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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

COVID-19 mitigation measures, including closures of schools and recreational facilities and alterations in eating behaviours and physical activity, may impact weight.To examine changes in body weight and body mass index (BMI) in children and adolescents with obesity participating in an obesity treatment program before and during the COVID-19 pandemic in Ontario, Canada.Body weight and BMI at baseline and 6 months were recorded for the 'historic' cohort (females = 34, males = 21) before the pandemic (November 1, 2018, to March 18, 2020) and for the 'pandemic' cohort (females = 30, males = 30) during the pandemic (March 19, 2020 to July 31, 2021). Analyses were adjusted for baseline weight/BMI, age, and ON-Marg score, a measure of the social determinants of health.In males, body weight (98.29 versus 89.28 kg, p 0.001) and BMI (36.46 versus 34.85 kg/mThe COVID-19 pandemic may have diminished the health impacts of a weight management program, particularly in males, leading to increased body weight and BMI.

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 (

OBJECTIVE The continuum of maternal glycemia in pregnancy shows continuous associations with both 1) neonatal birth weight at delivery and 2) subsequent adiposity later in childhood. While treating gestational diabetes mellitus (GDM) can lower birth weight and thereby disrupt the former association, it is unclear if such treatment reduces childhood adiposity. Thus, we sought to compare anthropometry across the 1st year of life between infants born to women who were treated for GDM and those with lesser degrees of gestational dysglycemia (untreated). RESEARCH DESIGN AND METHODS Anthropometric measurements were performed at 3 months and 12 months of life in 567 infants born to women comprising the following four gestational glucose tolerance groups: 1) women with normoglycemia on both glucose challenge test (GCT) and oral glucose tolerance test (OGTT) in pregnancy; 2) women with an abnormal GCT but normal OGTT; 3) those with mild gestational impaired glucose tolerance; and 4) women treated for GDM. RESULTS Birth weight progressively increased across the three untreated groups but was lowest in women treated for GDM (P = 0.0004). Similarly, women treated for GDM had the lowest rate of macrosomia (P = 0.02). Conversely, however, there were no differences among the four groups in weight z score, length z score, weight-for-length z score, or BMI z score at either 3 months or 12 months (all P values = NS). Similarly, there were no differences among the groups in triceps/biceps/subscapular/suprailiac skinfold thickness or sum of skinfolds at either 3 months or 12 months (all P values = NS). CONCLUSIONS Despite reducing birth weight and macrosomia, the treatment of GDM does not have analogous effects on infant adiposity across the 1st year of life.

The nuclear zinc-finger protein encoded by the hindsight (hnt) locus regulates several cellular processes in Drosophila epithelia, including the Jun N-terminal kinase (JNK) signaling pathway and actin polymerization. Defects in these molecular pathways may underlie the abnormal cellular interactions, loss of epithelial integrity, and apoptosis that occurs in hnt mutants, in turn causing failure of morphogenetic processes such as germ band retraction and dorsal closure in the embryo. To define the genetic pathways regulated by hnt, 124 deficiencies on the second and third chromosomes and 14 duplications on the second chromosome were assayed for dose-sensitive modification of a temperature-sensitive rough eye phenotype caused by the viable allele, hntpeb; 29 interacting regions were identified. Subsequently, 438 P-element-induced lethal mutations mapping to these regions and 12 candidate genes were tested for genetic interaction, leading to identification of 63 dominant modifier loci. A subset of the identified mutants also dominantly modify hnt308-induced embryonic lethality and thus represent general rather than tissue-specific interactors. General interactors include loci encoding transcription factors, actin-binding proteins, signal transduction proteins, and components of the extracellular matrix. Expression of several interactors was assessed in hnt mutant tissue. Five genes—apontic (apt), Delta (Dl), decapentaplegic (dpp), karst (kst), and puckered (puc)—are regulated tissue autonomously and, thus, may be direct transcriptional targets of HNT. Three of these genes—apt, Dl, and dpp—are also regulated nonautonomously in adjacent non-HNT-expressing tissues. The expression of several additional interactors—viking (vkg), Cg25, and laminin-α (LanA)—is affected only in a nonautonomous manner.

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.

Childhood type 2 diabetes (T2D) is increasing and may present differently across various populations. This study compares clinical features of T2D at diagnosis in Aboriginal children with Caucasian children and children from other high-risk ethnic groups.This retrospective observational study used data from a Canadian surveillance study where newly diagnosed cases of childhood T2D were reported (n = 227). Using descriptive statistics, clinical features at diagnosis of T2D were compared across different ethnic groups including Aboriginal (n = 100), Caucasian (n = 57), and other high-risk ethnic groups (n = 64). Comparisons were made between Aboriginal children living in central Canada (Manitoba/northwestern Ontario) (n = 74) and Aboriginal children from other regions of Canada (n = 26).Aboriginal children were younger, less obese, and less likely to have polycystic ovarian syndrome and dyslipidemia when compared to Caucasian children and children from other high-risk ethnic groups (p0.05). Aboriginal children from central Canada vs. those from other regions of Canada did not differ in age, body mass index z-score, family history of T2D, or presence of acanthosis nigricans. Those from central Canada had lower hemoglobin A1c levels (p0.05) and were less likely to have dyslipidemia than Aboriginal children from other regions (p0.05).Clinical features and rates of comorbidity in children with newly diagnosed T2D differ across various populations (Caucasian, Aboriginal, and children who belong to other high-risk ethnic groups) and across distinct Aboriginal populations (those living in central Canada vs. those living in other regions of Canada). Future research should determine specific genetic and environmental factors that contribute to these differences.

OBJECTIVE To determine in Canadian children aged

Maternally synthesized RNAs program early embryonic development in many animals. These RNAs are degraded rapidly by the midblastula transition (MBT), allowing genetic control of development to pass to zygotically synthesized transcripts. Here we show that in the early embryo of Drosophila melanogaster , there are two independent RNA degradation pathways, either of which is sufficient for transcript elimination. However, only the concerted action of both pathways leads to elimination of transcripts with the correct timing, at the MBT. The first pathway is maternally encoded, is targeted to specific classes of mRNAs through cis ‐acting elements in the 3′‐untranslated region and is conserved in Xenopus laevis . The second pathway is activated 2 h after fertilization and functions together with the maternal pathway to ensure that transcripts are degraded by the MBT.