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Measurements of liver volume from MR images can be valuable for both clinical and research applications. Automated methods using convolutional neural networks have been used successfully for this using a variety of different MR image types as input. In this work, we sought to determine which types of magnetic resonance images give the best performance when used to train convolutional neural networks for liver segmentation and volumetry. Abdominal MRI scans were performed at 3 Tesla on 42 adolescents with obesity. Scans included Dixon imaging (giving water, fat, and T2* images) and low-resolution T2-weighted scout images. Multiple convolutional neural network models using a 3D U-Net architecture were trained with different input images. Whole-liver manual segmentations were used for reference. Segmentation performance was measured using the Dice similarity coefficient (DSC) and 95% Hausdorff distance. Liver volume accuracy was evaluated using bias, precision, intraclass correlation coefficient, normalized root mean square error (NRMSE), and Bland-Altman analyses. The models trained using both water and fat images performed best, giving DSC = 0.94 and NRMSE = 4.2%. Models trained without the water image as input all performed worse, including in participants with elevated liver fat. Models using the T2-weighted scout images underperformed the Dixon-based models, but provided acceptable performance (DSC ≥ 0.92, NMRSE ≤ 6.6%) for use in longitudinal pediatric obesity interventions. The model using Dixon water and fat images as input gave the best performance, with results comparable to inter-reader variability and state-of-the-art methods.

BACKGROUND: There are limited data comparing the relative associations of various BMI metrics with adiposity and cardiometabolic risk factors in youth. OBJECTIVE: Examine correlations of 7 different BMI metrics with adiposity, cardiometabolic risk factors, and biomarkers (i.e. blood pressure, waist circumference, cholesterol, leptin, insulin, high molecular weight adiponectin, high-sensitivity c-reactive protein (hsCRP)). METHODS: This was a cross-sectional analysis of youth in all BMI categories. BMI metrics: BMI z-score (BMIz), extended BMIz (ext. BMIz), BMI percentile (BMIp), percent of the BMI 95th percentile (%BMI(p95)), percent of the BMI median (%BMI(p50)), triponderal mass index (TMI), and BMI (BMI). Correlations between these BMI metrics and adiposity, visceral adiposity, cardiometabolic risk factors and biomarkers were summarized using Pearson’s correlations. RESULTS: Data from 371 children and adolescents ages 8–21 years old were included in our analysis: 52% were female; 20.2% with Class I obesity, 20.5% with Class II, and 14.3% with Class III obesity. BMIp consistently demonstrated lower correlations with adiposity, risk factors, and biomarkers (r = 0.190–0.768) than other BMI metrics. The %BMI(p95) and %BMI(p50) were marginally more strongly correlated with measures of adiposity as compared to other BMI metrics. The ext.BMIz did not meaningfully outperform BMIz. CONCLUSION: Out of all the BMI metrics evaluated, %BMI(p95) and %BMI(p50) were the most strongly correlated with measures of adiposity. %BMI(p95) has the benefit of being used currently to define obesity and severe obesity in both clinical and research settings. BMIp consistently had the lowest correlations. Future research should evaluate the longitudinal stability of various BMI metrics and their relative associations with medium to long-term changes in adiposity and cardiometabolic outcomes in the context of intervention trials.

Aim: We assessed reproducibility of endothelial microparticles (EMPs) enumeration among youth. Methods & results: Four microparticle (MP) indices – total MP per microliter platelet free plasma (PFP), total EMPs per microliter PFP, percent activated EMPs and percent lactadherin positive (LACT[+]) of total EMPs – were measured at two visits (baseline and 7 ± 3 days follow-up) to determine reproducibility overall and by obesity status. We examined CD31+ or CD144+ with CD41-EMP events of size 0.3–1.0 μm. No statistically significant differences were observed between visits for any of the four MP indices. The within-participant and between-participant coefficient of variation was acceptable (range: 1.13–2.37) with good intraclass-correlation coefficient for all indices except total MP per microliter (range: 0.10–1.00). Conclusion: Total EMPs per microliter PFP, percent-activated EMPs and percent LACT(+) of total EMPs are reproducible among youth.

Purpose: Many adult survivors of childhood cancer are at high-risk of developing cardiovascular disease. Cancer therapy may cause damage to the vascular endothelium, thereby initiating atherosclero...

ObjectivePrevious research suggests attention and white matter (WM) abnormalities in individuals with mucopolysaccharidosis type I (MPS I); this cross-sectional comparison is one of the first to examine the relationship of WM structural abnormalities as measured by corpus callosum (CC) volumes with attention scores to evaluate this relationship in a larger sample of patients with MPS I.MethodsVolumetric MRI data and performance on a computerized measure of sustained attention were compared for 18 participants with the severe form of MPS I (MPS IH), 18 participants with the attenuated form of MPS I (MPS IATT), and 60 typically developing age-matched controls.ResultsThe MPS I groups showed below-average mean attention scores (p < 0.001) and smaller CC volumes (p < 0.001) than controls. No significant associations were found between attention performance and CC volume for controls. Attention was associated with posterior CC volumes in the participants with MPS IH (p = 0.053) and total (p = 0.007) and anterior (p < 0.001) CC volumes in participants with MPS IATT.ConclusionsWe found that attention and CC volumes were reduced in participants with MPS I compared to typically developing controls. Smaller CC volumes in participants with MPS I were associated with decreased attention; such an association was not seen in controls. While hematopoietic cell transplantation used to treat MPS IH may compound these effects, attention difficulties were also seen in the MPS IATT group, suggesting that disease effects contribute substantially to the clinical attentional difficulties seen in this population.

Background: Studies examining the association between hedonic hunger, that is, having frequent thoughts about food in the absence of an energy deficit, and obesity in youth show mixed results. This may be due to the confounding effect of binge eating, which has been associated with both hedonic hunger and obesity. The purpose of this study was to determine the extent to which hedonic hunger is associated with obesity independent of binge eating in youth. Methods: Data for this cross-sectional study were collected from youth enrolled in a larger study of cardiovascular disease and obesity. Linear regression models were used to assess the association between hedonic hunger measured by Power of Food Scale (PFS) and binge eating measured by Eating Disorder Examination-Questionnaire, on percent of the 95th BMI percentile (BMIp95). Results: Among 269 participants (mean age 12.8 years), 16.4% endorsed binge eating. PFS was positively associated with BMIp95 with a difference in percent of BMIp95 of 5.9% [95% confidence interval (1.5–10.3), p = 0.009]. However, when binge eating was added to the model, the relationship between PFS and BMIp95 was no longer significant. Conclusion: Hedonic hunger, above and beyond binge eating, may not be associated with BMI. Future research should examine whether screening for and targeting binge eating rather than hedonic hunger in weight management care may have more impact on obesity outcomes. Clinical Trial Registration number: NCT01508598.

Summary Background Weight loss in children and adolescents with type 2 diabetes (T2D) is associated with improved glycaemic control. Objectives To assess the effects of liraglutide vs placebo on body mass index (BMI) and weight parameters in children and adolescents with T2D using data from the ellipse trial (NCT01541215). Methods The ellipse trial randomized participants (10‐85th percentile, T2D, glycated haemoglobin [HbA1c] 7.0%‐11.0% [if diet‐ and exercise‐treated] or 6.5% to 11.0% [if treated with metformin, basal insulin or both]) to liraglutide or placebo. This post‐hoc analysis evaluated changes from baseline to weeks 26 and 52 in absolute BMI, percent change in BMI and other weight‐related parameters. Changes were assessed by liraglutide overall (all doses) and liraglutide by dose (0.6, 1.2 and 1.8 mg/day) vs placebo using a pattern mixture model of observed data, with missing observations imputed from each treatment group. Results In total, 134 participants were included. There were statistically significant differences between groups in certain parameters, including absolute BMI (estimated treatment difference [ETD] –0.89 kg/m2; 95% confidence interval [CI] –1.71,–0.06) and percent change in BMI (ETD –2.73%; 95% CI –5.15,–0.30) at week 52, but none at week 26. Dose‐dependent effects were not observed for liraglutide vs placebo for all BMI/weight parameters. Conclusions Compared with placebo, liraglutide was associated with statistically significant reductions in BMI/weight parameters at week 52, but not week 26, in children and adolescents with T2D.

Background Circulating endothelial cells (CECs) reflect early changes in endothelial health; however, the degree to which CEC number and activation is related to adiposity and cardiovascular risk factors in youth is not well described. Methods and Results Youth in this study (N=271; aged 8–20 years) were classified into normal weight (body mass index [BMI] percentage P >0.05). Youth with severe obesity had a higher degree of CEC activation compared with normal weight youth (8.3%; 95% CI, 1.1–15.6 [ P =0.024]). Higher CEC number was associated with greater body fat percentage (0.02 per percentage; 95% CI, 0.00–0.03 [ P =0.020]) and systolic blood pressure percentile (0.01 per percentage; 95% CI, 0.00–0.01 [ P =0.035]). Higher degree of CEC activation was associated with greater visceral adipose tissue (5.7% per kg; 95% CI, 0.4–10.9 [ P =0.034]) and non–high‐density lipoprotein cholesterol (0.11% per mg/dL; 95% CI, 0.01–0.21 [ P =0.039]). Conclusions Methods of CEC quantification are associated with adiposity and cardiometabolic risk factors and may potentially reflect accelerated atherosclerosis as early as childhood.

PurposeWe describe the item development and cognitive evaluation process used in creating the Prevention of Lower Urinary Tract Symptoms Bladder Health Instrument (PLUS-BHI).Materials and methodsQuestions assessing bladder health were developed using reviews of published items, expert opinion, and focus groups' transcript review. Candidate items were tested through cognitive interviews with community-dwelling women and an online panel survey. Items were assessed for comprehension, language, and response categories and modified iteratively to create the PLUS-BHI.ResultsExisting measures of bladder function (storage, emptying, sensation components) and bladder health impact required modification of time frame and response categories to capture a full range of bladder health. Of the women 167 (18-80 years old) completed individual interviews and 791 women (18-88 years) completed the online panel survey. The term "bladder health" was unfamiliar for most and was conceptualized primarily as absence of severe urinary symptoms, infection, or cancer. Coping mechanisms and self-management strategies were central to bladder health perceptions. The inclusion of prompts and response categories that captured infrequent symptoms increased endorsement of symptoms across bladder function components.ConclusionsBladder health measurement is challenged by a lack of awareness of normal function, use of self-management strategies to mitigate impact on activities, and a common tendency to overlook infrequent lower urinary tract symptoms. The PLUS-BHI is designed to characterize the full spectrum of bladder health in women and will be validated for research use.

Summary Background Lower urinary tract symptoms (LUTS) are common in children and adolescents. Non-invasive tests evaluating bladder function are generally preferred over invasive tests, yet few studies have explored the range of normative values for these tests in healthy, asymptomatic children. Objective To define normative reference ranges for non-invasive tests of bladder function in healthy, asymptomatic girls and adolescents. Study design A comprehensive search strategy was performed in seven electronic databases through October 2019. English-language studies reporting data on voiding frequency, voided and postvoid residual volumes (PVR) and uroflowmetry results in healthy, asymptomatic girls (mean age ≥ 5 years) were included. Two independent reviewers performed study review, data extraction, and quality assessment. Overall mean estimates and 95% confidence intervals for each bladder function parameter were calculated using random effects models, and 95% normative reference values were estimated. Results Ten studies met eligibility criteria for the meta-analysis (n = 2143 girls, age range: 3–18). Mean estimates of maximum voided volume and PVR were 233.4 ml (95% CI 204.3–262.6; n = 1 study) and 8.6 ml (95% CI 4.8–12.4; n = 2 studies) respectively. Pooled mean estimates for uroflowmetry parameters were: 21.5 ml/s (95% CI 20.5–2.5) for maximum flow rate (n = 6 studies), 12.5 ml/s (95% CI 11.2–13.8) for mean flow rate (n = 6 studies), 6.8 s (95% CI 4.4–9.3) for time to maximum flow (n = 3 studies), 15.7 s (95% CI 13.0–18.5) for flow time (n = 3 studies), and 198.7 ml (95% CI 154.2–234.2) for voided volume (n = 9 studies). No studies reported estimates of voiding frequency. Between-study heterogeneity was high (89.0–99.6%). Conclusions Although we were able to calculate pooled mean estimates for several parameters, the small number of included studies and the wide age ranges of participants preclude generalization of reference values to all healthy girls. Further research is needed to determine normative reference values within specific age groups.

Background The normal rate of subclinical vascular aging from adolescence to young adulthood has not been well‐characterized. We conducted a 5‐year longitudinal study among adolescents with normal‐weight, obesity, and/or type 2 diabetes mellitus to examine trajectories of early vascular aging. Methods and Results Adolescents (mean [SD] age 17.6 [3.5]; 35.3% male) had either normal weight (n=141), obesity (n=156), or type 2 diabetes mellitus (n=151) at baseline. Primary metrics used for early vascular aging included measures of vascular structure (carotid intima‐media thickness [cIMT]; common, internal, and bulb) and arterial stiffness (carotid‐femoral pulse wave velocity, and augmentation index). Longitudinal (5‐year) outcomes were examined using generalized estimating equations adjusting for baseline value, sex, race, and age. Compared with participants with normal weight, those with obesity had greater positive change in common cIMT (0.05 mm [0.03, 0.06]; P P =0.033), internal cIMT (0.03 mm [0.01, 0.05]; P P =0.001), and those with type 2 diabetes mellitus had greater positive change in common cIMT (0.05 mm [0.04, 0.07]; P P P P P P P =0.01), internal cIMT (0.008 mm [0.003, 0.013]; P =0.001), and pulse wave velocity carotid‐femoral (0.066 m/sec [0.002, 0.130]; P =0.042). Conclusions These longitudinal data support the hypothesis that the presence of obesity, type 2 diabetes mellitus, and elevated baseline systolic blood pressure in early life accelerates the progression of risk factors key in the development of early vascular aging.

We investigated the safety, feasibility, and efficacy of transcranial direct current stimulation (tDCS) combined with constraint-induced movement therapy (CIMT) in children and young adults with unilateral cerebral palsy. Twenty participants were randomized to receive active or sham tDCS. The intervention consisted of 10 consecutive weekday sessions of tDCS applied to the non-lesioned hemisphere (20 min) concurrently with CIMT (120 min). Participants, caregivers, and interventionists were blinded to group assignment. The primary safety outcome investigated adverse events. The primary behavioral outcome was the Assisting Hand Assessment. All 20 participants (mean age = 12.7 yrs, range = 7.4–21.6 years) were evaluated for the primary outcomes. No serious adverse events occurred, and the most commonly reported minor adverse events were headache and itchiness. Both groups demonstrated a significant improvement in hand function after the intervention, although no significant effect of tDCS was observed (between-group difference = −2.18, 95% CI = [−6.48, 2.12], p = 0.30). Although hand function improved overall, no significant differences between intervention groups were found. Children with preserved corticospinal tract circuitry from the lesioned hemisphere, compared to those without, showed greater improvement in hand function (mean difference = 3.04, 95% CI = [−0.64, 6.72], p = 0.099). Our study demonstrates the safety and feasibility of serial sessions of tDCS, and presents preliminary evidence for the effect of CST circuitry on outcomes following tDCS/CIMT. Future work in children with unilateral cerebral palsy should focus on the optimal dosing and consider individual brain circuitry when describing response to combined interventions. Clinical Trials Registration Clinicaltrials.gov NCT 02250092 .

Background. Neurorehabilitation interventions in children with unilateral cerebral palsy (UCP) target motor abilities in daily life yet deficits in hand skills persist. Limitations in the less-affected hand may affect overall bimanual hand skills. Objective. To compare hand function, by timed motor performance on the Jebsen-Taylor Test of Hand Function (JTTHF) and grip strength of children with UCP to children with typical development (CTD), aged 8 to 18 years old. Exploratory analyses compared hand function measures with regard to neurophysiological outcomes measured by transcranial magnetic stimulation and between group comparisons of hemispheric motor threshold. Methods. Baseline hand skills were evaluated in 47 children (21 UCP; 26 CTD). Single-pulse transcranial magnetic stimulation testing assessed corticospinal tract and motor threshold. Results. The mean difference of the less-affected hand of children with UCP to the dominant hand of CTD on the JTTHF was 21.4 seconds (95% CI = 9.32-33.46, P = .001). The mean difference in grip strength was −30.8 N (95% CI = −61.9 to 0.31, P = .052). Resting motor thresholds between groups were not significant, but age was significantly associated with resting motor threshold ( P < .001; P = .001). Children with UCP ipsilateral pattern of motor representation demonstrated greater mean differences between hands than children with contralateral pattern of motor representation ( P < .001). All results were adjusted for age and sex. Conclusions. The less-affected hand in children with UCP underperformed the dominant hand of CTD. Limitations were greater in children with UCP ipsilateral motor pattern. Rehabilitation in the less-affected hand may be warranted. Bilateral hand function in future studies may help identify the optimal rehabilitation and neuromodulatory intervention.

Transcranial direct current stimulation (tDCS) is increasingly researched as an adjuvant to motor rehabilitation for children with hemiparesis. The optimal method for the primary motor cortex (M1) somatotopic localization for tDCS electrode placement has not been established. The objective, therefore, was to determine the location of the M1 derived using the 10/20 electroencephalography (EEG) system and transcranial magnetic stimulation (TMS) in children with hemiparesis (CWH) and a comparison group of typically developing children (TDC). We hypothesized a difference in location for CWH but not for TDC. The 2 locations were evaluated in 47 children (21 CWH, 26 TDC). Distances between the locations were measured pending presence of a motor evoked potential. Distances between the EEG and TMS locations that exceeded the 2.5 cm × 2.5 cm rubber electrode area are reported in percentages [95% confidence interval] in CWH—nonlesioned hemisphere was 68.8% [41.3-89.0], lesioned: 85.7% [57.2-98.2]; TDC—dominant hemisphere 73.9% [51.6-89.8], nondominant: 82.6% [61.2-95.0]. Distances that exceeded the 3 × 5 cm electrode sponge area in CWH—nonlesioned was 25.0% [7.3-52.4], lesioned was 28.6% [8.4-58.1]; TDC—dominant was 52.2% [30.6-73.2], nondominant was 43.5 [23.2-65.5]). Distances that exceeded the 5 × 7 cm electrode sponge area in CWH—nonlesioned was 18.8% [4.0-45.6] and lesioned was 21.4% [4.7-50.8]; TDC—dominant was 21.7% [7.5-43.7] and nondominant was 26.1% [10.2-48.4]. Individual variability in brain somatotopic organization may influence surface scalp localization of underlying M1 in children regardless of neurologic impairment. Findings suggest further investigation of optimal tDCS electrode placement. EEG and TMS methods reveal variability in localizing M1 in children regardless of stroke diagnosis. This study was registered on clinicaltrials.gov NCT020I5338.

Background Mucopolysaccharidosis I (MPS IH) is a lysosomal storage disease treated with hematopoietic cell transplantation (HCT) because it stabilizes cognitive deterioration, but is insufficient to alleviate all somatic manifestations. Intravenous laronidase improves somatic burden in attenuated MPS I. It is unknown whether laronidase can improve somatic disease following HCT in MPS IH. The objective of this study was to evaluate the effects of laronidase on somatic outcomes of patients with MPS IH previously treated with HCT. Methods This 2-year open-label pilot study of laronidase included ten patients (age 5–13 years) who were at least 2 years post-HCT and donor engrafted. Outcomes were assessed semi-annually and compared to historic controls. Results The two youngest participants had a statistically significant improvement in growth compared to controls. Development of persistent high-titer anti-drug antibodies (ADA) was associated with poorer 6-min walk test (6MWT) performance; when patients with high ADA titers were excluded, there was a significant improvement in the 6MWT in the remaining seven patients. Conclusions Laronidase seemed to improve growth in participants

Central nervous system manifestations of mucopolysaccharidosis type I (MPS I) such as cognitive impairment, hydrocephalus, and spinal cord compression are inadequately treated by intravenously-administered enzyme replacement therapy with laronidase (recombinant human alpha-L-iduronidase). While hematopoietic stem cell transplantation treats neurological symptoms, this therapy is not generally offered to attenuated MPS I patients. This study is a randomized, open-label, controlled pilot study of intrathecal laronidase in eight attenuated MPS I patients with cognitive impairment. Subjects ranged between 12years and 50years old with a median age of 18years. All subjects had received intravenous laronidase prior to the study over a range of 4 to 10years, with a mean of 7.75years. Weekly intravenous laronidase was continued throughout the duration of the study. The randomization period was one year, during which control subjects attended all study visits and assessments, but did not receive any intrathecal laronidase. After the first year, all eight subjects received treatment for one additional year. There was no significant difference in neuropsychological assessment scores between control or treatment groups, either over the one-year randomized period or at 18 or 24months. However, there was no significant decline in scores in the control group either. Adverse events included pain (injection site, back, groin), headache, neck spasm, and transient blurry vision. There were seven serious adverse events, one judged as possibly related (headache requiring hospitalization). There was no significant effect of intrathecal laronidase on cognitive impairment in older, attenuated MPS I patients over a two-year treatment period. A five-year open-label extension study is underway.

INTRODUCTION Subclinical cardiovascular risks of secondhand smoke (SHS) exposure among children and adolescents remains insufficiently described. METHODS This was a cross-sectional study of 298 children and adolescents (48.0% male, body mass index: 27.0±8.9kg/m2), including 49 self-reported cases with SHS. Arterial elasticity and stiffness (distensibility, compliance, incremental elastic modulus [IEM]) were obtained via ultrasound imaging in the abdominal aorta, brachial, and carotid arteries. A one-way analysis of variance compared differences between groups, and multiple linear regression adjusted for covariates. RESULTS SHS was associated with lower abdominal aorta diameter distensibility (aDD) (13.4±3.6% vs. 16.0±5.2%, p=0.009), and abdominal aorta cross-sectional distensibility (aCSD) (28.8±8.3% vs. 35.1±12.2% p=0.009), as well as higher abdominal aorta IEM (aIEM) (1241±794mmHg vs. 935±388mmHg, p=0.001). After adjustment for covariates, aDD (p=0.047), aCSD (p=0.040), and aIEM (p=0.017) remained significant; this significance persisted with the additional adjustment of percent body fat. Measures of brachial and carotid compliance and distensibility were not associated with SHS. CONCLUSIONS SHS was associated with abdominal aorta stiffness; the majority of vascular measures within the brachial and carotid artery remained unaffected following adjustment for covariates, including hypertension and adiposity. SHS may predispose individuals to increased abdominal aorta stiffness, an artery previously reported to exhibit increased susceptibility to atherosclerosis.

Background: Epidemiologic observations have raised hypotheses regarding increased potato consumption as a correlate of weight gain, adiposity and diabetes risk, while nut consumption has been associated with weight control and metabolic health Furthermore, human diets are complex with phytochemicals potentially impacting the digestion and absorption of macro-and micronutrients We asked whether increased daily consumption of potatoes influences energy balance relative to almonds Methods: A randomized, controlled trial (30-day) of adult humans (n=180) prescribed daily, calorie-matched (300 kcal/day, n=60 subjects/group) consumption of either 1) almonds, 2) white potato French fries, or 3) white potato French fries with spices selected for alpha-glucosidase inhibitory properties Subjects were measured at baseline and completion (30-days) for primary (body fat measured by dual-energy x-ray absorptiometry, DXA) and secondary outcomes (body weight and markers of carbohydrate metabolism and insulin resistance) Results: A total of n=180 subjects were randomized to treatment groups, with sex (67 78% female), age (mean±SD, 30 35±8 74 years), BMI (26 11±4 15 kg/m2) and weight (75 56±15 44 kg) at baseline There were n=12 dropouts and n=3 terminations due to COVID19 follow-up limitations Change (completion minus baseline) in total fat mass by DXA was not significantly different among groups (mean (95% CI);Almonds: 214 88g (-5 15,434 92);Potatoes: 18 55g (-207 40,244 51);Potatoes+Spice mix: 231 05g (-1 33,463 43);p=0 347), nor change in fasting glucose (p=0 413), insulin (p=0 301) or HbA1c (p=0 234) Change in body weight was significantly different among groups (p=0 013;Almonds: 0 46kg (0 09,0 84);Potatoes: -0 26kg (-0 65,0 13);Potatoes+Spice mix: 0 45kg (0 06,0 85) Conclusions: There was no significant difference in the primary outcome of body fat change with 30 days of consumption of potatoes versus almonds

The purposes of this study were to characterize the impact of depression and anxiety on the severity of obesity among youth seeking weight management treatment and to determine the extent to which emotional eating mediates the relationship between depression and/or anxiety and degree of obesity. This cross-sectional, retrospective chart review of 102 adolescent patients from a weight management clinic analyzed demographics, body mass index, depression (Patient Health Questionnaire-9), and anxiety (Generalized Anxiety Disorder Scale-7) screens and the Child Eating Behavior Questionnaire, Emotional Over-Eating subscale. After adjusting for demographics and emotional eating, the odds of having severe obesity versus obesity were 3.5 times higher for patients with depression compared with those without (odds ratio [OR] = 3.5; 95% CI = 1.1, 11.3; P = .038) and nearly 5 times higher for those with anxiety (OR = 4.9; CI = 1.2, 20.9; P = .030). Emotional eating, however, was not a mediator between depression/anxiety and degree of adiposity.

Introduction: We examined the reproducibility of circulating endothelial cells (CEC) enumeration and activation among youth. Materials and methods: CECs from 151 youth were measured at baseline and 1 week follow-up. Enumeration of CEC in fresh whole blood was determined by direct assessment of buffy coat smears (CD146+ nucleated cells) and activated CEC (%VCAM-1 expression) was determined after immunomagnetic enrichment and co-staining of nuclei, plus positivity for P1H12 and VCAM-1. Results: No statistically significant difference in CEC enumeration (1.2 ± 2.5 vs 1.3 ± 2.2 CEC/milliliter of whole blood, p = 0.745) or activated CEC (57.1 ± 24.4 vs 58.0 ± 21.3 %VCAM-1, p = 0.592) between baseline and 1 week follow-up. Conclusion: On a cohort basis, CEC enumeration and activation are reproducible in youth. Relatively high individual biological variability may limit its clinical utility.

OBJECTIVE This study aimed to examine whether 1-month BMI improvement is predictive of superior 6- and 12-month BMI changes in a national sample of youth in pediatric weight management treatment. METHODS Participants were 4- to 18-year-olds from the Pediatric Obesity Weight Evaluation Registry, a prospective study collecting data from 31 pediatric weight management programs across the United States. Response at 1 month was defined as ≥ 3% BMI reduction; success at 6 and 12 months was defined as ≥ 5% BMI reduction from baseline. Analyses used linear and logistic regression with robust variance estimation. RESULTS Primary analyses were completed with 687 participants (mean age 12.2 years). One-month responders demonstrated significant improvements in BMI compared with nonresponders at 6 months (BMI, -2.05 vs. 0.05; %BMI, -5.81 vs. 0.23; P

OBJECTIVE: To evaluate the relationships of depression and anxiety symptoms with CVD risk factors and measures of vascular health in youth. Major Depressive Disorder and Bipolar Disorder are considered cardiovascular disease (CVD) risk factors in youth. STUDY DESIGN: Participants (n=202) were 8-18-year-olds from a cross-sectional study evaluating cardiovascular health across a wide range of BMI values (normal weight to severe obesity). CVD risk measurement included blood pressure, fasting lipids, glucose, insulin, carotid artery intima-media thickness, compliance and distensibility, brachial artery flow-mediated dilation, carotid-radial artery pulse wave velocity, body fat percentage, and a metabolic syndrome cluster score. Anxiety and depression symptoms were self-reported on the Screen for Child Anxiety Related Disorders and Center of Epidemiological Studies Depression Scale for Children. Two sets of adjustment variables were used in evaluation of differences between those with and without anxiety or depression symptomatology for the CVD risk factor and vascular outcomes. The first set included adjustment for Tanner stage, sex, and race; the second additionally adjusted for percent body fat. RESULTS: Anxiety was not significantly associated with CVD risk factors or vascular health in either model. Depression was associated with HDL cholesterol, triglycerides, and metabolic syndrome cluster score; these relationships were attenuated when accounting for percent body fat. CONCLUSIONS: When accounting for body fat, we found no clear relationship of self-reported depression or anxiety symptoms with CVD risk factors or vascular health in youth.

Background The American Heart Association set 2020 Strategic Impact Goals that defined cardiovascular risk factors to be included in the concept of ideal cardiovascular health ( ICH ). The prevalence of ICH among differing levels of adiposity in youth, especially severe obesity, is uncertain. Methods and Results The cross‐sectional study measured ICH metrics in 300 children and adolescents stratified by adiposity: normal weight, overweight/obese, and severely obese. ICH incorporates 7 behavioral and health metrics, and was characterized as poor, intermediate, or ideal. Individual ICH metrics were transformed into standardized sample z ‐scores; a summary ICH sample z ‐score was also calculated. Multivariable linear regression models were used to estimate differences in ICH sample z ‐scores by adiposity status. Of the 300 participants, 113 were classified as having normal weight, 87 as having overweight/obesity, and 100 as having severe obesity (mean age 12.8 years, SD 2.7; 48% female). No participants met the criteria for ICH ; 80% of those classified as having normal weight, 81% of those with overweight/obesity, and all of those with severe obesity were in poor cardiovascular health. After multivariable adjustment, those with overweight/obesity (sample z ‐score: −1.35; 95% confidence interval, −2.3, −1.1) and severe obesity (sample z ‐score: −1.45; 95% confidence interval, −2.9, −0.92) had lower overall ICH sample z ‐scores compared with participants with normal weight. Results were similar for individual ICH metrics. Conclusions Poor cardiovascular health was highly prevalent in youth; ICH sample z ‐scores increased across levels of adiposity. Youth with obesity, particularly those with severe obesity, remain a rich target for primary prevention efforts. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01508598.

Inflammation, oxidative stress and dysregulation of adipokines are thought to be pathophysiological mechanisms linking obesity to the development of insulin resistance and atherosclerosis. In adults, bariatric surgery reduces inflammation and oxidative stress, and beneficially changes the levels of several adipokines, but little is known about the postsurgical changes among adolescents.In two separate longitudinal cohorts we evaluated change from baseline of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), monocyte chemo-attractant protein-1 (MCP-1), oxidized low-density lipoprotein cholesterol (oxLDL), adiponectin, leptin and resistin up to 12 months following elective laparoscopic Roux-en-Y gastric bypass (RYGB) or vertical sleeve gastrectomy (VSG) surgery in adolescents with severe obesity.In cohort 1, which consisted of 39 adolescents (mean age 16.5±1.6 years; 29 females) undergoing either RYGB or VSG, IL-6 (baseline: 2.3±3.4 pg ml(-1) vs 12 months: 0.8±0.6 pg ml(-1), P0.01), leptin (baseline: 178±224 ng ml(-1) vs 12 months: 41.4±31.9 ng ml(-1), P0.001) and oxLDL (baseline: 41.6±11.6 U l(-1) vs 12 months: 35.5±11.1 U l(-1), P=0.001) significantly decreased and adiponectin significantly increased (baseline: 5.4±2.4 μg ml(-1) vs 12 months: 13.5±8.9 μg ml(-1), P0.001). In cohort 2, which consisted of 13 adolescents (mean age 16.5±1.6 years; 10 females) undergoing RYGB, results were similar: IL-6 (baseline: 1.7±0.9 pg ml(-1) vs 12 months: 0.4±0.9 pg ml(-1), P0.05) and leptin (baseline: 92.9±31.3 ng ml(-1) vs 12 months: 37.3±33.4 ng ml(-1), P0.001) significantly decreased and adiponectin significantly increased (baseline: 6.1±2.9 μg ml(-1) vs 12 months: 15.4±8.0 μg ml(-1), P0.001). When the cohorts were combined to evaluate changes at 12 months, oxLDL also significantly decreased (baseline: 39.8±16.7 U l(-1) vs 12 months: 32.7±11.9 U l(-1), P=0.03).Bariatric surgery produced robust improvements in markers of inflammation, oxidative stress and several adipokines among adolescents with severe obesity, suggesting potential reductions in risk for type 2 diabetes and cardiovascular disease.

Bariatric surgery produces robust weight loss, however, factors associated with long-term weight-loss maintenance among adolescents undergoing Roux-en-Y gastric bypass surgery are unknown. Fifty adolescents (mean±s.d. age and body mass index (BMI)=17.1±1.7 years and 59±11 kg m−2) underwent Roux-en-Y gastric bypass surgery, had follow-up visits at 1 year and at a visit between 5 and 12 years following surgery (Follow-up of Adolescent Bariatric Surgery at 5 Plus years (FABS-5+) visit; mean±s.d. 8.1±1.6 years). A non-surgical comparison group (n=30; mean±s.d. age and BMI=15.3±1.7 years and BMI=52±8 kg m−2) was recruited to compare weight trajectories over time. Questionnaires (health-related and eating behaviors, health responsibility, impact of weight on quality of life (QOL), international physical activity questionnaire and dietary habits via surgery guidelines) were administered at the FABS-5+ visit. Post hoc, participants were split into two groups: long-term weight-loss maintainers (n=23; baseline BMI=58.2 kg m−2; 1-year BMI=35.8 kg m−2; FABS-5+ BMI=34.9 kg m−2) and re-gainers (n=27; baseline BMI=59.8 kg m−2; 1-year BMI=36.8 kg m−2; FABS-5+ BMI=48.0 kg m−2) to compare factors which might contribute to differences. Data were analyzed using generalized estimating equations adjusted for age, sex, baseline BMI, baseline diabetes status and length of follow-up. The BMI of the surgical group declined from baseline to 1 year (−38.5±6.9%), which, despite some regain, was largely maintained until FABS-5+ (−29.6±13.9% change). The BMI of the comparison group increased from baseline to the FABS-5+ visit (+10.3±20.6%). When the surgical group was split into maintainers and re-gainers, no differences in weight-related and eating behaviors, health responsibility, physical activity/inactivity, or dietary habits were observed between groups. However, at FABS-5+, maintainers had greater overall QOL scores than re-gainers (87.5±10.5 vs 65.4±20.2, P

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but cardiovascular disease causes mortality in a significant percentage of survivors. Markers must be developed to predict MPS cardiac risk and monitor efficacy of investigational therapies.MPS patients underwent carotid artery ultrasonography from which carotid intima-media thickness (cIMT) and three measures of arterial stiffness were calculated: carotid artery distensibility (cCSD), compliance (cCSC), and incremental elastic modulus (cIEM). MPS carotid measurements were compared to corresponding data from pediatric and adult healthy cohorts. 33 MPS patients (17 MPS I, 9 MPS II, 4 MPS IIIA, and 3 MPS VI; mean age 12.5 ± 4.7 years), 560 pediatric controls (age 13.1 ± 4.0 years), and 554 adult controls (age 39.2 ± 2.2 years) were studied. Age and sex-adjusted aggregate MPS cIMT (0.56 ± 0.05 mm) was significantly greater than both pediatric (+0.12 mm; 95% CI +0.10 to +0.14 mm) and adult (+0.10 mm; 95% CI +0.06 to +0.14 mm) control cohorts; similar findings were observed for all MPS subtypes. Mean MPS cIMT approximated the 80th percentile of the adult cohort cIMT. MPS patients also demonstrated significantly increased adjusted arterial stiffness measurements, evidenced by reduced cCSD, cCSC, and increased cIEM, compared to pediatric and adult control cohorts. Regardless of treatment, MPS patients demonstrate increased cIMT and arterial stiffness compared to healthy pediatric and adult controls. These data suggest that relatively young MPS patients demonstrate a “structural vascular age” of at least 40 years old.

To compare markers of cardiovascular health in youth diagnosed with attention deficit hyperactivity disorder (ADHD) by the use of stimulant medication with healthy controls.Children and adolescents (n = 85; mean age 11.2 ± 2.8 years; 66 boys) diagnosed with ADHD using a stimulant and 53 siblings without ADHD (mean age 11.1 ± 3.8 years; 28 boys) were included in this cross-sectional study. Measured variables included blood pressure, heart rate (HR), HR variability: SD of the RR interval and low frequency to high frequency ratio, carotid-radial pulse wave velocity, carotid artery augmentation index (AIx), radial artery AIx, brachial artery flow-mediated dilation, and digital reactive hyperemic index.Compared with control patients, participants with ADHD had greater resting systolic blood pressure (3.9 mm Hg, 95% CI [1.2-6.7], P = .005), diastolic blood pressure (5.5 mm Hg, 95% CI [3.2-7.8], P .001), HR (9.2 beats/min, 95% CI [6.0-12.3], P .001), low frequency to high frequency ratio (0.55, 95% CI [0.22-0.89], P = .001), carotid AIx (7.2%, 95% CI [1.9-12.5], P = .008), and pulse wave velocity (0.36 m/s, 95% CI [-0.05, 0.78], P = .089), and lower SD of the RR interval (-33.7 milliseconds, 95% CI [-46.1, -21.3], P .001). Neither flow-mediated dilation nor reactive hyperemic index was significantly different.Children and adolescents being treated with a stimulant medication for ADHD exhibited signs of altered cardiac autonomic function, characterized by increased sympathetic tone, and showed evidence of arterial stiffening.

Treatments for mucopolysaccharidoses (MPSs) have increased longevity, but coronary artery disease (CAD) and cardiovascular complications cause mortality in a high percentage of patients. Non-invasive measures of sub-clinical atherosclerosis, such as carotid intima-media thickness (cIMT) and arterial stiffness, may be useful for prediction of CAD outcomes in MPS patients.The aim of the study was to determine if cIMT and arterial stiffness are abnormal in MPS I and II patients compared to healthy controls.MPS patients underwent carotid artery ultrasonography, and electronic wall-tracking software was used to measure cIMT, carotid artery cross-sectional compliance (cCSC), cross-sectional distensibility (cCSD), and incremental elastic modulus (cIEM). Control data from healthy subjects were obtained from a different study that utilized identical testing within the same laboratory.A total of 406 healthy controls and 25 MPS patients (16 MPS I, 9 MPS II) were studied. All MPS patients had or were receiving treatment: 15 patients (6 MPS I, 9 MPS II) were receiving enzyme replacement therapy (ERT), 9 patients (all MPS I) had received hematopoietic stem cell transplant (HSCT), and 1 patient with MPS I had received HSCT and was receiving enzyme replacement therapy (ERT). MPS patients had significantly higher mean (± SD) cIMT (0.56 ± 0.05 mm) compared to controls (0.44 ± 0.04 mm; adjusted p0.001). MPS patients also had increased stiffness compared to controls, showing significantly lower cCSC (0.14 ± 0.09 mm(2)/mmHg versus 0.16 ± 0.05 mm(2)/mmHg; adjusted p=0.019), and higher cIEM (1362 ± 877 mmHg versus 942 ± 396 mmHg; adjusted p0.001). cCSD in MPS patients was lower than that of controls (29.7 ± 16.4% versus 32.0 ± 8.2%) but was not statistically significant; p=0.12. Among MPS patients, cCSD showed a significant association with cIMT (p=0.047), while the association between cIEM and cIMT approached significance (p=0.077). No significant differences were observed in cIMT, cCSD, cCSC, and cIEM between MPS I and MPS II patients.Despite treatment, MPS patients had higher cIMT compared to healthy controls, indicating this marker of sub-clinical atherosclerosis may be a useful predictor of CAD outcomes. The association of arterial stiffness measures with cIMT suggests that mechanical and structural changes may occur in concert among MPS patients. Although yet to be confirmed, increased cIMT and arterial stiffness in MPS I and II patients may be a consequence of inflammatory signaling pathways triggered by heparan or dermatan sulfate-derived oligosaccharides. Prospective, longitudinal studies will need to be performed in order to evaluate the usefulness of these carotid measurements as predictors of adverse CAD outcomes in MPS patients.

PURPOSE: Skeletal disease causes significant morbidity in mucopolysaccharidoses (MPS), and bone remodeling processes in MPS have not been well characterized. The objective of this study was to determine if biomarkers of bone turnover are abnormal in children with specific MPS disorders (i.e. MSP-I, MPS-II, and MPS-VI) compared to healthy children. METHODS: A cross-sectional study was performed of serum biomarkers of bone formation (bone-specific alkaline phosphatase [BSAP], osteocalcin) and urine biomarkers of bone resorption (pyridinoline, deoxypyridinoline) in MPS and healthy controls. Measures of physical function and pain were obtained using the Children’s Health Questionnaire (CHQ). RESULTS: The cohort consisted of 39 children with MPS (MPS-I = 26; MPS-II = 11; MPS-VI = 4) and 51 healthy children. Adjusting for sex and Tanner stage group, MPS individuals had statistically significant increases for osteocalcin ( p< 0.001), with trends toward higher BSAP (p = 0.054) and urinary pyridinoline (p = 0.084). These biomarkers were not significantly associated with CHQ bodily pain and physical-function scores. CONCLUSION: Osteocalcin was increased in children with MPS disorders, with trends for increases in BSAP and urinary pyridinoline, suggesting that bone remodeling is altered in children with MPS. Future studies to assess the ability of these biomarkers to quantify and monitor MPS skeletal disease in response to therapy are needed.

To determine muscular strength differences in patients with MPS-I, II, and VI versus age- and sex-matched healthy controls.Dominant leg isokinetic knee extension strength was measured at 90 and 120 degrees per second (d/s) using a dynamometer in 30 subjects with MPS and 42 controls (5-16 yrs). MPS-I was further divided into MPS-IA (attenuated) and MPS-IH (severe). Strength measures analyzed were peak torque (PkT), peak torque per unit body weight (PkT/BW) and per unit lean body mass (PkT/LBM), and average power (AP).Following adjusting strength measures for age, MPS-IH and MPS-II had significantly lower strength measures for all variables at both angular velocities. MPS-VI had significantly lower PkT, PkT/LBM, and AP compared to controls at 90 and 120d/s. In contrast, MPS-IA was not significantly different from controls for any strength variable at either angular velocity.The results of this study suggest that decrements in skeletal muscle strength depend on MPS diagnosis and severity of disease. Children with MPS-IH demonstrate the greatest difference in muscular strength compared to healthy controls.

Phentermine is the most widely prescribed obesity medication in adults, yet studies of its use in the pediatric population are limited. We conducted a retrospective chart review of adolescents with obesity treated in a pediatric weight management clinic to examine the weight loss effectiveness of phentermine added to standard of care (SOC) lifestyle modification therapy versus SOC alone. All patients receiving phentermine plus SOC (n=25) were matched with a comparison group receiving only SOC (n=274). Differences at 1, 3 and 6 months were evaluated using generalized estimated equations adjusting for age, sex and baseline body mass index (BMI) and robust variance standard error estimates for confidence intervals and P-values. Phentermine use was associated with a greater percent change in BMI at 1 month (-1.6%; 95% confidence interval (CI): -2.6, -0.6%; P=0.001), 3 months (-2.9%; 95% CI: -4.5, -1.4%; P

Children and adults with the lysosomal storage diseases mucopolysaccharidosis (MPS) types I, II and VI live shortened lives permeated by chronic pain and physical disability. Current treatments do not alleviate these problems. Thus there is a critical need to understand the mechanism of chronic pain and disability in MPS in order to improve the way we treat patients. A potential target is inflammation.We hypothesized that excessive inflammation mediated by the tumor necrosis factor-α (TNF-α) inflammatory pathway is the fundamental cause of much of the chronic pain and physical disability in MPS.55 patients with MPS I, II, or VI were enrolled over the course of a 5-year prospective longitudinal natural history study and evaluated annually for 2-5years. 51 healthy controls were enrolled in a separate cross-sectional study of bone and energy metabolism. TNF-α was measured by ELISA. Pain and physical disability were measured by the Children's Health Questionnaire - Parent Form 50 (CHQ-PF50). Differences in log-transformed TNF-α levels and associations with CHQ domains were evaluated using a linear mixed effects model with random intercept.TNF-α levels were measured in 48 MPS (age: 5-17years; 35% female) and 51 controls (age: 8-17years; 53% female). Among MPS, 22 (46%) were treated with hematopoietic cell transplantation (HCT) alone, 24 (50%) with enzyme replacement therapy (ERT) alone, and 2 (4%) with both HCT and ERT. TNF-α levels are higher in MPS compared to healthy controls (p0.001). Higher TNF-α levels are associated with increased pain and decreased physical function, social limitations due to physical health, and physical summary score (all p0.05). TNF-α levels were not significantly associated with the general health score. TNF-α levels did not change significantly over time in MPS.Higher TNF-α levels are implicated in the pain and decreased physical function present in individuals with MPS despite treatment with ERT and/or HCT, suggesting that TNF-a inhibition could potentially be a useful adjunctive therapy. Further investigation into the role of TNF-α inhibition in MPS to decrease pain and improve physical function is indicated.

© 2015 Elsevier Inc.. Objectives: Precise characterization of cognitive outcomes and factors that contribute to cognitive variability will enable better understanding of disease progression and treatment effects in mucopolysaccharidosis type I (MPS I). We examined the effects on cognition of phenotype, genotype, age at evaluation and first treatment, and somatic disease burden. Methods: Sixty patients with severe MPS IH (Hurler syndrome treated with hematopoietic cell transplant and 29 with attenuated MPS I treated with enzyme replacement therapy), were studied with IQ measures, medical history, genotypes. Sixty-seven patients had volumetric MRI. Subjects were grouped by age and phenotype and MRI and compared to 96 normal controls. Results: Prior to hematopoietic cell transplant, MPS IH patients were all cognitively average, but post-transplant, 59% were below average, but stable. Genotype and age at HCT were associated with cognitive ability. In attenuated MPS I, 40% were below average with genotype and somatic disease burden predicting their cognitive ability. White matter volumes were associated with IQ for controls, but not for MPS I. Gray matter volumes were positively associated with IQ in controls and attenuated MPS I patients, but negatively associated in MPS IH. Conclusions: Cognitive impairment, a major difficulty for many MPS I patients, is associated with genotype, age at treatment and somatic disease burden. IQ association with white matter differed from controls. Many attenuated MPS patients have significant physical and/or cognitive problems and receive insufficient support services. Results provide direction for future clinical trials and better disease management.

We examined whether sympathetic nervous system activity influences hypertension status and systolic blood pressure (SBP) independent of adiposity in youth ranging from normal-weight to severe obesity.We examined the association of heart rate variability (HRV) with hypertension status and SBP among youth (6-18 y old; n = 188; 103 female). Seated SBP was measured using an automated cuff. Prehypertension (SBP percentile ≥ 90th to95th) and hypertension (SBP percentile ≥ 95th) were defined by age-, sex-, and height-norms. Autonomic nervous system activity was measured using HRV via SphygmoCor MM3 system and analyzed for time- and frequency-domains. Total body fat was measured via dual-energy X-ray absorptiometry.Logistic regression models demonstrated lower values in each time-domain HRV measure and larger low-frequency (LF):high-frequency (HF) ratio to be significantly associated with higher odds of being prehypertensive/hypertensive (11-47% higher odds) independent of total body fat (P0.05). In linear regression analysis, lower time-domain, but not frequency-domain, HRV measures were significantly associated with higher SBP independent of total body fat (P0.05).These data suggest that impaired cardiac autonomic nervous system function, at rest, is associated with higher odds of being prehypertensive/hypertensive and higher SBP which may be independent of adiposity in youth.

The phenotype of attenuated mucopolysaccharidosis type II (MPS II), also called Hunter syndrome, has not been previously studied in systematic manner. In contrast to the “severe” phenotype, the “attenuated” phenotype does not present with behavioral or cognitive impairment; however, the presence of mild behavior and cognitive impairment that might impact long-term functional outcomes is unknown. Previously, significant MRI abnormalities have been found in MPS II. Recent evidence suggests white matter abnormalities in many MPS disorders. Methods As the initial cross-sectional analysis of a longitudinal study, we studied the association of brain volumes and somatic disease burden with neuropsychological outcomes, including measures of intelligence, memory, and attention in 20 patients with attenuated MPS II with a mean age of 15.8. MRI volumes were compared to 55 normal controls. Results While IQ and memory were average, measures of attention were one standard deviation below the average range. Corpus callosum volumes were significantly different from age-matched controls, differing by 22%. Normal age-related volume increases in white matter were not seen in MPS II patients as they were in controls. Somatic disease burden and white matter and corpus callosum volumes were significantly associated with attention deficits. Neither age at evaluation nor age at starting treatment predicted attention outcomes. Conclusions Despite average intelligence, attention is compromised in attenuated MPS II. Results confirm an important role of corpus callosum and cortical white matter abnormality in MPS II as well as the somatic disease burden in contributing to attention difficulties. Awareness by the patient and caregivers with appropriate management and symptomatic support will benefit the attenuated MPS II patient.

Students Against Nicotine and Tobacco Addiction is a community-based participatory research project that engages local medical and mental health providers in partnership with students, teachers, and administrators at the Minnesota-based Job Corps. This intervention contains multiple and synchronous elements designed to allay the stress that students attribute to smoking, including physical activities, nonphysical activities, purposeful modifications to the campus's environment and rules/policies, and on-site smoking cessation education and peer support. The intent of the present investigation was to evaluate (a) the types of stress most predictive of smoking behavior and/or nicotine dependence, (b) which activities students are participating in, and (c) which activities are most predictive of behavior change (or readiness to change). Quantitative data were collected through 5 campus-wide surveys. Response rates for each survey exceeded 85%. Stressors most commonly cited included struggles to find a job, financial problems, family conflict, lack of privacy or freedom, missing family or being homesick, dealing with Job Corps rules, and other-unspecified. The most popular activities in which students took part were physically active ones. However, activities most predictive of beneficent change were nonphysical. Approximately one third of respondents were nicotine dependent at baseline. Nearly half intended to quit within 1 month and 74% intended to quit within 6 months. Interventions perceived as most helpful toward reducing smoking were nonphysical in nature. Future efforts with this and comparable populations should engage youth in advancing such activities within a broader range of activity choices, alongside conventional education and support.

The lysosomal enzyme α-L-iduronidase hydrolyzes terminal iduronic acid from heparan sulfate and dermatan sulfate, and is an essential step in GAG degradation. Mutations of its gene, IDUA, yield a spectrum of mucopolysaccharidosis (MPS) type I clinical disorders. The IDUA mutation, c.712TA (p.L238Q) was previously noted as a mild mutation. In a longitudinal study of MPS brain structure and function (Lysosomal Disease Network), we found this mutation in 6 of 14 Hurler-Scheie syndrome patients in the age range of 15 to 25 years. We hypothesized that L238Q, when paired with a nonsense mutation, is significantly more severe than other missense-nonsense combinations.Of 6 patients with a L238Q mutation, the L238Q allele was paired with a nonsense mutation in 4 patients, paired with a deletion in 1, and with a splice site mutation in another. This group was compared to 6 Hurler-Scheie patients closely matched in age and mutation type. IQ and other neuropsychological tests were administered as part of the protocol. Medical history was compiled into a Physical Symptom Score (PSS). Assessment of IQ, attention, memory, spatial ability, adaptive function and psychological status were measured.No group differences were found in mean age at evaluation (17.8 and 19.0 years), duration of ERT, or PSS. By history, all were reported to be average in IQ (4/6 with documentation) in early childhood. All (100%) of the L238Q group had a psychiatric history and sleep problems compared to none (0%) of the comparison group. Significant differences were found in depression and withdrawal on parent report measures. IQ was lower in the L238Q group (mean IQ 74) than the comparison group (mean IQ 95; p0.016). Attention, memory, and visual-spatial ability scores were also significantly lower. Three occurrences of shunted hydrocephalus, and 4 of cervical cord compression were found in the L238Q group; the comparison group had one occurrence of unshunted hydrocephalus and two of cord compression.The missense mutation L238Q, when paired with a nonsense mutation, is associated with significant, late-onset brain disease: psychiatric disorder, cognitive deficit, and general decline starting at a later age than in Hurler syndrome with a mutation-related rate of GAG accumulation and its pathologic sequelae. This particular genotype-phenotype may provide insight into the genesis of psychiatric illnesses more broadly. Consideration of methods for early, brain-targeted treatment in these patients might be considered.

Mucopolysaccharidosis Type IIIA (MPS IIIA) is a neurodegenerative disease with behavioral symptoms unique among the mucopolysaccharidoses. Children with MPS IIIA reportedly mouth things, explore novel environments almost continuously, disregard danger, and empathize/socialize and comply less with parents. These characteristics resemble Kluver-Bucy syndrome (K-Bs). To test the K-Bs hypothesis, 30 children with MPS IIIA were compared to 8 "posttransplant" mucopolysaccharidosis Type IH patients in an experimental "risk room." The room contained attractive and mildly frightening objects, exposure to a 92-dB startle noise triggered by contact with an attractive toy, mother's return after a brief absence, and compliance with her cleanup directive. Children with MPS IIIA: (a) left mother sooner, (b) wandered more, (c) were more likely to approach frightening objects, (d) were less likely to respond to loud noise with whole body startle, (e) were less likely to avoid the toy associated with the startle noise, (f) interacted less with mother upon her return, and (g) complied less with her cleanup command. K-Bs is associated with loss of amygdala function. Brain magnetic resonance imaging (MRI) of a subset of the children with MPS IIIA showed volume loss that was greater in the amygdala than in the hippocampus; only amygdala loss correlated with reduced fearfulness. MPS IIIA may be the first identified pediatric disease presenting systematically as a K-Bs variant. If validated by further studies, the K-Bs hypothesis of MPS IIIA would provide important clinical and theoretical information for the guidance of families as well as markers for natural disease progression and treatment effects.

Importance Medical treatment options for pediatric obesity remain limited. Glucagon-like peptide-1 (GLP-1) receptor agonists induce weight loss by suppressing appetite and increasing satiety, but few studies have evaluated this therapy as a treatment for obesity. Objective To evaluate the effects of exenatide on body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) and cardiometabolic risk factors in adolescents with severe obesity. Design Three-month, randomized, double-blind, placebo-controlled, multicenter clinical trial followed by a 3-month open-label extension. Setting An academic medical center and an outpatient pediatric endocrinology clinic. Patients A total of 26 adolescents (12-19 years of age) with severe obesity (BMI ≥ 1.2 times the 95th percentile or BMI ≥ 35). Intervention All patients received lifestyle modification counseling and were equally randomized to exenatide or placebo injection, twice per day. Main Outcome Measures The primary end point was the mean percent change in BMI measured at baseline and 3 months. Secondary end points included absolute change in BMI, body weight, body fat, blood pressure, hemoglobin A 1c , fasting glucose, fasting insulin, and lipids at 3 months. Results Twenty-two patients completed the trial. Exenatide elicited a greater reduction in percent change in BMI compared with placebo (−2.70% [95% CI, −5.02% to −0.37%]; P = .03). Similar findings were observed for absolute change in BMI (−1.13 [95% CI, −2.03 to −0.24]; P = .02) and body weight (−3.26 kg [95% CI, −5.87 to −0.66 kg]; P = .02). Although not reaching the level of statistical significance, reduction in systolic blood pressure was observed with exenatide. During the open-label extension, BMI was further reduced in those initially randomized to exenatide (cumulative BMI reduction of 4%). Conclusions and Relevance These results provide preliminary evidence supporting the feasibility, safety, and efficacy of GLP-1 receptor agonist therapy for the treatment of severe obesity in adolescents. Trial Registration clinicaltrials.gov Identifier: NCT01237197

Aim Although hematopoietic cell transplantation (HCT) arrests the cognitive decline in mucopolysaccharidosis type IH (Hurler syndrome, MPS IH), these children continue to have neuropsychological deficits as they age. Both compromised attention and effects on white matter have been observed in cancer patients who have had chemotherapy. Therefore, we explored the effects of disease and treatment on brain function in children with MPS I who have had HCT with those with attenuated MPS I treated with enzyme replacement therapy (ERT). Methods Subjects: 7 MPS IH participants at least 5 years post-HCT were compared with 7 attenuated participants who were treated with ERT. Measures: IQ, attention, spatial ability, and memory were assessed. Medical history and an unsedated MRI scan using diffusion tensor imaging (DTI) were acquired. Results Despite clinically equivalent IQ and memory, children with MPS IH had poorer attention span than those with attenuated MPS I as well as decreased fractional anisotropy (FA) of the corpus callosum. A relationship between attention scores and FA was found in the MPS IH group but not the attenuated group. FA was also related to the frequency of medical events. Interpretation In children with MPS IH, both the treatment and the disease affect attention functions associated with poor white matter integrity.

The objective of this pilot study was to evaluate the effects of exenatide on BMI (primary endpoint) and cardiometabolic risk factors in nondiabetic youth with extreme obesity. Twelve children and adolescents (age 9-16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m(2)) were enrolled in a 6-month, randomized, open-label, crossover, clinical trial consisting of two, 3-month phases: (i) a control phase of lifestyle modification and (ii) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase-order (i.e., starting with control or drug therapy) then crossed-over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance tests (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3-, and 6-months. The mean change over each 3-month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (-1.7 kg/m(2), 95% confidence interval (CI) (-3.0, -0.4), P = 0.01), body weight (-3.9 kg, 95% CI (-7.11, -0.69), P = 0.02), and fasting insulin (-7.5 mU/l, 95% CI (-13.71, -1.37), P = 0.02). Significant improvements were observed for OGTT-derived insulin sensitivity (P = 0.02) and β-cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well-tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well-controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.

The validity of using adult physiologic criteria to triage injured children in the out-of-hospital setting remains unproven. Among children meeting adult field physiologic criteria, we assessed the availability of physiologic information, the incidence of death or prolonged hospitalization, and whether age-specific criteria would improve the specificity of the physiologic triage step.We analyzed a prospective, out-of-hospital cohort of injured children agedor =14 years collected from December 2005 through February 2007 by 237 emergency medical services (EMS) agencies transporting to 207 acute care hospitals (trauma and nontrauma centers) in 11 sites across the United States and Canada. Inclusion criteria were standard adult physiologic values: systolic blood pressure (SBP)or =90 mmHg, respiratory rate10 or29 breaths/min, Glasgow Coma Scale (GCS) scoreor =12, and field intubation attempt. Seven physiologic variables (including age-specific values) and three demographic and mechanism variables were included in the analysis. "High-risk" children included those who died (field or in-hospital) or were hospitalized2 days. The decision tree was derived and validated using binary recursive partitioning.Nine hundred fifty-five children were included in the analysis, of whom 62 (6.5%) died and 117 (12.3%) were hospitalized2 days. Missing values were common, ranging from 6% (respiratory rate) to 53% (pulse oximetry), and were associated with younger age and high-risk outcome. The final decision rule included four variables (assisted ventilation, GCS score11, pulse oximetry95%, and SBP96 mmHg), which demonstrated improved specificity (71.7% [95% confidence interval (CI) 66.7-76.6%]) at the expense of missing high-risk children (sensitivity 76.5% [95% CI 66.4-86.6%]).The incidence of high-risk injured children meeting adult physiologic criteria is relatively low and the findings from this sample do not support using age-specific values to better identify such children. However, the amount and pattern of missing data may compromise the value and practical use of field physiologic information in pediatric triage.

To assess autism spectrum disorder (ASD) behaviors in children with mucopolysaccharidosis type IIIA (MPS IIIA) using a standard measure, understand the behavioral evolution of the disease, and provide specific guidelines for diagnosis.Children (n = 21) with documented enzyme deficiency and SGSH gene mutations, cognitive age-equivalent12 months, and early onset were administered the Autism Diagnostic Observation Schedule (ADOS) (module 1) and Bayley Scales of Infant Development-Third Edition. ADOS Social Affect and Restricted Repetitive Behavior total scores, as well as Bayley Scales of Infant Development-Third Edition cognitive age-equivalent scores, are reported using descriptive statistics and graphic presentations.Thirteen of the 21 children evaluated met the ADOS criteria for ASD/autism. ADOS score was strongly associated with age; all 11 children aged46 months met the criteria, compared with only 2 of 10 aged46 months. Social and affective abnormalities were most frequent; restricted interests and repetitive behaviors were largely absent. Lack of cognitive growth paralleled ADOS score.An increased incidence of ASD-like social behaviors was seen at age 3-4 years in children with early-onset MPS IIIA. Although more frequent in the severely impaired children, ASD-like behaviors were observed across the entire range of cognitive impairment. Clinicians must be aware that when a child acquires ASD-like behaviors, MPS IIIA should be included in the differential diagnosis.

Objectives To characterize the clinical course of mucopolysaccharidosis type IIIA (MPS IIIA), and identify potential endpoints for future treatment trials. Study design Children with a confirmed diagnosis of MPS IIIA, functioning above a developmental age of 1 year, were followed for up to 2 years. Cognitive status and brain atrophy were assessed by standardized tests and volumetric magnetic resonance imaging, respectively. Liver and spleen volumes and cerebrospinal fluid and urine biomarker levels were measured. Results Twenty-five children, from 1.1 to 18.4 years old, were enrolled, and 24 followed for at least 12 months. 19 exhibited a rapidly progressing (RP) form of MPS IIIA, and 5, a more slowly progressing form. Children with RP plateaued in development by 30 months, followed by rapid regression after 40-50 months. In patients with RP, cognitive developmental quotients showed consistent steep declines associated with progressive cortical gray matter atrophy. Children with slowly progressing had a similar but more prolonged course. Liver and spleen volumes were approximately double normal size, and cerebrospinal fluid and urine heparin sulfate levels were elevated and relatively constant over time. Conclusion Developmental quotient and cortical gray matter volume are sensitive markers of disease progression in MPS IIIA, and may have utility as clinical endpoints in treatment trials. For optimal outcomes, treatment may need to be instituted in children before the onset of steep cognitive decline and brain atrophy. Trial registration ClinicalTrials.gov: NCT01047306.