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PURPOSE: To investigate longitudinal associations between the vitamin D status and inflammatory markers in children and adolescents. METHODS: Children from eight European countries from the IDEFICS/I.Family cohort with repeated measurements were included in this study. A linear mixed-effect model was used to model the association of serum 25(OH)D as independent variable and z-scores of inflammatory markers [CRP, cytokines, adipokines, combined inflammation score] as dependent variables, where one level accounts for differences between individuals and the other for changes over age within individuals. RESULTS: A total of 1,582 children were included in the study. In the adjusted model, 25(OH)D levels were positively associated with adiponectin (ß = 0.11 [95% CI 0.07; 0.16]) and negatively with the inflammation score (ß = - 0.24 [95% CI - 0.40; - 0.08]) indicating that the adiponectin z-score increased by 0.11 units and the inflammation score decreased by 0.24 units per 12.5 nmol/l increase in 25(OH)D. In children with overweight or obesity, only a positive association between 25(OH)D and IP-10 was observed while in children with normal weight adiponectin was positively and the inflammation score was negatively associated. Associations of vitamin D with adiponectin and the inflammation score were stronger in girls than in boys and a positive association with TNF-α was observed only in girls. CONCLUSION: Our results suggest that an increase in vitamin D concentrations may help to regulate inflammatory biomarkers. However, it seems to be no benefit of a better vitamin D status in children with overweight/obesity unless their weight is managed to achieve an improved inflammatory marker status.

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CONTEXT: Vitamin D status has previously been associated with cardiometabolic risk markers in children and adolescents. In particular, it has been suggested that children with obesity are more prone to vitamin D deficiency and unfavorable metabolic outcomes compared with healthy-weight children. OBJECTIVE: To conduct a longitudinal study assessing this association in children and stratify by body mass index (BMI) category. METHODS: Children from the pan-European IDEFICS/I.Family cohort with at least one measurement of serum 25-hydroxyvitamin D [25(OH)D] at cohort entry or follow-up (n = 2171) were included in this study. Linear mixed-effect models were used to assess the association between serum 25(OH)D as an independent variable and z-scores of cardiometabolic risk markers (waist circumference, systolic [SBP] and diastolic blood pressure [DBP], high- [HDL] and low-density lipoprotein, non-HDL, triglycerides [TRG], apolipoprotein A1 [ApoA1] and ApoB, fasting glucose [FG], homeostatic model assessment for insulin resistance [HOMA-IR], and metabolic syndrome score) as dependent variables. RESULTS: After adjustment for age, sex, study region, smoking and alcohol status, sports club membership, screen time, BMI, parental education, and month of blood collection, 25(OH)D levels were inversely associated with SBP, DBP, FG, HOMA-IR, and TRG. The HOMA-IR z-score decreased by 0.07 units per 5 ng/mL increase in 25(OH)D. The 25(OH)D level was consistently associated with HOMA-IR irrespective of sex or BMI category. CONCLUSION: Low serum 25(OH)D concentrations are associated with unfavorable levels of cardiometabolic markers in children and adolescents. Interventions to improve vitamin D levels in children with a poor status early in life may help to reduce cardiometabolic risk.

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The effects of exposure to black carbon (BC) on various diseases remains unclear, one reason being potential exposure misclassification following modelling of ambient air pollution levels. Urinary BC particles may be a more precise measure to analyze the health effects of BC. We aimed to assess the risk of prediabetes and metabolic syndrome (MetS) in relation to urinary BC particles and ambient BC and to compare their associations in 5453 children from IDEFICS/I. Family cohort. We determined the amount of BC particles in urine using label-free white-light generation under femtosecond pulsed laser illumination. We assessed annual exposure to ambient air pollutants (BC, PM2.5 and NO2) at the place of residence using land use regression models for Europe, and we calculated the residential distance to major roads (≤250 m vs. more). We analyzed the cross-sectional relationships between urinary BC and air pollutants (BC, PM2.5 and NO2) and distance to roads, and the associations of all these variables to the risk of prediabetes and MetS, using logistic and linear regression models. Though we did not observe associations between urinary and ambient BC in overall analysis, we observed a positive association between urinary and ambient BC levels in boys and in children living ≤250 m to a major road compared to those living >250 m away from a major road. We observed a positive association between log-transformed urinary BC particles and MetS (ORper unit increase = 1.72, 95% CI = 1.21; 2.45). An association between ambient BC and MetS was only observed in children living closer to a major road. Our findings suggest that exposure to BC (ambient and biomarker) may contribute to the risk of MetS in children. By measuring the internal dose, the BC particles in urine may have additionally captured non-residential sources and reduced exposure misclassification. Larger studies, with longitudinal design including measurement of urinary BC at multiple time-points are warranted to confirm our findings.

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Bisphenol A (BPA) is a widely known endocrine disruptor (ED) found in many children's products such as toys, feeding utensils, and teething rings. Recent epidemiology association studies have shown postnatal BPA exposure resulted in developing various diseases such as diabetes, obesity, and neurodegeneration, etc., later in their lives. However, little is known about its sex-specific metabolism and consequently internal exposure. The aim of this study was to develop a sex-specific pediatric physiologically based pharmacokinetic model (PBPK) for BPA to compare their toxicokinetic differences. First, the published adult PBPK model was re-validated, and then this model was extended by interpolation to incorporate pediatric sex specific physiological and biochemical parameters. We used both the classical body weight and ontogeny-based scaling approach to interpolate the metabolic process. Then, the pharmacokinetic attributes of the models using the two-scaling approach mentioned above were compared with adult model. Further, a sex-specific PBPK model with an ontogeny scaling approach was preferred to evaluate the pharmacokinetic differences. Moreover, this model was used to reconstruct the BPA exposure from two cohorts (Helix and PBAT Cohort) from 7 EU countries. The half-life of BPA was found to be almost the same in boys and girls at the same exposure levels. Our model estimated BPA children's exposure to be about 1500 times higher than the tolerable daily intake (TDI) recently set by European Food Safety Authority (EFSA) i.e., 0.04 ng/kg BW/day. The model demonstrated feasibility of extending the adult PBPK to sex-specific pediatric, thus investigate a gender-specific health risk assessment.

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PURPOSE: Subclinical systemic inflammation may lead to development of type 2 diabetes, but there has been no investigation into its relationship with early progression of glycaemic deterioration and insulin resistance, especially in younger population. In this study we assessed longitudinal associations of pro- and anti-inflammatory markers with markers that evaluate glycaemia and insulin resistance. METHODS: This study includes 6537 initially nondiabetic children (mean age at baseline = 6.2 years) with repeated measurements from the IDEFICS/I.Family cohort study (mean follow-up = 5.3 years) from eight European countries. Markers of inflammation were used as independent variables and markers of glycaemia/insulin resistance as dependent variables. Associations were examined using two-level growth model. Models were adjusted for sex, age, major lifestyle, metabolic risk factors, early life markers, and other inflammatory markers in final model. RESULTS: Children with 6 years of follow-up showed that a one-unit increase in z-score of leptin level was associated with 0.38 (95% CI = 0.32 to 0.44) unit increase in HOMA-IR z-scores. Leptin continued to be associated with HOMA-IR even when analysis was limited to children with no overall obesity, no abdominal obesity, and low to normal triglyceride levels. An inverse association was observed between IL-15 and HOMA-IR (ß = -0.11, 95% CI = -0.15 to -0.07). CONCLUSIONS: IL-15 should be evaluated further in the prevention or treatment of prediabetes whereas leptin may prove to be useful in early detection of prediabetes via their association with markers of insulin resistance in European children.

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BACKGROUND: Vitamin D deficiency (VDD) is associated with depression and schizophrenia in adults. The effect of VDD in childhood on behavioral development is unknown. OBJECTIVES: We aimed to study the associations of VDD and vitamin D binding protein (DBP) in middle childhood with behavior problems in adolescence. METHODS: We quantified plasma total 25-hydroxyvitamin D [25(OH)D] and DBP in 273 schoolchildren aged 5-12 y at recruitment into a cohort study in Bogota, Colombia. Externalizing and internalizing behavior problems were assessed after a median 6-y follow-up by parental report [Child Behavior Checklist (CBCL)] and self-report [Youth Self-Report (YSR)]. We estimated mean problem score differences with 95% CIs between exposure categories using multivariable linear regression. We also compared the prevalence of clinical behavior problems (score >63) between exposure groups. We assessed whether the associations between DBP and behavior problems were mediated through VDD. RESULTS: Mean ± SD CBCL and YSR externalizing problems scores were 56.5 ± 9.3 and 53.2 ± 9.5, respectively. Internalizing problems scores averaged 57.1 ± 9.8 and 53.7 ± 9.8, respectively. VDD [25(OH)D <50 nmol/L] prevalence was 10.3%. VDD was associated with an adjusted 6.0 (95% CI: 3.0, 9.0) and 3.4 (95% CI: 0.1, 6.6) units higher CBCL and YSR externalizing problems scores, respectively, and an adjusted 3.6 (95% CI: 0.3, 6.9) units higher CBCL internalizing problems scores. The prevalence of clinical total externalizing problems was 1.8 (95% CI: 1.1, 3.1) times higher in children with VDD than that in children without VDD. DBP concentration below the population median was related to higher YSR aggressive behavior and anxious/depressed subscale scores and to higher prevalence of clinical total externalizing problems. The associations between DBP and behavior problems were not mediated through VDD. CONCLUSIONS: VDD and low DBP in middle childhood are related to behavior problems in adolescence.

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Studies measuring dichlorodiphenyltrichloroethane (DDT) exposure during key windows of susceptibility including the intrauterine period suggest that DDT exposure is associated with breast cancer risk. We hypothesized that prenatal DDT exposure is associated with DNA methylation. Using prospective data from 316 daughters in the Child Health and Development Study, we examined the association between prenatal exposure to DDTs and DNA methylation in blood collected in midlife (mean age: 49 years). To identify differentially methylated regions (DMRs) associated with markers of DDTs (p,p'-DDT and the primary metabolite of p,p'-DDT, p,p'-DDE, and o,p'-DDT, the primary constituents of technical DDT), we measured methylation in 30 genes important to breast cancer. We observed DDT DMRs in three genes, CCDC85A, CYP1A1 and ZFPM2, each of which has been previously implicated in pubertal development and breast cancer susceptibility. These findings suggest prenatal DDT exposure may have life-long consequence through alteration in genes relevant to breast cancer.

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BACKGROUND: Physical activity (PA) is one of the major protective behaviours to prevent non-communicable diseases. Positive effects of the built environment on PA are well investigated, although evidence of this association is mostly based on cross-sectional studies. The present study aims to investigate the longitudinal effects of built environment characteristics in terms of a moveability index on PA of children in their transition phase to adolescence using data of the IDEFICS/I.Family cohort. METHODS: We used data on 3394 accelerometer measurements of 2488 children and adolescents aged 3 to 15 years old from survey centres of three countries, Germany, Italy, and Sweden, who participated in up to three surveys over 6 years. In network-dependent home neighbourhoods, a moveability index was calculated based on residential density, land use mix, street connectivity, availability of public transport and public open spaces such as green spaces and public playgrounds in order to quantify opportunities for PA of children and adolescents. Linear trajectories of light PA (LPA) and moderate-to-vigorous PA (MVPA) were estimated using linear mixed models accounting for repeated measurements nested within individuals. Least squares means were estimated to quantify differences in trajectories over age. RESULTS: LPA and MVPA declined annually with age by approximately 20 min/day and 2 min/day respectively. In girls, the moveability index showed a consistent significantly positive effect on MVPA ([Formula: see text] = 2.14, 95% CI: (0.11; 4.16)) for all ages, while in boys the index significantly lessened the decline in LPA with age for each year. ([Formula: see text] = 2.68, 95% CI: (0.46; 4.90)). Availability of public open spaces was more relevant for MVPA in girls and LPA in boys during childhood, whereas in adolescence, residential density and intersection density became more important. CONCLUSION: Built environment characteristics are important determinants of PA and were found to have a supportive effect that ameliorates the decline in PA during the transition phase from childhood to adolescence. In childhood environmental support for leisure time PA through public open spaces was found to be the most protective factor whereas in adolescence the positive influence of street connectivity and residential density was most supportive of physical activity.

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BACKGROUND: Prospective, longitudinal studies examining the features of linear morphea are limited. OBJECTIVE: To utilize the Morphea in Adults and Children cohort to determine clinical characteristics, impact on life quality, and disease course of linear morphea in a prospective, longitudinal manner. METHODS: Characteristics of linear morphea versus other subtypes were compared in a cross-sectional manner. Next, linear morphea participants were examined in depth over a 3-year period. RESULTS: Linear morphea was the most common morphea subtype (50.1%, 291/581) in the cohort. Deep involvement was more common in linear (64.3%, 187/291) than other morphea subtypes. Linear morphea participants with deep involvement were more likely to have a limitation in range of motion (28.6%, 55/192) than those without (11.1%, 11/99, P < .001). Adult-onset disease occurred in 32.6% (95/291) of those with linear morphea. Frequency of deep involvement was similar between pediatric (66.8%, 131/196) and adult-onset linear morphea (58.9%, 56/95, P = .19). Quality of life and disease activity scores improved over time, while damage stabilized with treatment. LIMITATIONS: Results of the study are associative, and the University of Texas Southwestern Medical Center is a tertiary referral center. CONCLUSION: A substantial number of linear morphea patients have adult-onset disease. In all age groups, linear morphea with deep involvement was associated with functional limitations.

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The aim of this study is to investigate whether in addition to established early risk factors other, less studied pre-, peri-, and postnatal influences, like gestational hypertension or neonatal respiratory disorders and infections, may increase a child's risk of developing attention-deficit/hyperactivity disorders (ADHD). In the IDEFICS study more than 18,000 children, aged 2-11.9 years, underwent extensive medical examinations supplemented by parental questionnaires on pregnancy and early childhood. The present analyses are restricted to children whose parents also completed a supplementary medical questionnaire (n = 15,577), including the question whether or not the child was ever diagnosed with ADHD. Multilevel multivariable logistic regression was used to assess the association between early life influences and the risk of ADHD. Our study confirms the well-known association between maternal smoking during pregnancy and a child's risk of ADHD. In addition, our study showed that children born to mothers younger than 20 years old were 3-4 times more likely to develop ADHD as compared to children born to mothers aged 25 years and older. Moreover, we found that children whose mothers suffered from pregnancy-induced hypertension had an approximately twofold risk of ADHD (OR 1.95; 95% CI 1.09-3.48). This also holds true for infections during the first 4 weeks after birth (OR 2.06; 95% CI 1.05-4.04). In addition, although not statistically significant, we observed a noticeable elevated risk estimate for neonatal respiratory disorders (OR 1.76; 95% CI 0.91-3.41). Hence, we recommend that these less often studied pre-, peri, and postnatal influences should get more attention when considering early indicators or predictors for ADHD in children. However, special study designs such as genetically sensitive designs may be needed to derive causal conclusions.

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OBJECTIVE: Dental caries is frequently observed in children, particularly among those residing in developing countries. The most adapted strategies against this pathology remains prevention based on information, education, and communication (IEC), as well as on early diagnosis and treatment. We carried out a study that aimed to analyze the development of dental caries in a cohort of school children followed during their primary education. The objective was to assess the evolution of the dental status of a cohort of students during their elementary curriculum. MATERIALS AND METHODS: A cohort of school children was followed during 6 years from the first grade to the sixth grade. Monitoring of these school children focused every year on IEC based on learning methods of brushing messages, dietary advice, systematic visits, fluoride use, and primary dental care. During the school year, the students were periodically subjected to education and communication briefings (IEC). Primary care consisted of extracting and descaling rhizalyzed teeth in the same period. The data from this review were collected using the World Health Organization questionnaire, and statistical analysis was performed with the software Epi-info version 6.04 d. RESULTS: The mean age of the 171 school children was 6 years in the first grade and 11 years in the sixth grade. In the first grade, the decayed permanent teeth prevalence was 31.6% and the In permanent teeth: Decayed, missing or filled teeth (DMF/T) was 0.47. The decayed primary teeth prevalence was 75% and the in primary teeth: decayed or filled teeth (df/t) 2.23. In the sixth year, the prevalence of decayed permanent teeth was 51% and DMF/T 0.36 whereas the decayed primary teeth prevalence was 12% and the df/t was 0.19. The prevalence of decayed permanent teeth increased from 31.6 to 51% whereas the mean DMF/T was not statistically different between school children of the first and sixth grade class. CONCLUSION: The promotion of oral health by IEC messages and monitoring of children constitute an effective preventive method for children's oral care.

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BACKGROUND: Filaggrin (FLG) is a major protein component of the stratum corneum (SC) layer, and FLG loss-of-function mutations are a predisposing factor for atopic dermatitis (AD). Previous cohort studies of children from northern and western Europe have reported FLG loss-of-function mutation frequencies of 15.1-20.9% and 5.8-13.0% in AD and non-AD groups, respectively. OBJECTIVE: To elucidate the association between AD prevalence of FLG loss-of-function mutation carriers and climate conditions, we determined the AD prevalence and FLG loss-of-function mutation frequencies in a cohort of children from Ishigaki Island. Ishigaki Island has a subtropical climate with high humidity (monthly average, 60.8-78.7%) and high temperature (monthly average, 18.5-29.4°C) throughout the year. METHODS: We diagnosed AD prevalence and analyzed eight FLG loss-of-function mutations in the Japanese population against a cohort of 721 children from the Kyushu University Ishigaki Atopic Dermatitis Study (KIDS) cohort. Parents gave consent for the mutation analysis during their medical examinations from 2001 to 2006. RESULTS: Average AD prevalence was 7.3% per year, and a total of 127 children (17.6%) were diagnosed with AD at least once between 2001 and 2006. The average total serum IgE level differed significantly between the AD and non-AD groups (199.0 and 69.0IU/ml, respectively). Although five kinds of FLG loss-of-function mutations isolated in previous Japanese FLG mutation studies were identified, the FLG loss-of-function mutation frequency in children of the KIDS cohort was not significantly different between the AD and non-AD groups (7.9% and 6.1%, respectively; P=0.174). CONCLUSION: The FLG loss-of-function mutation frequency was not significantly different between the AD and non-AD groups in a cohort of children from Ishigaki Island, which has a subtropical climate, suggesting that FLG loss-of-function mutations are not always a predisposing factor for AD prevalence.

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BACKGROUND: Skin trauma may play a role in the development of morphea lesions. The association between trauma and the distribution of cutaneous lesions has never been examined to our knowledge. OBJECTIVE: We sought to determine whether patients enrolled in the Morphea in Adults and Children (MAC) cohort exhibit skin lesions distributed in areas of prior (isotopic) or ongoing (isomorphic) trauma. METHODS: This was a cross-sectional analysis of the MAC cohort. RESULTS: Of 329 patients in the MAC cohort, 52 (16%) had trauma-associated lesions at the onset of disease. Patients with lesions in an isotopic distribution had greater clinical severity as measured by a clinical outcome measure (mean modified Rodnan Skin Score of 13.8 vs 5.3, P = .004, 95% confidence interval 3.08-13.92) and impact on life quality (mean Dermatology Life Quality Index score 8.4 vs 4.1, P = .009, 95% confidence interval 1.18-7.50) than those with an isomorphic distribution. Most frequent associated traumas were chronic friction (isomorphic) and surgery/isotopic. LIMITATIONS: Recall bias for patient-reported events is a limitation. CONCLUSION: Of patients in the MAC cohort, 16% developed initial morphea lesions at sites of skin trauma. If these findings can be confirmed in additional series, they suggest that elective procedures and excessive skin trauma or friction might be avoided in these patients.

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BACKGROUND: Determining a disease's impact on life quality is important in clinical decision making, research, and resource allocation. Determinants of quality of life (QOL) in morphea are poorly understood. OBJECTIVE: We sought to ascertain demographic and clinical variables correlated with negative impact on self-reported QOL in morphea. METHODS: We conducted a cross-sectional survey of the Morphea in Adults and Children cohort. RESULTS: Symptoms (pruritus and pain) and functional impairment were correlated with decreased QOL in children and adults. This was true in both sexes and was independent of subtype and age. Patient-reported QOL correlated with physician-based measures of disease severity in adults, but not in children. Patients with linear and generalized morphea had the greatest impact on QOL. LIMITATIONS: Small sample size is a limitation. CONCLUSION: Symptoms and functional impairment were determinants of impaired life quality in both children and adults independent of morphea subtype. These results suggest that clinicians should consider suppressing the accumulation of new lesions (when rapidly accumulating) and symptoms (pain and pruritus) in the treatment of patients with morphea.

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