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Introduction Next-generation sequencing (NGS) in family-based study designs will be pivotal in unlocking the missing heritability of common complex diseases. Whilst our prior linkage- and association-based positional cloning studies in family- and population-based Australian cohorts, respectively, have discovered novel preeclampsia candidate genes ( INHBB , ACVR2A , LCT , LRP1B , RND3 , GCA , ERAP2 , TNFSF13B ), the full complement of causal genetic variation remains largely unknown. We have now sequenced the exomes of two Australian preeclampsia families in another step forward to unlocking preeclampsia's complex allelic architecture. Objectives Identify family-specific exon-centric loci segregating in preeclamptic women only. Methods The exomes of 18 women (7 preeclamptics,11 controls) from two Australian families contributing to our chromosome 5q (Family 1) and 13q (Family 2) susceptibility loci, respectively, were sequenced using Illumina's TruSeq Exome Enrichment assay and NGS technology. Sequence alignments, quality control assessment and variant calling were conducted on our 8000 parallel processor compute server, MEDUSA. As a first pass, we prioritized exome sequence data to non-synonymous variants within the 1-LOD drop intervals of our 5q and 13q loci. Prioritized exonic variants were also genotyped in the Western Australian Pregnancy (Raine) Cohort to assess their significance against a plethora of cardiovascular disease (CVD) related traits. Results In Family 1 we identified two missense SNPs and in Family 2 we identified one missense SNP to segregate in the preeclamptic women but not in the unaffected women. The first SNP in Family 1 (rs62375061) resides within the LYSMD3 gene, is predicted to "possibly" damage the focal protein and the only public record of this SNP is within the Watson genome. The second SNP in Family 1 (rs111033530) resides within the GPR98 gene, is predicted to "probably" damage the focal protein and is rare (1.7% population prevalence). The SNP in Family 2 (rs1805388) resides within the LIG4 gene, is predicted to be highly deleterious (F-SNP FSS=0.849) and is common (⩾17% population prevalence). In the Raine cohort the LIG4 SNP was also significantly associated with weight ( p =0.0085), total cholesterol ( p =0.0007), HDL cholesterol ( p =0.0067) and LDL cholesterol ( p =0.0324). Conclusion Our preliminary exome data documents the substantial potential to rapidly identify likely functional variants that influence preeclampsia risk. The GPR98 finding is of major interest to us as a recent genome-wide association study reported a significant association with diastolic blood pressure for a SNP at this same gene locus. Furthermore, our findings implicate LIG4 as a novel candidate susceptibility gene for CVD and add weight to the hypothesis of shared genetic risk factors for preeclampsia and CVD.

There is compelling evidence to support the hypothesis that a maternal constitutional predisposition to cardiovascular disease (CVD) is a key component in development of preeclampsia. In particular, CVD and preeclampsia share pathological features such as endothelial dysfunction and inflammation, and have several metabolic abnormalities in common. In support of this hypothesis, our recent genetic dissection of the Australian preeclampsia susceptibility locus on chromosome 2q22 revealed shared novel genetic risk factors for preeclampsia and CVD-related traits.To replicate association between our recently reported 2q22 preeclampsia risk variants and CVD-related traits in an independent Australian population based cohort.Four independent SNPs from four genes, rs35821928 (LRP1B), rs17783344 (GCA), rs115015150 (RND3) and rs2322659 (LCT), were recently found to be significantly associated with preeclampsia susceptibility and CVD-related traits. These SNPs were genotyped in a large independent Australian cohort rich in quantitative CVD risk traits; The Western Australian Pregnancy Cohort (Raine) Study. This cohort comprises of blood samples from 1246 mothers and 1461 adolescents and clinical measures such as, but not limited to, anthropometric measures of adiposity and lipid-related measures. Genetic association analyses of these four potential preeclampsia susceptibility SNPs against the CVD-related risk traits were performed using the software package R. All statistical analyses assumed an additive model of gene action.Several significant associations (p0.05) for all four SNPs with a variety of CVD-related risk traits were detected, both for the mothers and the adolescents. The LRP1B SNP was associated with HDL/cholesterol ratio, LDL cholesterol, triglycerides, skinfold measures and weight. The GCA SNP was associated with total cholesterol, HDL cholesterol, serum insulin, hemoglobin, blood glucose, BMI and skinfold measures. The RND3 SNP was associated with triglycerides and waist-hip ratio. The LCT SNP was associated with hemoglobin, blood glucose and abdominal skinfold.We have recently identified genetic variants within the LRP1B, GCA, RND3 and LCT genes to be significantly associated with preeclampsia susceptibility and CVD-related risk traits. We have now demonstrated thatthese specific genetic variants are associated with CVD-related risk traits in an independent population. Our collective findings provide substantial empirical data to support the hypothesis that genetic risk factors for preeclampsia and CVD are, at least in part, shared.

It is well established that preeclampsia (PE) increases later life cardiovascular disease (CVD) risk. Consequently, PE has started to gain a role as an early screening criterion for CVD. PE and CVD share several risk factors, pathological features and metabolic abnormalities. These common antecedents have drawn attention to the likelihood of shared genetic susceptibility.Results from our previous PE GWAS identified a significant association with the rs7579169 SNP and maternal PE susceptibility (odds ratio 1.57). This SNP resides near the Inhibin, beta B (INHBB) gene on chromosome 2q14. Therefore, this study sought to interrogate this PE susceptibility SNP against several CVD risk traits in an effort to highlight additional empirical evidence of likely shared PE/CVD genetic mechanisms.The rs7579169 SNP was genotyped in a large independent Australian cohort rich in quantitative CVD risk traits; The Western Australian Pregnancy Cohort (Raine) Study. This cohort comprises of fasting blood samples from 1246 mothers and 1461 adolescents (14- and 17-year-old) and clinical parameters pertaining, but not limited, to anthropometric measures of adiposity and lipid-related measures. Genetic association analyses of rs7579169 against the Raine CVD-related risk traits were performed using the software package R. All statistical analyses assumed an additive model of gene action.Significant associations (p0.05) for rs7579169 with CVD-related risk traits were detected, both for the mothers and the adolescents. Specifically, the minor rs7579169-T allele (MAF 0.400) was found to be significantly associated with elevated levels of triglycerides, total and LDL cholesterol, a greater average waist:hip circumference ratio and a greater average hip circumference.We have previously identified rs7579169 located near the INHBB gene on chromosome 2q14 to significantly associate with maternal PE susceptibility. We have now demonstrated that this SNP is also significantly associated with several CVD-related risk traits in an independent Caucasian population. We hereby present additional empirical evidence of possible shared genetic risk factors underlying both PE and CVD related traits.

Background: Relatively little is known about the relations between dietary patterns and bone health in adolescence, which is a period of substantial bone mass accrual. Objectives: We derived dietary patterns that were hypothesized to be related to bone health on the basis of their protein, calcium, and potassium contents and investigated their prospective associations with bone mineral density (BMD), bone area, and bone mineral content (BMC) in a cohort of young adults. Design: The study included 1024 young adults born to mothers who were participating in the Western Australian Pregnancy Cohort (Raine) Study. Dietary information was obtained from foodfrequency questionnaires at 14 and 17 y of age. Dietary patterns were characterized according to protein, calcium, and potassium intakes with the use of reduced-rank regression. BMD, bone area, and BMC were estimated with the use of a total body dual-energy X-ray absorptiometry scan at 20 y of age. Results: We identified 2 major dietary patterns. The first pattern was positively correlated with intakes of protein, calcium, and potassium and had high factor loadings for low-fat dairy products, whole grains, and vegetables. The second pattern was positively correlated with protein intake but negatively correlated with intakes of calcium and potassium and had high factor loadings for meat, poultry, fish, and eggs. After adjustment for anthropometric, sociodemographic, and lifestyle factors, a higher z score for the first pattern at 14 y of age was positively associated with BMD and BMC at 20 y of age [differences: 8.6 mg/cm 2 (95% CI: 3.0, 14.1 mg/cm 2 ) and 21.9 g (95% CI: 6.5, 37.3 g), respectively, per SD increase in z score]. The z score for this same pattern at 17 y of age was not associated with bone outcomes at 20 y of age. The second pattern at 14 or 17 y of age was not associated with BMD, BMC, or bone area. Conclusions: A dietary pattern characterized by high intakes of protein, calcium, and potassium in midadolescence was associated with higher BMD and BMC at 20 y of age. Our results indicate that high consumption of low-fat dairy products, whole grains, and vegetables in adolescence are associated with beneficial effects on bone development. Am J Clin Nutr 2015;102:1035‐43.

Pregnancy and birth cohorts have been utilised extensively to investigate the developmental origins of health and disease, particularly in relation to understanding the aetiology of obesity and related cardiometabolic disorders. Birth and pregnancy cohorts have been utilised extensively to investigate this area of research. The aim of the present review was twofold: first to outline the necessity of measuring cardiometabolic risk in children; and second to outline how it can be assessed. The major outcomes thought to have an important developmental component are CVD, insulin resistance and related metabolic outcomes. Conditions such as the metabolic syndrome, type 2 diabetes and CHD all tend to have peak prevalence in middle-aged and older individuals but assessments of cardiometabolic risk in childhood and adolescence are important to define early causal factors and characterise preventive measures. Typically, researchers investigating prospective cohort studies have relied on the thesis that cardiovascular risk factors, such as dyslipidaemia, hypertension and obesity, track from childhood into adult life. The present review summarises some of the evidence that these factors, when measured in childhood, may be of value in assessing the risk of adult cardiometabolic disease, and as such proceeds to describe some of the methods for assessing cardiometabolic risk in children.

Features of the metabolic syndrome comprise a major risk for cardiovascular disease and will increase in prevalence with rising childhood obesity. We sought to identify early life influences on development of obesity, hypertension and dyslipidemia in children. Cluster analysis was used on a subset of a longitudinal Australian birth cohort who had blood samples at age 8 (n=406). A quarter of these 8-year-olds fell into a cluster with higher body mass index, blood pressure (BP), more adverse lipid profile and a trend to higher serum glucose resembling adult metabolic syndrome. There was a U-shaped relationship between percentage of expected birth weight (PEBW) and likelihood of being in the high-risk cluster. The high-risk cluster had elevated BP and weight as early as 1 and 3 years old. Increased likelihood of the high-risk cluster group occurred with greatest weight gain from 1 to 8 years old (odds ratio (OR)=1.4, 95% confidence interval (CI)=1.3–1.5/kg) and if mothers smoked during pregnancy (OR=1.82, CI=1.05–3.2). Risk was lower if children were breast fed for ⩾4 months (OR=0.6, 95% CI=0.37–0.97). Newborns in the upper two quintiles for PEBW born to mothers who smoked throughout pregnancy were at greatest risk (OR=14.0, 95% CI=3.8–51.1) compared to the nadir PEBW quintile of non-smokers. A U-shaped relationship between birth weight and several components of the metabolic syndrome was confirmed in a contemporary, well-nourished Western population of full-term newborns, but post-natal weight gain was the dominant factor associated with the high-risk cluster. There was a prominence of higher as well as lowest birth weights in those at risk. Future health programs should focus on both pre- and post-natal factors (reducing excess childhood weight gain and smoking during pregnancy), and possibly the greatest benefits may arise from targeting the heaviest, as well as lightest newborns, especially with a history of maternal smoking during pregnancy.

Introduction: Systematic reviews suggest that a longer duration of breast-feeding is associated with a reduction in the risk of later overweight and obesity. Most studies examining breast-feeding in relation to adiposity have not used longitudinal analysis. In our study, we aimed to examine early infant feeding and adiposity risk in a longitudinal cohort from birth to young adulthood using new as well as published data. Methods: Data from the Western Australian Pregnancy Cohort (Raine) Study in Perth, W.A., Australia, were used to examine associations between breast-feeding and measures of adiposity at 1, 2, 3, 6, 8, 10, 14, 17, and 20 years. Results: Breast-feeding was measured in a number of ways. Longer breast-feeding (in months) was associated with reductions in weight z-scores between birth and 1 year (β = -0.027; p < 0.001) in the adjusted analysis. At 3 years, breast-feeding for Discussion: Breast-feeding until 6 months of age and beyond should be encouraged and is recommended for protection against increased adiposity in childhood, adolescence, and young adulthood. Adverse long-term effects of early growth acceleration are fundamental in later overweight and obesity. Formula feeding stimulates a higher postnatal growth velocity, whereas breast-feeding promotes slower growth and a reduced likelihood of overweight and obesity. Biological mechanisms underlying the protective effect of breast-feeding against obesity are based on the unique composition and metabolic and physiological responses to human milk.

BACKGROUND Childhood obesity creates a predisposition to develop adult hypertension and diabetes. We have identified distinct childhood adiposity trajectories associated with increased insulin resistance in early adolescence. Our aim was to investigate the relationship between these adiposity trajectories with childhood blood pressure (BP) development. METHODS Adiposity trajectories were previously developed by semiparametric modeling using serial anthropometry from birth to age 14 from the West Australian Pregnancy Cohort. The association between these trajectories and the prevalence of hypertension and prehypertension in 17 year olds was assessed by logistic regression. The relationship between adiposity trajectories and lifecourse BP was then assessed using linear mixed modeling. RESULTS The study includes 1,023 adolescents with BP measured at age 17 years. Three of 7 childhood adiposity trajectories (with accelerating adiposity) previously related to increased insulin resistance were associated with an increased risk of 17-year-old prehypertension or hypertension, compared to a referent trajectory of “stable average adiposity” (odds ratio (OR) = 2.9, P = 0.007; OR = 3.5, P < 0.001; and OR = 1.8, P = 0.041). One decelerating adiposity trajectory from high birth size was associated with significant interactions with age terms ( P values = 0.025–0.084 and 0.011–0.027), indicating an altered slope and therefore, relative decline in lifecourse BP compared to the reference adiposity trajectory. CONCLUSIONS Adiposity trajectories (which comprise 27% of the population) were associated with an increased risk of hypertension/prehypertension in adolescence. Higher BP was detectable as early as 3 years old. Consequently, targeting fat loss (catch-down growth) in the preschool years may prevent the development of hypertension and related metabolic disorders.

BACKGROUND: Studies in animal models and in cultured cells have shown that fatty acids can induce alterations in the DNA methylation of specific genes. There have been no studies of the effects of fatty acid supplementation on the epigenetic regulation of genes in adult humans.METHODS AND RESULTS: We investigated the effect of supplementing renal patients with 4 g daily of either n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) or olive oil (OO) for 8 weeks on the methylation status of individual CpG loci in the 5' regulatory region of genes involved in PUFA biosynthesis in peripheral blood mononuclear cells from men and women (aged 53 to 63 years). OO and n-3 LCPUFA each altered (>10% difference in methylation) 2/22 fatty acid desaturase (FADS)-2 CpGs, while n-3 LCPUFA, but not OO, altered (>10%) 1/12 ELOVL5 CpGs in men. OO altered (>6%) 8/22 FADS2 CpGs and (>3%) 3/12 elongase (ELOVL)-5 CpGs, while n-3 LCPUFA altered (>5%) 3/22 FADS2 CpGs and 2/12 (>3%) ELOVL5 CpGs in women. FADS1 or ELOVL2 methylation was unchanged. The n-3 PUFA supplementation findings were replicated in blood DNA from healthy adults (aged 23 to 30 years). The methylation status of the altered CpGs in FADS2 and ELOVL5 was associated negatively with the level of their transcripts.CONCLUSIONS: These findings show that modest fatty acid supplementation can induce altered methylation of specific CpG loci in adult humans, contingent on the nature of the supplement and on sex. This has implications for understanding the effect of fatty acids on PUFA metabolism and cell function.

Non-alcoholic fatty liver disease (NAFLD) and serum 25-hydroxyvitamin D (s25[OH]D) concentrations are both associated with adiposity and insulin resistance (IR) and thus may be pathogenically linked. We aimed to determine the prevalence of vitamin D deficiency in adolescents with NAFLD and to investigate the prospective and cross-sectional associations between s25[OH]D concentrations and NAFLD.Participants in the population-based West Australian Pregnancy (Raine) Cohort had seasonally adjusted s25(OH)D concentrations determined at ages 14 and then 17 years. NAFLD was diagnosed at 17 years using liver ultrasonography. Associations were examined after adjusting for potential confounders. Odds ratios (ORs) and confidence intervals (CIs) are reported per standard deviation in s25(OH)D concentrations.NAFLD was present in 16% (156/994) of adolescents. The majority of participants with NAFLD had either insufficient (51%) or deficient (17%) vitamin D status. s25(OH)D concentrations at 17 years were inversely associated with risk of NAFLD (OR 0.74, 95% CI 0.56, 0.97; P = 0.029), after adjusting for sex, race, physical activity, television/computer viewing, body mass index, and IR. The effect of s25(OH)D concentrations at 17 years was minimally affected after further adjusting for s25(OH)D concentrations at 14 years (OR 0.76, 95% CI 0.56, 1.03; P = 0.072).Lower s25(OH)D concentrations are significantly associated with NAFLD, independent of adiposity and IR. Screening for vitamin D deficiency in adolescents at risk of NAFLD is appropriate, and clinical trials investigating the effect of vitamin D supplementation in the prevention and treatment of NAFLD may be warranted.

Objective Four putative single nucleotide polymorphism (SNP) risk variants at the preeclampsia susceptibility locus on chromosome 2q22; rs2322659 (LCT), rs35821928 (LRP1B), rs115015150 (RND3) and rs17783344 (GCA), were recently shown to associate with known cardiovascular risk factors in a Mexican American cohort. This study aimed to further evaluate the pleiotropic effects of these preeclampsia risk variants in an independent Australian population-based cohort. Methods The four SNPs were genotyped in the Western Australian Pregnancy Cohort (Raine) Study that included DNA, clinical and biochemical data from 1246 mothers and 1404 of their now adolescent offspring. Genotype association analyses were undertaken using the SOLAR software. Results Nominal associations (P < 0.05) with cardiovascular risk factors were detected for all four SNPs. The LCT SNP was associated with decreased maternal height (P = 0.005) and decreased blood glucose levels in adolescents (P = 0.022). The LRP1B SNP was associated with increased maternal height (P = 0.026) and decreased maternal weight (P = 0.044). The RND3 SNP was associated with decreased triglycerides in adolescents (P = 0.001). The GCA SNP was associated with lower risk in adolescents to be born of a preeclamptic pregnancy (P = 0.003) and having a mother with prior preeclamptic pregnancy (P = 0.033). Conclusions Our collective findings support the hypothesis that genetic mechanisms for preeclampsia and CVD are, at least in part, shared, but need to be interpreted with some caution as a Bonferroni correction for multiple testing adjusted the statistical significance threshold (adjusted P < 0.001). This is the authors’ accepted and refereed manuscript to the article. Author's post-print is released with a Creative Commons Attribution Non-Commercial No Derivatives License, CC-BY-NC-ND

Objective: Abdominal pain is a common problem in childhood and accounts for a significant workload in general practice. The aim of this study was assess the nature of abdominal pain in a sample of Australian children attending a Western Australian general practice for any reason, and to determine factors associated with the reporting of such pain. Methodology: A prospective study of children and their families attending a rural general practice was undertaken using a parental survey to assess the frequency and nature of abdominal pain, demographic features, physical and behavioural characteristics. Results: Abdominal pain was common in this population; 44% (70 of 164) of parents reported that the index child had experienced abdominal pain in the past 12 months. The average age of children who experienced recent abdominal pain was 9 years and 9 months. Multivariate analysis suggested that children experiencing abdominal pain in the preceding 12 months were more likely to be anxious (odds ratio (OR) = 3.74, P = 0.01), to have a family history of similar problems in siblings (OR = 4.26, P = 0.01) and to experience sleep disturbance (OR = 3.90, P = 0.02) than children without abdominal pain. Consumption of three or more serves of wholemeal bread or cereals per day had a significant protective effect on reported abdominal pain in children (OR = 0.12, P = 0.03). The majority of families (66%) dealt with the pain without resorting to medical care. Conclusions: Abdominal pain remains a common problem of children attending an Australian general practice, and was associated with features suggesting that it is related to anxiety and coping ability. Abdominal pain is not usually associated with disease; most families recognize this and cope with abdominal pain without medical consultation.

SUMMARY 1 The worldwide epidemic of obesity in adults has been mirrored in children in developed and developing countries. 2 Central obesity appears to be driving a cluster of abnormalities often referred to as the metabolic syndrome. 3 The definition of the metabolic syndrome in children is not suited to arbitrary cut-offs and a definition using the significant clustering of risk factors that is already evident in childhood and adolescent populations may be preferable. 4 An Australian population study showed that 25% of 8-year-olds and 29% of 14-year-olds could be described by the high risk cluster with features similar to adult metabolic syndrome. 5 The high risk cluster was significantly linked to high and low birthweight, shorter duration of breast-feeding, larger postnatal weight gains after 12 months of age and raised C-reactive protein, gamma glutamyl transferase and alanine transaminase levels. At-risk young adults have also been shown to have macroscopic atherosclerosis in post-mortem studies. 6 Identification of at-risk children has obvious benefits for the individual and as well, for prevention of a future cohort with raised cardiovascular morbidity and mortality; however, complexities and controversies exist in doing so. Familial, genetic and lifestyle risk factors aggregate and labelling children with predisease may be problematic. Committed political and societal changes are necessary to reduce childhood obesity and subsequent adult cardiovascular disease.

SUMMARY 1. Longitudinal studies from the US, Australia and Europe have demonstrated tracking of childhood risk factors for cardiovascular disease from adolescence into adult life. These factors include obesity, blood cholesterol levels, blood pressure and measures of insulin resistance. Worldwide increases in childhood obesity and overweight are already resulting in increases in adolescent diabetes and are likely to translate into earlier onset hypertension and cardiovascular disease in adults. 2. Low birth weight has also been associated with increased risk of adult cardiovascular disease, diabetes and high blood pressure, but there is considerable debate as to the relative importance of pre- and postnatal influences. 3. These issues are discussed in the context of results of a longitudinal cohort study of cardiovascular and metabolic risk factors in Western Australia, the ‘Raine’ childhood cohort, which showed that in a well-nourished Australian population at age 8

Background: High sugar-sweetened beverage (SSB) consumption is associated with cardiometabolic disturbances in adults, but this relation is relatively unexplored in children and adolescents. Objective: We tested the hypothesis that higher SSB intakes are associated with increases in cardiometabolic risk factors between 14 and 17 y of age. Design: Data were provided by 1433 adolescent offspring from the Western Australian Pregnancy Cohort (Raine) Study. At 14 and 17 y of age, SSB intakes were estimated by using a food-frequency questionnaire; body mass index (BMI), waist circumference, blood pressure, fasting serum lipids, glucose, and insulin were measured, and overall cardiometabolic risk was estimated. Prospective associations between cardiovascular disease risk factors and SSB intake were examined with adjustment for age, pubertal stage, physical fitness, socioeconomic status, and major dietary patterns. Results: The average SSB intake in consumers (89%) was 335 g/d or 1.3 servings/d. Girls who moved into the top tertile of SSB consumption (.1.3 servings/d) between 14 and 17 y of age had increases in BMI (3.8%; 95% CI: 1.8%, 5.7%), increased overweight and obesity risk (OR: 4.8, 95% CI: 2.1, 11.4), and greater overall cardiometabolic risk (OR: 3.2; 95% CI: 1.6, 6.2) (all P-trend # 0.001). Girls and boys who moved into the top tertile of SSB intake showed increases in triglycerides (7.0‐8.4%; P-trend # 0.03), and boys showed reductions in HDL cholesterol (23.1%; 95% CI: 26.2%, 0.1%; P-trend , 0.04) independent of BMI. Some associations were attenuated after adjustment for major dietary patterns. Conclusion: Increased SSB intake may be an important predictor of cardiometabolic risk in young people, independent of weight status. Am J Clin Nutr doi: 10.3945/ajcn.112.051383.

Background The insulin-like growth factor 2 (IGF2) and H19 imprinted genes control growth and body composition. Adverse in-utero environments have been associated with obesity-related diseases and linked with altered DNA methylation at the IGF2/H19 locus. Postnatally, methylation at the IGF2/H19 imprinting control region (ICR) has been linked with cerebellum weight. We aimed to investigate whether decreased IGF2/H19 ICR methylation is associated with decreased birth and childhood anthropometry and increased contemporaneous adiposity. DNA methylation in peripheral blood (n = 315) at 17 years old was measured at 12 cytosine-phosphate-guanine sites (CpGs), analysed as Sequenom MassARRAY EpiTYPER units within the IGF2/H19 ICR. Birth size, childhood head circumference (HC) at six time-points and anthropometry at age 17 years were measured. DNA methylation was investigated for its association with anthropometry using linear regression. Results The principal component of IGF2/H19 ICR DNA methylation (representing mean methylation across all CpG units) positively correlated with skin fold thickness (at four CpG units) (P-values between 0.04 to 0.001) and subcutaneous adiposity (P = 0.023) at age 17, but not with weight, height, BMI, waist circumference or visceral adiposity. IGF2/H19 methylation did not associate with birth weight, length or HC, but CpG unit 13 to 14 methylation was negatively associated with HC between 1 and 10 years. β-coefficients of four out of five remaining CpG units also estimated lower methylation with increasing childhood HC. Conclusions As greater IGF2/H19 methylation was associated with greater subcutaneous fat measures, but not overall, visceral or central adiposity, we hypothesize that obesogenic pressures in youth result in excess fat being preferentially stored in peripheral fat depots via the IGF2/H19 domain. Secondly, as IGF2/H19 methylation was not associated with birth size but negatively with early childhood HC, we hypothesize that the HC may be a more sensitive marker of early life programming of the IGF axis and of fetal physiology than birth size. To verify this, investigations of the dynamics of IGF2/H19 methylation and expression from birth to adolescence are required.

Objective The current prevalence of mental health problems in Western populations is approximately 20% and half of all adult mental health disorders are estimated to originate in adolescence. Diet plays an important role in modulating psychological wellbeing and B-vitamins are vital for the synthesis of neurotransmitters such as serotonin. We aimed to examine the relationship between B-group vitamins and adolescent mental health and behaviour. Methods This is a cross-sectional analysis of the West Australian Pregnancy Cohort (Raine) Study. The 17-year follow-up included collection of a food frequency questionnaire allowing B-vitamin intake calculation. Mental health was assessed using the Youth Self Report (YSR) which measures total, internalising (withdrawn/depressed) and externalising (aggressive/delinquent) behaviour scores. Multiple linear regression was used to analyse associations between B-vitamins and mental health with adjustment for relevant confounders (n = 709). Results Lower intake of vitamins B1, B2, B3, B5, B6, and folate was associated with higher externalising behaviour scores (p ≤ 0.05). Reduced intake of vitamin B6 and folate was associated with higher internalising behaviour scores (p ≤ 0.05). Conclusions Poor nutrition may contribute to the pathogenesis of mental health problems in adolescence. The role of B-vitamins requires further investigation in randomised controlled trials.

Birth weight and childhood adiposity are associated with subsequent cardiovascular risk.We investigated the associations between metabolic clusters in young adults with body fat distribution from early childhood, focusing on sex differences.A total of 1053 17 yr olds from an Australian birth cohort had measures of anthropometry, blood pressure, and fasting insulin, glucose, and lipids.Two-step cluster analysis identified 17 yr olds at high metabolic risk. The two risk groups were compared by sex with regard to birth weight and serial anthropometry, including skinfold thickness from nine time-points.The "high-risk" metabolic cluster at age 17 yr included 16% of males and 19% of females. Compared to the "low-risk" group, the high-risk cluster participants had greater waist circumference, triglycerides, insulin, and systolic blood pressure and lower high-density lipoprotein-cholesterol (all P0.0001). There was a significant birth weight by sex interaction upon the metabolic cluster outcome (P = 0.011). Compared to their low-risk counterparts, females in the high-risk cluster at 17 yr were heavier from birth (odds ratio, 1.8; 95% confidence interval, 1.0, 3.2) (P = 0.034), with consistently higher body mass index and skinfold thickness thereafter. In contrast, there was no statistical difference in birth weight between high- and low-risk males (odds ratio, 0.62; 95% confidence interval, 0.38, 1.02).These data show sexual dimorphism in effects of early life body mass index and fat distribution upon cardiometabolic risk factors. Females in a contemporary population are particularly prone to increased risk when born heavier. This has implications for targeted prevention of obesity and metabolic diseases with increasing maternal obesity and gestational diabetes.

Evidence that intake of polyunsaturated fatty acids (PUFAs) may modify blood pressure (BP) is generally limited to middle-aged or hypertensive populations. This study examined cross-sectional associations between BP and dietary intake of PUFAs in 814 adolescents aged 13-15 years participating in the Western Australian Pregnancy Cohort (Raine) Study. Fatty acid intakes were assessed using 3-day diet records and resting BP was determined using multiple oscillometric readings. In multivariate regression models, systolic BP was inversely associated with intakes of polyunsaturated (b=-0.436, P

Objective To determine prevalence of metabolic syndrome in adolescents with polycystic ovary syndrome (PCOS) and derive features suggestive of propensity for development of metabolic syndrome. Design Prospective cohort study. Setting Population-based cohort of adolescents in Western Australia. Participant(s) Metabolic data from 1,377 children aged 14 years, features of PCOS obtained from 244 girls aged 14 to 17 years. Intervention(s) Assessment for features of PCOS and subsequent fasting blood samples. Main Outcome Measure(s) Relationship between features of PCOS and features of metabolic syndrome. Result(s) With use of five definitions of metabolic syndrome the maximal prevalence of metabolic syndrome recorded was 11.8% in girls with PCOS (National Institutes of Health [NIH]) and 6.6% (Rotterdam) (non-PCOS 0.6% and 0.7%, respectively). With use of cluster analysis of metabolic risk (a technique to cluster the adolescents according to multidimensional relationships of established cardiovascular risk factors), 35.3% with PCOS-NIH were at risk for metabolic syndrome and 26.2% with PCOS-Rotterdam (non-PCOS 15.4% and 15.4%, respectively). Menstrual irregularity and high free T (PCOS-NIH) were associated with high metabolic syndrome risk (odds ratio 3.00, confidence interval 1.3–6.4), not after controlling for body mass index. Of PCOS features, an elevated free T level was most predictive of insulin resistance. Menstrual irregularity and polycystic ovary morphology were not associated with insulin resistance (56.3% vs. 52.9% and 60.0% vs. 34.4%, respectively). Conclusion(s) Despite the low prevalence of metabolic syndrome in girls with PCOS, one third have features putting them at high risk for development of metabolic syndrome.

The aim of the study was to compare commonly used anthropometry for cardiovascular risk factors in 14-year-olds.A total of 1 149 children of an Australian pregnancy (Raine) cohort with recruitment 1989-1991 were assessed for anthropometry and fasting lipids, insulin, and blood pressure.There were significant distinctions in the associations between anthropometry and groups of cardiovascular risk factors. These distinctions differed by gender. Insulin resistance, triglycerides, C-reactive protein levels, low density lipoprotein (LDH)/high density lipoprotein (HDL) and total/HDL cholesterol ratios had the strongest association with waist, waist/height ratio and body mass index. By contrast, in boys, height was the strongest independent predictor (in a negative direction) of total and LDL-cholesterol. Blood pressure and uric acid was most strongly correlated with body weight and height (heavier and taller boys). Taller male adolescents had highest blood pressures and lowest cholesterol levels.No single adolescent anthropometric measure best predicted all cardiovascular risk factors. Each measure showed distinct relationships with specific groups of risk factors. Contrasting associations may reflect different pathogenesis by which gender, puberty, and adiposity affect metabolic risk. No single anthropometric measurement in childhood would appear to be superior or sufficient when investigating the developmental origins of cardiovascular health and related metabolic disease.

Background and aims Overweight and other risk factors for cardiovascular disease (CVD) as well as their clustering, are increasingly prevalent among adolescents. We examined dietary patterns, CVD risk factors, and the clustering of these risk factors in 1139 14-year-olds living in Western Australia. Methods and results Usual dietary intake was assessed using a food frequency questionnaire. Two dietary patterns, ‘Western' and ‘Healthy', were identified using factor analysis. Associations between these dietary patterns and BMI, waist circumference, systolic blood pressure, fasting levels of serum glucose, insulin, total cholesterol, HDL-C, LDL-C, triglycerides and insulin resistance were assessed using ANOVA. Cluster analysis identified a high risk group (the ‘high risk metabolic cluster') with features akin to adult metabolic syndrome. Belonging to the ‘high risk metabolic cluster' was examined in relation to dietary patterns using logistic regression, adjusting for aerobic fitness and socio-demographic factors. Higher ‘Western' dietary pattern scores were associated with greater odds for the ‘high risk metabolic cluster' ( p for trend=0.02) and greater mean values for total cholesterol ( p for trend=0.03), waist circumference ( p for trend=0.03) and BMI ( p for trend=0.02) in girls, but not boys. Scores for the ‘Healthy' dietary pattern were not related to the ‘high risk metabolic cluster' but were inversely associated with serum glucose in boys and girls ( p for trend=0.01 and 0.04, respectively) and were positively associated with HDL-C in boys ( p for trend=0.02). Conclusions Dietary patterns are associated with CVD risk factors and the clustering of these risk factors in adolescence.

Objectives Offspring of hypertensive pregnancies have increased cardiovascular risk factors during childhood. We hypothesised that offspring of hypertensive pregnancies would demonstrate increased clinical levels of hypertension by young adult life, which would be proportional to the severity of the pregnancy complication. Design Prospective birth cohort study Setting Tertiary obstetric hospital. Participants 2868 young adult offspring of women enrolled during pregnancy into the Western Australia Pregnancy Cohort (Raine) Study. Main outcome measures Cardiovascular risk, including incidence of hypertension and metabolic disease, in those born to hypertensive compared to normotensive pregnancies. Results Young adult offspring of hypertensive pregnancies were 2.5 times (95% CI 1.32 to 4.56, p=0.004) more likely to have global lifetime risk (QRISK) scores above the 75th centile. Thirty per cent of 20 year olds with hypertensive blood pressures were born following a hypertensive pregnancy. Pre-eclampsia or hypertension resulting in preterm birth associated with a threefold (95% CI 1.3 to 7.0, p=0.01) greater risk of being hypertensive by age 20 years, with no differences in body mass index. Whereas pregnancy-induced hypertension associated with a smaller 3±1 mm Hg blood pressure rise (p=0.001) and a twofold (95% CI 1.5 to 2.8, p=0.001) greater risk of being obese or overweight. Risk factor associations were consistent throughout early life and independent of other birth-factors. Conclusions Incidence of offspring hypertension was significantly increased in those whose mothers had a more complicated pregnancy history, including preterm birth and pre-eclampsia.

Findings: BMI, WAISTC and RLF increased over time. Average growths and variations across individuals were statistically significant. As RLF rose over time, BMI and WAISTC decreased, that is, positive growth in RLF was associated with reduced growth in BMI and WAISTC. Statistically significant associations between growth intercepts remained even when accounting for individualand area-level covariates. Conclusion: Longitudinal analysis using growth models enabled the estimation of individual trajectories and to examine the extent to which they are associated to each other. Although rising RLF was associated with reduced growth in BMI and WAISTC, other factors such as diet and active lifestyle could contribute to changes in BMI and WAISTC [1—3].

The present paper reports a retrospective cohort of preterm infants admitted to our hospital who delivered outside the normal geographical catchment area of the mother's local level three neonatal nursery. Nineteen mothers had 21 preterm infants (23.1-34.9 weeks, 500-2330 g born) where 14 infants required ventilation (median 57 h, range 3-428). Eighteen survivors had a median length of stay of 41 days (range 3-91). Twelve of 19 mothers were interviewed: all described isolation, loneliness, poor social support and significant financial hardship related to getting their infants back to a local hospital or home. To avoid these problems, we recommend confining travel to within a short distance from home or local maternity unit after 22 weeks.

BACKGROUND: Gastro‐oesophageal reflux (GOR) is common in infants, and feed thickeners are often used to manage it in infants as they are simple to use and perceived to be harmless. However, conflicting evidence exists to support the use of feed thickeners. OBJECTIVES: To evaluate the use of feed thickeners in infants up to six months of age with GOR in terms of reduction in a) signs and symptoms of GOR, b) reflux episodes on pH probe monitoring or intraluminal impedance or a combination of both, or c) histological evidence of oesophagitis. SEARCH METHODS: We used the standard search strategy of the Cochrane Neonatal Review Group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2016, Issue 2), MEDLINE via PubMed (1966 to 22 November 2016), Embase (1980 to 22 November 2016), and CINAHL (1982 to 22 November 2016). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials. SELECTION CRITERIA: We included randomised controlled trials if they examined the effects of feed thickeners as compared to unthickened feeds (no treatment or placebo) in treating GOR in term infants up to six months of age or six months of corrected gestational age for those born preterm. DATA COLLECTION AND ANALYSIS: Two review authors independently identified eligible studies from the literature search. Two review authors independently performed data extraction and quality assessments of the eligible studies. Differences in opinion were resolved by discussion with a third review author, and consensus was reached among all three review authors. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS: Eight trials recruiting a total of 637 infants met the inclusion criteria for the systematic review. The infants included in the review were mainly formula‐fed term infants. The trials were of variable methodological quality. Formula‐fed term infants with GOR on feed thickeners had nearly two fewer episodes of regurgitation per day (mean difference ‐1.97 episodes per day, 95% confidence interval (CI) ‐2.32 to ‐1.61; 6 studies, 442 infants, moderate‐certainty evidence) and were 2.5 times more likely to be asymptomatic from regurgitation at the end of the intervention period (risk ratio 2.50, 95% CI 1.38 to 4.51; number needed to treat for an additional beneficial outcome 5, 95% CI 4 to 13; 2 studies, 186 infants, low‐certainty evidence) when compared to infants with GOR on unthickened feeds. No studies reported failure to thrive as an outcome. We found low‐certainty evidence based on 2 studies recruiting 116 infants that use of feed thickeners improved the oesophageal pH probe parameters of reflux index (i.e. percentage of time pH < 4), number of reflux episodes lasting longer than 5 minutes, and duration of longest reflux episode. No major side effects were reported with the use of feed thickeners. Information was insufficient to conclude which type of feed thickener is superior. AUTHORS' CONCLUSIONS: Gastro‐oesophageal reflux is a physiological self resolving phenomenon in infants that does not necessarily require any treatment. However, we found moderate‐certainty evidence that feed thickeners should be considered if regurgitation symptoms persist in term bottle‐fed infants. The reduction of two episodes of regurgitation per day is likely to be of clinical significance to caregivers. Due to the limited information available, we were unable to assess the use of feed thickeners in infants who are breastfeeding or preterm nor could we conclude which type of feed thickener is superior.

Commentary on: A Tirosh, I Shai, A Afek, et al.Adolescent BMI trajectory and risk of diabetes versus coronary disease.N Engl J Med2011;364:1315–25.

This retrospective cohort study included 19 women who delivered 21 preterm infants while away from their usual site of residence and outside the geographic catchment area of the local level 3 neonatal nursery. A majority of these mothers were traveling on holiday, but some were visiting relatives or attending weddings. Nine of the pregnancies (47%) were considered to be at high risk of preterm delivery. Two women required urgent cesarean section because of antepartum hemorrhage. The median gestational age was 30.2 weeks, and the median birth weight was 1230 g. Twelve of the 21 infants (57%) were transferred in utero from another hospital. Two thirds of infants required ventilation for a median time of 57 hours. Three infants died before discharge. The other 18 had a median hospital stay of 41 days. Ten of them were then transferred to a hospital nearer home, and 8 were discharged home. All 12 mothers who agreed to a telephone interview reported having experienced a mix of emotions, including feelings of isolation, loneliness, and separation. There was concern for the partner and his ability to cope with the separation. All parents mentioned the financial burden of having a baby away from home. All but 10% described missing the support of family and friends. It seems important to make prospective mothers aware of the possible consequences of traveling during pregnancy. There are no indications that travel itself increases the risk of preterm delivery, but difficulties could be expected in this situation. It might be reasonable to suggest to prospective parents that they limit travel to less than a 1-hour drive from home or the local maternity unit after 22 weeks gestation.

Aim: To examine the efficacy of lifestyle intervention on obese children and adolescents (6—16 years) at Princess Margaret Hospital, Western Australia. Strict inclusion criteria exists for this intervention so that participants have significant obesity or obesity with co morbidities. Method: A 12-month group-based multidisciplinary lifestyle programme was attended by 114 subjects (February 2008—May 2011). Anthropometry and cardio-metabolic parameters were assessed at baseline, 10 weeks and 12 months. Non-parametric Wilcoxon signed ranked test was used to test for improvement between pre-treatment and post-treatment parameters. Results: 114 patients were available for analysis (58% female; 44%children