Maternal metabolites during pregnancy are associated with newborn outcomes and hyperinsulinaemia across ancestries.

AIMS/HYPOTHESIS: We aimed to determine the association of maternal metabolites with newborn adiposity and hyperinsulinaemia in a multi-ethnic cohort of mother-newborn dyads. METHODS: Targeted and non-targeted metabolomics assays were performed on fasting and 1 h serum samples from a total of 1600 mothers in four ancestry groups (Northern European, Afro-Caribbean, Mexican American and Thai) who participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study, underwent an OGTT at ~28 weeks gestation and whose newborns had anthropometric measurements at birth. RESULTS: In this observational study, meta-analyses demonstrated significant associations of maternal fasting and 1 h metabolites with birthweight, cord C-peptide and/or sum of skinfolds across ancestry groups. In particular, maternal fasting triacylglycerols were associated with newborn sum of skinfolds. At 1 h, several amino acids, fatty acids and lipid metabolites were associated with one or more newborn outcomes. Network analyses revealed clusters of fasting acylcarnitines, amino acids, lipids and fatty acid metabolites associated with cord C-peptide and sum of skinfolds, with the addition of branched-chain and aromatic amino acids at 1 h. CONCLUSIONS/INTERPRETATION: The maternal metabolome during pregnancy is associated with newborn outcomes. Maternal levels of amino acids, acylcarnitines, lipids and fatty acids and their metabolites during pregnancy relate to fetal growth, adiposity and cord C-peptide, independent of maternal BMI and blood glucose levels.

Cord Blood Metabolites Associated with Newborn Adiposity and Hyperinsulinemia.

OBJECTIVE: To evaluate the association between cord blood amino acid and acylcarnitine profiles and measures of adiposity and hyperinsulinemia in healthy newborns. STUDY DESIGN: A cross-sectional study of 118 full-term infants born to mothers without gestational diabetes was performed. Cord blood leptin, C-peptide, acylcarnitine, and amino acid levels were measured. Body composition was measured by air displacement plethysmography. Multivariate linear regression and principal component analysis were used to analyze associations of cord blood metabolites with newborn anthropometrics, leptin, and C-peptide. RESULTS: Acylcarnitines AC C2, AC C4-DC/Ci4-DC, and AC C8:1-OH/C6:1-DC were positively associated with leptin, and AC C14, AC C14:2, AC C16, AC C18, and AC C18:2 were negatively associated with C-peptide (P ≤ .0016). Principal component analysis revealed a positive association between factor 1(AC C2, AC C3, AC C5, AC C4/Ci4, AC C4-OH, AC C4-DC/Ci4-DC, glutamate/glutamine, and glycine) and adiposity measures. CONCLUSIONS: The positive association of AC C2 and AC C4-DC/Ci4-DC levels with leptin may reflect excess fat stores, higher fatty acid oxidation rate, and mitochondrial dysfunction leading to accumulation of acylcarnitine intermediates. Principal component analysis revealed a positive association between branched chain amino acid and ketone body metabolites and adiposity, confirming prior findings in adults. Cord blood acylcarnitine profiles may identify at-risk children before obesity or insulin resistance develops.

Noninvasive encapsulated follicular variant of papillary thyroid carcinoma: Should it also be reclassified in children?

BACKGROUND: Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (noniEFVPTC) has low risk of adverse outcome in adults, warranting reclassification as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). In children, thyroid nodules have higher risk of malignancy and it is unknown if encapsulated FVPTC (EFVPTC) and infiltrative FVPTC (IFVPTC) tumors have different behavior. We analyzed the clinicopathologic features of follicular variant of papillary thyroid carcinoma (FVPTC) subtypes in our pediatric population to determine if noniEFVPTC has an indolent course as reported in adults. PROCEDURE: We retrospectively studied all patients diagnosed with FVPTC at our institution. The clinicopathologic characteristics of the histologic subtypes were compared. RESULTS: Eighteen patients were identified, all treated with total thyroidectomy. No significant differences in age, sex, tumor size, focality, or prior malignancy were detected between subtypes. Extrathyroidal extension had significantly higher incidence in IFVPTC (5/8) compared with EFVPTC (1/10, P = 0.03), translating in significantly more T3 tumors within IFVPTC subtype (5/8), whereas most EFVPTC cases had T1 staging (6/10, T1 vs. T3, P = 0.05). EFVPTC had significantly lower rate of lymph node involvement (N1 in 2/8) compared with IFVPTC (N1 in 8/8, P = 0.003). Only one patient diagnosed with IFVPTC developed extranodal recurrence. When noniEFVPTC and iEFVPTC were separately compared, the noninvasive form showed no propensity for invasive growth (T3 staging: 0/4 vs. 2/6), lymph node metastasis (N1: 0/3 vs. 2/5) or extranodal recurrence. CONCLUSION: In children, noniEFVPTC/NIFTP has indolent behavior, warranting consideration of less aggressive management, similar to adults.

Neonatal adiposity increases with rising cord blood IGF-1 levels.

OBJECTIVE: Infants with higher adiposity at birth may be at greater risk of developing obesity later in life. IGF-1 is important for intrauterine growth and may be a useful early life marker of adiposity, and thus later obesity risk. The aim of this study was to determine the relationship between cord blood IGF-1, neonatal anthropometrics and markers of neonatal adiposity. DESIGN, PATIENTS AND MEASUREMENTS: A cross-sectional study design was utilized to study a multiethnic cohort of full-term neonates born to healthy mothers with normal glucose tolerance at a large university hospital. Neonatal cord blood was collected after birth and assayed for IGF-1, leptin and C-peptide. Neonatal body composition was measured between 24 and 72 h of life using the method of air displacement plethysmography. RESULTS: Cord blood IGF-1 was positively and significantly associated with markers of neonatal adiposity in models adjusted for maternal age at delivery, race, maternal prepregnancy BMI, gestational age at delivery and neonatal sex: birthweight (r = 0·62, P < 0·001), leptin (r = 0·33, P = 0·018), fat mass (r = 0·52, P < 0·001) and percent body fat (r = 0·51, P < 0·001). Cord blood IGF-1 was not associated with cord blood C-peptide. CONCLUSIONS: Cord blood IGF-1 is strongly associated with all measures of neonatal adiposity suggesting that IGF-1 may be an important contributor to in utero neonatal fat accumulation.

Creation of a Novel Hands-on Model to Teach Breast Tanner Staging to Pediatric Learners.

INTRODUCTION: Pubertal Tanner staging is a standard part of the pediatric physical examination and provides valuable insight into a child's growth and development. In practice, pediatric care practitioners have varying levels of confidence and expertise with Tanner staging. Currently, breast Tanner staging is taught via illustrated images or limited hands-on practice on real patients during pediatric residency training. METHODS: We used synthetic materials to develop a lifelike, 3-dimensional, hands-on educational tool aimed at teaching medical students and pediatric resident physicians how to identify and distinguish among the 5 breast Tanner stages. This tool was evaluated by a group of experienced pediatric endocrinologists. RESULTS: Thirty pediatric endocrinologists with an average of 16.7 years of clinical experience evaluated the model, and all participants believed the model was a valuable teaching tool for medical students and pediatric resident physicians. Tanner stages 1, 2, 3, 4, and 5 were correctly identified by 100%, 93%, 90%, 100%, and 73% of participants, respectively. CONCLUSIONS: We show that the use of a synthetic, 3-dimensional, lifelike breast model to teach breast Tanner staging may be valuable within the context of pediatric medical education. Further refinement of the model as well as curriculum development and evaluation is necessary before broadly disseminating this model as an educational tool.

Association of cord blood methylation with neonatal leptin: An epigenome wide association study.

BACKGROUND: Neonatal adiposity is a risk factor for childhood obesity. Investigating contributors to neonatal adiposity is important for understanding early life obesity risk. Epigenetic changes of metabolic genes in cord blood may contribute to excessive neonatal adiposity and subsequent childhood obesity. This study aims to evaluate the association of cord blood DNA methylation patterns with anthropometric measures and cord blood leptin, a biomarker of neonatal adiposity. METHODS: A cross-sectional study was performed on a multiethnic cohort of 114 full term neonates born to mothers without gestational diabetes at a university hospital. Cord blood was assayed for leptin and for epigenome-wide DNA methylation profiles via the Illumina 450K platform. Neonatal body composition was measured by air displacement plethysmography. Multivariable linear regression was used to analyze associations between individual CpG sites as well as differentially methylated regions in cord blood DNA with measures of newborn adiposity including anthropometrics (birth weight, fat mass and percent body fat) and cord blood leptin. False discovery rate was estimated to account for multiple comparisons. RESULTS: 247 CpG sites as well as 18 differentially methylated gene regions were associated with cord blood leptin but no epigenetic changes were associated with birth weight, fat mass or percent body fat. Genes of interest identified in this study are DNAJA4, TFR2, SMAD3, PLAG1, FGF1, and HNF4A. CONCLUSION: Epigenetic changes in cord blood DNA are associated with cord blood leptin levels, a measure of neonatal adiposity.

Cord Blood Metabolomics: Association With Newborn Anthropometrics and C-Peptide Across Ancestries.

CONTEXT: Newborn adiposity is associated with childhood obesity. Cord blood metabolomics is one approach that can be used to understand early-life contributors to adiposity and insulin resistance. OBJECTIVE: To determine the association of cord blood metabolites with newborn adiposity and hyperinsulinemia in a multiethnic cohort of newborns. DESIGN: Cross-sectional, observational study. SETTING: Hyperglycemia and Adverse Pregnancy Outcome study. PARTICIPANTS: One thousand six hundred multiethnic mother-newborn pairs. MAIN OUTCOME MEASURE: Cord blood C-peptide, birthweight, and newborn sum of skinfolds. RESULTS: Meta-analyses across four ancestry groups (Afro-Caribbean, Northern European, Thai, and Mexican American) demonstrated significant associations of cord blood metabolites with cord blood C-peptide, birthweight, and newborn sum of skinfolds. Several metabolites, including branched-chain amino acids (BCAAs), medium- and long-chain acylcarnitines, nonesterified fatty acids, and triglycerides were negatively associated with cord C-peptide but positively associated with birthweight and/or sum of skinfolds. 1,5-Anhydroglucitol, an inverse marker of recent maternal glycemia, was significantly inversely associated with birthweight and sum of skinfolds. Network analyses revealed groups of interrelated amino acid, acylcarnitine, and fatty acid metabolites associated with all three newborn outcomes. CONCLUSIONS: Cord blood metabolites are associated with newborn size and cord blood C-peptide levels after adjustment for maternal body mass index and glucose during pregnancy. Negative associations of metabolites with C-peptide at birth were observed. 1,5-Anhydroglucitol appears to be a marker of adiposity in newborns. BCAAs were individually associated with birthweight and demonstrated possible associations with newborn adiposity in network analyses.

Use of Metformin for Weight Management in Children and Adolescents With Obesity in the Clinical Setting.

Use of metformin for weight loss for children in a clinical setting has not been well described; therefore, we aimed to identify characteristics of obese patients prescribed metformin in a clinical setting and evaluate changes in anthropometric measures. Records of obese patients aged 10 to 18 years without diabetes attending an academic endocrinology practice from 2009 to 2013 were reviewed. Analyses assessed changes in anthropometric measures (weight, body mass index [BMI], and BMI z-score) over 12 months between those prescribed metformin (n = 49) and those not prescribed metformin (n = 142). Outcomes were standardized before using multivariable linear regression models. Patients prescribed metformin were significantly older, more often female, and had larger baseline anthropometric measures (all P < .05). In the models, subjects prescribed metformin had significantly less gain in standardized weight, BMI, and BMI z-score over 6 and 12 months (all P < .05). Metformin may be a useful weight management aid in children in a clinical setting.

The Relationship of Insulin-Like Growth Factor 2 to Fetal Growth and Adiposity.

Insulin-like growth factor 2 (IGF-2) is necessary for adequate human growth. Overexpression of the IGF2 gene is associated with fetal overgrowth and may play a role in the intrauterine programming of adipose tissue. As obesity in children is a major public health problem associated with early onset of comorbid metabolic diseases, identifying early life markers of obesity may serve as useful tool for counseling and implementation of preventive efforts before obesity develops. The relationship between IGF-2 and body composition is an emerging field of study and existing data are conflicting. In this review, we discuss the IGF2 gene and its function, highlight the proposed mechanisms for the effects of IGF-2 on adiposity, and examine the current literature studying the relationships between IGF-2 levels, changes within the IGF2 gene, weight, and adiposity. With additional study, IGF-2 may emerge as a useful marker of future obesity risk in infants.

Diabetes insipidus in infants and children.

Diabetes insipidus, the inability to concentrate urine resulting in polyuria and polydipsia, can have different manifestations and management considerations in infants and children compared to adults. Central diabetes insipidus, secondary to lack of vasopressin production, is more common in children than is nephrogenic diabetes insipidus, the inability to respond appropriately to vasopressin. The goal of treatment in both forms of diabetes insipidus is to decrease urine output and thirst while allowing for appropriate fluid balance, normonatremia and ensuring an acceptable quality of life for each patient. An infant's obligate need to consume calories as liquid and the need for readjustment of medication dosing in growing children both present unique challenges for diabetes insipidus management in the pediatric population. Treatment modalities typically include vasopressin or thiazide diuretics. Special consideration must be given when managing diabetes insipidus in the adipsic patient, post-surgical patient, and in those undergoing chemotherapy or receiving medications that alter free water clearance.

Proceedings of the Working Group Session on Fertility Preservation for Individuals with Gender and Sex Diversity.

Children and adolescents with gender and sex diversity include (1) gender-nonconforming and transgender individuals for whom gender identity or expression are incongruent with birth-assigned sex (heretofore, transgender) and (2) individuals who have differences in sex development (DSD). Although these are largely disparate groups, there is overlap in the medical expertise necessary to care for individuals with both gender and sex diversity. In addition, both groups face potential infertility or sterility as a result of desired medical and surgical therapies. The Ann & Robert H. Lurie Children's Hospital of Chicago (Lurie Children's) gender and sex development program (GSDP) provides specialized multidisciplinary care for both transgender and DSD patients. In response to patient concerns that recommended medical treatments have the potential to affect fertility, the Lurie Children's GSDP team partnered with experts from the Oncofertility Consortium at Northwestern University to expand fertility preservation options to gender and sex diverse youth. This article summarizes the results of a meeting of experts across this field at the annual Oncofertility Consortium conference with thoughts on next steps toward a unified protocol for this patient group.

Squamosal Suture Craniosynostosis Due to Hyperthyroidism Caused by an Activating Thyrotropin Receptor Mutation (T632I).

BACKGROUND: Congenital hyperthyroidism can be a cause of failure to thrive, hyperactivity, developmental delay, and craniosynostosis during infancy. Most commonly, the condition occurs in the setting of maternal autoimmune thyroid disease. Rarely, congenital hyperthyroidism can also occur secondary to activating mutations within the thyrotropin (TSH) receptor. PATIENT FINDINGS: A Hispanic male infant presented at age 6 months with severe thyrotoxicosis. At the time of presentation he was being evaluated for squamosal suture synostosis and he was noted to have significant developmental delays. SUMMARY: The patient's thyrotoxicosis was initially treated with antithyroid medication, and he subsequently underwent craniosynostosis repair leading to neurodevelopmental improvement. DNA from the patient and his parents was submitted for mutational analysis of exons 9 and 10 of the TSH receptor. He was found to carry a monoallelic transition 1895C>T in exon 10 that resulted in the substitution of threonine at position 632 by isoleucine (T32I). This mutation resulted in constitutive activation of the TSH receptor. Neither parent carried this mutation indicating that the child has acquired a de novo germline mutation. CONCLUSIONS: We report the first case of squamosal suture craniosynostosis in a patient with non-autoimmune hyperthyroidism. Squamosal suture craniosynotosis is rare, often has a subtle presentation, and should be considered in all patients with this condition because prompt treatment of hyperthyroidism and craniosynotosis repair can lead to normalization of neurodevelopment.

Administration of chondroitinase ABC rostral or caudal to a spinal cord injury site promotes anatomical but not functional plasticity.

Growth-inhibitory chondroitin sulfate proteoglycans (CSPG) are a primary target for therapeutic strategies after spinal cord injury because of their contribution to the inhibitory nature of glial scar tissue, a major barrier to successful axonal regeneration. Chondroitinase ABC (ChABC) digestion of CSPGs promotes axonal regeneration beyond a lesion site with subsequent functional improvement. ChABC also has been shown to promote sprouting of spared fibers but it is not clear if functional recovery results from such plasticity. Here we sought to better understand the roles rostral or caudal sprouting may play in ChABC-mediated functional improvement. To achieve this, ChABC or vehicle was injected rostral or caudal to a unilateral C5 injury. When injected rostral to a hemisection, ChABC promoted significant sprouting of 5HT+ fibers into dorsal and ventral horns. When ChABC was injected into tissue caudal to a hemisection, no additional sprouting was observed. When injected caudal to a hemicontusion injury, ChABC promoted sprouting of 5HT+ fibers into the ventral horn but not the dorsal horn. None of this sprouting resulted in a change in the synaptic component synapsin, nor did it impact performance in behavioral tests assessing motor function. These data suggest that ChABC-mediated sprouting of spared fibers does not necessarily translate into functional recovery.

Symptom burden among cancer survivors: impact of age and comorbidity.

BACKGROUND: Previous research among specific cancer populations has shown high but variable symptom burden; however, very little is known about its extent and pattern among the entire population of US cancer survivors, which is more clinically relevant to primary care physicians. METHODS: To determine the prevalence of ongoing symptom burden among cancer survivors and compare it with the general population without cancer, we analyzed data from the 2002 National Health Interview Survey, which included 1,904 cancer survivors and 29,092 controls. Main outcome measures included self-reported ongoing pain, psychological distress, and insomnia. Multivariate logistic regression models were used to adjust for confounders and test for interactions. RESULTS: The rates of ongoing pain, psychological distress, and insomnia among cancer survivors were 34%, 26%, and 30%, respectively, and were significantly higher (all P<.001) than controls without a history of cancer (18%, 16%, and 17%). Compared with controls in the same age groups, younger survivors (younger than 50) were much more likely to report ongoing symptoms than older survivors (older than 64); adjusted odds ratios were 2.96 and 1.36 for pain in the respective age groups (P<.001). Comorbidities also interact with cancer status and contribute to a marked increase in reports of ongoing symptom burden among cancer survivors, with a greater number of comorbidities leading to greater degree of symptom burden in a dose-dependent manner (P<.001). CONCLUSIONS: The symptom burden among cancer survivors on a population level is substantial and can be impacted by other comorbidities. Thus, engaging primary care physicians in the design, testing, and implementation of effective interventions is important to reduce the symptom burden among cancer survivors.