BACKGROUND. Currently, there is no disease-specific therapy for osteogenesis imperfecta (OI). Preclinical studies demonstrate that excessive TGF-β signaling is a pathogenic mechanism in OI. Here, we evaluated TGF-β signaling in children with OI and conducted a phase I clinical trial of TGF-β inhibition in adults with OI. METHODS. Histology and RNA-Seq were performed on bones obtained from children. Gene Ontology (GO) enrichment assay, gene set enrichment analysis (GSEA), and Ingenuity Pathway Analysis (IPA) were used to identify dysregulated pathways. Reverse-phase protein array, Western blot, and IHC were performed to evaluate protein expression. A phase I study of fresolimumab, a TGF-β neutralizing antibody, was conducted in 8 adults with OI. Safety and effects on bone remodeling markers and lumbar spine areal bone mineral density (LS aBMD) were assessed. RESULTS. OI bone demonstrated woven structure, increased osteocytes, high turnover, and reduced maturation. SMAD phosphorylation was the most significantly upregulated GO molecular event. GSEA identified the TGF-β pathway as the top activated signaling pathway, and IPA showed that TGF-β1 was the most significant activated upstream regulator mediating the global changes identified in OI bone. Treatment with fresolimumab was well-tolerated and associated with increases in LS aBMD in participants with OI type IV, whereas participants with OI type III and VIII had unchanged or decreased LS aBMD. CONCLUSION. Increased TGF-β signaling is a driver pathogenic mechanism in OI. Anti–TGF-β therapy could be a potential disease-specific therapy, with dose-dependent effects on bone mass and turnover. TRIAL REGISTRATION. ClinicalTrials.gov NCT03064074. FUNDING. Brittle Bone Disorders Consortium (U54AR068069), Clinical Translational Core of Baylor College of Medicine Intellectual and Developmental Disabilities Research Center (P50HD103555) from National Institute of Child Health and Human Development, USDA/ARS (cooperative agreement 58-6250-6-001), and Sanofi Genzyme.

Short sleep durations are related to risks for obesity in preschool children. However, the underlying mechanism or mechanisms are not clear. We evaluated the relationships between sleep characteristics and body composition, energetics, and weight-regulating behaviors in preschool-aged children, as well as the longitudinal associations between children's sleep and eating patterns and body composition at a 1-year follow-up. Data were drawn from a longitudinal study of 118 children aged 3–5 years. Sleep (duration, midpoint, regularity) and physical activity (PA) were measured by accelerometry over 6 consecutive days; total energy expenditure (TEE) was measured using the doubly labeled water method; body composition (fat mass, fat-free mass, and percent body fat) was measured by DXA; and dietary intake (energy intake, timing) was measured using two 24-hour recalls. Multivariable regression was used to estimate interindividual associations of sleep parameters with body composition, PA, TEE, and dietary outcomes and to examine the relationships between sleep and dietary behaviors and body composition 1 year later. Cross-sectionally, later sleep midpoint is associated with having a greater fat mass (0.33; 95% CI: 0.05, 0.60) and a higher percent body fat (0.92; 95% CI: 0.15, 1.70). Later sleep midpoint was associated with delayed morning mealtimes (0.51; 95% CI: 0.28, 0.74) and evening mealtimes (0.41; 95% CI: 0.29, 0.53), higher nighttime energy intakes (45.6; 95% CI: 19.7, 71.4), and lower morning energy intakes (−44.8; 95% CI: −72.0, −17.6). Longitudinally, shorter sleep duration (−0.02; 95% CI: −0.03, 0.00) and later meal timing (0.83; 95% CI: 0.24, 1.42) were associated with higher percent body fat measurements 1 year later. Shorter sleep duration and later meal timing are associated with adiposity gains in preschoolers.

Skin carotenoid measurement by reflection spectroscopy (RS) offers a non-invasive biomarker of carotenoid intake, but feasibility, reliability, and validity are not established in infants. To determine feasibility and reliability of 4 month-old infant skin carotenoid score (SCS) measurement and its correlation with total carotenoid intake and plasma concentrations. : SCSs were measured in a prospective, observational study by a modified, portable RS device at the index finger and heel of the foot in 4-months olds (n = 21). Infant plasma, human milk, and formula carotenoid concentrations were measured by HPLC-PDA, and carotenoid intake was estimated from 7-day food diaries corrected for actual milk carotenoid content. Mean SCS, time to acquire measurements, replicate intraclass correlations, and bivariate correlations between SCS, carotenoid intake, and plasma carotenoids were examined. Exploratory analyses of returning 6- (n = 12), and 8- (n = 9) month old infants were conducted. Mean ± SD finger and heel SCS in 4, 6, and 8-month-olds were 92 ± 57 and 92 ± 51; 109 ± 41 and 119 ± 44; and 161 ± 89 and 197 ± 128 units, respectively. Replicate SCS measurements were reliable, with high intra-correlation (≥0.70) within subject-visits. Four-month olds’ finger SCSs were correlated with carotenoid intake (rho = 0.48, P = 0.0033), and finger and heel SCS were correlated with total plasma carotenoid concentrations (rho = 0.71, P < 0.0001 and rho = 0.57, P = 0.0006, respectively). Eight-month olds’ finger and heel SCSs were correlated with total carotenoid intake (rho = 0.73, P < 0.001; rho = 0.58, P = 0.0014, respectively), while SCSs in 6-month olds’, in transition from exclusive milk to complementary feeding, did not correlate with plasma carotenoid or dietary carotenoids, despite correlation between plasma and dietary carotenoid intake (rho = 0.86, P = 0.0137). Mixed models suggest plasma total carotenoid concentration, age, carotenoid intake, and age*carotenoid intake, but not measurement site, are determinants of infant SCS. Infant skin carotenoids are feasibly and reliably measured by RS, and may provide a biomarker of carotenoid intake in 4-month olds. ClinicalTrials.gov [NCT03996395].

Background: Television viewing among children is associated with developmental and health outcomes, yet measurement techniques for television viewing are prone to errors, biases, or both. Objective: This study aims to develop a system to objectively and passively measure children’s television viewing time. Methods: The Family Level Assessment of Screen Use in the Home-Television (FLASH-TV) system includes three sequential algorithms applied to video data collected in front of a television screen: face detection, face verification, and gaze estimation. A total of 21 families of diverse race and ethnicity were enrolled in 1 of 4 design studies to train the algorithms and provide proof of concept testing for the integrated FLASH-TV system. Video data were collected from each family in a laboratory mimicking a living room or in the child’s home. Staff coded the video data for the target child as the gold standard. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each algorithm, as compared with the gold standard. Prevalence and biased adjusted κ scores and an intraclass correlation using a generalized linear mixed model compared FLASH-TV’s estimation of television viewing duration to the gold standard. Results: FLASH-TV demonstrated high sensitivity for detecting faces (95.5%-97.9%) and performed well on face verification when the child’s gaze was on the television. Each of the metrics for estimating the child’s gaze on the screen was moderate to good (range: 55.1% negative predictive value to 91.2% specificity). When combining the 3 sequential steps, FLASH-TV estimation of the child’s screen viewing was overall good, with an intraclass correlation for an overall time watching television of 0.725 across conditions. Conclusions: FLASH-TV offers a critical step forward in improving the assessment of children’s television viewing.

The association of prenatal phthalate exposure with physical reasoning was assessed in 159 (78 female; 81 male) 4.5-month-old infants from a prospective cohort. Phthalate metabolites were quantified in urine from 16–18 gestational weeks and a pool of five urines from across pregnancy. Infants’ looking times to physically impossible and possible events were recorded via infrared eye-tracking. Infants that recognize that one of the events is impossible will look at that event longer. Associations of phthalate biomarkers with looking time differences (impossible–possible) were adjusted for maternal age, infant sex, and order of event presentation, and effect modification by infant sex was assessed. Each interquartile range (IQR) increase of monoethyl phthalate in the pooled sample was associated with females’ increased looking time (β = 1.0; 95%CI = 0.3, 1.7 s) to the impossible event. However, for males, an IQR increase in monoethyl phthalate at 16–18 weeks (β = −2.5; 95%CI = −4.4,−0.6 s), the sum of di(isononyl) phthalate metabolites in the pooled sample (β = −1.0; 95%CI = −1.8, −0.1 s), and the sum of all phthalate metabolites in both samples (β = −2.3; 95%CI = −4.4, −0.2 s) were associated with increased looking to the possible event, suggesting that higher prenatal phthalate exposure is associated with poorer physical reasoning in male infants.