Exposure to per- and polyfluoroalkyl substances and alterations in plasma microRNA profiles in children.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are synthetic chemicals that persist in the environment and can accumulate in humans, leading to adverse health effects. MicroRNAs (miRNAs) are emerging biomarkers that can advance the understanding of the mechanisms of PFAS effects on human health. However, little is known about the associations between PFAS exposures and miRNA alterations in humans. OBJECTIVE: To investigate associations between PFAS concentrations and miRNA levels in children. METHODS: Data from two distinct cohorts were utilized: 176 participants (average age 17.1 years; 75.6% female) from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort in the United States, and 64 participants (average age 6.5 years, 39.1% female) from the Rhea study, a mother-child cohort in Greece. PFAS concentrations and miRNA levels were assessed in plasma samples from both studies. Associations between individual PFAS and plasma miRNA levels were examined after adjusting for covariates. Additionally, the cumulative effects of PFAS mixtures were evaluated using an exposure burden score. Ingenuity Pathways Analysis was employed to identify potential disease functions of PFAS-associated miRNAs. RESULTS: Plasma PFAS concentrations were associated with alterations in 475 miRNAs in the Teen-LABs study and 5 miRNAs in the Rhea study (FDR p < 0.1). Specifically, plasma PFAS concentrations were consistently associated with decreased levels of miR-148b-3p and miR-29a-3p in both cohorts. Pathway analysis indicated that PFAS-related miRNAs were linked to numerous chronic disease pathways, including cardiovascular diseases, inflammatory conditions, and carcinogenesis. CONCLUSION: Through miRNA screenings in two independent cohorts, this study identified both known and novel miRNAs associated with PFAS exposure in children. Pathway analysis revealed the involvement of these miRNAs in several cancer and inflammation-related pathways. Further studies are warranted to enhance our understanding of the relationships between PFAS exposure and disease risks, with miRNA emerging as potential biomarkers and/or mediators in these complex pathways.

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.

Prediction of adult class II/III obesity from childhood BMI: the i3C consortium.

BACKGROUND AND OBJECTIVES: Adult class II/III obesity (BMI ≥ 35 kg/m2) has significant adverse health outcomes. Early prevention and treatment are critical, but prospective childhood risk estimates are lacking. This study aimed to define the prospective risk of adult class II/III obesity, using childhood BMI. METHODS: Children ages 3-19 years enrolled in cohorts of the International Childhood Cardiovascular Cohort (i3C) consortium with measured BMI assessments in childhood and adulthood were included. Prospective risk of adult class II/III obesity was modeled based on childhood age, sex, race, and BMI. RESULTS: A total of 12,142 individuals (44% male, 85% white) were assessed at median age 14 [Interquartile range, IQR: 11, 16] and 33 [28, 39] years. Class II/III adult obesity developed in 6% of children with normal weight; 29% of children with overweight; 56% of children with obesity; and 80% of children with severe obesity. However, 38% of the 1440 adults with class II/III obesity (553/1440) were normal weight as children. Prospective risk of adult class II/III obesity varied by age, sex, and race within childhood weight status classifications, and is notably higher for girls, black participants, and those in the United States. The risk of class II/III obesity increased with older adult age. CONCLUSIONS: Children with obesity or severe obesity have a substantial risk of adult class II/III obesity, and observed prospective risk estimates are now presented by age, sex, race, and childhood BMI. Clinical monitoring of children's BMI for adult class II/III obesity risk may be especially important for females and black Americans.

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.

Longitudinal Changes in Weight Status from Childhood and Adolescence to Adulthood.

OBJECTIVES: To study the change in body mass index (BMI) from childhood and adolescence and development of obesity into adulthood. STUDY DESIGN: We performed a longitudinal study of 480 individuals (49% male; 67% white) with height and weight measures in childhood (mean age 7 years), repeated in adolescence (mean age 16 years) and adulthood (mean age 39 years). Weight status in childhood was defined as low normal weight (0-<50 BMI percentile); high normal weight (50-<85 BMI percentile); overweight (85-<95 BMI percentile); obese (≥95 BMI percentile). Adult weight status was defined as normal weight (18.5-<25 kg/m2); overweight (25-<30 kg/m2); obese (>30 kg/m2). RESULTS: Adult obesity (%) increased with weight status in childhood (low normal weight 17%; high normal weight 40%; overweight 59%; obesity 85%) and similarly with adolescence. Children in a lower category in adolescence than in childhood had lower risk of having adult obesity than did those who maintained their childhood category. Among adults with obesity, 59% (111 out of 187) were normal weight as children, with 75% (83 out of 111) from the high normal weight children; and 50% of adults with obesity were normal weight (n = 94/187) as adolescents, with 84% (81 out of 94) from the high normal weight adolescents. Only 6% of 143 normal weight adults had either overweight (n = 9) or obesity (n = 0) during childhood. CONCLUSIONS: This study shows the high risk for adult obesity in children and adolescents who have overweight or obesity. A majority of adults with obesity had a 50-85 BMI percentile as children. Those who did not move to higher weight status between childhood and adolescence had lower probability of adult obesity.

Adverse Childhood Experiences and Weight Status among Adolescents.

OBJECTIVE: To investigate the relationship between adverse childhood experiences (ACEs) and weight status among adolescents. STUDY DESIGN: Data were drawn from the Minnesota Student Survey, a large (n = 105 759), statewide, anonymous survey of public school students in eighth, ninth, and eleventh grades. Self-reported height and weight were used to calculate body mass index. Multinomial logistic regression was used to examine associations between self-reported ACEs and weight status, controlling for key sociodemographic characteristics. RESULTS: ACEs were positively associated with weight status; adolescents with more ACEs were more likely to have overweight, obesity, and severe obesity than adolescents with no ACEs. Adolescents who reported an ACE were 1.2, 1.4, and 1.5 times as likely to have overweight, obesity, and severe obesity, respectively, compared with their peers with no ACEs. There was no relationship between ACEs and underweight. CONCLUSIONS: The results of this large sample of adolescents with anonymous data support the hypothesis that ACEs and obesity are strongly associated. The directionality of this relationship needs to be understood. Moreover, these findings suggest that child health professionals may need to screen for ACEs as an important aspect of clinical weight management.

High-intensity interval exercise attenuates but does not eliminate endothelial dysfunction after a fast food meal.

We investigated whether two different bouts of high-intensity interval exercise (HIIE) could attenuate postprandial endothelial dysfunction. Thirteen young (27 ± 1 yr), nonexercise-trained men underwent three randomized conditions: 1) four 4-min intervals at 85-95% of maximum heart rate separated by 3 min of active recovery (HIIE 4 × 4), 2) 16 1-min intervals at 85-95% of maximum heart rate separated by 1 min of active recovery (HIIE 16 × 1), and 3) sedentary control. HIIE was performed in the afternoon, ~18 h before the morning fast food meal (1,250 kcal, 63g of fat). Brachial artery flow-mediated dilation (FMD) was performed before HIIE ( baseline 1), during fasting before meal ingestion ( baseline 2), and 30 min, 2 h, and 4 h postprandial. Capillary glucose and triglycerides were assessed at fasting, 30 min, 1 h, 2 h, and 4 h (triglycerides only). Both HIIE protocols increased fasting FMD compared with control (HIIE 4 × 4: 6.1 ± 0.4%, HIIE 16 × 1: 6.3 ± 0.5%, and control: 5.1 ± 0.4%, P < 0.001). For both HIIE protocols, FMD was reduced only at 30 min postprandial but never fell below baseline 1 or FMD during control at any time point. In contrast, control FMD decreased at 2 h (3.8 ± 0.4%, P < 0.001) and remained significantly lower than HIIE 4 × 4 and 16 × 1 at 2 and 4 h. Postprandial glucose and triglycerides were unaffected by HIIE. In conclusion, HIIE performed ~18 h before a high-energy fast food meal can attenuate but not entirely eliminate postprandial decreases in FMD. This effect is not dependent on reductions in postprandial lipemia or glycemia. NEW & NOTEWORTHY Two similar high-intensity interval exercise (HIIE) protocols performed ∼18 h before ingestion of a high-energy fast food meal attenuated but did not entirely eliminate postprandial endothelial dysfunction in young men largely by improving fasting endothelial function. Both HIIE protocols produced essentially identical results, suggesting high reproducibility of HIIE effects.

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.

High-flow-mediated constriction in adults is not influenced by biomarkers of cardiovascular and metabolic risk.

PURPOSE: During reactive hyperemia, the brachial artery in some individuals constricts prior to dilation. Our aim was to describe the frequency of high-flow-mediated constriction (H-FMC) in adults, and its relationship to body composition and biomarkers of cardiovascular and metabolic risk. METHODS: Two hundred forty-six adults (124 male, 122 female; 36 ± 7 years old) were assessed for H-FMC via sonographic imaging of the brachial artery. Blood pressure, glucose, insulin, lipids, and body composition assessed via dual energy X-ray absorptiometry were collected. H-FMC was characterized as a 10-second average of maximal postocclusion constriction. Independent t test was used to compare H-FMC versus non-H-FMC individuals. RESULTS: H-FMC was observed in approximately 69% of adult participants (54 obese, 57 overweight, and 59 normal weight). Total body mass (82.3 ± 17.5 versus 76.3 ± 16.3 kg, p = 0.012), fat mass (27.7 ± 11.5 versus 23.8 ± 10.5 kg, p = 0.012), body mass index (27.7 ± 4.9 versus 26.1 ± 5.0 kg/m2 , p = 0.018), and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio (2.41 ± 1.03 versus 2.09 ± 0.72, p = 0.007) were higher in H-FMC than in non-H-FMC individuals. Flow-mediated dilatation (FMD) (6.12 ± 3.48 versus 8.09 ± 3.02%, p < 0.001) was lower in H-FMC subjects. However, there was no difference in brachial artery dilation between groups (7.57 ± 3.69 versus 8.09 ± 3.02%, p = 0.250) when H-FMC was added to FMD. CONCLUSIONS: Increased body mass, fat mass, and body mass index were associated with a greater H-FMC. When H-FMC was present, the FMD response to reactive hyperemia was significantly lower. Because H-FMC has been observed to negatively affect FMD response to reactive hyperemia, we suggest that H-FMC should be noted when analyzing and interpreting FMD data. H-FMC may be an ancillary measure of endothelial health. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 45:35-42, 2017.

Relations among Adiposity and Insulin Resistance with Flow-Mediated Dilation, Carotid Intima-Media Thickness, and Arterial Stiffness in Children.

OBJECTIVE: To determine the associations of adiposity and insulin resistance with measures of vascular structure and function in children. STUDY DESIGN: A cross-sectional study included 252 children (age 15.1 ± 2.4 years; body mass index percentile 68.2 ± 26.5%; Tanner 2-5). Measurements of body fat percentage were obtained with dual-energy X-ray absorptiometry and visceral adipose tissue (VAT) with computed tomography. Insulin resistance was measured with hyperinsulinemic euglycemic clamp. Vascular measurements for endothelial function (brachial artery flow-mediated dilation [FMD]), vascular structure (carotid intima-media thickness [cIMT]), vascular stiffness (carotid incremental elastic modulus), and pulse wave velocity were analyzed by tertiles of adiposity and insulin resistance. Additional analyses with ANCOVA and linear regression were adjusted for Tanner, sex, race, and family relationship; FMD was also adjusted for baseline artery diameter. RESULTS: FMD was positively associated with high adiposity (body mass index, body fat percentage, and VAT) (P < .01 all). Insulin resistance was not associated with FMD. cIMT was significantly, positively related to obesity, VAT, and insulin resistance (P < .05 all). No differences in carotid incremental elastic modulus and pulse wave velocity were observed in relation to adiposity or insulin resistance. CONCLUSIONS: The findings suggest that adiposity is associated with higher FMD, and insulin resistance and VAT are associated with higher cIMT in children. Further research is needed to clarify the progression of these relations.

Utility of Body Mass Index in Identifying Excess Adiposity in Youth Across the Obesity Spectrum.

OBJECTIVES: To determine the proportion of youth within a given body mass index (BMI) obesity category with excess adiposity using dual energy x-ray absorptiometry (DXA). Furthermore, to examine whether mean differences in cardiometabolic risk factors based upon various excess adiposity cutpoints were present. STUDY DESIGN: DXA data from the National Health and Nutrition Examination Survey 1999-2006 (n = 10 465; 8-20 years of age) were used for this analysis. Obesity categories were defined using Centers for Disease Control and prevention definitions for age and sex. Excess adiposity was defined using cohort-specific cutpoints at 75th, 85th, and 90th percentiles of DXA body fat (%) by age and sex using quantile regression models. Additionally, we examined differences in cardiometabolic risk factors among youth (BMI percentile >85th) above and below various excess adiposity cutpoints. RESULTS: Nearly all youth with class 3 obesity (100% male, 100% female; 97% male, 99% female; and 95% male, 96% female; using the 75th, 85th, and 90th DXA percentiles, respectively) and a high proportion of those with class 2 obesity (98% male, 99% female; 92% male, 91% female; and 76% male, 76% female) had excess adiposity. Significant discordance was observed between BMI categorization and DXA-derived excess adiposity among youth with class 1 obesity or overweight. Elevated cardiometabolic risk factors were present in youth with excess adiposity, regardless of the cutpoint used. CONCLUSIONS: BMI correctly identifies excess adiposity in most youth with class 2 and 3 obesity but a relatively high degree of discordance was observed in youth with obesity and overweight. Cardiometabolic risk factors are increased in the presence of excess adiposity, regardless of the cutpoint used.

Impaired cardiac autonomic nervous system function is associated with pediatric hypertension independent of adiposity.

BACKGROUND: 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. METHODS: 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 to <95th) 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. RESULTS: 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 (P < 0.05). In linear regression analysis, lower time-domain, but not frequency-domain, HRV measures were significantly associated with higher SBP independent of total body fat (P < 0.05). CONCLUSION: 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.

Exercise for obese youth: refocusing attention from weight loss to health gains.

Despite evidence to the contrary, exercise interventions for obese youth target weight loss as a means of improving health. Using Exercise is Medicine® as a framework, we present a conceptual model for the beneficial effects of exercise independent of weight loss in obese youth and highlight novel biomarkers of cardiometabolic health that could prove useful as interventional targets for this population.

Predictors of fat mass changes in response to aerobic exercise training in women.

Aerobic exercise training in women typically results in minimal fat loss, with considerable individual variability. We hypothesized that women with higher baseline body fat would lose more body fat in response to exercise training and that early fat loss would predict final fat loss. Eighty-one sedentary premenopausal women (age: 30.7 ± 7.8 years; height: 164.5 ± 7.4 cm; weight: 68.2 ± 16.4 kg; fat percent: 38.1 ± 8.8) underwent dual-energy x-ray absorptiometry before and after 12 weeks of supervised treadmill walking 3 days per week for 30 minutes at 70% of (Equation is included in full-text article.). Overall, women did not lose body weight or fat mass. However, considerable individual variability was observed for changes in body weight (-11.7 to +4.8 kg) and fat mass (-11.8 to +3.7 kg). Fifty-five women were classified as compensators and, as a group, gained fat mass (25.6 ± 11.1 kg to 26.1 ± 11.3 kg; p < 0.001). The strongest correlates of change in body fat at 12 weeks were change in body weight (r = 0.52) and fat mass (r = 0.48) at 4 weeks. Stepwise regression analysis that included change in body weight and body fat at 4 weeks and submaximal exercise energy expenditure yielded a prediction model that explained 37% of the variance in fat mass change (R = 0.37, p < 0.001). Change in body weight and fat mass at 4 weeks were moderate predictors of fat loss and may potentially be useful for identification of individuals who achieve less than expected weight loss or experience unintended fat gain in response to exercise training.

Soluble receptor for advanced glycation end products independently predicts cardiometabolic syndrome in Latino youth.

OBJECTIVE: The soluble receptor for advanced glycation end products (sRAGE) has anti-atherogenic properties in adults, however, little is known about the relationship between sRAGE and cardiometabolic disease risk in pediatric populations. Therefore, the purpose of this investigation is to examine the relationship between sRAGE and cardiometabolic risk factors in Latino youth. RESEARCH DESIGN AND METHODS: Data from 133 Latino youth (58% female; age 16.3 ± 2.8 yr) enrolled in the Arizona Insulin Resistance Registry were analyzed. Cardiometabolic syndrome was determined using a continuous risk score normalized to the population. Components included waist circumference, high-density lipoprotein cholesterol (HDL-c), triglycerides, mean arterial pressure (MAP), and homeostatic assessment of insulin resistance (HOMA-IR). sRAGE levels were determined from fasting serum using an enzyme-linked immunosorbent assay. RESULTS: In univariate analysis, sRAGE was inversely associated with waist circumference (r = -0.22, p = 0.01), MAP (r = -0.15, p = 0.09), and HOMA-IR (r = -0.29, p < 0.01) and positively associated with HDL-c (r = 0.19, p < 0.05). In multiple regression analysis with age, sex, and BMI, sRAGE remained an independent predictor of cardiometabolic syndrome risk score (R(2) = 0.55, p < 0.001). CONCLUSIONS: These data suggest that sRAGE may be an early independent biomarker of cardiometabolic disease risk in youth. Prospective studies are needed to establish the predictive utility of sRAGE for long-term disease outcomes.

Financial Incentives and Treatment Outcomes in Adolescents With Severe Obesity: A Randomized Clinical Trial.

Importance: Adolescent severe obesity is usually not effectively treated with traditional lifestyle modification therapy. Meal replacement therapy (MRT) shows short-term efficacy for body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) reduction in adolescents, and financial incentives (FIs) may be an appropriate adjunct intervention to enhance long-term efficacy. Objective: To evaluate the effect of MRT plus FIs vs MRT alone on BMI, body fat, and cardiometabolic risk factors in adolescents with severe obesity. Design, Setting, and Participants: This was a randomized clinical trial of MRT plus FIs vs MRT alone at a large academic health center in the Midwest conducted from 2018 to 2022. Participants were adolescents (ages 13-17 y) with severe obesity (≥120% of the 95th BMI percentile based on sex and age or ≥35 BMI, whichever was lower) who were unaware of the FI component of the trial until they were randomized to MRT plus FIs or until the end of the trial. Study staff members collecting clinical measures were blinded to treatment condition. Data were analyzed from March 2022 to February 2024. Interventions: MRT included provision of preportioned, calorie-controlled meals (~1200 kcals/d). In the MRT plus FI group, incentives were provided based on reduction in body weight from baseline. Main Outcomes and Measures: The primary end point was mean BMI percentage change from randomization to 52 weeks. Secondary end points included total body fat and cardiometabolic risk factors: blood pressure, triglyceride to high-density lipoprotein ratio, heart rate variability, and arterial stiffness. Cost-effectiveness was additionally evaluated. Safety was assessed through monthly adverse event monitoring and frequent assessment of unhealthy weight-control behaviors. Results: Among 126 adolescents with severe obesity (73 female [57.9%]; mean [SD] age, 15.3 [1.2] years), 63 participants received MRT plus FIs and 63 participants received only MRT. At 52 weeks, the mean BMI reduction was greater by -5.9 percentage points (95% CI, -9.9 to -1.9 percentage points; P = .004) in the MRT plus FI compared with the MRT group. The MRT plus FI group had a greater reduction in mean total body fat mass by -4.8 kg (95% CI, -9.1 to -0.6 kg; P = .03) and was cost-effective (incremental cost-effectiveness ratio, $39 178 per quality-adjusted life year) compared with MRT alone. There were no significant differences in cardiometabolic risk factors or unhealthy weight-control behaviors between groups. Conclusions and Relevance: In this study, adding FIs to MRT resulted in greater reductions in BMI and total body fat in adolescents with severe obesity without increased unhealthy weight-control behaviors. FIs were cost-effective and possibly promoted adherence to health behaviors. Trial Registration: ClinicalTrials.gov Identifier: NCT03137433.

SMART use of medications for the treatment of adolescent severe obesity: A sequential multiple assignment randomized trial protocol.

BACKGROUND: Severe obesity is a complex, chronic disease affecting nearly 9% of adolescents in the U.S. Although the current mainstay of treatment is lifestyle therapy, pediatric clinical practice guidelines recommend the addition of adjunct anti-obesity medication (AOM), such as phentermine and topiramate. However, guidance regarding when adjunct AOM should be started and how AOM should be used is unclear. Furthermore, an inherent limitation of current treatment guidelines is their "one-size-fits-all" approach, which does not account for the heterogeneous nature of obesity and high degree of patient variability in response to all interventions. METHODS: This paper describes the study design and methods of a sequential multiple assignment randomized trial (SMART), "SMART Use of Medications for the Treatment of Adolescent Severe Obesity." The trial will examine 1) when to start AOM (specifically phentermine) in adolescents who are not responding to lifestyle therapy and 2) how to modify AOM when there is a sub-optimal response to the initial pharmacological intervention (specifically, for phentermine non-responders, is it better to add topiramate to phentermine or switch to topiramate monotherapy). Critically, participant characteristics that may differentially affect response to treatment will be assessed and evaluated as potential moderators of intervention efficacy. CONCLUSION: Data from this study will be used to inform the development of an adaptive intervention for the treatment of adolescent severe obesity that includes empirically-derived decision rules regarding when and how to use AOM. Future research will test this adaptive intervention against standard "one-size-fits-all" treatments.

Circulating microRNA expression and nonalcoholic fatty liver disease in adolescents with severe obesity.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in children and adolescents. NAFLD ranges in severity from isolated hepatic steatosis to nonalcoholic steatohepatitis (NASH), wherein hepatocellular inflammation and/or fibrosis coexist with steatosis. Circulating microRNA (miRNA) levels have been suggested to be altered in NAFLD, but the extent to which miRNA are related to NAFLD features remains unknown. This analysis tested the hypothesis that plasma miRNAs are significantly associated with histological features of NAFLD in adolescents. AIM: To investigate the relationship between plasma miRNA expression and NAFLD features among adolescents with NAFLD. METHODS: This study included 81 adolescents diagnosed with NAFLD and 54 adolescents without NAFLD from the Teen-Longitudinal Assessment of Bariatric Surgery study. Intra-operative core liver biopsies were collected from participants and used to characterize histological features of NAFLD. Plasma samples were collected during surgery for miRNA profiling. A total of 843 plasma miRNAs were profiled using the HTG EdgeSeq platform. We examined associations of plasma miRNAs and NAFLD features using logistic regression after adjusting for age, sex, race, and other key covariates. Ingenuity Pathways Analysis was used to identify biological functions of miRNAs that were associated with multiple histological features of NAFLD. RESULTS: We identified 16 upregulated plasma miRNAs, including miR-193a-5p and miR-193b-5p, and 22 downregulated plasma miRNAs, including miR-1282 and miR-6734-5p, in adolescents with NAFLD. Moreover, 52, 16, 15, and 9 plasma miRNAs were associated with NASH, fibrosis, ballooning degeneration, and lobular inflammation, respectively. Collectively, 16 miRNAs were associated with two or more histological features of NAFLD. Among those miRNAs, miR-411-5p was downregulated in NASH, ballooning, and fibrosis, while miR-122-5p, miR-1343-5p, miR-193a-5p, miR-193b-5p, and miR-7845-5p were consistently and positively associated with all histological features of NAFLD. Pathway analysis revealed that most common pathways of miRNAs associated with multiple NAFLD features have been associated with tumor progression, while we also identified linkages between miR-122-5p and hepatitis C virus and between miR-199b-5p and chronic hepatitis B. CONCLUSION: Plasma miRNAs were associated with NAFLD features in adolescent with severe obesity. Larger studies with more heterogeneous NAFLD phenotypes are needed to evaluate miRNAs as potential biomarkers of NAFLD.

Exposure to 4,4'-DDE in visceral adipose tissue and weight loss in adolescents from the Teen-LABS cohort.

OBJECTIVE: Dichlorodiphenyldichloroethylene (DDE), an obesogen accumulating in adipose tissue, is released into circulation with weight loss, although its impact is underexplored among adolescents. We tested the association using an integrative translational approach of epidemiological analysis among adolescents with obesity and in vitro measures exploring the impact of DDE on adipogenesis via preadipocytes. METHODS: We included 63 participants from the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) cohort. We assessed 4,4'-DDE in visceral adipose tissue at surgery and BMI and waist circumference at surgery and 0.5, 1, 3, and 5 years after. We conducted longitudinal analysis to estimate the interaction on weight loss between DDE and time since surgery. In vitro analysis quantified adipogenic differentiation in commercial human preadipocytes exposed to 4,4'-DDE via fluorescent staining and imaging. RESULTS: A dose-response relationship was observed, with the low-exposure group having a greater reduction in BMI during the first year compared to higher-exposure groups and showing smaller regains compared to higher-exposure groups after the first year. In vitro analysis of preadipocytes treated with 4,4'-DDE during adipogenic differentiation for 12 days showed a concentration-dependent increase in lipid accumulation. CONCLUSIONS: DDE could contribute to weight trajectory among adolescents undergoing bariatric surgery, potentially mediated via promoted adipogenesis in preadipocytes.