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Heavy metals, including lead and manganese, air pollution, pesticides, environmental tobacco smoke, and flame retardants are among the known and suspected environmental neurotoxicant exposures examined with magnetic resonance imaging (MRI)-based studies of pediatric populations. Many studies feature morphological changes associated with the exposures while others employ magnetic resonance spectroscopy, diffusion imaging, task-based, and resting state functional magnetic resonance imaging to reveal abnormal metabolic concentrations, white matter disorganization, and atypical patterns of activation. Some studies follow pregnant women and their offspring throughout the lifespan with collection of individual specimens as exposure biomarkers. Others innovatively make use of public databases to obtain relevant exposure biomarkers while taking advantage of these studies in their efforts to monitor developmental features in large, population-based, imaging cohorts. As exposures to neurotoxicants in the womb and throughout childhood have life-long impacts on health and well-being, the importance of these innovative neuroimaging investigations is ever increasing.

BACKGROUND AND AIM: No studies have examined whether previously observed associations between higher gestational PFAS exposure and worse offspring cardiometabolic outcomes might be ameliorated thro...

Background. Individuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS. Increasing evidence points to the role of both structural and functional alterations of prefrontal and limbic brain regions regarding the experience of premonitory urges to tic in TS. This study examined the contribution of brain GABA and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS.Methods. Edited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing controls (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity. Results. GABA+ and Glx of the right SM1, SMA and insula were comparable between the children with TS and typically developing controls. In children with TS, lower levels of SMA GABA+ was associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity. Conclusions. These results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS.

Introduction Sleep is a predictor of cardiometabolic disease (CMD) risk, and new evidence links early childhood sleep to later CMD risk. This study examines the impact of early childhood sleep duration, bedtime timing, and sleep disturbance on a CMD risk score in early adolescence. Methods Within the Health Outcomes and Measures of Environment (HOME) Study, a prospective pregnancy and birth cohort study, we assessed sleep patterns among 346 children using the Children’s Sleep Habits Questionnaire from ages 2 to 8 years. We calculated cardiometabolic risk scores ate age 12 for 183 of these children from visceral adiposity area, blood pressure, fasting serum triglyceride, high density lipoprotein, leptin, and adiponectin concentrations. We used a group-based semi-parametric mixture model to identify distinct trajectories in sleep duration, bedtime timing, and sleep disturbance for the entire sample. We then examined the associations between sleep trajectories and CMD risk score using general linear models for children with a CMD risk score, using both an unadjusted model (no covariates) and an adjusted model (adjusting for child pubertal stage, child sex, duration of breastfeeding, household income, and maternal education). Results Three sleep trajectories emerged for bedtime timing (late timing, medium timing, and early timing) and for sleep disturbance (high, medium, and low), and two for sleep duration (high and low). In the unadjusted model, we found significant differences in CMD risk scores by trajectories of sleep disturbance. Children in the ‘high’ trajectory had higher CMD risk scores (Least Square Mean=1.51; 95% CI: 0.39, 2.64) than those in the ‘low’ trajectory (Least Square Mean =-0.51; 95% CI: -1.16, 0.15; p=.002) and ‘medium’ trajectory (Least Square Mean=-0.15; 95% CI: -1.14, 0.85; p=.03). These findings only approached significance after adjusting for covariates. No significant differences in CMD risk were observed for bedtime timing or total sleep time trajectories in the unadjusted or adjusted models. Conclusion In this cohort, parent-reported sleep disturbance in early childhood was associated with more adverse cardiometabolic profiles in early adolescence. Our findings suggest that trials to reduce CMD risk via sleep interventions – which have been conducted in adolescents and adults – may be implemented too late. Support (If Any) National Institute of Environmental Health Sciences grants PO1 ES11261, R01 ES014575, R01 ES020349, R01 ES027224, R01 ES025214.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is the most common pediatric chronic liver disease. Little is known about outcomes in recognized youth. METHODS: We compared paired liver biopsies from 122 of 139 children with NAFLD (74% male; 64% white; 71% Hispanic; mean age, 13 ± 3 years; age range, 8–17 years) who received placebo and standard of care lifestyle advice in 2 double-blind, randomized clinical trials within the nonalcoholic steatohepatitis (NASH) clinical research network from 2005 through 2015. We analyzed histologic changes with respect to baseline and longitudinal change in clinical variables using regression analysis. RESULTS: At enrollment, 31% of the children had definite NASH, 34% had borderline zone 1 NASH, 13% had borderline zone 3 NASH, and 21% had fatty liver but not NASH. Over a mean period of 1.6 ± 0.4 years, borderline or definite NASH resolved in 29% of the children, whereas 18% of the children with fatty liver or borderline NASH developed definite NASH. Fibrosis improved in 34% of the children but worsened in 23%. Any progression to definite NASH or in fibrosis occurred in 36% of the children, and both occurred in 11% of the children. Any improvement in NASH or fibrosis occurred in 52%, and both occurred in 20% of children. Type 2 diabetes developed in 5% of the cohort. Any progression to NASH and/or fibrosis was associated with adolescent age, higher waist circumference, levels of alanine or aspartate aminotransferase, total and low-density lipoprotein-cholesterol at baseline, increasing level of alanine aminotransferase, and hemoglobin A1C (P < .05). Progression to NASH and/or fibrosis were also associated with increasing level of gamma-glutamyl transferase and development of type 2 diabetes (P < .01). Increasing level of gamma-glutamyl transferase also associated with reduced odds of any improvement (P = .003). CONCLUSIONS: One-third of children with NAFLD enrolled in placebo groups of clinical trials had histologic features of progression within 2 years, in association with increasing obesity and serum levels of aminotransferases and loss of glucose homeostasis.

To examine the distribution of birth weight in children with nonalcoholic fatty liver disease (NAFLD) compared with the general US population, and to investigate the relationship between birth weight and severity of NAFLD.A multicenter, cross-sectional study of children with biopsy-proven NAFLD enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network Database. Birth weight was categorized as low birth weight (LBW), normal birth weight (NBW), or high birth weight (HBW) and compared with the birth weight distribution in the general US population. The severity of liver histology was assessed by birth weight category.Children with NAFLD (n = 538) had overrepresentation of both LBW and HBW compared with the general US population (LBW, 9.3%; NBW, 75.8%; HBW, 14.9% vs LBW, 6.1%; NBW, 83.5%; HBW 10.5%; P .0001). Children with HBW had significantly greater odds of having more severe steatosis (OR, 1.82, 95% CI. 1.15-2.88) and nonalcoholic steatohepatitis (OR, 2.03; 95% CI, 1.21-3.40) compared with children with NBW. In addition, children with NAFLD and LBW had significantly greater odds of having advanced fibrosis (OR, 2.23; 95% CI, 1.08-4.62).Birth weight involves maternal and in utero factors that may have long-lasting consequences. Children with both LBW and HBW may be at increased risk for developing NAFLD. Among children with NAFLD, those with LBW or HBW appear to be at increased risk for more severe disease.

SummaryBackground Non-alcoholic fatty liver disease (NAFLD) is a complex, multifactorial disease affected by diet, lifestyle and genetics. Proinflammatory cytokines like IL-1β and IL-6 have been shown to be elevated in non-alcoholic steatohepatitis (NASH). Aim To investigate the relationship between IL1B and IL6 gene polymorphisms and histological features of NAFLD in the NASH CRN cohort. Methods A total of 604 adult (≥18 years) non-Hispanic Caucasians with biopsy-proven NAFLD were genotyped for the following SNPs: IL1B, rs16944, rs1143634; IL6, rs1800795, rs10499563. Logistic regression was used to examine the relationship between genotype and a definitive diagnosis and advanced histological features of NASH after controlling for the following variables selected a priori: age, sex, diabetes, obesity and HOMA-IR level. Results The IL6 rs10499563 C allele was independently associated with the presence of definitive NASH, and increased ballooning and Mallory bodies. The IL1B rs1143634 TT genotype was associated with advanced fibrosis and increased Mallory bodies. The IL6 rs1800795 C allele was associated with not only increased risk for severe steatosis, >66% but also decreased risk for advanced fibrosis and lobular inflammation and Mallory body formation. Conclusions These results suggest that common variants in the IL6 and IL1B genes may increase susceptibility for NASH and confer a higher risk of hepatic parenchymal damage including increased ballooning, increased Mallory bodies, and bridging fibrosis or cirrhosis. In contrast, the IL6 rs1800795 C allele may confer a higher risk for steatosis, but less parenchymal damage. Our findings support the development of therapeutics aimed at IL-1β and IL-6 suppression.

BACKGROUND & AIMS: Focal zone 1 steatosis, although rare in adults with nonalcoholic fatty liver disease (NAFLD), does occur in children with NAFLD. We investigated whether focal zone 1 steatosis and focal zone 3 steatosis are distinct subphenotypes of pediatric NAFLD. We aimed to determine associations between the zonality of steatosis and demographic, clinical, and histologic features in children with NAFLD. METHODS: We performed a cross-sectional study of baseline data from 813 children (age less than 18 years; mean age, 12.8±2.7 years). The subjects had biopsy-proven NAFLD and were enrolled in the NASH Clinical Research Network. Liver histology was reviewed using the Nonalcoholic Steatohepatitis Clinical Research Network scoring system. RESULTS: Zone 1 steatosis was present in 18% of children with NAFLD (n=146) and zone 3 steatosis was present in 32% (n=244). Children with zone 1 steatosis were significantly younger (10 vs 14 years; P

OBJECTIVE:To determine the percentage of children with nonalcoholic fatty liver disease (NAFLD) in whom intervention for low-density lipoprotein cholesterol or triglycerides was indicated based on National Heart, Lung, and Blood Institute guidelines. STUDY DESIGN:This multicenter, longitudinal cohort study included children with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network. Fasting lipid profiles were obtained at diagnosis. Standardized dietary recommendations were provided. After 1 year, lipid profiles were repeated and interpreted according to National Heart, Lung, and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction. Main outcomes were meeting criteria for clinically actionable dyslipidemia at baseline, and either achieving lipid goal at follow-up or meeting criteria for ongoing intervention. RESULTS:There were 585 participants, with a mean age of 12.8 years. The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention. Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications. CONCLUSIONS:More than one-half of children with NAFLD met intervention thresholds for dyslipidemia. Based on the burden of clinically relevant dyslipidemia, lipid screening in children with NAFLD is warranted. Clinicians caring for children with NAFLD should be familiar with lipid management.