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Pre registration of the analysis plan of the study of the associations between exposure to phthalates during pregnancy and early infancy and Eye Tracker scores at 24 months

Phthalates are used in a wide range of consumer products including personal care products (e.g., cosmetics, fragrances, and shampoos), food packaging and indoor residential environments (e.g., polyvinyl chloride (PVC) flooring and plastics, vinyl tiles, and shower curtains) (Li et al. 2009). Several phthalates have been banned in France for use in children’s toys and food packaging, however that does not include all of the sources of exposure (e.g., cosmetics, PVC plastics) and little is known regarding the health effect of their substitutes. In rodents, exposure to phthalates has been associated with impairments in spatial learning and reference memory (Li et al. 2009), decreased grooming behavior (Hoshi and Ohtsuka 2009) and increased activity (Ishido et al. 2004). Several epidemiologcial studies have reported associations between prenatal exposure to phthalates and child neurodevelopment in humans (Kahn et al. 2020). Most studies measured phthalate biomarkers in a small number (

International audience; Background: Synthetic phenols and phthalates can interfere with biological pathways involved in brain development. Despite the high within-subject temporal variability of urinary concentrations observed for their metabolites, studies investigating effects of phenols and phthalates on child behaviour often relied on a limited number of spot biospecimens to assess exposure. Besides, the majority did not consider mixture effects.Objectives: To study the combined effect of prenatal exposure to synthetic phenols and phthalates on child behaviour using repeated exposure measurements.Methods: We assessed concentrations of 12 phenols, 13 phthalate and 2 non-phthalate plasticizer metabolites in within-subject pools of multiple urine samples (median = 21 samples per individual pool) collected at two distinct time points during pregnancy in 416 mother-child pairs from the French SEPAGES cohort. Child behaviour was evaluated at two years using the Child Behaviour Checklist 1.5-5 (CBCL). Associations between a mixture of biomarkers of exposure and externalizing and internalizing behaviour scores were studied using adjusted Weighted Quantile Sum (WQS) regressions with a repeated holdout validation (100 repetitions).Results: The positive WQS indexes were associated with both the externalizing and internalizing behaviour scores in the whole population, indicating greater risk of behavioural problems. Stratification for child sex suggested stronger associations in girls than boys. On average, girls externalizing and internalizing scores increased by 3.67 points (95% CI: 1.24, 6.10) and 2.47 points (95 %CI: 0.60, 4.33) respectively, for an increase of one tertile in the WQS index, compared with 1.70 points (95 %CI: -0.42, 3.81) and 1.17 points (95 %CI: -0.50, 2.84) in boys. Main contributors for the associations observed in girls were bisphenol A (weight of 18%), triclosan (17%) and monoethyl phthalate (MEP, 15%) for the externalizing score and MEP (19%), mono-benzyl phthalate (MBzP, 19%) and mono-n-butyl phthalate (MnBP, 16%) for the internalizing score.Discussion: Our results suggest adverse associations between in utero exposure to a mixture of phenols and phthalates and child behaviour, mainly in girls. Public health consequences may be substantial due to the widespread exposure of the population to these compounds.

International audience; Background: Exposure to certain synthetic phenols is of growing concern, in particular among pregnant women, because of their endocrine disrupting nature. Many phenols are still authorized in personal care products (PCP). We aimed to assess if use of PCPs, by pregnant women could influence their urinary concentrations of synthetic phenols.Methods: We used a panel design with intense urine sample collection. Eight women completed a diary with exact time and use of PCPs in three weeks. We measured the concentrations of phenols (four parabens, bisphenol A and S, two dichlorophenols, triclosan, and benzophenone-3) in 178 urine samples, collected during 7 consecutive days at 3 time points during pregnancy. We characterized PCP use as the total number of PCP applications or as a single PCP use (yes/no) in three time windows (0–6, 6 to 12 and 12 to 24h before each urine sample collection). We used adjusted linear and Tobit regressions to assess associations between PCP use and phenol urinary concentrations.Results: The total number of PCP applications was positively associated with ethylparaben, propylparaben and butylparaben concentrations. We observed a peak in urinary concentration of ethylparaben, butylparaben and propylparaben at 2.86, 2.55 and 2.67 h since last PCP use, respectively and twelve different types of PCPs were positively associated with at least one of these parabens. The bisphenol S concentration increased by 12.4% (95%CI: confidence interval: 5.9; 19.3) for each additional PCP application in the 12 to 24 time window and use of specific PCPs such as anti-stretchmarks cream, facial cleanser and shower gel. Associations varied by time window.Conclusion: Our study showed that PCP use was associated with a short-term increase in the urinary concentration of ethylparaben, butylparaben and propylparaben, but not methylparaben. This study also reported a positive association between the use of PCPs and the bisphenol S concentration, a finding that warrants further investigation in cohorts with repeated collection of urine samples and detailed information on PCP use.

IFP group develops catalysts and has to guarantee their performances. It is therefore crucial to have good predictive models for all new catalysts. These models are built upon very expensive experimental data. In order to minimize costs, we aim at reducing the number of new data points to measure to fit a model on the new catalyst, that is by using the knowledge available in the previous model. This paper describes our work on linear model transfer using Bayesian inference., Le groupe IFP commercialise des catalyseurs et doit s’engager sur leur performance. Il est donc nécessaire de disposer de modèles prédictifs fiables pour chaque nouvelle génération de catalyseurs. Ces modèles sont construits à partir de données expérimentales très couteuses. Afin d’optimiser les coûts, notre ambition est de réduire le nombre d’expérimentations nécessaires pour estimer un modèle associé à un nouveau type de catalyseur, en transférant l’information contenue dans les modèles d’anciennes générations. Cet article décrit nos travaux sur le transfert de modèle linéaire par inférence bayésienne.

International audience; Background: Parabens, bisphenol A and triclosan have been forbidden or restricted in specific types of consumer goods in Europe and France. Limited biomonitoring data are available in France since the implementation of these regulations, and exposure data on infants is scarce worldwide. Understanding the predictors of phenol urinary concentrations will help identify potential targets for prevention.Aim: We described levels, variability and predictors of exposure to 12 phenols in pregnant women and infants recruited between 2014 and 2017 in a French couple-child cohort.Methods: Among 479 pregnant women and 150 of their infants, we studied phenol urinary concentrations in within-subject, within-period pools of repeated urine samples collected during the second and third trimesters of pregnancy (up to 42 samples per woman), at 2 months and 12 months (up to 14 samples per infant). Time trends and associations with demographic, protocol, occupational and behavioral factors were studied using interval censored models to accommodate for undetected and unquantified urine concentrations.Results: Detection rates were above 90% for bisphenol A, ethylparaben, methylparaben, benzophenone-3 and triclosan and below 5% for bisphenol AF, B, F and triclocarban. Median levels of bisphenol A, bisphenol S, methylparaben, ethylparaben and propylparaben at 12 months were similar or higher than during pregnancy. For pregnant women all phenols but benzophenone-3 and bisphenol S showed a linear decrease between 2014 and 2017 (p-values < 0.02). Women with the shortest education (primary and secondary school) had higher urinary concentrations of triclosan (β = 0.58 (95% confidence interval (CI), −0.04; 1.20)), ethyl (β = 0.43 (95%CI, 0.03; 0.84)) and propyl paraben (β = 1.39 (95%CI, 0.55; 2.24)) than those with the longest education. Cashiers had higher conccentrations of bisphenol S (β = 0.99 (95%CI, −0.11; 2.09)) but not of bisphenol A (β = −0.04 (95%CI, −0.26; 0.19)) than unemployed women.Conclusions: Despite recent regulations, bisphenol A, triclosan and paraben detection rates were high in women and young infants. High bisphenol and paraben median levels at 12 months require further investigation as early infancy is a sensitive period for exposure to environmental contaminants.

Background: The exposome is defined as encompassing all environmental exposures one undergoes from conception onwards. Challenges of the application of this concept to environmental-health association studies include a possibly high false-positive rate. Objectives: We aimed to reduce the dimension of the exposome using information from DNA methylation as a way to more efficiently characterize the relation between exposome and child body mass index (BMI). Methods: Among 1,173 mother-child pairs from HELIX cohort, 216 exposures ("whole exposome") were characterized. BMI and DNA methylation from immune cells of peripheral blood were assessed in children at age 6-10 years. A priori reduction of the methylome to preselect BMI-relevant CpGs was performed using biological pathways. We then implemented a tailored Meet-in-the-Middle approach to identify from these CpGs candidate mediators in the exposome-BMI association, using univariate linear regression models corrected for multiple testing: this allowed to point out exposures most likely to be associated with BMI ("reduced exposome"). Associations of this reduced exposome with BMI were finally tested. The approach was compared to an agnostic exposome-wide association study (ExWAS) ignoring the methylome. Results: Among the 2284 preselected CpGs (0.6% of the assessed CpGs), 62 were associated with BMI. Four factors (3 postnatal and 1 prenatal) of the exposome were associated with at least one of these CpGs, among which postnatal blood level of copper and PFOS were directly associated with BMI, with respectively positive and negative estimated effects. The agnostic ExWAS identified 18 additional postnatal exposures, including many persistent pollutants, generally unexpectedly associated with decreased BMI. Discussion: Our approach incorporating a priori information identified fewer significant associations than an agnostic approach. We hypothesize that this smaller number corresponds to a higher specificity (and possibly lower sensitivity), compared to the agnostic approach. Indeed, the latter cannot distinguish causal relations from reverse causation, e.g. for persistent compounds stored in fat, whose circulating level is influenced by BMI. The study has received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement n° 308,333 – the HELIX project for data collection and analyses. The Norwegian Mother and Child Cohort Study is supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01-ES-75558), NIH/NINDS (grant n°0.1 UO1 NS 047537–01 and grant no.2 UO1 NS 047537-06A1). We also received support from Région Auvergne-Rhône-Alpes for collaborations with Catalunya. Dr. Chatzi was supported by NIH P30ES007048, R21ES029681, R01ES029944, R01ES030364, R21ES028903, and by Environmental Protection Agency RD-83544101.

Background: Increasing numbers of HIV-infected pregnant women receive antiretroviral therapy (ART) to prevent mother-to-child transmission (PMTCT). Studies suggested that HIV-exposed uninfected (HEU) children face higher mortality than HIV-unexposed children, but evidence mostly relates to the pre-ART era, breastfeeding of limited duration and considerable maternal mortality. Maternal ART and prolonged breastfeeding under cover of ART may improve survival, although this has not been reliably quantified. Methods: Individual data on 19,219 HEU children from 21 PMTCT trials/cohorts undertaken 1995-2015 in Africa and Asia were pooled and the association between 24-month mortality and maternal/infant factors quantified using random-effects Cox proportional hazards models accounting for between-study heterogeneity. Adjusted attributable fractions of risks computed using the predict function in the R package "frailtypack" estimate the relative contribution of risk factors to overall mortality in HEU children. Results: Cumulative incidence of death was 5.5% (95%CI: 5.1-5.9) by age 24 months. Low birth weight (LBW

International audience; Background: There are concerns that the implementation of Universal Test and Treat (UTT) could increase populationlevel sexual risk behaviours. We analysed the effect of universal ART vs CD4-guided ART (start at CD4≥350 then ≥500) on sexual behaviours over time, in the context of the cluster-randomised TasP trial.Methods: As part of the 6-monthly home-based survey rounds conducted in 11x2 clusters, a sexual behaviour questionnaire was administered to all residents ≥16 years. We used GEE modelling stratified by gender, to compare reported condom use at last sex (CLS), and multi-partnership (≥2 sexual partners) among those sexually-active in the previous six months across trial arms. We tested whether the sexual behaviours changed over time differently in each arm by inclusion of an interaction term between survey round and arm, using the Quasi-likelihood Independence Criterion (QIC) statistic to compare models.Results: The analysis included 43,106 reports of partnerships (22,974 control, 20,132 intervention) across 7 survey rounds (SR), between 03/2012 and 06/2016. There were no consistent or substantive changes in CLS over time neither by gender nor by arm (fig 1a, 1b); inclusion of an interaction term improved the model fit, reflecting small differences between arms in CLS over time. Less than 1.5% of women reported multiple partnerships at any SR, too few for modelling (fig 1d). The proportion of men reporting multiple partnerships decreased significantly during the study (aOR 0.79, 95% CI 0.75, 0.83, p < 0.001), similarly for each arm (interaction not significant), with overall a small, but significant higher proportion reported in the universal ART arm (13.7%) vs CD4-guided ART (12.1%) (OR=1.15, 95% CI (1.03, 1.27), p=0.02 (fig 1c).(Figure 1)Conclusions: There is no evidence of increased unprotected sex with universal ART in this South African population. Continued monitoring of population-level sexual behaviour indicators, in particular multiple partnerships, is needed as theUTT strategy is rolled out.

In this work, we aim to better understand the flow patterns in a random arrangement of particles that might affect local mass transfer and effective reactor performance. Using the DEM code Grains3D, spherical or cylindrical particles are randomly inserted inside a horizontally biperiodic container and fall under gravity. Hydrodynamic simulations are performed with PeliGRIFF, a Fictitious Domain/Finite Volume numerical model. Simulations parameters are the bed height and particulate Reynolds number. Effect of random packing on the flow field is analysed in terms of the probability distribution function (PDF) of the normalized vertical velocity. A higher Reynolds number makes more backward flow zones and changes the PDF curves that we interpret as thinner boundary layers. Unexpectedly, internal variability is independent of bed height. We propose that the probability of occurrence of random structures increases with bed volume in opposition with volume averaging effects. Internal and external variability are similar for beds of spheres and cylinders of aspect ratio (< 2). However, for longer cylinders (higher aspect ratio), subdomains with same thickness are statistically different from one bed to another. We propose that the subdomain thickness required to average out sources of variability increases with high particle aspect ratio.

In order to lower costs, testing of catalytic pellets (spheres or extrudates) is performed in ever smaller fixed bed reactors whereas catalytic pellet size is unchanged. The object of this thesis is to explore domains where downsizing leads to new questions in terms of physics, repeatability and modeling. The thesis is built in 5 chapters, 1) a detailed introduction of the context and a review of the literature on small fixed bed reactors, 2) a discussion about flow patterns in fixed beds filled with fine powder where capilary effects are not negligible, 3) a presentation of a methodology to assess the impact of sampling small number of pellets out of a non uniform set and results for internally mass transfer limited reactions, 4) a study of the effect of randomness in fixed beds first through a pore network model with a good ability to predict trends but lacking accuracy, then using direct numerical simulation of a reactive flow in fixed beds made of 8 cylinders arranged in several configuration showing that packing effects occur, concurrently with external mass transfer limitations, when cross flow diffusion is not fast enough to level out convection and reaction induced gradients, 5) a conclusion that summarizes design criteria and offers a few perspectives for R&D in downsizing, Pour des raisons de coûts, les tests de catalyseur mis en forme (billes, extrudés, …) en réacteur est lit fixe sont mis en œuvre dans des réacteurs de plus en plus petits alors que la taille des objets catalytiques ne change pas. L'objet de cette thèse est d'explorer les domaines où la réduction d'échelle conduit à des questionnements nouveaux en termes de physique, répétabilité, représentativité et modélisation. Le document s'articule autour de 5 chapitres : 1) une introduction détaillée du contexte avec un état de l'art sur les réacteurs à lit fixe de petite taille et l'identification des questions en suspens, 2) une réflexion autour de la nature des écoulements gaz-liquide descendant dans des lits fixes quand les forces capillaires ne sont plus négligeables, 3) la présentation d'une méthodologie et d'un critère sur un nombre minimal de grain nécessaire pour limiter les conséquences d'une distribution granulométrique en présence de limitations au transfert interne, 4) l'étude des effets d'empilements aléatoires sur la performance apparente du réacteur, d'abord par un modèle réseau de pores qui décrit assez bien les tendances observées expérimentalement mais manque de capacité de prédiction, puis par simulation numérique directe d'écoulement réactif dans des empilements de 8 cylindres qui montre que les effets d'empilements apparaissent, avec les limitations au transfert externe, quand la diffusion moléculaire transverse n'est pas assez rapide pour compenser les gradients dus à la réaction et à la convection, 5) une conclusion qui résume les critères de conception de réacteurs de tests à petite échelle, et propose des pistes de continuation du travail