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Aim of the study: Occurrence of hand-foot syndrome (HFS) during capecitabine treatment often results in treatment interruptions (26 %) or treatment discontinuation (17 %), and can severely decrease quality of life. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism – other than DPYD – are associated with an increased risk for capecitabine-induced HFS. Methods: Patients treated with capecitabine according to standard of care were enrolled after providing written informed consent for genotyping purposes. Prospectively collected blood samples were used to extract genomic DNA, which was subsequently genotyped for SNPs in CES1, CES2 and CDA. SNPs and clinical baseline factors that were univariably associated with HFS with P ≤ 0.10, were tested in a multivariable model using logistic regression. Results: Of the 446 patients eligible for analysis, 146 (32.7 %) developed HFS, of whom 77 patients (17.3 %) experienced HFS ≥ grade 2. In the multivariable model, CES1 1165–33 C>A (rs2244613, minor allele frequency 19 %) and CDA 266 + 242 A>G (rs10916825, minor allele frequency 35 %) variant allele carriers were at higher risk of HFS ≥ grade 2 (OR 1.888; 95 %CI 1.075–3.315; P = 0.027 and OR 1.865; 95 %CI 1.087–3.200; P = 0.024, respectively). Conclusions: We showed that CES1 1165–33 C>A and CDA 266 + 242 A>G are significantly associated with HFS grade 2 and grade 3 in patients treated with capecitabine. Prospective studies should assess whether this increased risk can be mitigated in carriers of these SNPs, when pre-emptive genotyping is being followed by dose adjustment or by alternative treatment by a fluoropyrimidine that is not substrate to CES1, such as S1.

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 (-0.12 SD, 95% CI:-0.20;-0.05), the uncinate fasciculus (-0.12 SD, 95% CI:-0.19;-0.05), and the forceps major (-0.11 SD, 95% CI:-0.18;-0.03), 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.

Simple Summary Tamoxifen is an important adjuvant endocrine therapy in estrogen receptor (ER)-positive breast cancer patients. It is mainly catalyzed by the enzyme CYP2D6 into the most active metabolite endoxifen. Genetic variation in the CYP2D6 gene influences endoxifen formation and thereby potentially therapy outcome. However, the association between CYP2D6 genotype and clinical outcome on tamoxifen is still under debate, as contradictory outcomes have been published. This review describes the latest insights in both CYP2D6 genotype and endoxifen concentrations, as well CYP2D6 genotype and clinical outcome, from 2018 to 2020. Abstract 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.

Background: Severe maternal iodine deficiency during pregnancy leads to marked intellectual disability in the offspring. Although recent studies showed that even mild-to-moderate maternal iodine deficiency is associated with lower intelligence quotient and attention deficit hyperactivity disorder in offspring, the underlying neurobiological mechanism of these associations remains unknown. The aim of this study was to investigate the association of maternal iodine excretion during pregnancy with offspring brain morphology during pre-adolescence. Methods: This study was embedded within Generation R, a prospective population-based birth cohort in Rotterdam, the Netherlands. We included 990 mother–child pairs with data on urinary iodine concentration (UIC) and creatinine during pregnancy. The UIC was assessed at

Key Points Question Is exposure to ambient air pollution in the first trimester associated with thyroid function throughout pregnancy? Findings Among 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. Meaning The findings of this study raise the possibility that exposure to particulate matter might disrupt thyroid function in pregnant women., This cohort study evaluates the short-term association of exposure to air pollution in the first trimester with thyroid function throughout pregnancy among European and US cohorts., Importance Air pollutants interact with estrogen nuclear receptors, but their effect on thyroid signaling is less clear. Thyroid function is of particular importance for pregnant women because of the thyroid’s role in fetal brain development. Objective To determine the short-term association of exposure to air pollution in the first trimester with thyroid function throughout pregnancy. Design, Setting, and Participants In this cohort study, 9931 pregnant women from 4 European cohorts (the Amsterdam Born Children and Their Development Study, the Generation R Study, Infancia y Medio Ambiente, and Rhea) and 1 US cohort (Project Viva) with data on air pollution exposure and thyroid function during pregnancy were included. The recruitment period for the Amsterdam Born Children and Their Development Study was January 2003 to March 2004; for Generation R, April 2002 to January 2006; for Infancia y Medio Ambiente, November 2003 to January 2008; for Rhea, February 2007 to February 2008; and for Project Viva, April 1999 to November 2002. Statistical analyses were conducted from January 2018 to April 2019. Main Outcomes and Measures Residential air pollution concentrations (ie, nitrogen oxide and particulate matter [PM]) during the first trimester of pregnancy were estimated using land-use regression and satellite-derived aerosol optical depth models. Free thyroxine, thyrotropin, and thyroid peroxidase antibody levels were measured across gestation. Hypothyroxinemia was defined as free thyroxine below the fifth percentile of the cohort distribution with normal thyrotropin levels, following the American Thyroid Association guidelines. Results Among 9931 participants, the mean (SD) age was 31.2 (4.8) years, 4853 (48.9%) had more than secondary educational levels, 5616 (56.6%) were nulliparous, 404 (4.2%) had hypothyroxinemia, and 506 (6.7%) tested positive for thyroid peroxidase antibodies. Concentrations of nitrogen dioxide and PM with an aerodynamic diameter of 2.5 μm or less (PM2.5) were lower and had less variation in women in the US cohort than those in European cohorts. No associations of nitrogen oxide with thyroid function were found. Higher exposures to PM2.5 were associated with higher odds of hypothyroxinemia in pregnant women (odds ratio per 5-μg/m3 change, 1.21; 95% CI, 1.00-1.47). Although exposure to PM with an aerodynamic diameter of 10 μm or less was not significantly associated with hypothyroxinemia, the coefficient was similar to that for the association of PM2.5 with hypothyroxinemia (odds ratio per 10-μg/m3 change, 1.18; 95% CI, 0.93-1.48). Absorbances of PM2.5 and PM with aerodynamic diameter from 2.5 to 10 μg and were not associated with hypothyroxinemia. There was substantial heterogeneity among cohorts with respect to thyroid peroxidase antibodies (P for heterogeneity

Summary Background Adequate thyroid hormone availability during pregnancy is necessary for optimal fetal brain development. During the first 18–20 weeks of gestation, fetal thyroid hormone availability largely depends on the placental transfer of maternal thyroxine. Although various studies have shown that maternal thyroid dysfunction is associated with suboptimal child neurodevelopmental outcomes, the most vulnerable time window remains to be identified. The aim of this study is to examine the association of maternal thyroid function with child brain morphology and to study whether any association depends on the timing of thyroid assessment. Methods This prospective cohort study was part of the Generation R Study in Rotterdam, Netherlands, with a prospective population-based birth cohort. Pregnant women living in Rotterdam with an expected delivery date between April 1, 2002, and Jan 1, 2006, were eligible. Other inclusion criteria were maternal serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) measurement in early or mid-pregnancy (≤18 weeks) and available brain MRI data for child at age 10 years. Exclusion criteria were pre-existing thyroid disorder, thyroid disorder treatment, twin pregnancy, in-vitro fertilisation-induced pregnancy, and suboptimal-quality MRI data or major incidental finding on MRI. The main outcome was the association between maternal TSH and FT4 concentrations with brain MRI outcomes of children. Regression analyses accounted for gestational age at blood sampling, maternal age, ethnicity, education level, smoking, thyroid peroxidase antibody positivity, child sex, age at MRI, and total intracranial volume. Effect modification by gestational age at blood sampling was also investigated. Findings Between Dec 1, 2001, and June 30, 2005, 7069 women were enrolled during early or mid-pregnancy (≤18 weeks of gestation), of whom 5088 were not included because they did not have available data on maternal serum TSH or FT4 concentrations (n=1175), their child did not have brain MRI done (n=3377), or they met exclusion criteria (n=536). Thus, 1981 mother–child pairs were included in the study, with TSH and FT4 concentrations measured during pregnancy at a median of 13·1 weeks of gestation (IQR 12·1–14·5) and offspring brain morphology assessed by MRI at a median age of 9·9 years (9·7–10·2). Maternal TSH had an inverted U-shaped association with offspring total grey matter volume (p=0·007) and with cortical grey matter volume (p=0·022). The association of maternal TSH with child total grey matter volume (pinteraction=0·053) and cortical volume (pinteraction=0·086) differed by the duration of gestation. Analyses stratified for gestational age at blood sampling showed an inverted U-shaped association of maternal TSH with child total grey matter volume and cortical grey matter volume, which was most evident at 8 weeks gestation. After about 14 weeks of gestation, TSH was no longer associated with child brain morphology. Maternal FT4 concentrations were not associated with child total grey matter volume after adjusting for total intracranial volume (p=0·75). Interpretation Here, we show that both low and high maternal thyroid function are associated with smaller child total grey matter and cortical volume. To the best of our knowledge, this study is the first to show that an association with a neurodevelopmental outcome is most evident when maternal thyroid function is measured early in pregnancy. These novel findings suggest that embryonic brain development is particularly vulnerable to altered maternal thyroid function. Funding Netherlands Organisation for Health Research and Development and the Sophia Children's Hospital Foundation.

Background: Thyroid hormone is essential for optimal fetal brain development. Evidence suggests that both low and high maternal thyroid hormone availability may have adverse effects on child neurodevelopmental outcomes, but the effect on behavioral problems remains unclear. We studied the association of maternal thyrotropin (TSH) and free thyroxine (fT4) concentrations during the first 18 weeks of pregnancy with child attention-deficit hyperactivity disorder (ADHD). Methods: A total of 7669 mother-child pairs with data on maternal thyroid function and child ADHD were selected from three prospective population-based birth cohorts: INfancia y Medio Ambiente (INMA; N = 1073, Spain), Generation R (N = 3812, The Netherlands), and Avon Longitudinal Study of Parents and Children (ALSPAC; N = 2784, United Kingdom). Exclusion criteria were multiple pregnancy, fertility treatment, usage of medication affecting the thyroid, and pre-existing thyroid disease. We used logistic regression models to study the association of maternal thyroid function with the primary outcome, ADHD, assessed via the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria by parents and/or teachers at a median child age of 4.5 to 7.6 years, and with the secondary outcome, an ADHD symptom score above the 90th percentile. Effect modification by gestational age and sex was tested with interaction terms and stratified analyses. Results: Overall, 233 (3%) children met the criteria for ADHD. When analyzed continuously, neither fT4 nor TSH was associated with a higher risk of ADHD (odds ratio [OR] 1.1, 95% confidence interval [CI 1.0-1.3], p = 0.060 and OR 0.9 [CI 0.9-1.1], p = 0.385, respectively) or with high symptom scores. When investigating effect modification by gestational age, a higher fT4 was associated with symptoms above the 90th percentile but only in the first trimester (for fT4 per 1 SD: OR 1.2 [CI 1.0-1.4], p = 0.027). 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.

Background: Animal studies suggest that organophosphate (OP) pesticides exposure affects thyroid function, but evidence in humans remains sparse and inconclusive. Gestational exposure is of particular interest, since thyroid hormone is essential for fetal brain development. OP pesticides are able to cross the placental and blood-brain barrier and may interfere with fetal development processes regulated by thyroid hormone. Objective: To investigate the association of gestational OP pesticides exposure during pregnancy with maternal and cord blood thyroid hormone concentrations. Methods: This study was embedded within Generation R (Rotterdam, the Netherlands), a prospective population-based birth cohort. Mother-child pairs with OP pesticides assessment and maternal (N = 715) or cord blood (N = 482) thyroid hormone measurements were included. OP pesticides exposure was assessed at 25 weeks gestation by measuring six urinary dialkylphosphate (DAP) metabolites. Thyroid stimulating hormone (TSH) and free thyroxine (FT4) were measured in maternal and cord blood. Maternal measures also included total thyroxine (TT4) and TPO antibodies (TPOAbs). To study the association of creatinine-adjusted DAP metabolite concentrations with thyroid function and TPO antibodies, multivariable linear regression models including relevant confounders were used. Results: There was no association of DAP metabolites with maternal TSH, FT4, TT4 or TPOAb concentrations during pregnancy. Similarly, there was no association of DAP metabolites with cord blood TSH or FT4. Results did not change when DAP concentrations were analyzed at individual time points or as mean gestational exposure. Conclusion: Gestational OP pesticides exposure, as assessed by repeatedly measured urinary DAP metabolite concentrations in an urban population, was not associated with maternal or cord blood thyroid hormone concentrations. These findings do not support a mediating role for serum thyroid hormone availability in the relation of early life exposure to low levels of OP pesticides with child neurodevelopment. However, disruption of the thyroid system at tissue level cannot be excluded. In addition, this is one of the first studies on this subject and measurement error in DAP metabolites might have resulted in imprecise estimates. Future studies should use more urine samples to increase precision and should investigate specific OP pesticide metabolites. Keywords: Organophosphate pesticides, Repeated measurements, Thyroid function, Pregnancy, Cord blood, Newborns