Once-Weekly Semaglutide in Adolescents with Obesity.

BACKGROUND: A once-weekly, 2.4-mg dose of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist, is used to treat obesity in adults, but assessment of the drug in adolescents has been lacking. METHODS: In this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The primary end point was the percentage change in BMI from baseline to week 68; the secondary confirmatory end point was weight loss of at least 5% at week 68. RESULTS: A total of 201 participants underwent randomization, and 180 (90%) completed treatment. All but one of the participants had obesity. The mean change in BMI from baseline to week 68 was -16.1% with semaglutide and 0.6% with placebo (estimated difference, -16.7 percentage points; 95% confidence interval [CI], -20.3 to -13.2; P<0.001). At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group (estimated odds ratio, 14.0; 95% CI, 6.3 to 31.0; P<0.001). Reductions in body weight and improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo. The incidence of gastrointestinal adverse events was greater with semaglutide than with placebo (62% vs. 42%). Five participants (4%) in the semaglutide group and no participants in the placebo group had cholelithiasis. Serious adverse events were reported in 15 of 133 participants (11%) in the semaglutide group and in 6 of 67 participants (9%) in the placebo group. CONCLUSIONS: Among adolescents with obesity, once-weekly treatment with a 2.4-mg dose of semaglutide plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone. (Funded by Novo Nordisk; STEP TEENS ClinicalTrials.gov number, NCT04102189.).

Current and future state of pharmacological management of pediatric obesity.

Pediatric obesity is a highly prevalent chronic disease, which has traditionally been treated with lifestyle therapy alone. Yet for many youth, lifestyle intervention as a monotherapy is often insufficient for achieving clinically significant and durable BMI reduction. While metabolic/bariatric surgery achieves robust and long-lasting outcomes, it is neither widely accessible nor wanted by most pediatric patients and families. In the past 3 years, this treatment gap between lifestyle therapy and metabolic/bariatric surgery has been filled with a number of landmark clinical trials examining the safety and efficacy of anti-obesity medication (AOM) for use in children and adolescents. These trials include studies of liraglutide, phentermine/topiramate ER, semaglutide, and setmelanotide, all of which have led to FDA and/or EMA approval. Concurrent with this developing evidence base, in 2023, the American Academy of Pediatrics published their first Clinical Practice Guideline on the assessment and management of childhood obesity. The Guideline includes the recommendation that pediatric health care providers should offer AOM to youth ages ≥12 years with obesity. Recognizing that AOM use in the pediatric population will likely become the standard of care and to provide perspective on the recently generated data regarding new AOM, this narrative review summarizes the published randomized controlled trials (RCTs) from the past 10 years that examine AOM for the pediatric population. This report additionally includes RCTs examining AOM for special populations of pediatric obesity including monogenic obesity, Bardet Biedl syndrome, Prader Willi syndrome, and hypothalamic obesity. Finally, the clinical application of AOM for children and adolescents, as well as future directions and challenges are discussed.

A Randomized, Controlled Trial of Liraglutide for Adolescents with Obesity.

BACKGROUND: Obesity is a chronic disease with limited treatment options in pediatric patients. Liraglutide may be useful for weight management in adolescents with obesity. METHODS: In this randomized, double-blind trial, which consisted of a 56-week treatment period and a 26-week follow-up period, we enrolled adolescents (12 to <18 years of age) with obesity and a poor response to lifestyle therapy alone. Participants were randomly assigned (1:1) to receive either liraglutide (3.0 mg) or placebo subcutaneously once daily, in addition to lifestyle therapy. The primary end point was the change from baseline in the body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) standard-deviation score at week 56. RESULTS: A total of 125 participants were assigned to the liraglutide group and 126 to the placebo group. Liraglutide was superior to placebo with regard to the change from baseline in the BMI standard-deviation score at week 56 (estimated difference, -0.22; 95% confidence interval [CI], -0.37 to -0.08; P = 0.002). A reduction in BMI of at least 5% was observed in 51 of 113 participants in the liraglutide group and in 20 of 105 participants in the placebo group (estimated percentage, 43.3% vs. 18.7%), and a reduction in BMI of at least 10% was observed in 33 and 9, respectively (estimated percentage, 26.1% vs. 8.1%). A greater reduction was observed with liraglutide than with placebo for BMI (estimated difference, -4.64 percentage points) and for body weight (estimated difference, -4.50 kg [for absolute change] and -5.01 percentage points [for relative change]). After discontinuation, a greater increase in the BMI standard-deviation score was observed with liraglutide than with placebo (estimated difference, 0.15; 95% CI, 0.07 to 0.23). More participants in the liraglutide group than in the placebo group had gastrointestinal adverse events (81 of 125 [64.8%] vs. 46 of 126 [36.5%]) and adverse events that led to discontinuation of the trial treatment (13 [10.4%] vs. 0). Few participants in either group had serious adverse events (3 [2.4%] vs. 5 [4.0%]). One suicide, which occurred in the liraglutide group, was assessed by the investigator as unlikely to be related to the trial treatment. CONCLUSIONS: In adolescents with obesity, the use of liraglutide (3.0 mg) plus lifestyle therapy led to a significantly greater reduction in the BMI standard-deviation score than placebo plus lifestyle therapy. (Funded by Novo Nordisk; NN8022-4180 ClinicalTrials.gov number, NCT02918279.).

Household Income, Cortisol, and Obesity During Early Childhood: A Prospective Longitudinal Study.

OBJECTIVE: To prospectively evaluate the relationship between household income, children's cortisol, and body mass index (BMI) trajectories over a 3-year period in early childhood. STUDY DESIGN: Household income, child hair cortisol levels, and BMI were measured at baseline, 12-, 24-, and 36-month follow-up visits in the Now Everybody Together for Amazing and Healthful Kids (NET-Works) Study (n = 534, children ages 2-4 years, and household income <$65 000/year at baseline). Relationships were examined between very low household income (<$25 000/year) at baseline, income status over time (remained <$25 000/year or had increasing income), cortisol accumulation from hair samples, and BMI percent of the 95th percentile (BMIp95) trajectories using adjusted linear growth curve modeling. Households with baseline income between $25 000 and $65 000/year were the reference group for all analyses. RESULTS: Children from very low-income households at baseline had annual changes in BMIp95 that were higher (P < .001) than children from reference group households (0.40 vs -0.62 percentage units/year). Annual increases in BMIp95 were also greater among children from households that remained very low income (P < .01, .34 percentage units/year) and among those with increasing income (P = .01, .51 percentage units/year) compared with the reference group (-0.61 percentage units/year). Children from households that remained very low income had higher hair cortisol accumulations (0.22 pg/mg, P = .02) than reference group children, whereas hair cortisol concentrations of children from households with increasing income (0.03 pg/mg) did not differ significantly from the reference group. Cortisol was not related to BMIp95. CONCLUSIONS: The economic circumstances of families may impact children's BMI trajectories and their developing stress systems, but these processes may be independent of one another.

Muscle-to-Bone and Soft Tissue-to-Bone Ratio in Children and Adolescents with Obesity.

OBJECTIVES: To explore the total and regional muscle-to-bone ratio in children and adolescents with obesity and compare the muscle-to-bone ratio (MBR) and soft tissue-to-bone ratio (SBR) to their peers with normal weight or overweight. STUDY DESIGN: A total of 219 male and female pediatrics (mean age=12.3±2.5 years) participated in this study. Body composition was assessed with a total body dual X-ray absorptiometry. The MBR was calculated by dividing lean mass by bone mineral content. The SBR was determined by dividing the soft tissue mass (i.e., lean mass+fat mass) by bone mineral content. Differences in total and regional body composition measures between body mass index (BMI) percentile groups was assessed by ANOVA. RESULTS: The obesity group had significantly higher MBR compared to the normal weight group for total (19.24±1.56 vs. 18.26±1.64), arm (17.11±1.67 vs. 15.88±1.81), and leg (18.41±1.68 vs. 16.62±1.55). Similarly, the obesity group had significantly higher MBR in the leg (18.41±1.68) compared to the overweight group (17.24±1.45). However, the overweight group was not significantly different from the normal weight or the obesity group for total and arm MBR. The total, arm, and leg SBR was significantly different between all BMI groups. Across the entire sample, MBR and SBR were negatively associated with high-density lipoprotein. SBR was positively associated with insulin, HOMA-IR, low-density lipoprotein, very low-density lipoprotein, triglycerides, and systolic blood pressure. CONCLUSIONS: Children with obesity had a higher MBR and SBR compared to their normal weight peers. In addition, there were significant associations between SBR, higher levels of insulin, atherogenic lipoproteins, and increased systolic blood pressure. Thus, SBR may be useful as a marker for increased cardiometabolic disease risk, though more research in this area is warranted.

BMI metrics and their association with adiposity, cardiometabolic risk factors, and biomarkers in children and adolescents.

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 (%BMIp95), percent of the BMI median (%BMIp50), 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 %BMIp95 and %BMIp50 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, %BMIp95 and %BMIp50 were the most strongly correlated with measures of adiposity. %BMIp95 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.

Cardiovascular Risk Reduction in High-Risk Pediatric Patients: A Scientific Statement From the American Heart Association.

This scientific statement presents considerations for clinical management regarding the assessment and risk reduction of select pediatric populations at high risk for premature cardiovascular disease, including acquired arteriosclerosis or atherosclerosis. For each topic, the evidence for accelerated acquired coronary artery disease and stroke in childhood and adolescence and the evidence for benefit of interventions in youth will be reviewed. Children and adolescents may be at higher risk for cardiovascular disease because of significant atherosclerotic or arteriosclerotic risk factors, high-risk conditions that promote atherosclerosis, or coronary artery or other cardiac or vascular abnormalities that make the individual more vulnerable to the adverse effects of traditional cardiovascular risk factors. Existing scientific statements and guidelines will be referenced when applicable, and suggestions for risk identification and reduction specific to each setting will be described. This statement is directed toward pediatric cardiologists, primary care providers, and subspecialists who provide clinical care for these young patients. The focus will be on management and justification for management, minimizing information on pathophysiology and epidemiology.

Relationship of Apolipoproteins with Subclinical Cardiovascular Risk in Youth.

OBJECTIVE: To examine the association of apolipoproteins with arterial stiffness and carotid artery structure in children and adolescents. STUDY DESIGN: A total of 338 children and adolescents (178 female) with a mean age 13.0 ± 2.8 years were examined. Apolipoproteins (AI, AII, B100, CII, CIII, and E) were measured via human apolipoprotein magnetic bead panel. Applanation tonometry determined pulse wave velocity and ultrasound imaging measured carotid intima-media thickness. Dual X-ray absorptiometry measured total body fat percent. Linear regression models were adjusted for Tanner stage, sex, and race with further adjustments for body fat percent. Linear regression models also examined the interaction between Tanner stage and apolipoproteins. RESULTS: There was a significant positive association between pulse wave velocity and apolipoproteins: AI (0.015 m/s/10 µg/mL [CI 0.005-0.026], P = .003), AII (0.036 m/s/10 µg/mL [0.017-0.056], P < .001), B100 (0.009 m/s/10 µg/mL [0.002-0.016], P = .012), E (0.158 m/s/10 µg/mL [0.080-0.235], P < .001), and CIII:CII (0.033/µg/mL [0.014-0.052], P < .001). After we added body fat percent to the models, pulse wave velocity (PWV) remained positively associated with greater levels of apolipoproteins: AI, AII, B100, E, and CIII:CII. Both with and without the adjustment for body fat percent, there were no significant associations between any apolipoprotein and carotid intima-media thickness. There were no significant interactions between Tanner stage and apolipoproteins. CONCLUSIONS: These findings suggest that greater levels of apolipoprotein AII, E, and CIII:CII are associated with increased arterial stiffness in children and adolescents, both with and without adjusting for percent body fat. These specific apolipoproteins may be useful as biomarkers of cardiovascular risk.

Relation of secondhand smoke exposure to vascular phenotypes in children and adolescents.

BACKGROUND: 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 ± 8.9 kg/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 ± 794 vs. 935 ± 388 mmHg, 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.

Early characteristics of bone deficits in children with Fontan palliation.

BACKGROUND: This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation. METHODS: We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children's hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls. RESULTS: All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences -30.13 mg/cm3 (p = 0.041), -0.31 mm (p = 0.043), and -6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were -0.46 ± 1.1 and -0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex. CONCLUSIONS: In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.

Sedentary Behaviors in Today's Youth: Approaches to the Prevention and Management of Childhood Obesity: A Scientific Statement From the American Heart Association.

This scientific statement is about sedentary behavior and its relationship to obesity and other cardiometabolic outcomes in youth. A deleterious effect of sedentary behavior on cardiometabolic health is most notable for screen-based behaviors and adiposity; however, this relation is less apparent for other cardiometabolic outcomes or when sedentary time is measured with objective movement counters or position monitors. Increasing trends of screen time are concerning; the portability of screen-based devices and abundant access to unlimited programming and online content may be leading to new patterns of consumption that are exposing youth to multiple pathways harmful to cardiometabolic health. This American Heart Association scientific statement provides an updated perspective on sedentary behaviors specific to modern youth and their impact on cardiometabolic health and obesity. As we reflect on implications for practice, research, and policy, what emerges is the importance of understanding the context in which sedentary behaviors occur. There is also a need to capture the nature of sedentary behavior more accurately, both quantitatively and qualitatively, especially with respect to recreational screen-based devices. Further evidence is required to better inform public health interventions and to establish detailed quantitative guidelines on specific sedentary behaviors in youth. In the meantime, we suggest that televisions and other recreational screen-based devices be removed from bedrooms and absent during meal times. Daily device-free social interactions and outdoor play should be encouraged. In addition, parents/guardians should be supported to devise and enforce appropriate screen time regulations and to model healthy screen-based behaviors.

Vascular Structure and Function in Cancer Survivors after Hematopoietic Stem Cell Transplantation.

This study examined the effects of hematopoietic cell transplantation (HCT) and associated preparative regimens on vascular structure and function. Measures of carotid artery stiffness and brachial artery endothelial-dependent dilation were obtained in patients who had survived ≥ 2 years after HCT for hematologic malignancy and were diagnosed at ≤21 years. HCT survivors (n = 108) were examined: 66 received total body irradiation (TBI) alone or with a low-dose cranial radiation boost (TBI±LD-CRT), 19 received TBI plus high-dose cranial radiation (TBI+HD-CRT), and 23 received a chemotherapy-only preparative regimen (CHEMO). Siblings (n = 83) were invited to participate as control subjects. Although endothelial-dependent dilation did not differ between siblings and HCT survivors, carotid cross-sectional compliance, cross-sectional distensibility, diameter compliance, and diameter distensibility were greater in siblings than HCT survivors. Comparing the HCT preparative regimens, carotid cross-sectional compliance, cross-sectional distensibility, diameter compliance, diameter distensibility, and incremental elastic modulus were significantly lower in the TBI+HD-CRT group compared with siblings or with TBI±LD-CRT and CHEMO treatment groups. Cross-sectional distensibility and diameter compliance were significantly lower in the TBI±LD-CRT group compared with siblings. TBI±LD-CRT and CHEMO groups did not differ from each other in these vascular measures. HCT preparative regimens containing TBI+HD-CRT resulted in greater arterial decrements, indicating increased risk for cardiovascular disease.

Health Outcomes of Youth in Clinical Pediatric Weight Management Programs in POWER.

OBJECTIVE: To describe treatment outcomes of children and adolescents enrolled in the Pediatric Obesity Weight Evaluation Registry, a consortium of multicomponent pediatric weight management programs in the US. STUDY DESIGN: This multicenter prospective observational cohort study, established in 2013, includes youth (2-18 years of age) with obesity enrolled from 31 Pediatric Obesity Weight Evaluation Registry (POWER) sites over a 2-year period and followed up to 12 months. Weight status was evaluated by the percentage of the 95th percentile for body mass index (%BMIp95). Associations of weight status outcomes with patient characteristics and program exposure were analyzed with multivariable mixed effects modeling. RESULTS: We included 6454 children and adolescents (median age, 11 years; IQR, 9-14 years; 53% white, 32% Hispanic; 73% with severe obesity) who were enrolled in POWER. Median changes in %BMIp95 for this cohort were -1.88 (IQR, -5.8 to 1.4), -2.50 (IQR, -7.4 to 1.8), -2.86 (IQR, -8.7 to 1.9), at 4-6, 7-9, and 10-12 of months follow-up, respectively (all P < .05). Older age (≥12 years), greater severity of obesity, and Hispanic race/ethnicity were associated with better improvement in %BMIp95. A 5-percentage point decrease in %BMIp95 was associated with improvement in cardiometabolic risk factors. CONCLUSIONS: Overall, treatment in pediatric weight management programs is associated with a modest median decrease in BMI as measured by change in %BMIp95. Further studies are needed to confirm these findings, as well as to identify additional strategies to enhance the effectiveness of these multicomponent interventions for youth with severe obesity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02121132.

Metabolic Syndrome and Cardiovascular Risk Factors after Hematopoietic Cell Transplantation in Severe Mucopolysaccharidosis Type I (Hurler Syndrome).

Hematopoietic cell transplantation is a life-saving procedure, but one associated with increasing long-term cardiovascular risk requiring frequent long-term follow-up. This therapy has significantly lengthened survival in mucopolysaccharidosis type IH (Hurler syndrome), a disease with known coronary artery involvement. Metabolic syndrome-a constellation of central obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose-is associated with increased cardiovascular risk, and occurs when any 3 or more of these 5 components is present within a single individual. The incidence of metabolic syndrome and its components is poorly defined after transplantation for Hurler syndrome. Chart review of all long-term survivors of hematopoietic cell transplantation for Hurler syndrome ≥9 years of age for factors comprising the metabolic syndrome: obesity, high blood pressure, low high-density lipoprotein cholesterol, elevated triglycerides, and fasting blood glucose. Sixty-three patients were evaluated, 20 of whom had components of the metabolic syndrome available for review. There was no significant difference in age at transplantation, sex, number of transplants, pretransplant radiation, or percent engraftment between those with and without these data. Median follow-up after transplantation for the 20 patients with data was 14.3 years. Only 1 (5%) patient of this group fulfilled the criteria for metabolic syndrome. Fifty-three percent of the patients had 1 or more components of metabolic syndrome: the most common was high blood pressure occurring in 40%. Metabolic syndrome is uncommon in this cohort of long-term survivors of hematopoietic cell transplantation for Hurler syndrome but almost half of the patients had 1 or more components of the syndrome, with high blood pressure being the most common. Further studies are needed to develop guidelines in this diagnosis as well as other nonmalignant diseases of children.

Working toward precision medicine approaches to treat severe obesity in adolescents: report of an NIH workshop.

Adolescent severe obesity is a prevalent, chronic, and serious disease with few effective and safe treatment options. To address this issue, a National Institutes of Health-sponsored workshop entitled "Developing Precision Medicine Approaches to the Treatment of Severe Obesity in Adolescents," was convened, bringing together a multidisciplinary group of experts to review the current state of the science and identify (1) what is known regarding the epidemiology and biopsychosocial determinants of severe obesity in adolescents, (2) what is known regarding effectiveness of treatments for severe obesity in adolescents and predictors of response, and (3) gaps and opportunities for future research to develop more effective and targeted treatments for adolescents with severe obesity. Major topical areas discussed at the workshop included: appropriate BMI metrics, valid measures of phenotypes and predictors, mechanisms associated with the development of severe obesity, novel treatments informed by biologically and psychosocially plausible mechanisms, biopsychosocial phenotypes predicting treatment response, standardization of outcome measures and results reporting in research, and improving clinical care. Substantial gaps in knowledge were identified regarding the basic behavioral, psychosocial, and biological mechanisms driving the development of severe obesity and the influence of these factors on treatment response. Additional exploratory and observational studies are needed to better understand the heterogeneous etiology of severe obesity and explain the high degree of variability observed with interventions. Tailored treatment strategies that may be developed by achieving a better understanding of individual differences in genetic endowment, clinical, metabolic, psychological, and behavioral phenotypes, and response to environmental exposures need to be tested. It is anticipated that these recommendations for future research, including strategies to enhance methodological rigor, will advance precision medicine approaches to treat severe obesity in adolescents more effectively.

Early Life Adversity with Height Stunting Is Associated with Cardiometabolic Risk in Adolescents Independent of Body Mass Index.

OBJECTIVE: To evaluate cardiovascular and metabolic function in youths adopted internationally from orphanages/institutions (postinstitutionalized) who were height-stunted at adoption. STUDY DESIGN: A total of 30 postinstitutionalized youths (age, 9-18 years; body mass index [BMI] percentile, 7.2-90.4) who were height-stunted at adoption were compared with age- and BMI percentile-matched youths (n = 90). Measurements included total body fat and visceral adipose tissue (dual radiograph absorptiometry), arterial stiffness (augmentation index and pulse wave velocity), cardiac autonomic function (heart rate variability), blood pressure, and fasting lipid, glucose, and insulin levels. Linear regression analyses were computed controlling for parent education, age, trunk tissue fat, height-for-age, sex, and race. RESULTS: Compared with controls of the same age, sex, and BMI, the postinstitutionalized children had higher systolic blood pressure (P = .018), augmentation index (P= .033), total cholesterol (P= .047), low-density lipoprotein cholesterol (P= .03), triglycerides (P= .048), insulin (P= .005), and HOMA-IR (P= .01) values. The postinstitutionalized children had a lower low-frequency to high-frequency ratio (P = .008), indicating lower sympathetic tone, as well as a lower total lean mass (P = .016), a lower gynoid lean mass (P = .039), and a higher proportion of trunk tissue fat (P = .017). The postinstitutionalized and control children did not differ in any other body composition measures. CONCLUSIONS: Early life stress, as represented by height-stunted growth in institutional care, may be associated with early pathways to cardiovascular and metabolic risk in youths even after moving into well-resourced homes early in life and in the absence of increased adiposity. These findings suggest that postinstitutionalized youths with a history of height stunting may need to be closely monitored for emergent cardiometabolic risk factors.

Relationships of Anxiety and Depression with Cardiovascular Health in Youth with Normal Weight to Severe Obesity.

OBJECTIVE: To evaluate the relationships of depression and anxiety symptoms with cardiovascular disease (CVD) risk factors and measures of vascular health in youth. STUDY DESIGN: Participants (n = 202) were 8- to 18-year-olds from a cross-sectional study evaluating cardiovascular health across a wide range of body mass index 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 for 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 was 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 high-density lipoprotein 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.

Bone mineral density and body composition in children with congenital adrenal hyperplasia.

OBJECTIVE: Children with congenital adrenal hyperplasia (CAH) are exposed to fluctuating cortisol and androgen levels. The effects these hormonal states have on bone mineral density (BMD) and body composition are not well studied. The study's objective was to compare BMD and body composition, including visceral adipose tissue (VAT) and Android:Gynoid (A:G) ratio, in children with CAH vs healthy age-matched, sex-matched and BMI-matched controls. DESIGN: Total body BMD (TBMD) Z-scores were adjusted for height-for-age Z-scores (TBMDHAZ). Hydrocortisone dose (mg/m2/d) was averaged over the past year. Bone age Z-scores were used as a surrogate for long-term androgen exposure in cases. Statistical analyses comparing cases and controls accounted for matched groups using mixed linear models. PATIENTS: Forty-two cases with CAH (average age 12.3 years [SE 3]; 17 males) and 101 controls underwent a dual-energy X-ray absorptiometry scan. RESULTS: Children with CAH had lower TBMD (0.81 vs 1.27, P = .003) and TBMDHAZ Z-scores (-0.51 vs -0.01, P = .001) than controls. In CAH cases, TBMD and TBMDHAZ Z-scores were positively correlated with bone age Z-scores (r = .63, P < .0001; r = .51, P = .001, respectively) but were not associated with HC dose. VAT and the A:G ratio did not differ significantly between children with CAH and controls and neither was associated with HC dose.VAT was not associated with bone age Z-score. CONCLUSION: Lower BMD was observed in CAH cases compared with controls although no differences in body composition were identified. Among CAH cases, increased chronic androgen exposure, as measured by bone age Z-scores, was associated with higher BMD but was not associated with VAT.