Investigating resilience and its association with stress, anthropometrics, and metabolic health in adolescents with obesity: a pilot study.

The increasing prevalence of children with obesity has contributed to a higher risk of developing cardiometabolic comorbidities. Adversity and chronic stress are negatively linked to cardiometabolic outcomes, and resilience is positively associated with improved outcomes. However, whether resilience is protective against metabolic disturbances preceding disease presentation is less understood. This study explored correlations between stress, anthropometrics, and metabolic parameters with resilience (total, individual, family, peers, school, community), and determined which resilience domains predict metabolically unhealthy obesity. Adolescents with obesity (n = 39; 12-18y) completed anthropometrics, an oral glucose tolerance test, the Adolescent Resilience Questionnaire, and Perceived Stress Scale. Lower stress (r = -0.70, p < 0.001), BMI (r = -0.42, p = 0.01), fat mass (ρ = -0.41, p = 0.01), and fat-free mass (ρ = -0.41, p = 0.01) were associated with greater resilience. Greater school resilience was associated with lower risk for having metabolically unhealthy obesity (odds ratio = 0.87, 95% Confidence Intervals, 0.78-0.98, p = 0.02). Our findings suggest that resilience is associated with lower adiposity, and that lower school resilience is an independent predictor of having metabolically unhealthy obesity. Further work exploring correlations between school resilience, perceived stress, and metabolic outcomes, would optimize programs for obesity-related chronic conditions.

Individual and family characteristics associated with health indicators at entry into multidisciplinary pediatric weight management: findings from the CANadian Pediatric Weight management Registry (CANPWR).

OBJECTIVES: (1) To explore individual and family characteristics related to anthropometric and cardiometabolic health indicators and (2) examine whether characteristics that correlate with cardiometabolic health indicators differ across severity of obesity at time of entry to Canadian pediatric weight management clinics. METHODS: We conducted a cross-sectional analysis of 2-17 year olds with overweight or obesity who registered in the CANadian Pediatric Weight Management Registry (CANPWR) between May 2013 and October 2017 prior to their first clinic visit. Individual modifiable health behaviors included dietary intake, physical activity, screen time, and sleep. Family characteristics included parental BMI, family medical history, socioeconomic status and family structure. Linear mixed effects stepwise regression analysis was performed to determine which characteristics were related to each health indicator: BMI z-score; waist circumference; waist to height ratio; blood pressure; glycemia; HDL cholesterol; non-HDL cholesterol; triglycerides. RESULTS: This study included 1296 children (mean age ± standard deviation: 12.1 ± 3.5 years; BMI z-score: 3.55 ± 1.29; 95.3% with obesity). Hours spent sleeping (estimated ß = -0.10; 95% CI [-0.15, -0.05], p = 0.0001), hours per week of organized physical activity (estimated ß = -0.32; 95% CI [-0.53, -0.11], p = 0.0026), daily sugared drink intake (estimated ß = 0.06; 95% CI [0.01, 0.10], p = 0.0136) and maternal BMI (estimated ß = 0.03; 95% CI [0.02, 0.04], p < 0.0001) were associated with BMI z-score (adj. R2 = 0.2084), independent of other individual and family characteristics. Physical activity, total sugared drink intake and sleep duration were associated with glycemia and non-HDL cholesterol, independent of child BMI z-score. However, irrespective of obesity severity, little of the variance (0.86-11.1%) in cardiometabolic health indicators was explained by individual modifiable health behaviors. CONCLUSIONS: Physical activity, total sugared drink intake and hours spent sleeping were related to anthropometric and some cardiometabolic health indicators in children entering pediatric weight management programs. This highlights the importance of these modifiable health behaviors on multiple health indicators in children with obesity.

"Counting Carbs to Be in Charge": A Comparison of an Internet-Based Education Module With In-Class Education in Adolescents With Type 1 Diabetes.

Carbohydrate counting is an essential component of type 1 diabetes education but can be difficult for adolescents to learn. Because adolescents are avid users of technology, an Internet-based education module was compared with an in-class education session in terms of carbohydrate counting accuracy in adolescents with type 1 diabetes. Adolescent participants displayed increased carbohydrate counting accuracy after attending an in-class education session compared with an Internet-based education module. These results suggest that online education is best reserved as an adjunctive therapy to in-class teaching in this population.

Careful conversations: an educational video to support parents in communicating about weight with their children.

BACKGROUND: Parents may struggle to initiate healthy weight-related conversations with their children. Educational videos may be an effective tool for improving parents' knowledge and self-efficacy on this topic. The aim of this pilot study was to develop an educational video to assist parents in weight-related conversations with their child, and to assess changes in parents' self-efficacy on this topic. METHODS: Video development was based on a scoping review and semi-structured interviews with parents. Respondent demographics and user satisfaction were assessed at pre- and post- video, and 4-6 months later. Self-efficacy scores were compared between parent groups based on weight concerns over time. RESULTS: Fifty-seven parents participated in the video questionnaires, and 40 repeated measures 4-6 months later. Significant improvements in self-efficacy in "raising the issue of weight" and "answering questions or concerns" were found after watching the video (p ≤ 0.002) compared to baseline, and scores 4-6 months post baseline remained slightly elevated, but non-significant. Parents with concerns about their child being overweight had significantly lower perceived self-efficacy scores compared to parents with no concerns about their child's weight (p = 0.031). The video was found to be positively received and of relevance to parents across a number of different domains. CONCLUSION(S): Preliminary findings suggest an educational video about initiating weight-related conversations may be an effective tool for increasing parents' perceived self-efficacy in the short term. Further work is needed to validate findings in a randomized controlled trial, and with diverse parent populations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03664492 . Registered 10 September 2018 - Retrospectively registered.

Association of accelerated body mass index gain with repeated measures of blood pressure in early childhood.

BACKGROUND/OBJECTIVES: We examined the association for rates of age- and sex-standardized body mass index (zBMI) gain between 0-3, 3-18, and 18-36 months with BP in children at 36-72 months of age. METHODS: We collected repeated measures of zBMI and BP in 2502 children. zBMI was calculated using the World Health Organization standards. Each child's zBMI at birth and rates of zBMI gain in each period from birth to 36 months were estimated using linear spline multilevel models. Generalized estimating equations were used to determine whether zBMI at birth and zBMI gain between 0-3, 3-18, and 18-36 months were each associated with repeated measures of BP at 36-72 months of age. We sequentially conditioned on zBMI at birth and zBMI gain in each period prior to each period tested, as covariates, and adjusted for important socio-demographic, familial, and study design covariates. We examined whether these associations were modified by birthweight or maternal obesity, by including interaction terms. RESULTS: After adjusting for all covariates and conditioning on prior zBMI gains, a 1 standard deviation unit faster rate of zBMI gain during 0-3 months, (ß = 0.59 mmHg; 95% CI 0.31, 0.86) and 3-18 months (ß = 0.74 mmHg; 95% CI 0.46, 1.03) were each associated with higher systolic BP at 36-72 months. No significant associations were observed, however, for zBMI at birth or zBMI gain in the 18-36 month growth period. zBMI gains from 0-3 and 3-18 months were also associated with diastolic BP. Birthweight significantly modified the relationship during the 3-18 month period (p = 0.02), with the low birthweight group exhibiting the strongest association for faster rate of zBMI gain with higher systolic BP (ß = 1.31 mmHg; 95% CI 0.14, 2.48). CONCLUSIONS: Given that long-term exposure to small elevations in BP are associated with subclinical cardiovascular disease, promoting interventions targeting healthy growth in infancy may be important.

Acute decrease in plasma testosterone and appetite after either glucose or protein beverages in adolescent males.

OBJECTIVE: Chronic testosterone blood concentrations associate with food intake (FI), but acute effects of testosterone on appetite and effect of protein and glucose consumption on testosterone response have had little examination. METHODS: In a randomized, crossover study, twenty-three adolescent (12-18 years old) males were given beverages containing either: (a) whey protein (1 g/kg body weight), (b) glucose (1 g/kg body weight) or (c) a calorie-free control (C). Plasma testosterone, luteinizing hormone (LH), GLP-1 (active), ghrelin (acylated), glucose, insulin and subjective appetite were measured prior (0) and at 20, 35 and 65 minutes after the consumption of the beverage. FI at an ad libitum pizza meal was assessed at 85 minutes. RESULTS: Testosterone decreased acutely to 20 minutes after both protein and glucose with the decrease continuing after protein but not glucose to 65 minutes (P = 0.0382). LH was also decreased by both protein and glucose, but glucose had no effect at 20 minutes in contrast to protein (P < 0.001). Plasma testosterone concentration correlated positively with LH (r = 0.58762, P < 0.0001) and negatively with GLP-1 (r = -0.50656, P = 0.0003). No associations with appetite, ghrelin or glycaemic markers were found. Food intake was not affected by treatments. CONCLUSION: Protein or glucose ingestion results in acute decreases in both plasma testosterone and LH in adolescent males. The physiological significance of this response remains to be determined as no support for testosterone's role in acute regulation of food intake was found.

Development and Validation of Bioelectrical Impedance Analysis Equations in Adolescents with Severe Obesity.

BACKGROUND: Body mass index measures excess weight for size, and does not differentiate between fat mass (FM) and fat-free mass (FFM). Bioelectrical impedance analysis (BIA) is most commonly used to assess FM and FFM as it is simple and inexpensive. Variables from BIA measurements are used in predictive equations to estimate FM and FFM. To date, these equations have not been validated for use in adolescents with severe obesity. OBJECTIVES: In a cohort of adolescents with severe obesity (SO), a BMI ≥ 120% of the 95th percentile, this study aimed to 1) derive a BIA predictive equation data from air displacement plethysmography (ADP) measurements; 2) reassess the equation in a second validation cohort; and 3) compare the accuracy of existing body composition equations. METHODS: Adolescents with SO were assessed using ADP and BIA. FM values derived from ADP measurements from the first cohort (n = 27) were used to develop a BIA predictive equation (i.e., Hamilton). A second cohort (n = 65) was used to cross-validate the new and 9 existing BIA predictive equations. RESULTS: Ninety-two adolescents (15.8 ± 1.9 y; BMI: 46.1 ± 9.9 kg/m2) participated. Compared with measured FFM using ADP: 1) the Lazzer, Hamilton, Gray, and Kyle equations were without significant bias; 2) the Hamilton and Gray equations had the smallest absolute and relative differences; 3) the Kyle and Gray equations showed the strongest correlation; 4) the Hamilton equation most accurately predicted FFM within ± 5% of measured FFM; and 5) 8 out of 9 equations had similar root mean squared prediction error values (6.03-6.64 kg). CONCLUSION: The Hamilton BIA equation developed in this study best predicted body composition values for groups of adolescents with severe obesity in a validation cohort.

One potato, two potato, assessing carbohydrate counting accuracy in adolescents with type 1 diabetes.

BACKGROUND/OBJECTIVE: Carbohydrate (CHO) counting is a recommended daily practice to help manage blood glucose levels in type 1 diabetes. Evidence suggests that CHO estimates should be within 10 to 15 g of the actual meal for optimal postprandial blood glucose control. The objective of this study was to assess accuracy of CHO counting in adolescents with type 1 diabetes. METHODS: Adolescents (aged 12-18 years) with type 1 diabetes who self-identified as regular CHO counters were recruited from the SickKids Diabetes Clinic, Toronto, Canada. Adolescents completed the PedsCarbQuiz (PCQ) and estimated CHO content of test trays (three meals and three snack trays) that were randomly assigned. Analyses were conducted to identify factors associated with accuracy of counting and CHO counting knowledge (PCQ score). RESULTS: A total of 140 adolescents (78 females, mean age 14.7, SD = 1.8) participated. The average PCQ score was 81 ± 10%. Forty-two percent of adolescents were accurate in estimating meal trays (ie, within 10 g of the actual CHO content), 44% estimated inaccurately (within 10-20 g), while 14% were significantly inaccurate counters (>20 g variation). PCQ scores were higher in teens who CHO counted accurately than in those with significant inaccuracy (>20 g) (P < 0.05), and a longer duration of diabetes corresponded significantly with a lower PCQ score. No demographics correlated significantly with CHO counting accuracy. CONCLUSIONS: Less than half of the teens in our study were accurate CHO counters. These results indicate the need for regular clinical accuracy check and reeducation.

Obesity, sex and pubertal status affect appetite hormone responses to a mixed glucose and whey protein drink in adolescents.

BACKGROUND AND OBJECTIVES: Little information is available on how food intake regulatory hormones may be altered during pubertal development and across the weight spectrum in adolescents. Therefore, the effect of obesity, sex and pubertal status on subjective appetite and appetite hormones in response to a mixed glucose and whey protein drink was determined in 8-18 year old adolescents. PATIENTS AND METHODS: A cross-sectional cohort study was conducted at the Hospital for Sick Children, Toronto. After a 12 h fast, normal weight (n = 5 female, 4 male) and obese (n = 5 female, 4 male) adolescents (Experiment 1), and pre-early pubertal (n = 10) and mid-late pubertal (n = 10) obese male adolescents (Experiment 2) consumed a 250 ml glucose (30 g) and whey protein (30 g) beverage. Insulin, PYY, ghrelin and subjective appetite were measured over 120 min. RESULTS: Obese adolescents (Experiment 1) have higher insulin, PYY and lower ghrelin (P < 0·006) than normal weight controls, with a more pronounced effect in males (P < 0·037). Puberty (Experiment 2) did not affect insulin (P = 0·305), but the change in PYY in response to the drink was greater (P = 0·032) and ghrelin was lower (P = 0·026) in mid-late pubertal than pre-early pubertal obese males. Average appetite 60 min post-drink was higher in obese and mid-late pubertal adolescents, but not related to hormone changes. CONCLUSIONS: Obesity, sex and pubertal status affect macronutrient-stimulated appetite hormone secretion and these factors may alter food intake in obese children during pubertal development.

Antepartum determinants of rapid early-life weight gain in term infants born to women with and without gestational diabetes.

OBJECTIVE: Rapid weight gain in the first 3 months of life has been associated with an unfavourable cardio-metabolic phenotype in adulthood. However, little is known about the antepartum determinants of this rapid weight gain, which may reflect key developmental exposures that program metabolic pathways. Thus, we sought to characterize the antepartum determinants of rapid weight gain in the first 3 months of life in infants exposed to gestational diabetes mellitus (GDM), a patient population at risk for early cardio-metabolic disease. DESIGN: Prospective observational cohort study. PATIENTS: Pregnant women with (n = 90) and without GDM (n = 250) underwent detailed antepartum metabolic characterization, followed by assessment of their term offspring at age 3 months. MEASUREMENTS: Rapid infant weight gain in the first 3 months was defined as weight gain ≥ 0·5 SD. RESULTS: No features of maternal metabolic function in pregnancy (including insulin sensitivity, lipid profile, adiponectin, leptin and C-reactive protein) were associated with infant weight gain in either the GDM or non-GDM group. Interestingly, although all infants were born at term (≥37 weeks), length of gestation was inversely associated with weight gain at 3 months in the infants of women with GDM (ß = -148·5, P = 0·01). In these infants, length of gestation <39 weeks was an independent predictor of rapid weight gain (OR = 7·9, 95%CI 1·7-38, P = 0·009) in the fully adjusted model. These associations were not observed in infants of women without GDM. CONCLUSIONS: Delivery before 39 weeks is independently associated with rapid weight gain in the first 3 months of life in term infants of women with GDM and hence may be an antepartum marker of future cardio-metabolic risk.

Delivery by Caesarean section and infant cardiometabolic status at one year of age.

OBJECTIVE: Disruption of the gut microbiome has been associated with overweight/obesity, insulin resistance, and type 2 diabetes. Recently, it has been reported that Caesarean section disrupts the normal gut microbiome of neonates. As such, these data have raised the intriguing possibility that CS could lead to an adverse cardiometabolic risk profile early in life. Thus, we sought to compare the cardiometabolic status of infants delivered by CS to that of infants delivered vaginally. METHODS: In this prospective observational cohort study, 104 women underwent cardiometabolic evaluation in pregnancy followed by similar assessment of their infants at one year of age, thereby enabling comparison of infants delivered vaginally (n = 74) to those delivered by CS (n = 30). Infant assessment included anthropometric evaluation and measurement of variables associated with cardiometabolic risk. RESULTS: At one year of age, there were no differences between infants delivered vaginally and those delivered by CS with respect to mean BMI, sum of skinfolds, fasting glucose, insulin resistance, total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, C-reactive protein, leptin, and adiponectin, both before and after covariate adjustment. Of note, maternal and infant levels of adiponectin (r = 0.31, P = 0.007) and of total cholesterol, LDL-cholesterol, and HDL-cholesterol (all r ≥ 0.23, P < 0.05) were associated in the vaginal delivery group only, whereas the analogous association for leptin was observed only in the CS group (r = 0.44, P = 0.02). CONCLUSION: Caesarean section was not found to be associated with an adverse infant cardiometabolic risk profile at one year of age, although it potentially may affect the impact of maternal determinants of this profile.

Objectif : La perturbation du microbiome intestinal a été associée à la surcharge pondérale / à l'obésité, à l'insulinorésistance et au diabète de type 2. On a récemment signalé que la césarienne perturbe le microbiome intestinal normal du nouveau-né. Ainsi, ces données ont soulevé l'intrigante hypothèse selon laquelle la césarienne pourrait mener à un profil de risque cardiométabolique indésirable tôt aux débuts de la vie. Nous avons donc cherché à comparer l'état cardiométabolique de nouveau-nés issus d'une césarienne à celui de nouveau-nés issus d'un accouchement vaginal. Méthodes : Dans le cadre de cette étude de cohorte observationnelle prospective, 104 femmes se sont soumises à une évaluation cardiométabolique pendant la grossesse, le tout ayant été suivi d'une évaluation semblable de leurs nouveau-nés à l'âge d'un an, ce qui a permis la comparaison des nouveau-nés issus d'un accouchement vaginal (n = 74) et des nouveau-nés issus d'une césarienne (n = 30). L'évaluation des nouveau-nés comprenait un examen anthropométrique et la mesure des variables associées au risque cardiométabolique. Résultats : À l'âge d'un an, aucune différence n'a été constatée entre les nouveau-nés issus d'un accouchement vaginal et les nouveau-nés issus d'une césarienne en ce qui concerne l'IMC moyen, la somme des plis cutanés, la glycémie à jeun, l'insulinorésistance, le cholestérol total, le cholestérol LDL, le cholestérol HDL, les triglycérides, la protéine C-réactive, la leptine et l'adiponectine, tant avant qu'après la neutralisation des effets des covariables. Fait à souligner, les taux maternels et infantiles d'adiponectine (r = 0,31, P = 0,007) et de cholestérol total, de cholestérol LDL et de cholestérol HDL (tous r ≥ 0,23, P < 0,05) n'ont été associés qu'au sein du groupe « accouchement vaginal ¼, tandis qu'une association analogue pour ce qui est de la leptine n'a été constatée qu'au sein du groupe « césarienne ¼ (r = 0,44, P = 0,02). Conclusion : Nous n'avons pas constaté que la césarienne était associée à un profil de risque cardiométabolique indésirable chez l'enfant à l'âge d'un an; toutefois, il est possible qu'elle puisse affecter les effets des déterminants maternels de ce profil.

Gut Microbiome Alterations Accompany Metabolic Normalization Following Bariatric Surgery in ROHHAD Syndrome.

Rapid onset obesity with hypoventilation, hypothalamic, and autonomic dysregulation (ROHHAD) syndrome in childhood is characterized by abrupt onset weight gain and dysautonomia with variable neuroendocrine involvement. In the absence of definitive disease-modifying therapies, the primary management strategy remains symptom control. This case report describes the first successful correction of obesity, dysautonomia, and metabolic derangement in a patient with ROHHAD following Roux-en-Y gastric bypass. Anthropometrics, metabolic profiling, and stool microbiome composition were assessed in a longitudinal fashion. In the 48-month period following surgery, the patient body mass index (BMI) reduced by 9.5 kg/m2 and metabolic status improved, evidenced in weaning of insulin, and improved glycated hemoglobin, lipid profile, and hepatic enzymes. Chronic diarrhea resolved after surgery and prior to significant weight loss. Evaluation of stool bacterial composition and biomass demonstrated shifts in absolute abundance and taxonomic composition in longitudinal samples following surgery. This case demonstrates the potential efficacy of bariatric surgery in correcting the metabolic disruption of ROHHAD syndrome, producing long-term changes in gut microbiome composition and biomass.

The impact of gestational diabetes on functional capacity of the infant gut microbiome is modest and transient.

Gestational diabetes mellitus (GDM) is a metabolic complication that manifests as hyperglycemia during the later stages of pregnancy. In high resource settings, careful management of GDM limits risk to the pregnancy, and hyperglycemia typically resolves after birth. At the same time, previous studies have revealed that the gut microbiome of infants born to mothers who experienced GDM exhibit reduced diversity and reduction in the abundance of several key taxa, including Lactobacillus. What is not known is what the functional consequences of these changes might be. In this case control study, we applied 16S rRNA sequence surveys and metatranscriptomics to profile the gut microbiome of 30 twelve-month-old infants - 16 from mothers with GDM, 14 from mothers without - to examine the impact of GDM during pregnancy. Relative to the mode of delivery and sex of the infant, maternal GDM status had a limited impact on the structure and function of the developing microbiome. While GDM samples were associated with a decrease in alpha diversity, we observed no effect on beta diversity and no differentially abundant taxa. Further, while the mode of delivery and sex of infant affected the expression of multiple bacterial pathways, much of the impact of GDM status on the function of the infant microbiome appears to be lost by twelve months of age. These data may indicate that, while mode of delivery appears to impact function and diversity for longer than anticipated, GDM may not have persistent effects on the function nor composition of the infant gut microbiome.

Medical students' perceived comfort and competence performing physical examinations on patients with obesity: A mixed-methods needs assessment.

Physicians are unsatisfied with their training in the care of patients with obesity. Physical examination is a key component of care, and modifications to techniques are often necessary for patients with obesity. To determine learning needs, we examined medical students' perceived comfort and competency in conducting physical examinations on patients with obesity. This mixed-methods study of Canadian medical students used a questionnaire and semi-structured focus groups to assess medical students' perceived comfort and competence in examining patients with obesity. Participants included 175 Canadian medical students. A minority of medical students felt comfortable (42%) or competent (14%) examining patients with obesity. Physical exam challenges included modifying exam manoeuvres, interpreting findings and communicating sensitively around weight. Lack of early exposure to patients with obesity, minimal instruction by preceptors and a lack of curricular focus on obesity were felt to be barriers to improving these skills. Students perceived their lack of confidence as negatively impacting their ability to manage patients with obesity and more training in this area was desired to prevent disparities in care. Medical students feel that adequate training on how to perform an obesity-specific physical examination is lacking. Developing curricula and including formal teaching around these key competencies within medical education is essential.

An evaluation of early cardiometabolic risk factors in children and adolescents with Turner syndrome.

BACKGROUND AND OBJECTIVES: Turner syndrome (TS) confers increased lifetime risk of type 2 diabetes mellitus and cardiovascular disease. We compared cardiometabolic risk factors and measures of subcutaneous, visceral adipose tissue and intra-myocellular lipid between young TS girls and an age- and BMI-standard deviation scores (SDS)-matched healthy female cohort. PATIENTS AND METHODS: A cross-sectional cohort study was conducted at the Hospital for Sick Children, Toronto. Nineteen TS and 17 control girls (13.7 ± 2.5 vs 12.7 ± 3.4 years of age, respectively, P = 0.30). Multiple-sample oral glucose tolerance test with measurement of fasting insulin, LDL, HDL, triglycerides, adiponectin and highly sensitive C-reactive protein (hsCRP) was performed. Subcutaneous adipose tissue, visceral adipose tissue intramyocellular lipid levels evaluated by magnetic resonance techniques. Insulin secretion (IS), sensitivity (Si) and the insulin secretion-sensitivity index (ISSI-2) were calculated from oral glucose tolerance test data. RESULTS: Five TS and no controls had impaired fasting glucose or impaired glucose tolerance; none had type 2 diabetes mellitus. Insulin sensitivity and insulin secretion were similar between groups; ISSI-2 was lower in TS (923.5 ± 307.3 vs 659.1 ± 387.3; P = 0.03). TS girls had higher blood pressure (82.5 ± 13.6 vs 73.5 ± 5.5 mmHg; P = 0.0146), waist circumference (76.0 ± 11.8 vs 65.9 ± 9.7; P = 0.0087) and subcutaneous adipose tissue (135.6 ± 88.6 vs 69.3 ± 59.9; P = 0.01) than controls. Visceral adipose tissue, intramyocellular lipid levels and adiponectin were not different between groups. TS girls also had higher triglycerides (1.1 ± 0.6 vs 0.7 ± 0.3; P = 0.003), total cholesterol (4.4 ± 0.7 vs 3.9 ± 0.4; P = 0.02) and hsCRP (2.0 ± 1.9 vs 0.8 ± 0.3; P = 0.01). CONCLUSIONS: TS girls exhibit more cardiometabolic risk factors and reduced beta cell function compared with age- and BMI-SDS-matched girls. Increased awareness of early risk of type 2 diabetes mellitus and hypertension in TS girls is needed.

Vitamin D status and cardiometabolic assessment in infancy.

BACKGROUND: Infants are at risk of vitamin D insufficiency, owing to their limited exposure to direct sunlight and the low levels of vitamin D in breast milk. Although vitamin D insufficiency has been associated with cardiometabolic risk factors in children, these associations have not been studied in infants, despite their unique risks. Therefore, we sought to determine whether vitamin D status was associated with cardiometabolic measures in infants. METHODS: Ninety-nine full-term infants were evaluated at the age of 1 y with measurement of 25-hydroxy vitamin D (25-OH-D) and an array of traditional (fasting glucose, insulin, low-density-lipoprotein cholesterol, high-density-lipoprotein cholesterol, triglycerides) and emerging (C-reactive protein, adiponectin, leptin) cardiometabolic risk factors. On the basis of 25-OH-D levels, infants were classified as vitamin D sufficient (n = 59), vitamin D insufficient (n = 29), or vitamin D deficient (n = 11). RESULTS: Duration of exclusive breastfeeding and prevalence of nonwhite ethnicity were highest in the vitamin D-deficient group (P = 0.05 and 0.03, respectively). Current use of vitamin D supplementation was highest in the sufficient group (P = 0.02). Of note, however, there were no significant differences among the three groups in any of the cardiometabolic risk factors, on both unadjusted and covariate-adjusted analyses. CONCLUSION: Vitamin D insufficiency/deficiency is not associated with an adverse cardiometabolic risk factor profile in 1-y-old infants.

From diarrhea to obesity in prohormone convertase 1/3 deficiency: age-dependent clinical, pathologic, and enteroendocrine characteristics.

GOALS: The aim of this report is to delineate the clinical, pathologic, and enteroendocrine (EE) features of prohormone convertase 1/3 (PC1/3) deficiency in children. BACKGROUND: Prohormone convertases play a pivotal role in the activation of biologically inactive hormones. Congenital defects in the EE axis, such as PC1/3 deficiency, have been rarely reported and their pathophysiological mechanisms are largely unknown. STUDY: EE function and pathology was evaluated in 4 males (1, 2, 7, and 10 y old) from 2 families with PC1/3 deficiency at a university children's hospital. Clinical course, pathology analysis including immunohistochemistry for PC1/3, PC2, and glucagon-like peptide 1 (GLP-1) and electron microscopy, as well as EE function tests (GLP-1, GLP-2, oral glucose tolerance test) were performed. RESULTS: All (n=4) suffered from congenital severe diarrhea associated with malabsorption. The diarrhea improved during the first year of life and hyperphagia with excessive weight gain (BMI>97th percentile) became the predominant phenotype at an older age. Analysis of the enteroendocrine axis revealed high proinsulin levels (57 to 1116 pmol/L) in all patients, low serum GLP-2 levels, and impaired insulin and GLP-1 secretion after an oral glucose tolerance test at a young age, with improvement in 1 older child tested. Electron microscopy showed normal ultrastructure of enterocytes and EE cells. Immunohistochemistry revealed normal expression of chromogranin A, a marker of EE cells but markedly reduced immunostaining for PC1/3 and PC2 in all patients. CONCLUSIONS: PC1/3 deficiency is associated with an age dependent, variable clinical phenotype caused by severe abnormalities in intestinal and EE functions. Serum level of proinsulin can be used as an effective screening tool.

Intranasal Carbetocin Reduces Hyperphagia, Anxiousness, and Distress in Prader-Willi Syndrome: CARE-PWS Phase 3 Trial.

CONTEXT: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by endocrine and neuropsychiatric problems including hyperphagia, anxiousness, and distress. Intranasal carbetocin, an oxytocin analog, was investigated as a selective oxytocin replacement therapy. OBJECTIVE: To evaluate safety and efficacy of intranasal carbetocin in PWS. DESIGN: Randomized, double-blind, placebo-controlled phase 3 trial with long-term follow-up. SETTING: Twenty-four ambulatory clinics at academic medical centers. PARTICIPANTS: A total of 130 participants with PWS aged 7 to 18 years. INTERVENTIONS: Participants were randomized to 9.6 mg/dose carbetocin, 3.2 mg/dose carbetocin, or placebo 3 times daily during an 8-week placebo-controlled period (PCP). During a subsequent 56-week long-term follow-up period, placebo participants were randomly assigned to 9.6 mg or 3.2 mg carbetocin, with carbetocin participants continuing at their previous dose. MAIN OUTCOME MEASURES: Primary endpoints assessed change in hyperphagia (Hyperphagia Questionnaire for Clinical Trials [HQ-CT]) and obsessive-compulsive symptoms (Children's Yale-Brown Obsessive-Compulsive Scale [CY-BOCS]) during the PCP for 9.6 mg vs placebo, and the first secondary endpoints assessed these same outcomes for 3.2 mg vs placebo. Additional secondary endpoints included assessments of anxiousness and distress behaviors (PWS Anxiousness and Distress Behaviors Questionnaire [PADQ]) and clinical global impression of change (CGI-C). RESULTS: Because of onset of the COVID-19 pandemic, enrollment was stopped prematurely. The primary endpoints showed numeric improvements in both HQ-CT and CY-BOCS which were not statistically significant; however, the 3.2-mg arm showed nominally significant improvements in HQ-CT, PADQ, and CGI-C scores vs placebo. Improvements were sustained in the long-term follow-up period. The most common adverse event during the PCP was mild to moderate flushing. CONCLUSIONS: Carbetocin was well tolerated, and the 3.2-mg dose was associated with clinically meaningful improvements in hyperphagia and anxiousness and distress behaviors in participants with PWS. CLINICAL TRIALS REGISTRATION NUMBER: NCT03649477.