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Once called a "classically non-describable two-valuedness" by Pauli , the electron spin is a natural resource for long-lived quantum information since it is mostly impervious to electric fluctuations and can be replicated in large arrays using silicon quantum dots, which offer high-fidelity control. Paradoxically, one of the most convenient control strategies is the integration of nanoscale magnets to artificially enhance the coupling between spins and electric field, which in turn hampers the spin's noise immunity and adds architectural complexity. Here we demonstrate a technique that enables a \emph{switchable} interaction between spins and orbital motion of electrons in silicon quantum dots, without the presence of a micromagnet. The naturally weak effects of the relativistic spin-orbit interaction in silicon are enhanced by more than three orders of magnitude by controlling the energy quantisation of electrons in the nanostructure, enhancing the orbital motion. Fast electrical control is demonstrated in multiple devices and electronic configurations, highlighting the utility of the technique. Using the electrical drive we achieve coherence time $T_{2,{\rm Hahn}}\approx50 \mu$s, fast single-qubit gates with ${T_{\pi/2}=3}$ ns and gate fidelities of 99.93 % probed by randomised benchmarking. The higher gate speeds and better compatibility with CMOS manufacturing enabled by on-demand electric control improve the prospects for realising scalable silicon quantum processors.

Aims To examine associations of assisted reproductive technology (ART) conception (vs. natural conception: NC) with offspring cardiometabolic health outcomes and whether these differ with age. Methods and results Differences in systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR), lipids, and hyperglycaemic/insulin resistance markers were examined using multiple linear regression models in 14 population-based birth cohorts in Europe, Australia, and Singapore, and results were combined using meta-analysis. Change in cardiometabolic outcomes from 2 to 26 years was examined using trajectory modelling of four cohorts with repeated measures. 35 938 (654 ART) offspring were included in the meta-analysis. Mean age ranged from 13 months to 27.4 years but was Conclusion These findings of small and statistically non-significant differences in offspring cardiometabolic outcomes should reassure people receiving ART. Longer-term follow-up is warranted to investigate changes over adulthood in the risks of hypertension, dyslipidaemia, and preclinical and clinical cardiovascular disease.

Objective: To evaluate whether characterization of maternal and foetoplacental factors beyond birthweight can enable early identification of children at risk of developing prehypertension/hypertension. Methods: We recruited 693 mother-offspring dyads from the GUSTO prospective mother-offspring cohort. Prehypertension/hypertension at age 6 years was identified using the simplified paediatric threshold of 110/70mmHg. We evaluated the associations of pregnancy complications (gestational diabetes, excessive/inadequate gestational weight gain, hypertensive disorders of pregnancy), foetal growth deceleration (decline in foetal abdominal circumference at least 0.67 standard deviations between second and third trimesters), high foetoplacental vascular resistance (third trimester umbilical artery systolic-to-diastolic ratio ≥90th centile), preterm birth, small-for-gestational age and neonatal kidney volumes with risk of prehypertension/hypertension at age 6 years, after adjusting for sex, ethnicity, maternal education and prepregnancy BMI. Results: Pregnancy complications, small-for-gestational age, preterm birth, and low neonatal kidney volume were not associated with an increased risk of prehypertension/hypertension at age 6 years. In contrast, foetal growth deceleration was associated with a 72% higher risk [risk ratio (RR) ¼ 1.72, 95% confidence interval (CI) 1.18-2.52]. High foetoplacental vascular resistance was associated with a 58% higher risk (RR ¼ 1.58, 95% CI 0.96-2.62). Having both these characteristics, relative to having neither, was associated with over two-fold higher risk (RR ¼ 2.55, 95% CI 1.26-5.16). Over 85% of the foetuses with either of these characteristics were born appropriate or large for gestational age. Conclusion: Foetal growth deceleration and high foetoplacental vascular resistance may be helpful in prioritizing high-risk children for regular blood pressure monitoring and preventive interventions, across the birthweight spectrum.

The International Journal of Epidemiology (IJE) Education Corner was introduced in 2012, providing educational articles on epidemiological concepts and methods. We conducted a survey of the use and impact of the IJE Education Corner articles in relation to teaching, research and practice, collating suggestions on how we might increase their utility.

BACKGROUND: Previous studies focusing on the association between gestational diabetes and breastfeeding duration have been inconclusive. OBJECTIVES: We aimed to determine whether maternal gestational hyperglycemia is associated with the duration of breastfeeding and the concentrations of markers linked to breastmilk production. METHODS: Data from the prospective, multiethnic Growing Up in Singapore Towards Healthy Outcomes study were used to assess the association of fasting plasma glucose (FPG) and 2-h postglucose challenge (2hPG) measured at 26-28 wk of gestation with duration of breastfeeding and concentrations of protein, lactose, citrate, sodium, potassium, and zinc in breastmilk 3 wk postpartum. RESULTS: Of the 1035 participants, 5.2% and 9.5% had elevated FPG and 2hPG, respectively, consistent with a diagnosis of gestational diabetes mellitus based on International Association of Diabetes and Pregnancy Study Groups criteria. FPG ≥5.1 mmol/L was associated with a crude reduction in median breastfeeding duration of 2.3 mo. In a model adjusted for maternal prepregnancy BMI and intention to breastfeed, FPG ≥5.1 mmol/L predicted earlier termination of any breastfeeding (adjusted HR: 1.47; 95% CI: 1.04, 2.08) but not full breastfeeding (adjusted HR: 1.08; 0.76, 1.55). 2hPG ≥8.5 mmol/L was not significantly associated with the durations of any (adjusted HR: 0.86; 95% CI: 0.62, 1.19) or full (adjusted HR: 0.85; 95% CI: 0.62, 1.18) breastfeeding. Maternal FPG was significantly and positively associated with breastmilk sodium (adjusted coefficient: 1.28; 95% CI: 1.08, 1.51) and sodium-to-potassium ratio (adjusted coefficient: 1.29; 95% CI: 1.08, 1.54) but not with other measured breastmilk components. CONCLUSIONS: Women with FPG ≥5.1 mmol/L during pregnancy breastfeed for a shorter duration. Future work involving measurement of milk production is needed to determine whether low milk production predicts breastfeeding duration among women with elevated FPG. This trial was registered at www.clinicaltrials.gov as NCT01174875.

Context An inverse relationship between brown adipose tissue (BAT) and obesity has previously been reported in older children and adults but is unknown in young children. Objective We investigated the influence of BAT in thermoneutral condition on adiposity and metabolic profile in Asian preschool children. Design, Setting, and Participants A total of 198 children aged 4.5 years from a prospective birth cohort study, Growing Up in Singapore Towards Healthy Outcomes (GUSTO) were successfully studied with water-fat magnetic resonance imaging of the supraclavicular and axillary fat depot (FDSA). Regions within FDSA with fat-signal-fraction between 20% and 80% were considered BAT, and percentage BAT (%BAT; 100*BAT volume/ FDSA volume) was calculated. Main Outcome Measures Abdominal adipose tissue compartment volumes, ectopic fat in the soleus muscle and liver, fatty liver index, metabolic syndrome scores, and markers of insulin sensitivity. Results A 1% unit increase in %BAT was associated with lower body mass index, difference (95% CI), −0.08 (−0.10, −0.06) kg/m2 and smaller abdominal adipose tissue compartment volumes. Ethnicity and sex modified these associations. In addition, each unit increase in %BAT was associated with lower ectopic fat at 4.5 years in the liver, −0.008% (−0.013%, −0.003%); soleus muscle, −0.003% (−0.006%, −0.001%) of water content and lower fatty liver index at 6 years. Conclusions Higher %BAT is associated with a more favorable metabolic profile. BAT may thus play a role in the pathophysiology of obesity and related metabolic disorders. The observed ethnic and sex differences imply that the protective effect of BAT may vary among different groups.

Recent studies of silicon spin qubits at temperatures above 1 K are encouraging demonstrations that the cooling requirements for solid-state quantum computing can be considerably relaxed. However, qubit readout mechanisms that rely on charge sensing with a single-island single-electron transistor (SISET) quickly lose sensitivity due to thermal broadening of the electron distribution in the reservoirs. Here we exploit the tunneling between two quantized states in a double-island single-electron transistor (SET) to demonstrate a charge sensor with an improvement in the signal-to-noise ratio by an order of magnitude compared to a standard SISET, and a single-shot charge readout fidelity above 99% up to 8 K at a bandwidth greater than 100 kHz. These improvements are consistent with our theoretical modeling of the temperature-dependent current transport for both types of SETs. With minor additional hardware overhead, these sensors can be integrated into existing qubit architectures for a high-fidelity charge readout at few-kelvin temperatures.

PURPOSE: There is altered breastmilk composition among mothers with gestational diabetes and conflicting evidence on whether breastfeeding is beneficial or detrimental to their offspring’s cardiometabolic health. We aimed to investigate associations between breastfeeding and offspring’s cardiometabolic health across the range of gestational glycemia. METHODS: We included 827 naturally-conceived, term singletons from a prospective mother-child cohort. We measured gestational (26-28weeks) fasting plasma glucose (FPG) and 2-hour plasma glucose (2hrPG) after an oral glucose tolerance test as continuous variables. Participants were classified into 2 breastfeeding categories (high/intermediate vs. low) according to their breastfeeding duration and exclusivity. Main outcome measures included magnetic resonance imaging (MRI)-measured abdominal fat, intramyocellular lipids (IMCL), and liver fat, quantitative magnetic resonance (QMR)-measured body fat mass, blood pressure, blood lipids, and insulin resistance at 6 years old (all continuous variables). We evaluated if gestational glycemia (FPG & 2hrPG) modified the association of breastfeeding with offspring outcomes after adjusting for confounders using a multiple linear regression model that included a ‘gestational glycemia x breastfeeding’ interaction term. RESULTS: With increasing gestational FPG, high/intermediate (vs. low) breastfeeding was associated with lower levels of IMCL (p-interaction=0.047), liver fat (p-interaction=0.033), and triglycerides (p-interaction=0.007), after adjusting for confounders. Specifically, at 2 standard deviations above the mean gestational FPG level, high/intermediate (vs. low) breastfeeding was linked to lower adjusted mean IMCL (0.39% of water signal [0.29,0.50] vs. 0.54% of water signal [0.46,0.62]), liver fat (0.39% by weight [0.20,0.58] vs. 0.72% by weight [0.59,0.85]), and triglycerides (0.62mmol/L [0.51,0.72] vs. 0.86mmol/L [0.75,0.97]). 2hrPG did not significantly modify the association between breastfeeding and childhood cardiometabolic risk. CONCLUSION: Our findings suggest breastfeeding may confer protection against adverse fat partitioning and higher triglyceride concentration among children exposed to increased glycemia in utero.

Background Exploratory null-hypothesis significance testing (e.g. GWAS, EWAS) form the backbone of molecular epidemiology, however methods to identify true causal signals are underdeveloped. Via plasmode simulation, I evaluate two approaches to quantitatively control for shared unmeasured confounding and recover unbiased effects using complementary epigenomes and biologically-informed structural assumptions. Methods I adapt proposed negative control-based estimators, the control outcome calibration approach (COCA) and proximal g-computation (PG) to case studies in perinatal molecular epidemiology. COCA may be employed when maternal epigenome has no direct effects on phenotype and proxy shared unmeasured confounders and PG further with suitable genetic instruments (e.g. mQTLs). Baseline covariates were extracted from 777 mother-child pairs in a birth cohort with maternal blood and fetal cord DNA methylation array data. Treatment and outcome values were simulated in 2000 bootstraps. Bootstrapped, ordinary (COCA) and 2-stage (PG) least squares were fitted to estimate treatment effects and standard errors under various common settings of missing confounders (e.g. paternal data). Doubly-robust, machine learning estimators were explored. Results COCA and PG performed well in simplistic data generating processes. However, in real-world cohort simulations, COCA performed acceptably only in settings with strong proxy confounders, but otherwise poorly (median bias 610%; coverage 29%). PG performed slightly better. Alternatively, simple covariate adjustment for maternal methylation outperformed (median bias 22%; 71% coverage) COCA, PG, and machine learning estimators. Discussion Molecular epidemiology provides key opportunity to leverage biological knowledge against unmeasured confounding. Negative control calibration or adjustments may help under limited scenarios where assumptions are fulfilled, but should be tested with suitable simulations. Key messages Quantitative approaches for unmeasured confounding in molecular epidemiology are a critical gap. Negative control calibration or adjustment may help under limiting scenarios. Proposed estimators should be tested in simulation settings that closely mimic target data.

Randomised controlled trials in reproductive medicine are often subject to outcome truncation, where study outcomes are only defined in a subset of participants. Examples include birthweight (measurable only in the subgroup of participants who give birth) and miscarriage (which can only occur in participants who become pregnant). These are typically analysed by making a comparison between treatment arms within the subgroup (comparing birthweights in the subgroup who gave birth, or miscarriages in the subgroup who became pregnant). However, this approach does not represent a randomised comparison when treatment influences the probability of being observed (i.e. survival). The practical implications of this for reproductive trials are unclear. We developed a simulation platform to investigate the implications of outcome truncation for reproductive medicine trials. We used this to perform a simulation study, in which we considered the bias, Type 1 error, coverage, and precision of standard statistical analyses for truncated continuous and binary outcomes. Increasing treatment effect on the intermediate variable, strength of confounding between the intermediate and outcome variables, and interactions between treatment and confounder were found to adversely affect performance. However, within parameter ranges we would consider to be more realistic, the adverse effects were generally not drastic. For binary outcomes, the study highlighted that outcome truncation may lead to none of the participants in a study arm experiencing the outcome event. This was found to have severe consequences for inferences, and this may have implications for meta-analysis., Comment: 63 pages (including supplementary files). 49 Figures (7 in main document, 42 supplementary figures). Code available at, https://osf.io/gzqbr/

An error-corrected quantum processor will require millions of qubits, accentuating the advantage of nanoscale devices with small footprints, such as silicon quantum dots. However, as for every device with nanoscale dimensions, disorder at the atomic level is detrimental to quantum dot uniformity. Here we investigate two spin qubits confined in a silicon double quantum dot artificial molecule. Each quantum dot has a robust shell structure and, when operated at an occupancy of 5 or 13 electrons, has single spin-\documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$\frac{1}{2}$$\end{document}12 valence electron in its p- or d-orbital, respectively. These higher electron occupancies screen static electric fields arising from atomic-level disorder. The larger multielectron wavefunctions also enable significant overlap between neighbouring qubit electrons, while making space for an interstitial exchange-gate electrode. We implement a universal gate set using the magnetic field gradient of a micromagnet for electrically driven single qubit gates, and a gate-voltage-controlled inter-dot barrier to perform two-qubit gates by pulsed exchange coupling. We use this gate set to demonstrate a Bell state preparation between multielectron qubits with fidelity 90.3%, confirmed by two-qubit state tomography using spin parity measurements., Multielectron quantum dots offer a promising platform for high-performance spin qubits; however, previous demonstrations have been limited to single-qubit operation. Here, the authors report a universal gate set and two-qubit Bell state tomography in a high-occupancy double quantum dot in silicon.

The Singapore Preconception Study of Long-Term Maternal and Child Outcomes (S-PRESTO) is a preconception, longitudinal cohort study that aims to study the effects of nutrition, lifestyle, and maternal mood prior to and during pregnancy on the epigenome of the offspring and clinically important outcomes including duration of gestation, fetal growth, metabolic and neural phenotypes in the offspring. Between February 2015 and October 2017, the S-PRESTO study recruited 1039 Chinese, Malay or Indian (or any combinations thereof) women aged 18 to 45 years and who intended to get pregnant and deliver in Singapore, resulting in 1032 unique participants and 373 children born in the cohort. The participants were followed up for 3 visits during the preconception phase and censored at 12 months of follow up if pregnancy was not achieved (N=557 censored). Women who successfully conceived (N=475) were characterised at gestational weeks 6-8, 11-13, 18-21, 24-26, 27-28 and 34-36. Follow up of their index offspring (N=373 singletons) is on-going at birth, 1, 3 and 6 weeks, 3, 6, 12, 18, 24 and 36 months and beyond. Women are also being followed up post-delivery. Data is collected via interviewer-administered questionnaires, metabolic imaging (magnetic resonance imaging), standardized anthropometric measurements and collection of diverse specimens, i.e. blood, urine, buccal smear, stool, skin tapes, epithelial swabs at numerous timepoints. S-PRESTO has extensive repeated phenotypic data collected which include genetic and epigenetic sampling from preconception which is unique in mother-offspring epidemiological cohorts This enables prospective assessment of a wide array of potential determinants of future health outcomes in women from preconception to post-delivery and in their offspring across the earliest development from embryonic stages into early childhood. In addition the S-PRESTO study, draws from the three major Asian ethnic groups that represent 50% of the global population, increasing the relevance of its findings to global efforts to address non-communicable diseases.

Background Maternal obesity increases the risk of adverse long-term health outcomes in mother and child including childhood obesity. We aimed to investigate the association between interpregnancy weight gain between first and second pregnancies and risk of overweight and obesity in the second child. Methods We analysed the healthcare records of 4789 women in Hampshire, UK with their first two singleton live births within a population-based anonymised linked cohort of routine antenatal records (August 2004 and August 2014) with birth/early life data for their children. Measured maternal weight and reported height were recorded at the first antenatal appointment of each pregnancy. Measured child height and weight at 4–5 years were converted to age- and sex-adjusted body mass index (BMI z-score). Log-binomial regression was used to examine the association between maternal interpregnancy weight gain and risk of childhood overweight and obesity in the second child. This was analysed first in the whole sample and then stratified by baseline maternal BMI category. Results The prevalence of overweight/obesity in the second child was 19.1% in women who remained weight stable, compared with 28.3% in women with ≥3 kg/m2 weight gain. Interpregnancy gain of ≥3 kg/m2 was associated with increased risk of childhood overweight/obesity (adjusted relative risk (95% CI) 1.17 (1.02–1.34)), with attenuation on adjusting for birthweight of the second child (1.08 (0.94–1.24)). In women within the normal weight range at first pregnancy, the risks of childhood obesity (≥95th centile) were increased with gains of 1–3 kg/m2 (1.74 (1.07–2.83)) and ≥3 kg/m2 (1.87 (1.18–3.01)). Conclusion Children of mothers within the normal weight range in their first pregnancy who started their second pregnancy with a considerably higher weight were more likely to have obesity at 4–5 years. Supporting return to pre-pregnancy weight and limiting weight gain between pregnancies may achieve better long-term maternal and offspring outcomes.

Context Cardiometabolic profiles of different body composition phenotypes are poorly characterized in young children, where it is well established that high adiposity is unfavorable, but the role of lean mass is unclear. Objective We hypothesized that higher lean mass attenuates cardiometabolic risk in children with high fat mass. Methods In 6-year-old children (n = 377) from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) prospective birth cohort, whole-body composition was measured by quantitative magnetic resonance, a novel validated technology. Based on fat mass index (FMI) and lean mass index (LMI), 4 body composition phenotypes were derived: low FMI-low LMI (LF-LL), low FMI-high LMI (LF-HL), high FMI-low LMI (HF-LL), high FMI-high LMI (HF-HL). Main Outcome Measures Body mass index (BMI) z-score, fasting plasma glucose, insulin resistance, metabolic syndrome risk score, fatty liver index, and blood pressure Results Compared with the LF-HL group, children in both high FMI groups had increased BMI z-score (HF-HL: 1.43 units 95% CI [1.11,1.76]; HF-LL: 0.61 units [0.25,0.96]) and metabolic syndrome risk score (HF-HL: 1.64 [0.77,2.50]; HF-LL: 1.28 [0.34,2.21]). The HF-HL group also had increased fatty liver index (1.15 [0.54,1.77]). Girls in HF-HL group had lower fasting plasma glucose (–0.29 mmol/L [–0.55,–0.04]) and diastolic blood pressure (–3.22 mmHg [–6.03,–0.41]) than girls in the HF-LL group. No similar associations were observed in boys. Conclusion In a multi-ethnic Asian cohort, lean mass seemed to protect against some cardiometabolic risk markers linked with adiposity, but only in girls. The FMI seemed more important than lean mass index in relation to cardiometabolic profiles of young children.

Background Using longitudinal ultrasounds as an improved fetal growth marker, we aimed to investigate if fetal growth deceleration followed by rapid postnatal weight gain is associated with childhood cardiometabolic risk biomarkers in a contemporary well-nourished population. Methods We defined fetal growth deceleration (FGD) as ultrasound-measured 2nd-3rd-trimester abdominal circumference decrease by ≥0.67 standard deviation score (SDS) and rapid postnatal weight gain (RPWG) as 0–2-year-old weight increase by ≥0.67 SDS. In the GUSTO mother-offspring cohort, we grouped 797 children into four groups of FGD-only (14.2%), RPWG-only (23.3%), both (mismatch, 10.7%) or neither (reference, 51.8%). Adjusting for confounders and comparing with the reference group, we tested associations of these growth groups with childhood cardiometabolic biomarkers: magnetic resonance imaging (MRI)-measured abdominal fat (n = 262), liver fat (n = 216), intramyocellular lipids (n = 227), quantitative magnetic resonance-measured overall body fat % (BF%) (n = 310), homeostasis model assessment of insulin resistance (HOMA-IR) (n = 323), arterial wall thickness (n = 422) and stiffness (n = 443), and blood pressure trajectories (ages 3–6 years). Results Mean±SD birthweights were: FGD-only (3.11 ± 0.38 kg), RPWG-only (3.03 ± 0.37 kg), mismatch (2.87 ± 0.31 kg), reference (3.30 ± 0.36 kg). FGD-only children had elevated blood pressure trajectories without correspondingly increased BF%. RPWG-only children had altered body fat partitioning, higher BF% [BF = 4.26%, 95% confidence interval (CI) (2.34, 6.19)], HOMA-IR 0.28 units (0.11, 0.45)] and elevated blood pressure trajectories. Mismatch children did not have increased adiposity, but had elevated ectopic fat, elevated HOMA-IR [0.29 units (0.04,0.55)] and the highest blood pressure trajectories. Associations remained even after excluding small-for-gestational-age infants from analyses. Conclusions Fetal growth deceleration coupled with rapid postnatal weight gain was associated with elevated childhood cardiometabolic risk biomarkers without correspondingly increased BF%.

Background Pyrethroids are the most widely used insecticides globally for domestic, agricultural, and malaria vector control. In 10 countries, dichlorodiphenyl trichloroethane (DDT) is also used for the latter. Thus, high exposure to pyrethroids and DDT have been reported among women and children from rural and/or malaria-endemic areas. Experimental studies suggest that fetal exposure to pyrethroids, particularly cypermethrin, and DDT may have sex-specific growth effects. However, epidemiologic investigations are scarce and inconsistent and have not considered postnatal environment or susceptibility factors. Methods In 665 mother-child dyads participating in the Venda Health Examination of Mothers, Babies, and their Environment (VHEMBE), a rural South African birth cohort with high insecticide exposure, we examined associations of maternal peripartum uri-nary pyrethroid metabolites and serum DDT concentrations with child anthropometrics at 3.5 years using multivariable linear regression. We investigated effect modification by child sex, maternal nutrition and HIV status, and household poverty. Results Pyrethroid metabolites cis-3-(2,2-dibromovinyl)-2,2-dimethyl-cyclopropane carboxylic acid (cis-DBCA), cis-3-(2,2,-dicholorvinyl)-2,2-dimethyl-cyclopropane carboxylic acid (cis-DCCA), trans-DCCA, and 3-phenoxybenzoic acid (3-PBA) were quantified in nearly all mothers. A 10-fold increase in cis-DCCA concentration was associated with 0.21 kg/m2 lower body mass index (95% confidence interval = -0.41, -0.01), with similar estimates for other cypermethrin or permethrin metabolites (trans-DCCA and 3-phenoxybenzoic acid). In stratified analyses, stronger associations were observed with lower weight, body mass index, arm circumference, and weight-for-height among boys relative to girls. Associations with cis-3-(2,2-dibromovinyl)-2,2-dimethyl-cyclopropane carboxylic acid, a metabolite specific to deltamethrin, were weaker or absent. No substantial associations were observed with DDT. Discussion In a population with ubiquitous pyrethroid exposure, maternal concentrations of metabolites of cypermethrin and permethrin were associated with thinness at 3.5 years.

Contains fulltext : 225413.pdf (Publisher’s version ) (Closed access) Despite development of new technologies for caries control, tooth decay in primary teeth remains a major global health problem. Caries risk assessment (CRA) models for toddlers and preschoolers are rare. Among them, almost all models use dental factors (e.g., past caries experience) to predict future caries risk, with limited clinical/community applicability owing to relatively uncommon dental visits compared to frequent medical visits during the first year of life. The objective of this study was to construct and evaluate risk prediction models using information easily accessible to medical practitioners to forecast caries at 2 and 3 y of age. Data were obtained from the Growing Up in Singapore Towards Healthy Outcomes (GUSTO) mother-offspring cohort. Caries was diagnosed using modified International Caries Detection and Assessment System criteria. Risk prediction models were constructed using multivariable logistic regression coupled with receiver operating characteristic analyses. Imputation was performed using multiple imputation by chained equations to assess effect of missing data. Caries rates at ages 2 y (n = 535) and 3 y (n = 721) were 17.8% and 42.9%, respectively. Risk prediction models predicting overall caries risk at 2 and 3 y demonstrated area under the curve (AUC) (95% confidence interval) of 0.81 (0.75-0.87) and 0.79 (0.74-0.84), respectively, while those predicting moderate to extensive lesions showed 0.91 (0.85-0.97) and 0.79 (0.73-0.85), respectively. Postimputation results showed reduced AUC of 0.75 (0.74-0.81) and 0.71 (0.67-0.75) at years 2 and 3, respectively, for overall caries risk, while AUC was 0.84 (0.76-0.92) and 0.75 (0.70-0.80), respectively, for moderate to extensive caries. Addition of anterior caries significantly increased AUC in all year 3 models with or without imputation (all P < 0.05). Significant predictors/protectors were identified, including ethnicity, prenatal tobacco smoke exposure, history of allergies before 12 mo, history of chronic maternal illness, maternal brushing frequency, childbearing age, and so on. Integrating oral-general health care using medical CRA models may be promising in screening caries-susceptible infants/toddlers, especially when medical professionals are trained to "lift the lip" to identify anterior caries lesions.

Assisted reproductive technologies (ART) are increasingly used, however little is known about the long-term health of ART-conceived offspring. Weak selection of comparison groups and poorly characterized mechanisms impede current understanding. In a prospective cohort (Growing Up in Singapore Towards healthy Outcomes; GUSTO; Clinical Trials ID: NCT01174875) including 83 ART-conceived and 1095 spontaneously-conceived singletons, we estimate effects of ART on anthropometry, blood pressure, serum metabolic biomarkers, and cord tissue DNA methylation by emulating a pragmatic trial supported by machine learning-based estimators. We find ART-conceived children to be shorter (−0.5 SD [95% CI: −0.7, −0.2]), lighter (−0.6 SD [−0.9, −0.3]) and have lower skinfold thicknesses (e.g. −14% [−24%, −3%] suprailiac), and blood pressure (−3 mmHg [−6, −0.5] systolic) at 6-6.5 years, with no strong differences in metabolic biomarkers. Differences are not explained by parental anthropometry or comorbidities, polygenic risk score, breastfeeding, or illnesses. Our simulations demonstrate ART is strongly associated with lower NECAB3 DNA methylation, with negative control analyses suggesting these estimates are unbiased. However, methylation changes do not appear to mediate observed differences in child phenotype., Huang and colleagues used machine-learning estimators to analyse a broad range of parameters in a prospective cohort consisting ART and spontaneously conceived children. Small differences in stature and growth could not be explained by parental or perinatal environment factors, nor differences in fetal DNA methylation. No strong differences in metabolic parameters were seen.

Studies investigating the associations between exposure of young men to polybrominated diphenyl ethers (PBDEs) or phthalates and hormone levels or semen quality have produced inconsistent results. Our goal was to investigate the association of exposure to PBDEs or phthalate metabolites with changes in markers of thyroid (TSH, free T3 and free T4) and reproductive function (sperm concentrations, motility, and quality; serum LH and testosterone) in 153 healthy young men from the greater Montreal area. Using covariate-adjusted models, we found that each 10-fold increase in BDE-47 was associated with lower TSH levels (−17.3%; 95% CI: −31.5, 0.0; p = 0.05). BDE-47 exposure was also associated with a decrease in sperm concentration (−19.7%; 95% CI: −36.8; 2.0; p = 0.07) and motility (−25.5%; 95% CI: −44.5, 0.1; p = 0.05). Trends towards decreases in these parameters were also observed in association with exposure to BDE-100 and the sum of BDE-47, -99, and -100 (∑3BDEs). These associations were not accompanied by effects on sperm chromatin quality, as assessed with the HT-COMET assay. There were no substantial associations between urinary phthalate metabolite concentrations, either individually or grouped by molecular weight or parent compound, and sperm quality parameters; however, there was a positive association between elevated MECCP and free T4 (0.98; 95% CI: 0.02, 1.94; p = 0.05). Inverse associations between BDE-47 and ∑3BDEs and free T3 and positive associations between MEHP and free T3 were stronger among individuals with BMI ≥ 25, suggesting that weight status may modify the effects of these endocrine disrupting chemicals. Keywords: PBDE, Phthalate, Thyroid, Reproduction, Endocrine disruption, Sperm quality

BACKGROUND Maternal education in a child's early life may directly affect the child's adult cardiometabolic health, but this is difficult to disentangle from biological, social, and behavioral life course processes that are associated with maternal education. These processes may also differ between males and females. METHODS Using data from the National Longitudinal Study of Adolescent to Adult Health (1995-2009) (N = 4,026 females and 3,192 males), we estimated sex-stratified associations between maternal attainment of less than high school (

Aim: To investigate the role of maternal gestational weight gain (GWG) and prepregnancy BMI on programming offspring DNA methylation. Methods: Among 589 adult (age = 32) women participants of the Jerusalem Perinatal Study, we quantified DNA methylation in five candidate genes. We used inverse probability-weighting and parametric g-formula to estimate direct effects of maternal prepregnancy BMI and GWG on methylation. Results: Higher maternal GWG, but not prepregnancy BMI, was inversely related to offspring ABCA1 methylation (β = -1.1% per quartile; 95% CI: -2.0, -0.3) after accounting for ancestry, parental and offspring exposures. Total and controlled direct effects were nearly identical suggesting included offspring exposures did not mediate this relationship. Results were robust to sensitivity analyses for missing data and model specification. Conclusion: We find some support for epigenetic programming and highlight strengths and limitations of these methods relative to other prevailing approaches.

Recently, ethicists have posited that consideration of epigenetic mechanisms presents novel challenges to concepts of justice and equality of opportunity, such as elevating the importance of environments in bioethics and providing a counterpoint to gross genetic determinism. We argue that new findings in epigenetic sciences, including those regarding intergenerational health effects, do not necessitate reconceptualization of theories of justice or the environment. To the contrary, such claims reflect a flawed understanding of epigenetics and its relation to genetics that may unintentionally undermine appeals to social justice. We provide a brief summary of epigenetic sciences, focusing on phenomena central to the current ethical discourse. We identify three fallacious modes of reasoning arising from the emergent literature on the ethical and policy implications of epigenetics, including mischaracterization, undue extrapolation, and exceptionalism. We end by discussing how these issues may work against mobilizing health equity policies and present a more modest claim regarding the value of new epigenetic knowledge to health justice by setting this discourse within the context of known themes in biomedical ethics and health policy.

BackgroundIndoor residual spraying (IRS) of insecticides, conducted in low- and middle-income countries to control malaria, may result in high exposure to dichlorodiphenyltrichloroethane (DDT), its breakdown product dichlorodiphenyldichloroethylene (DDE), or pyrethroids. Animal studies suggest in utero exposure to these chemicals may increase childhood infection frequency.ObjectivesWe investigated associations between maternal DDT/E and pyrethroid metabolite concentration and child infection associations in an IRS setting in which susceptibility factors are common and infections are leading causes of child morbidity and mortality.MethodsUsing gas chromatography-mass spectrometry, we measured serum DDT/E and urinary pyrethroid metabolite concentrations in peripartum samples from 674 women participating in the Venda Health Examination of Mother, Babies and their Environment (VHEMBE) study. Counts of persistent child fevers, otitis media, and severe sore throat between 1 and 2 y of age were ascertained from maternal interviews. Associations between DDT/E and pyrethroid metabolite concentrations and infections were estimated using zero-inflated Poisson regression. We estimated relative excess risks due to interaction (RERI) with poverty, maternal energy intake, and maternal HIV status.ResultsConcentrations of DDT/E, particularly p,p'-DDE, were associated with higher rates of persistent fevers [IRR=1.21 (95% CI: 1.01, 1.46)], for a 10-fold increase in p,p'-DDE). This association was stronger among children from households below versus above the South African food poverty line [IRR=1.31 (95% CI: 1.08, 1.59) vs. IRR=0.93 (95% CI: 0.69, 1.25), respectively] and for children whose mothers had insufficient versus sufficient caloric intake during pregnancy [IRR=1.30 (95% CI: 1.07, 1.58) vs. IRR=0.96 (95% CI: 0.72, 1.28), respectively].ConclusionsIn utero IRS insecticide exposure may increase childhood infection rates. This was particularly apparent among children from poorer households or whose mothers had low energy intake during pregnancy. https://doi.org/10.1289/EHP2657.

BackgroundRoad traffic deaths are a substantial barrier to population health improvement in low-income and middle-income countries (LMICs). In South Africa, the road-traffic injury mortality (RTM) rate of 27 per 100 000 population is twice the global average, over 60% of which are alcohol-related. Recent US studies suggest the Uber ride-sharing service may reduce alcohol-related RTM, however RTM burden in the USA is relatively low and transport behaviours differ from LMICs.MethodsUsing certification data from all deaths occurring in South Africa in the years 2010–2014 (n=2 498 216), we investigated the relative change in weekly road traffic-related death counts between provinces which received Uber services (beginning in 2013) against those that did not using a difference-in-differences approach.ResultsWeekly road traffic-related deaths in provinces with Uber were lower following Uber introduction than in comparison provinces without Uber. The effect size was larger in the province which had Uber the longest (Gauteng) and among young adult males (aged 17–39 years). However, the absolute effects were very small (ConclusionsOverall, findings did not support either an increase or large decrease in province-level road traffic-related deaths associated with Uber introduction to South Africa. More localised investigations in South Africa and other LMICs are needed.

Background: Racial/ethnic disparities in preterm birth (PTB) are well documented in the epidemiological literature, but little is known about the relative contribution of different social and environmental determinants of such disparities in birth outcome. Furthermore, increased focus has recently turned toward modifiable aspects of the environment, including physical characteristics, such as neighborhood air pollution, to reduce disparities in birth outcomes. Objectives: To apply decomposition methods to understand disparities in preterm birth (PTB) prevalence between births of non-Hispanic black individuals and births of non-Hispanic white individuals in California, according to individual demographics, neighborhood socioeconomic environment, and neighborhood air pollution. Methods: We used all live singleton births in California spanning 2005 to 2010 and estimated PTBs and other adverse birth outcomes for infants borne by non-Hispanic black mothers and white mothers. To compare individual-level, neighborhood-level, and air pollution [Particulate Matter, 2.5 micrometers or less (PM2.5) and nitrogen dioxide (NO2)] predictors, we conducted a nonlinear extension of the Blinder–Oaxaca method to decompose racial/ethnic disparities in PTB. Results: The predicted differences in probability of PTB between black and white infants was 0.056 (95% CI: 0.054, 0.058). All included predictors explained 37.8% of the black–white disparity. Overall, individual (17.5% for PTB) and neighborhood-level variables (16.1% for PTB) explained a greater proportion of the black–white difference in birth outcomes than air pollution (5.7% for PTB). Conclusions: Our results suggest that, although the role of individual and neighborhood factors remains prevailing in explaining black–white differences in birth outcomes, the individual contribution of PM2.5 is comparable in magnitude to any single individual- or neighborhood-level factor. https://doi.org/10.1289/EHP490

Grandmaternal education may be related to grandchild birth weight (GBW) through maternal early-life development; however, conventional regression models may be endogenously confounded. Alternative models employing explicit structural assumptions may provide incrementally clearer evidence. We used data from the US National Longitudinal Study of Adolescent to Adult Health (1995–2009; 1,681 mother-child pairs) to estimate “direct effects” of grandmaternal educational level (less than high school, high school diploma or equivalent, or college degree) at the time of the mother's birth on GBW, adjusted for maternal life-course factors: maltreatment as a child, education and income as an adult, prepregnancy overweight, and prenatal smoking. Using conventional and marginal structural model (MSM) approaches, we estimated 54-g (95% confidence interval: −14.0, 122.1) and 87-g (95% confidence interval: 10.9, 162.5) higher GBWs per increase in educational level, respectively. The MSM allowed simultaneous mediation by and adjustment for prepregnancy overweight. Estimates were insensitive to alternate structural assumptions and mediator parameterizations. Bias analysis suggested that a single unmeasured confounder would have to have a strong influence on GBW (approximately 150 g) or be greatly imbalanced across exposure groups (approximately 25%) to completely explain the findings. Coupling an MSM with sensitivity analyses provides some evidence that maternal early-life socioeconomic environment is directly associated with offspring birth weight.

Background While associations of vitamin D deficiency with type 2 diabetes have been well demonstrated, investigations of vitamin D and risk of gestational diabetes mellitus (GDM) reported inconsistent findings. We examined associations of vitamin D status with GDM. Methods In a nested case-cohort study (135 GDM cases and 517 non-GDM controls), we measured maternal serum vitamin D status (total 25[OH]D and 25[OH]D3) in early pregnancy (16 weeks on average) using liquid chromatography-tandem mass spectroscopy. GDM was diagnosed according to the American Diabetes Association guidelines. We calculated adjusted odds ratios and 95% confidence intervals (CIs) using logistic regression models. Results GDM cases had lower mean total 25[OH]D (27.3 vs. 29.3 ng/mL) and 25[OH]D3 (23.9 vs. 26.7 ng/mL) concentrations compared with women who did not develop GDM (both P-values

Maternal low birthweight (

ObjectivesImmune response to cytomegalovirus (CMV) impacts adult chronic disease. This study investigates associations of childhood and adulthood social environment, socioeconomic position (SEP) and social mobility with CMV response in young adults.DesignHistorical prospective study design.SettingSubcohort of all 17 003 births to residents of Jerusalem between 1974 and 1976.ParticipantsParticipants included 1319 young adults born in Jerusalem with extensive archival and follow-up data, including childhood and adulthood SEP-related factors and anti-CMV IgG titre levels and seroprevalence measured at age 32.Main exposure and outcome measuresPrincipal component analysis was used to transform correlated social environment and SEP-related variables at two time points (childhood and adulthood) into two major scores reflecting household (eg, number of siblings/children, religiosity) and socioeconomic (eg, occupation, education) components. Based on these components, social mobility variables were created. Linear and Poisson regression models were used to investigate associations of components and mobility with anti-CMV IgG titre level and seroprevalence, adjusted for confounders.ResultsLower levels of household and socioeconomic components in either childhood or adulthood were associated with higher anti-CMV IgG titre level and seropositivity at age 32. Compared with individuals with stable favourable components, anti-CMV IgG titre level and risk for seropositivity were higher in stable unfavourable household and socioeconomic components (household: β=3.23, PConclusionsOur study provides evidence that accumulating low SEP from childhood through adulthood and social mobility may compromise immune response in young adulthood.

In recent years, significant efforts have been made toward elucidating the potential of the human brain. Spanning fields as disparate as psychology, biomedicine, computer science, mathematics, electrical engineering, and chemistry, research venturing into the growing domains of cognitive neuroscience and brain research has become fundamentally interdisciplinary. Among the most interesting and consequential applications to international security are the military and defense community's interests in the potential of cognitive neuroscience findings and technologies. In the United States, multiple governmental agencies are actively pursuing such endeavors, including the Department of Defense, which has invested over $3 billion in the last decade to conduct research on defense-related innovations. This study explores governance and security issues surrounding cognitive neuroscience research with regard to potential security-related applications and reports scientists' views on the role of researchers in these areas through a survey of over 200 active cognitive neuroscientists.

Grandmaternal education may be related to grandchild birth weight (GBW) through maternal early-life development; however, conventional regression models may be endogenously confounded. Alternative models employing explicit structural assumptions may provide incrementally clearer evidence. We used data from the US National Longitudinal Study of Adolescent to Adult Health (1995-2009; 1,681 mother-child pairs) to estimate "direct effects" of grandmaternal educational level (less than high school, high school diploma or equivalent, or college degree) at the time of the mother's birth on GBW, adjusted for maternal life-course factors: maltreatment as a child, education and income as an adult, prepregnancy overweight, and prenatal smoking. Using conventional and marginal structural model (MSM) approaches, we estimated 54-g (95% confidence interval: -14.0, 122.1) and 87-g (95% confidence interval: 10.9, 162.5) higher GBWs per increase in educational level, respectively. The MSM allowed simultaneous mediation by and adjustment for prepregnancy overweight. Estimates were insensitive to alternate structural assumptions and mediator parameterizations. Bias analysis suggested that a single unmeasured confounder would have to have a strong influence on GBW (approximately 150 g) or be greatly imbalanced across exposure groups (approximately 25%) to completely explain the findings. Coupling an MSM with sensitivity analyses provides some evidence that maternal early-life socioeconomic environment is directly associated with offspring birth weight.

Recent studies suggest that epigenetic programming may mediate the relationship between early life environment, including parental socioeconomic position, and adult cardiometabolic health. However, interpreting associations between early environment and adult DNA methylation may be difficult because of time-dependent confounding by life-course exposures. Among 613 adult women (mean age = 32 years) of the Jerusalem Perinatal Study Family Follow-up (2007–2009), we investigated associations between early life socioeconomic position (paternal occupation and parental education) and mean adult DNA methylation at 5 frequently studied cardiometabolic and stress-response genes ( ABCA1 , INS-IGF2 , LEP , HSD11B2 , and NR3C1 ). We used multivariable linear regression and marginal structural models to estimate associations under 2 causal structures for life-course exposures and timing of methylation measurement. We also examined whether methylation was associated with adult cardiometabolic phenotype. Higher maternal education was consistently associated with higher HSD11B2 methylation (e.g., 0.5%-point higher in 9–12 years vs. ≤8 years, 95% confidence interval: 0.1, 0.8). Higher HSD11B2 methylation was also associated with lower adult weight and total and low-density lipoprotein cholesterol. We found that associations with early life socioeconomic position measures were insensitive to different causal assumption; however, exploratory analysis did not find evidence for a mediating role of methylation in socioeconomic position-cardiometabolic risk associations.

Maternal low birthweight and vitamin D deficiency in pregnancy are associated with a similar spectrum of adverse pregnancy outcomes including pre-eclampsia and gestational diabetes. However, the relationship between maternal birthweight and subsequent vitamin D concentrations in early pregnancy is largely unknown.We assessed whether self-reported maternal birthweight was associated with risk of early pregnancy vitamin D deficiency (≤20 ng/mL) among a pregnancy cohort (n = 658). Serum 25-hydroxyvitamin D [25(OH)D] was measured using liquid chromatography-tandem mass spectroscopy.Adjusting for maternal characteristics and month of blood draw, a 100-g higher maternal birthweight was associated with a 5.7% decreased risk of early pregnancy 25(OH)D deficiency [odds ratio (OR) = 0.94; 95% confidence interval (CI) 0.90, 0.99]. Low-birthweight (2500 g) women were 3.7 times as likely to have early pregnancy 25(OH)D deficiency compared with normal-birthweight women [OR = 3.69; 95% CI 1.63, 8.34]. These relationships were not modified by either pre-pregnancy overweight status [body mass index (BMI) ≥25 kg/m(2)] or adulthood weight trajectory (BMI change ≥2 kg/m(2) from age 18 to pre-pregnancy).Further research on shared developmental mechanisms that determine birthweight and vitamin D homeostasis may help identify targets and related preventative measures for adverse pregnancy and birth outcomes.