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BACKGROUND AND PURPOSE: Understanding predictors of changes in employment status among people living with multiple sclerosis (MS) can assist health care providers to develop appropriate work retention/rehabilitation programs. We aimed to model longitudinal transitions of employment status in MS and estimate the probabilities of retaining employment status or losing or gaining employment over time in individuals with a first clinical diagnosis of central nervous system demyelination (FCD). METHODS: This prospective cohort study comprised adults (aged 18-59 years) diagnosed with FCD (n = 237) who were followed for more than 11 years. At each review, participants were assigned to one of three states: unemployed, part-time, or full-time employed. A Markov multistate model was used to examine the rate of state-to-state transitions. RESULTS: At the time of FCD, participants with full-time employment had an 89% chance of being in the same state over a 1-year period, but this decreased to 42% over the 10-year follow-up period. For unemployed participants, there was a 92% likelihood of remaining unemployed after 1 year, but this probability decreased to 53% over 10 years. Females, those who progressed to clinically definite MS, those with a higher relapse count, and those with a greater level of disability were at increased risk of transitioning to a deteriorated employment state. In addition, those who experienced clinically significant fatigue over the follow-up period were less likely to gain employment after being unemployed. CONCLUSIONS: In our FCD cohort, we found a considerable rate of employment transition during the early years post-diagnosis. Over more than a decade of follow-up post-FCD, we found that females and individuals with a greater disability and a higher relapse count are at higher risk of losing employment.

Consensus statements can be very influential in medicine and public health. Some of these statements use systematic evidence synthesis but others fail on this front. Many consensus statements use panels of experts to deduce perceived consensus through Delphi processes. We argue that stacking of panel members toward one particular position or narrative is a major threat, especially in absence of systematic evidence review. Stacking may involve financial conflicts of interest, but nonfinancial conflicts of strong advocacy can also cause major bias. Given their emerging importance, we describe here how such consensus statements may be misleading, by analyzing in depth a recent high-impact Delphi consensus statement on COVID-19 recommendations as a case example. We demonstrate that many of the selected panel members and at least 35% of the core panel members had advocated toward COVID-19 elimination (Zero-COVID) during the pandemic and were leading members of aggressive advocacy groups. These advocacy conflicts were not declared in the Delphi consensus publication, with rare exceptions. Therefore, we propose that consensus statements should always require rigorous evidence synthesis and maximal transparency on potential biases toward advocacy or lobbyist groups to be valid. While advocacy can have many important functions, its biased impact on consensus panels should be carefully avoided.

Prediction markets are a successful information aggregation structure, however the exact mechanism by which private information is incorporated into the price remains poorly understood. We introduce a novel method based on the “Kyle model” to identify traders who contribute valuable information to the market price. Applied to a large field prediction market dataset, we identify traders whose trades have positive informational price impact. In contrast to others, these traders realize profit (on average) in excess of a theoretical expected informed lower bound. Results are replicated on other field prediction market datasets, providing strong evidence in favor of the Kyle model.

BACKGROUND: The beneficial off-target effects of Bacille Calmette-Guérin (BCG) vaccination potentially include protection against allergy. OBJECTIVE: In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants. METHODS: In this randomised controlled trial, 1272 neonates were allocated to BCG-Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3-monthly online questionnaires and oral food challenges. Data were analysed by intention-to-treat using binary regression. CLINICALTRIALS: gov (NCT01906853). RESULTS: Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI -1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI -3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration). CONCLUSIONS AND CLINICAL RELEVANCE: Neonatal BCG-Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life.

Vitamin D deficiency is a risk factor for developing multiple sclerosis. The PrevANZ trial was conducted to determine if vitamin D3 supplementation can prevent recurrent disease activity in people with a first demyelinating event. As a sub-study of this trial, we investigated the effect of supplementation on peripheral immune cell gene expression. Participants were randomized to 1000, 5000 or 10,000 international units daily of vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks and sent for ribonucleic acid sequencing. Datasets from 55 participants were included. Gene expression was modulated by high dose supplementation. Antigen presentation and viral response pathways were upregulated. Oxidative phosphorylation and immune signaling pathways, including tumor necrosis factor-alpha and interleukin-17 signaling, were downregulated. Overall, vitamin D3 supplementation for 12 weeks modulated the peripheral immune cell transcriptome with induction of anti-inflammatory gene expression profiles. Our results support a dose-dependent effect of vitamin D3 supplementation on immune gene expression.

Male sex, early life chemical exposure and the brain aromatase enzyme have been implicated in autism spectrum disorder (ASD). In the Barwon Infant Study birth cohort (n = 1074), higher prenatal maternal bisphenol A (BPA) levels are associated with higher ASD symptoms at age 2 and diagnosis at age 9 only in males with low aromatase genetic pathway activity scores. Higher prenatal BPA levels are predictive of higher cord blood methylation across the CYP19A1 brain promoter I.f region (P = 0.009) and aromatase gene methylation mediates (P = 0.01) the link between higher prenatal BPA and brain-derived neurotrophic factor methylation, with independent cohort replication. BPA suppressed aromatase expression in vitro and in vivo. Male mice exposed to mid-gestation BPA or with aromatase knockout have ASD-like behaviors with structural and functional brain changes. 10-hydroxy-2-decenoic acid (10HDA), an estrogenic fatty acid alleviated these features and reversed detrimental neurodevelopmental gene expression. Here we demonstrate that prenatal BPA exposure is associated with impaired brain aromatase function and ASD-related behaviors and brain abnormalities in males that may be reversible through postnatal 10HDA intervention.

BACKGROUND: Maternal dietary choline has a central role in foetal brain development and may be associated with later cognitive function. However, many countries are reporting lower than recommended intake of choline during pregnancy. METHODS: Dietary choline was estimated using food frequency questionnaires in pregnant women participating in population-derived birth cohort, the Barwon Infant Study (BIS). Dietary choline is reported as the sum of all choline-containing moieties. Serum total choline-containing compounds (choline-c), phosphatidylcholine and sphingomyelin were measured using nuclear magnetic resonance metabolomics in the third trimester. The main form of analysis was multivariable linear regression. RESULTS: The mean daily dietary choline during pregnancy was 372 (standard deviation (SD) 104) mg/day. A total of 236 women (23%) had adequate choline intake (440 mg/day) based on the Australian and New Zealand guidelines, and 27 women (2.6%) took supplemental choline ([Formula: see text] 50 mg/dose) daily during pregnancy. The mean serum choline-c in pregnant women was 3.27 (SD 0.44) mmol/l. Ingested choline and serum choline-c were not correlated (R2) = - 0.005, p = 0.880. Maternal age, maternal weight gain in pregnancy, and a pregnancy with more than one infant were associated with higher serum choline-c, whereas gestational diabetes and environmental tobacco smoke during preconception and pregnancy were associated with lower serum choline-c. Nutrients or dietary patterns were not associated with variation in serum choline-c. CONCLUSION: In this cohort, approximately one-quarter of women met daily choline recommendations during pregnancy. Future studies are needed to understand the potential impact of low dietary choline intake during pregnancy on infant cognition and metabolic intermediaries.

BACKGROUND: There are currently no specific biomarkers for multiple sclerosis (MS). Identifying robust biomarkers for MS is crucial to improve disease diagnosis and management. METHODS: This study first used six Mendelian randomisation methods to assess causal relationship of 174 metabolites with MS, incorporating data from European-ancestry metabolomics (n=8569-86 507) and MS (n=14 802 MS cases, 26 703 controls) genomewide association studies. Genetic scores for identified causal metabolite(s) were then computed to predict MS disability progression in an independent longitudinal cohort (AusLong study) of 203 MS cases with up to 15-year follow-up. RESULTS: We found a novel genetic causal effect of serine on MS onset (OR=1.67, 95% CI 1.51 to 1.84, p=1.73×10-20), such that individuals whose serine level is 1 SD above the population mean will have 1.67 times the risk of developing MS. This is robust across all sensitivity methods (OR ranges from 1.49 to 1.67). In an independent longitudinal MS cohort, we then constructed time-dynamic and time-fixed genetic scores based on serine genetic instrument single-nucleotide polymorphisms, where higher scores for raised serum serine level were associated with increased risk of disability worsening, especially in the time-dynamic model (RR=1.25, 95% CI 1.10 to 1.42, p=7.52×10-4). CONCLUSIONS: These findings support investigating serine as an important candidate biomarker for MS onset and disability progression.

INTRODUCTION: The association between air pollution and poor respiratory health outcomes is well established, however less is known about the biological mechanisms, especially in early life. Children are particularly at risk from air pollution, especially during the prenatal period as their organs and systems are still undergoing crucial development. Therefore, our study aims to investigate if maternal exposure to air pollution during pregnancy is associated with oxidative stress (OS) and inflammation in pregnancy or infant lung function at 4 weeks of age, and the extent to which the association is modified by an infant's genetic risk of OS. METHODS: The Barwon Infant Study (BIS) is a longitudinal study of Australian children from the region of Geelong, Victoria. A total of 314 infants had available lung function and maternal OS markers. Exposure to annual air pollutants (NO 2 and PM 2.5 ) were estimated using validated, satellite-based, land-use regression models. Infant lung function was measured by multiple-breath washout, and the ratio of peak tidal expiratory flow over expiratory time was calculated at 4 weeks of age. An inflammation biomarker, glycoprotein acetyls (GlycA), was measured in maternal (36 weeks) and cord blood, and oxidative stress (OS) biomarkers, 8-hydroxyguanine (8-OHGua) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were measured in maternal urine at 28 weeks. A genetic pathway score for OS (gPFS ox ) was calculated for each infant participant in the BIS cohort, and high risk defined as score >8. Linear regression was used to explore the association of maternal air pollution exposure with infant lung function, and potential modification by OS genotype was tested through use of interaction terms and other methods. RESULTS: There was no evidence of a relationship between maternal exposure to air pollution and infant lung function in the whole population. We did not find an association between air pollution and GlycA or OS during pregnancy. We found e

Background: Oral immunotherapy is effective at inducing desensitisation to allergens and induces sustained unresponsiveness (ie, clinical remission) in a subset of patients, but causes frequent reactions. We aimed to investigate whether addition of a probiotic adjuvant improved the efficacy or safety of peanut oral immunotherapy. Method(s): PPOIT-003, a multicentre, randomised, phase 2b trial, was conducted in three tertiary hospitals in Australia (Adelaide [SA], Melbourne [VIC], and Perth [WA]) in children aged 1-10 years, weighing more than 7 kg, with peanut allergy confirmed by a double-blind placebo-controlled food challenge (cumulative 4950 mg dose of peanut protein) and positive peanut skin prick test (>=3 mm) or peanut-specific IgE (>=0.35 kU/L). Children were randomly assigned (2:2:1) to receive probiotic and peanut oral immunotherapy (PPOIT), placebo probiotic and peanut oral immunotherapy (OIT), or placebo probiotic and placebo OIT (placebo) for 18 months, and were followed up until 12 months after completion of treatment. Oral immunotherapy consisted of increasing doses of peanut protein (commercially available food-grade 12% defatted peanut flour [50% peanut protein]) until a 2000 mg daily maintenance dose was reached. The probiotic adjuvant was a daily dose of 2 x 1010 colony-forming units of the probiotic Lactobacillus rhamnosus ATCC 53103. Placebo immunotherapy comprised maltodextrin, brown food colouring, and peanut essence, and placebo probiotic was maltodextrin. Dual primary outcomes were 8-week sustained unresponsiveness, defined as no reaction to a cumulative dose of 4950 mg peanut protein at treatment completion and 8 weeks after treatment completion, in the PPOIT versus placebo groups and the PPOIT versus OIT groups, analysed by intention to treat. Safety endpoints were adverse events during the treatment phase, and peanut ingestion and reactions in the 12-month post-treatment period. This study is registered with the Australian New Zealand Cli

The developing brain is highly sensitive to environmental disturbances, and adverse exposures can act through oxidative stress. Given that oxidative stress susceptibility is determined partly by genetics, multiple studies have employed genetic scores to explore the role of oxidative stress in human disease. However, traditional approaches to genetic score construction face a range of challenges, including a lack of interpretability, bias towards the disease outcome, and often overfitting to the study they were derived on. Here, we develop an alternative strategy by first generating a genetic pathway function score for oxidative stress (gPFSox) based on the transcriptional activity levels of the oxidative stress response pathway in brain and other tissue types. Then, in the Barwon Infant Study (BIS), a population-based birth cohort (n = 1074), we show that a high gPFSox, indicating reduced ability to counter oxidative stress, is linked to higher autism spectrum disorder risk and higher parent-reported autistic traits at age 4 years, with AOR values (per 2 additional pro-oxidant alleles) of 2.10 (95% CI (1.12, 4.11); p = 0.024) and 1.42 (95% CI (1.02, 2.01); p = 0.041), respectively. Past work in BIS has reported higher prenatal phthalate exposure at 36 weeks of gestation associated with offspring autism spectrum disorder. In this study, we examine combined effects and show a consistent pattern of increased neurodevelopmental problems for individuals with both a high gPFSox and high prenatal phthalate exposure across a range of outcomes, including high gPFSox and high DEHP levels against autism spectrum disorder (attributable proportion due to interaction 0.89; 95% CI (0.62, 1.16); p < 0.0001). The results highlight the utility of this novel functional genetic score and add to the growing evidence implicating gestational phthalate exposure in adverse neurodevelopment.

BACKGROUND: Prenatal exposure to phthalates has been associated with adverse health and neurodevelopmental outcomes. DNA methylation (DNAm) alterations may be a mechanism underlying these effects, but prior investigations of prenatal exposure to phthalates and neonatal DNAm profiles are limited to placental tissue and umbilical cord blood. OBJECTIVE: Conduct an epigenome-wide association study (EWAS) of the associations between prenatal exposure to phthalates and DNAm in two accessible infant tissues, venous buffy coat blood and buccal epithelial cells (BECs). METHODS: Participants included 152 maternal-infant pairs from the Alberta Pregnancy Outcomes and Nutrition (APrON) study. Maternal second trimester urine samples were analyzed for nine phthalate metabolites. Blood (n = 74) or BECs (n = 78) were collected from 3-month-old infants and profiled for DNAm using the Infinium HumanMethylation450 (450K) BeadChip. Robust linear regressions were used to investigate the associations between high (HMWPs) and low molecular weight phthalates (LMWPs) and change in methylation levels at variable Cytosine-phosphate-Guanine (CpG) sites in infant tissues, as well as the sensitivity of associations to potential confounders. RESULTS: One candidate CpG in gene RNF39 reported by a previous study examining prenatal exposure to phthalates and cord blood DNAm was replicated. The EWAS identified 12 high-confidence CpGs in blood and another 12 in BECs associated with HMWPs and/or LMWPs. Prenatal exposure to bisphenol A (BPA) associated with two of the CpGs associated with HMWPs in BECs. DISCUSSION: Prenatal exposure to phthalates was associated with DNAm variation at CpGs annotated to genes associated with endocrine hormone activity (i.e., SLCO4A1, TPO), immune pathways and DNA damage (i.e., RASGEF1B, KAZN, HLA-A, MYO18A, DIP2C, C1or109), and neurodevelopment (i.e., AMPH, NOTCH3, DNAJC5). Future studies that characterize the stability of these associations in larger samples, multiple coh

BACKGROUND: The risk of adult onset cardiovascular and metabolic (cardiometabolic) disease accrues from early life. Infection is ubiquitous in infancy and induces inflammation, a key cardiometabolic risk factor, but the relationship between infection, inflammation, and metabolic profiles in early childhood remains unexplored. We investigated relationships between infection and plasma metabolomic and lipidomic profiles at age 6 and 12 months, and mediation of these associations by inflammation. METHODS: Matched infection, metabolomics, and lipidomics data were generated from 555 infants in a pre-birth longitudinal cohort. Infection data from birth to 12 months were parent-reported (total infections at age 1, 3, 6, 9, and 12 months), inflammation markers (high-sensitivity C-reactive protein [hsCRP]; glycoprotein acetyls [GlycA]) were quantified at 12 months. Metabolic profiles were 12-month plasma nuclear magnetic resonance metabolomics (228 metabolites) and liquid chromatography/mass spectrometry lipidomics (776 lipids). Associations were evaluated with multivariable linear regression models. In secondary analyses, corresponding inflammation and metabolic data from birth (serum) and 6-month (plasma) time points were used. RESULTS: At 12 months, more frequent infant infections were associated with adverse metabolomic (elevated inflammation markers, triglycerides and phenylalanine, and lower high-density lipoprotein [HDL] cholesterol and apolipoprotein A1) and lipidomic profiles (elevated phosphatidylethanolamines and lower trihexosylceramides, dehydrocholesteryl esters, and plasmalogens). Similar, more marked, profiles were observed with higher GlycA, but not hsCRP. GlycA mediated a substantial proportion of the relationship between infection and metabolome/lipidome, with hsCRP generally mediating a lower proportion. Analogous relationships were observed between infection and 6-month inflammation, HDL cholesterol, and apolipoprotein A1. CONCLUSIONS: Infants with a gre

BACKGROUND: There is mounting evidence that in utero and early life exposures may predispose an individual to metabolic disorders in later life; and dysregulation of lipid metabolism is critical in such outcomes. However, there is limited knowledge about lipid metabolism and factors causing lipid dysregulation in early life that could result in adverse health outcomes in later life. We studied the effect of antenatal factors such as gestational age, birth weight, and mode of birth on lipid metabolism at birth; changes in the circulating lipidome in the first 4 years of life and the effect of breastfeeding in the first year of life. From this study, we aim to generate a framework for deeper understanding into factors effecting lipid metabolism in early life, to provide early interventions for those at risk of developing metabolic disorders including cardiovascular diseases. METHODS: We performed comprehensive lipid profiling of 1074 mother-child dyads in the Barwon Infant Study (BIS), a population-based pre-birth cohort and measured 776 distinct lipid features across 39 lipid classes using ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). We measured lipids in 1032 maternal serum samples at 28 weeks' gestation, 893 cord serum samples at birth, 793, 735, and 511 plasma samples at 6, 12 months, and 4 years, respectively. Cord serum was enriched with long chain poly-unsaturated fatty acids (LC-PUFAs), and corresponding cholesteryl esters relative to the maternal serum. We performed regression analyses to investigate the associations of cord serum lipid species with antenatal factors: gestational age, birth weight, mode of birth and duration of labour. RESULTS: The lipidome differed between mother and newborn and changed markedly with increasing child's age. Alkenylphosphatidylethanolamine species containing LC-PUFAs increased with child's age, whereas the corresponding lysophospholipids and triglycerides decreased. Majority of the cord

BACKGROUND: Measurement of cashew-specific IgE (sIgE) is often used to confirm sensitization but does not reliably diagnose clinical allergy. Ana o 3 is the dominant cashew allergen detected in 75-100% of patients with cashew allergy but not currently used in clinical practice. OBJECTIVES: To determine if component-resolved diagnostics using specific IgE to the 2 S albumin from cashew, Ana o 3, improves the accuracy of diagnosing cashew allergy, thereby circumventing the need for an oral food challenge (OFC) in some patients. METHODS: A population-based sample of 5276 children was recruited at age 1 year and followed up at age 6 years. Children with positive cashew skin prick test at age 6 underwent an OFC to clarify allergy status. Forty-seven children (mean age 5.02 ± 0.2) (33 cashew-allergic and 14 cashew-tolerant) had cashew sIgE and Ana o 3 sIgE quantified by ImmunoCAP System FEIA. RESULTS: A cutoff of >0.32 kUA/L for Ana o 3 sIgE provided 95% specificity and 90% sensitivity and correctly identified 90% of clinical cashew allergy. At the same specificity, the sensitivity for cashew sIgE (>8.5 kUA/L) was only 26%. Sequential measurement of cashew sIgE followed by Ana o 3 sIgE diagnosed 90% of children with cashew allergy without the need for an OFC. CONCLUSION: Ana o 3 sIgE testing provides higher diagnostic accuracy than cashew sIgE. Sequential measurement of cashew sIgE followed by Ana o 3 removed the need for a food challenge from 66% down to 12.8% (5-fold) of children compared with cashew sIgE testing alone.

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine could play a role in counteracting the rising prevalence of atopic diseases, through its beneficial off-target effects. We aimed to determine whether neonatal BCG vaccination reduces the incidence of eczema in infants. METHODS: Randomized controlled trial with 1272 infants allocated to receive BCG-Denmark or no BCG at birth. The primary outcome was the 12-month incidence of eczema based on 3-monthly questionnaires. Eczema was also assessed at a 12-month clinic visit. ClinicalTrial.gov: NCT01906853. RESULTS: The 12-month eczema incidence was 32.2% in the BCG group compared with 36.6% in the control group (adjusted risk difference (aRD) -4.3%, 95% CI -9.9% to 1.3%, multiple imputation model). In addition, comparing infants in the BCG group with the control group, 15.7% vs. 19.2% had eczema lesions at the 12-month visit (aRD -3.5%, 95% CI -8.0% to 1.0%); 35.7% vs. 39.0% reported using topical steroids (aRD -3.3, 95% CI -9.2 to 2.7); and 7.3% vs. 10.2% had severe eczema scores (aRD -3.0%, 95% CI -8.8% to 2.7%). In 344 high-risk infants (two atopic parents), the 12-month eczema incidence was 35.3% in the BCG group compared with 46.8% in the control group (aRD -11.5%, 95% CI -21.9% to -1.2%; number needed to treat 8.7, 95% CI 4.6 to 83.3). CONCLUSION: There is insufficient evidence to recommend neonatal BCG vaccination in all infants for the prevention of eczema in the first year of life; however, a modest beneficial effect was observed among high-risk infants. A single dose of BCG-Denmark soon after birth could reduce the incidence of eczema in infants with two atopic parents.

Early childhood is characterised by repeated infectious exposures that result in inflammatory responses by the innate immune system. In addition, this inflammatory response to infection is thought to contribute to the epidemiological evidence linking childhood infection and adult non-communicable diseases. Consequently, the relationship between innate immune responses and inflammation during early life may inform prevention of NCDs later in life. In adults, non-genetic host factors such as age, sex, and obesity, strongly impact cytokine production and circulating mediators, but data in children are lacking. Here, we assessed cytokine responses and inflammatory markers in a population of healthy preschool children (mean age 4.2 years). We studied associations between cytokines, plasma inflammatory markers and non-genetic host factors, such as sex, age, adiposity, season, and immune cell composition. Similar to adults, boys had a higher inflammatory response than girls, with IL-12p70 and IL-10 upregulated following TLR stimulation. Adiposity and winter season were associated with increased circulating inflammatory markers but not cytokine production. The inflammatory markers GlycA and hsCRP were positively associated with production of a number of cytokines and may therefore reflect innate immune function and inflammatory potential. This dataset will be informative for future prospective studies relating immune parameters to preclinical childhood NCD phenotypes.

BACKGROUND: The association between physical activity and adiposity in preschool-aged children is unclear. OBJECTIVE: To assess the cross-sectional association between objectively measured physical activity and body fat in preschool-aged children. METHODS: In the preschool review in an Australian birth cohort study (n = 1074), mean duration and time accumulated in ≥1-min bouts of physical activity at light-intensity (LPA), moderate- to vigorous-intensity (MVPA) and light- to vigorous-intensity (LMVPA) were computed from accelerometer (ActiGraph GT3X+) data. Percent body fat was assessed by bioelectrical impedance. Associations between physical activity and percent body fat were examined by multiple regression, adjusted for accelerometer wear time, MVPA (in analyses of LPA), maternal body mass index (BMI) and maternal education. RESULTS: A total of 450 participants (n = 450) had valid data. There was evidence of associations between physical activity and adiposity: each additional hour of LVPA was associated with 0.6% (CI95 -0.2%, 1.3%) higher body fat; ≥1-min bouts of LPA was associated with 1.0% (CI95 0.1%, 1.9%) higher body fat; each additional hour of MVPA was associated with -0.8% (CI95 -1.6%, -0.1%) less body fat; and ≥1-min bouts of MVPA was associated with -1.3% (CI95 -2.5%, -0.1%) body fat. CONCLUSIONS: Among a cohort of preschool-aged children, there was evidence that more intensive physical activity assessed by an accelerometer is associated with reduced body fat.

Understanding the predictors of progression from a first to a second demyelinating event (and formerly, a diagnosis of clinically definite multiple sclerosis) is important clinically. Previous studies have focused on predictors within a single domain, e.g. radiological, lacking prospective data across multiple domains. We tested a comprehensive set of personal, environmental, neurological, MRI and genetic characteristics, considered together, as predictors of progression from a first demyelinating event to clinically definite multiple sclerosis. Participants were aged 18-59 years and had a first demyelinating event during the study recruitment period (1 November 2003-31 December 2006) for the Ausimmune Study (n = 216) and had follow-up data to 2-3 years post-initial interview. Detailed baseline data were available on a broad range of demographic and environmental factors, MRI, and genetic and viral studies. Follow-up data included confirmation of clinically definite multiple sclerosis (or not) and changes in environmental exposures during the follow-up period. We used multivariable logistic regression and Cox proportional hazards regression modelling to test predictors of, and time to, conversion to clinically definite multiple sclerosis. On review, one participant had an undiagnosed event prior to study recruitment and was excluded (n = 215). Data on progression to clinically definite multiple sclerosis were available for 91.2% (n = 196); 77% were diagnosed as clinically definite multiple sclerosis at follow-up. Mean (standard deviation) duration of follow-up was 2.7 (0.7) years. The set of predictors retained in the best predictive model for progression from a first demyelinating event to clinically definite multiple sclerosis were as follows: younger age at first demyelinating event [adjusted odds ratio (aOR) = 0.92, 95% confidence interval (CI) = 0.87-0.97, per additional year of age); being a smoker at baseline (versus not) (aOR = 2.55, 95% CI 0.85-7.69); lower

BACKGROUND: Lipids play a vital role in health and disease, but changes to their circulating levels and the link with obesity remain poorly characterized in expecting mothers and their offspring in early childhood. METHODS: LC-MS/MS-based quantitation of 480 lipid species was performed on 2491 plasma samples collected at 4 time points in the mother-offspring Asian cohort GUSTO (Growing Up in Singapore Towards healthy Outcomes). These 4 time points constituted samples collected from mothers at 26-28 weeks of gestation (n=752) and 4-5 years postpartum (n=650), and their offspring at birth (n=751) and 6 years of age (n=338). Linear regression models were used to identify the pregnancy and developmental age-specific variations in the plasma lipidomic profiles, and their association with obesity risk. An independent birth cohort (n=1935), the Barwon Infant Study (BIS), comprising mother-offspring dyads of Caucasian origin was used for validation. RESULTS: Levels of 36% of the profiled lipids were significantly higher (absolute fold change > 1.5 and Padj < 0.05) in antenatal maternal circulation as compared to the postnatal phase, with phosphatidylethanolamine levels changing the most. Compared to antenatal maternal lipids, cord blood showed lower concentrations of most lipid species (79%) except lysophospholipids and acylcarnitines. Changes in lipid concentrations from birth to 6 years of age were much higher in magnitude (log2FC=-2.10 to 6.25) than the changes observed between a 6-year-old child and an adult (postnatal mother) (log2FC=-0.68 to 1.18). Associations of cord blood lipidomic profiles with birth weight displayed distinct trends compared to the lipidomic profiles associated with child BMI at 6 years. Comparison of the results between the child and adult BMI identified similarities in association with consistent trends (R2=0.75). However, large number of lipids were associated with BMI in adults (67%) compared to the children (29%). Pre-pregnancy BMI was specif

BACKGROUND: Preclinical studies have shown that maternal gut microbiota during pregnancy play a key role in prenatal immune development but the relevance of these findings to humans is unknown. The aim of this prebirth cohort study was to investigate the association between the maternal gut microbiota in pregnancy and the composition of the infant's cord and peripheral blood immune cells over the first year of life. METHODS: The Barwon Infant Study cohort (n=1074 infants) was recruited using an unselected sampling frame. Maternal fecal samples were collected at 36 weeks of pregnancy and flow cytometry was conducted on cord/peripheral blood collected at birth, 6 and 12 months of age. Among a randomly selected sub-cohort with available samples (n=293), maternal gut microbiota was characterized by sequencing the 16S rRNA V4 region. Operational taxonomic units (OTUs) were clustered based on their abundance. Associations between maternal fecal microbiota clusters and infant granulocyte, monocyte and lymphocyte subsets were explored using compositional data analysis. Partial least squares (PLS) and regression models were used to investigate the relationships/associations between environmental, maternal and infant factors, and OTU clusters. RESULTS: We identified six clusters of co-occurring OTUs. The first two components in the PLS regression explained 39% and 33% of the covariance between the maternal prenatal OTU clusters and immune cell populations in offspring at birth. A cluster in which Dialister, Escherichia, and Ruminococcus were predominant was associated with a lower proportion of granulocytes (p=0.002), and higher proportions of both central naïve CD4+ T cells (CD4+/CD45RA+/CD31-) (p<0.001) and naïve regulatory T cells (Treg) (CD4+/CD45RA+/FoxP3low) (p=0.02) in cord blood. The association with central naïve CD4+ T cells persisted to 12 months of age. CONCLUSION: This birth cohort study provides evidence consistent with past preclinical models that the maternal

INTRODUCTION: Probiotic and Peanut Oral Immunotherapy (PPOIT) is effective at inducing sustained unresponsiveness (SU) at end-of-treatment and this effect persists up to four years post-treatment, referred to as persistent SU. We sought to evaluate (i) how PPOIT altered peanut-specific humoral immune indices, and (ii) how such longitudinal indices relate to persistent SU. METHODS: Longitudinal serum/plasma levels of whole peanut- and peanut component- (Ara-h1, -h2, -h3, -h8, -h9) specific-IgE (sIgE) and specific-IgG4 (sIgG4) antibodies were measured by ImmunoCAP and salivary peanut-specific-IgA (sIgA) by ELISA in children (n=62) enrolled in the PPOIT-001 randomised trial from baseline (T0) to 4-years post-treatment (T5). Multivariate regression analyses of log-transformed values were used for point-in-time between group comparisons. Generalised estimating equations (GEE) were used for longitudinal comparisons between groups. RESULTS: PPOIT was associated with changes in sIgE and sIgG4 over time. sIgE levels were significantly reduced post-treatment [T5, PPOIT v.s. Placebo ratio of geometric mean (GM): Ara-h1 0.07, p=0.008; Ara-h2 0.08, p=0.007; Ara-h3 0.15, p=0.021]. sIgG4 levels were significantly increased by end-of-treatment (T1, PPOIT v.s. Placebo ratio of GM: Ara-h1 3.77, p=0.011; Ara-h2 17.97, p<0.001; Ara-h3 10.42, p<0.001) but levels in PPOIT group decreased once treatment was stopped and returned to levels comparable with Placebo group by T5. Similarly, salivary peanut sIgA increased during treatment, as early as 4 months of treatment (PPOIT v.s. Placebo, ratio of GM: 2.04, p=0.014), then reduced post-treatment. CONCLUSION: PPOIT was associated with broad reduction in peanut specific humoral responses which may mediate the clinical effects of SU that persists to 4-years post-treatment.

BACKGROUND: Australia has one of the highest prevalence of childhood food allergy in the world, but there are no data on its economic burden in Australia. METHODS: We used data from the HealthNuts study, a population-based longitudinal study undertaken in Melbourne, Australia. Infants were recruited at age 12 months between Sept 2007 and Aug 2011 with food allergy diagnosed using oral food challenges. Health care costs of out-of-hospital services were collected through data linkage to Australia's universal health insurance scheme Medicare. Two-part model was used to compare costs after controlling for potential confounders. RESULTS: 2919 children were included, and 390 (13.4%) had challenge-confirmed food allergy at age 1 year. Compared with children without food allergy, children with food allergy had significantly higher costs for GP visits, specialist visits, tests, and prescriptions in the first four years of life. The total Medicare cost associated with food allergy from age 1 to 4 years was estimated to be AUD$889.7 (95% CI $566.1-$1188.3) or €411.0 (95% CI €261.5-€549.0) per child. This was projected into an annual Medicare cost of AUD$26.1 million (95% CI $20.1-$32.3 million) or €12.1 (95% CI €9.3-€14.9 million) based on population size in 2020. CONCLUSIONS: Childhood food allergy causes considerable Medicare costs for out-of-hospital services in the first four years after birth in Australia. These findings can help anticipate the financial impact on the health care system associated with childhood food allergy, act as a useful costing resource for future evaluations, and inform management of childhood food allergy internationally.

Limited studies have been conducted to identify and validate multiple sclerosis (MS) genetic loci associated with disability progression. We aimed to identify MS genetic loci associated with worsening of disability over time, and to develop and validate ensemble genetic learning model(s) to identify people with MS (PwMS) at risk of future worsening. We examined associations of 208 previously established MS genetic loci with the risk of worsening of disability; we learned ensemble genetic decision rules and validated the predictions in an external dataset. We found 7 genetic loci (rs7731626: HR 0.92, P = 2.4 × 10-5; rs12211604: HR 1.16, P = 3.2 × 10-7; rs55858457: HR 0.93, P = 3.7 × 10-7; rs10271373: HR 0.90, P = 1.1 × 10-7; rs11256593: HR 1.13, P = 5.1 × 10-57; rs12588969: HR = 1.10, P = 2.1 × 10-10; rs1465697: HR 1.09, P = 1.7 × 10-128) associated with risk worsening of disability; most of which were located near or tagged to 13 genomic regions enriched in peptide hormones and steroids biosynthesis pathways by positional and eQTL mapping. The derived ensembles produced a set of genetic decision rules that can be translated to provide additional prognostic values to existing clinical predictions, with the additional benefit of incorporating relevant genetic information into clinical decision making for PwMS. The present study extends our knowledge of MS progression genetics and provides the basis of future studies regarding the functional significance of the identified loci.

BACKGROUND: In Western countries, Asian children have higher food allergy risk than Caucasian children. The early-life environmental exposures for this discrepancy are unclear. We aimed to compare prevalence of food allergy and associated risk factors between Asian children in Singapore and Australia. METHODS: We studied children in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) birth cohort (n = 878) and children of Asian ancestry in the HealthNuts cohort (n = 314). Food allergy was defined as a positive SPT ≥3 mm to egg or peanut AND either a convincing history of IgE-mediated reaction at 18 months (GUSTO) or a positive oral food challenge at 14-18 months (HealthNuts). Eczema was defined as parent-reported doctor diagnosis. RESULTS: Food allergy prevalence was 1.1% in Singapore and 15.0% in Australia (P<0.001). Egg introduction was more often delayed (>10 months) in Singapore (63.5%) than Australia (16.3%; P<0.001). Prevalence of early-onset eczema (<6 months) was lower in Singapore (8.4%) than Australia (30.5%) (P<0.001). Children with early-onset eczema were more likely to have food allergy than those without eczema in Australia [aOR 5.11 (2.34-11.14); P<0.001] and Singapore [aOR4.00 (0.62-25.8); P = 0.145]. CONCLUSIONS: Among Asian children, prevalence of early-onset eczema and food allergy was higher in Australia than Singapore. Further research with larger sample sizes and harmonized definitions of food allergy between cohorts is required to confirm and extend these findings. Research on environmental factors influencing eczema onset in Australia and Singapore may aid understanding of food allergy pathogenesis in different parts of the world.