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Key PointsQuestionIs exposure to ambient air pollution in the first trimester associated with thyroid function throughout pregnancy?FindingsAmong 9931 pregnant women in 4 European cohorts and 1 US cohort, an increase of 5 μg/m3 in exposure to particulate matter with an aerodynamic diameter of 2.5 μm or less was associated with 20% higher odds of hypothyroxinemia.MeaningThe findings of this study raise the possibility that exposure to particulate matter might disrupt thyroid function in pregnant women.

Background: Sleep problems occur in up to 30% of children and have been associated with adverse developmental outcomes. However, due to a lack of longitudinal neuroimaging studies, the neurobiological changes that may underlie some of these associations have remained unclear. This study explored the association between sleep problems during childhood and white matter (WM) microstructure in preadolescence. Methods: Children from the population-based birth cohort, the Generation R Study, who had repeatedly assessed sleep problems between 1.5 and 10 years of age and a MRI scan at age 10 (N = 2,449), were included. Mothers reported on their child's sleep problems using the Child Behavior Checklist (CBCL 1.5-5) when children were 1.5, 3, and 6 years of age. At age 2, mothers completed very similar questions. At age 10, both children and their mothers reported on sleep problems. We used whole-brain and tract-specific fractional anisotropy (FA) and mean diffusivity (MD) values obtained through diffusion tensor imaging as measures of WM microstructure. Results: Childhood sleep problems at 1.5, 2, and 6 years of age were associated with less WM microstructural integrity (approximately 0.05 SD lower global FA score per 1-SD sleep problems). In repeated-measures analyses, children with more sleep problems (per 1-SD) at baseline had lower FA values at age 10 in particular in the corticospinal tract (À0.12 SD, 95% CI:-0.20;-0.05), the uncinate fasciculus (À0.12 SD, 95% CI:À0.19;À0.05), and the forceps major (-0.11 SD, 95% CI:À0.18;À0.03), although effect estimates across the tracts did not differ substantially. Conclusions: Childhood sleep disturbances are associated with less WM microstructural integrity in preadolescence. Our results show that early neurodevelopment may be a period of particular vulnerability to sleep problems. This study cannot demonstrate causality but suggests that preventive interventions addressing sleep problems should be further explored to test whether they impact adverse neurodevelopment.Sleep problems have been associated with adverse developmental outcomes, but the neurobiological changes underlying this association have remained unclear.In this population-based cohort of 2,449 children, repeatedly measured sleep problems at 1.5, 2, and 6 years were associated with less white matter microstructural integrity as assessed with fractional anisotropy in preadolescence.Our results primarily suggest an association with global white matter microstructure, with the most pronounced associations observed in the corticospinal tract, uncinate fasciculus, and forceps major.Early childhood sleep problems are related to less white matter microstructural integrity in preadolescence and constitute a candidate mechanism underlying the long-term neurodevelopmental consequences of poor sleep.

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

Cytochrome P450 3A4 (CYP3A4) is the most important drug metabolizing enzyme in the liver, responsible for the oxidative metabolism of ∼50% of clinically prescribed drugs. Therefore, genetic variation in CYP3A4 could potentially affect the pharmacokinetics, toxicity and clinical outcome of drug treatment. Thus far, pharmacogenetics for CYP3A4 has not received much attention. However, the recent discovery of the intron 6 single-nucleotide polymorphism (SNP) rs35599367C > T, encoding the CYP3A4∗22 allele, led to several studies into the pharmacogenetic effect of CYP3A4∗22 on different drugs. This allele has a relatively minor allele frequency of 3-5% and an effect on CYP3A4 enzymatic activity. Thus far, no review summarizing the data published on several drugs is available yet. This article therefore addresses the current knowledge on CYP3A4∗22. This information may help in deciding if, and for which drugs, CYP3A4∗22 genotype-based dosing could be helpful in improving drug therapy. CYP3A4∗22 was shown to significantly influence the pharmacokinetics of several drugs, with currently being most thoroughly investigated tacrolimus, cyclosporine, and statins. Additional studies, focusing on toxicity and clinical outcome, are warranted to demonstrate clinical utility of CYP3A4∗22 genotype-based dosing.

However, these differential effects by gestational age were not consistent. No significant effect modification by sex was observed. Conclusions: We found no clear evidence of an association between maternal thyroid function and child ADHD.

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