders, including strength training, education, smoking, diet, alcohol consumption and parity, were self-reported. Rank correlation was used for analysis. RESULTS: Sitting time per weekend day, but not per weekday, was correlated with arterial stiffness (males r=0.11 p<0.01, females r=0.08, p<0.05) and cardiorespiratory fitness (males r = -0.14, females r = -0.08, p<0.05), and also with fatness and resting heart rate. One additional hour of sitting per weekend day was associated with 5.6% (males p=0.046) and 8.6% (females p=0.05) higher risk of having metabolic syndrome. These associations were independent of physical activity and other potential confounders. The association of sitting time per weekend day with arterial stiffness was not mediated by resting heart rate, fatness or metabolic syndrome. CONCLUSIONS: Our study demonstrates a positive association of sitting time with arterial stiffness. The greater role of sitting time per weekend day in prediction of arterial stiffness and cardiometabolic risk than that of sitting time per weekday may be due to better refle

BACKGROUND: Little is known about the effect of common mental disorders (CMD) among women in the perinatal period on infant development in low-income countries. The aim of this study was to examine the effect of exposures to maternal symptoms of ante- and post-natal CMD on infant social-emotional development in a low-income setting. METHODS: A prospective community-based investigation in which a cohort of pregnant women was recruited in rural northern Vietnam and followed until 6 months postpartum. Psychosocial and biological data were collected in four assessment waves. The outcome was 6-month old infants' scores on the Bayley Scales of Infant and Toddler Development Social-Emotional Questionnaire. Direct and indirect effects of maternal CMD on the outcome were tested simultaneously with path analysis. RESULTS: Complete data were available for 378 mother-infant dyads. There were no direct effects of ante- or post-natal CMD on infant Social-Emotional scores. However, there was an indirect pathway (path coefficient -1.11, 95% CI -1.79 to -0.42) in which antenatal CMD were associated with increased likelihood of postnatal CMD, which were associated with reduced parenting self-efficacy and less affectionate and warm parenting practices, which were associated with lower infant social-emotional scores. Parenting self-efficacy and practices also mediated the adverse effects of a woman being young or of high parity or experiencing poverty, intimate partner violence, a poor relationship with her own mother, non-economic life adversity and insufficient breastmilk, on infant social-emotional development. LIMITATIONS: We acknowledge some limitations including (1) a moderate rate of attrition, (2) the use of a screening test for perinatal CMD, (3) the Bayley scales are not yet validated for use in Vietnam and (4) possible response bias in which maternal perceptions of their infants were influenced by their mood. CONCLUSIONS: These data indicate that women's antenatal and postna

UNLABELLED: The aim of this birth cohort study was to determine whether early life factors (birth weight, breastfeeding, and maternal smoking) were associated with bone mass and fractures in 16-year-old adolescents. The results suggest that breastfeeding is associated with higher bone mass and lower fracture risk at age 16 but not in utero smoking or birth weight. INTRODUCTION: There are limited data on early life influences on bone mass in adolescence but we have previously reported in utero smoking, breastfeeding, and birth weight were associated with bone mass at age 8. METHODS: Birth weight, breastfeeding intention and habit, and maternal smoking during pregnancy were assessed at phase one in 1988-1999 and by recall during phase two in 1996-1997. Bone mineral density (BMD) was measured by dual-energy X-ray densitometry. Fractures were assessed by questionnaire. Subjects included 415 male and female adolescents from Southern Tasmania representing 29 % of those who originally took part in a birth cohort study in 1988 and 1989. RESULTS: Breastfeeding (assessed in a number of ways) was associated with a 2-3 % increase in BMD at all sites apart from the radius and around a one third reduction in fracture risk which persisted after adjustment for confounders. In univariate analysis, birth weight was associated with BMD at the hip, radius, and total body but this did not persist in multivariate analysis and there was no association with fracture. Smoking in utero had no association with BMD at any site or fracture. CONCLUSIONS: Breastfeeding is associated with a beneficial increase in bone mass at age 16 and a reduction in fracture risk during adolescence. The association previously observed at 8 years of age is no longer present for birth weight or smoking in utero.