Early sex-dependent differences in metabolic profiles of overweight and adiposity in young children: a cross-sectional analysis.

BACKGROUND: Childhood obesity is a global health concern and can lead to lifetime cardiometabolic disease. New advances in metabolomics can provide biochemical insights into the early development of obesity, so we aimed to characterize serum metabolites associated with overweight and adiposity in early childhood and to stratify associations by sex. METHODS: Nontargeted metabolite profiling was conducted in the Canadian CHILD birth cohort (discovery cohort) at age 5 years (n = 900) by multisegment injection-capillary electrophoresis-mass spectrometry. Clinical outcome was defined using novel combined measures of overweight (WHO-standardized body mass index ≥ 85th percentile) and/or adiposity (waist circumference ≥ 90th percentile). Associations between circulating metabolites and child overweight/adiposity (binary and continuous outcomes) were determined by multivariable linear and logistic regression, adjusting for covariates and false discovery rate, and by subsequent sex-stratified analysis. Replication was assessed in an independent replication cohort called FAMILY at age 5 years (n = 456). RESULTS: In the discovery cohort, each standard deviation (SD) increment of branched-chain and aromatic amino acids, glutamic acid, threonine, and oxoproline was associated with 20-28% increased odds of overweight/adiposity, whereas each SD increment of the glutamine/glutamic acid ratio was associated with 20% decreased odds. All associations were significant in females but not in males in sex-stratified analyses, except for oxoproline that was not significant in either subgroup. Similar outcomes were confirmed in the replication cohort, where associations of aromatic amino acids, leucine, glutamic acid, and the glutamine/glutamic acid ratio with childhood overweight/adiposity were independently replicated. CONCLUSIONS: Our findings show the utility of combining measures of both overweight and adiposity in young children. Childhood overweight/adiposity at age 5 years has a specific serum metabolic phenotype, with the profile being more prominent in females compared to males.

Associations of intrapartum antibiotics and growth, atopy, gastrointestinal and sleep outcomes at one year of age.

BACKGROUND: Studies investigating neonatal outcomes following intrapartum antibiotic exposure show conflicting results. METHODS: Data were collected prospectively in pregnancy to 1-year-of-age, from 212 mother-infant pairs. Adjusted multivariable regression models estimated relationships following exposure to intrapartum antibiotics among vaginally-born, full-term infants and outcomes related to growth, atopic disease, gastrointestinal symptoms, and sleep at 1-year. RESULTS: Intrapartum antibiotic exposure (n = 40) was not associated with mass, ponderal index, BMI z-score (1- year), lean mass index (5-months) or height. Antibiotic exposure in labour ≥4-h was associated with increase in fat mass index at 5-months (ß 0.42 [95% CI: 0.03, 0.80], p = 0.03). Intrapartum antibiotic was associated with atopy in the first year (OR: 2.93 [95% CI: 1.34, 6.43], p = 0.007). Antibiotic exposure during intrapartum or day 1-7 was associated with newborn fungal infection requiring antifungal therapy (OR 3.04 [95% CI: 1.14, 8.10], p = 0.026), and number of fungal infections (IRR: 2.90 [95% CI: 1.02, 8.27], p = 0.046). CONCLUSION: Intrapartum and early life exposure to antibiotics were independently associated with measures of growth, atopy, and fungal infections suggesting that intrapartum and early neonatal antibiotics be used prudently following careful risk-benefit analysis. IMPACT: This prospective study: Shows a shift in fat mass index at 5 months associated with antibiotic administration ≥4 h in labour; an earlier age than previously reported; Shows atopy reported less frequently among those not exposed to intrapartum antibiotics; Supports earlier research of increased likelihood of fungal infection following exposure to intrapartum or early-life antibiotics; Adds to growing evidence that antibiotics used intrapartum and in early neonatal periods influence longer-term outcomes for infants. Suggests that use of intrapartum and early neonatal antibiotics should be used prudently after careful consideration of risk and benefit.

Cohort profile update: The Canadian Maternal-Infant Research on Environmental Chemicals Child Development study (MIREC-CD PLUS).

BACKGROUND: The pan-Canadian Maternal-Infant Research on Environmental Chemicals (MIREC) study was established to determine whether maternal environmental chemical exposures were associated with adverse pregnancy outcomes in 2001 pregnant women. OBJECTIVES: The MIREC-Child Development (CD PLUS) study followed this cohort with the goal of assessing the potential effects of prenatal exposures on anthropometry and neurodevelopment in early childhood. POPULATION: MIREC families with children between the ages of 15 months and 5 years who had agreed to be contacted for future research (n = 1459) were invited to participate in MIREC-CD PLUS which combines data collected from an online Maternal Self-Administered Questionnaire with biomonitoring and neurodevelopment data collected from two in-person visits. PRELIMINARY RESULTS: Between April 2013 and March 2015, 803 children participated in the Biomonitoring visit where we collected anthropometric measures, blood, and urine from the children. The Behavioural Assessment System for Children-2, Behaviour Rating Inventory of Executive Function, MacArthur-Bates Communicative Development Inventories and the Communication subscale of the Adaptive Behaviour Scale from the Bayley Scales of Infant and Toddler Development-III are available on close to 900 children. There were 610 singleton children who completed in-person visits for neurodevelopment assessments including the Social Responsiveness Scale, Wechsler Preschool Primary Scale of Intelligence-III and NEuroPSYchological assessments (NEPSY). Currently, we are following the cohort into early adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). CONCLUSIONS: Data collection for the MIREC-CD PLUS study is complete and analysis of the data continues. We are now extending the follow-up of the cohort into adolescence to measure the impact of early life exposures on endocrine and metabolic function (MIREC-ENDO). MIREC-CD PLUS is limited by loss to follow-up and the fact that mothers are predominately of higher socioeconomic status and 'White' ethnicity, which limits our generalizability. However, the depth of biomonitoring and clinical measures in MIREC provides a platform to examine associations of prenatal, infancy and childhood exposures with child growth and development.

Measuring severe obesity in pediatrics using body mass index-derived metrics from the Centers for Disease Control and Prevention and World Health Organization: a secondary analysis of CANadian Pediatric Weight management Registry (CANPWR) data.

To examine the (i) relationships between various body mass index (BMI)-derived metrics for measuring severe obesity (SO) over time based the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) references and (ii) ability of these metrics to discriminate children and adolescents based on the presence of cardiometabolic risk factors. In this cohort study completed from 2013 to 2021, we examined data from 3- to 18-year-olds enrolled in the CANadian Pediatric Weight management Registry. Anthropometric data were used to create nine BMI-derived metrics based on the CDC and WHO references. Cardiometabolic risk factors were examined, including dysglycemia, dyslipidemia, and elevated blood pressure. Analyses included Pearson correlations, intraclass correlation coefficients (ICC), and receiver operator characteristic area-under-the-curve (ROC AUC). Our sample included 1,288 participants (n = 666 [52%] girls; n = 874 [68%] white). The prevalence of SO varied from 60-67%, depending on the definition. Most BMI-derived metrics were positively and significantly related to one another (r = 0.45-1.00); ICCs revealed high tracking (0.90-0.94). ROC AUC analyses showed CDC and WHO metrics had a modest ability to discriminate the presence of cardiometabolic risk factors, which improved slightly with increasing numbers of risk factors. Overall, most BMI-derived metrics rated poorly in identifying presence of cardiometabolic risk factors.    Conclusion: CDC BMI percent of the 95th percentile and WHO BMIz performed similarly as measures of SO, although neither showed particularly impressive discrimination. They appear to be interchangeable in clinical care and research in pediatrics, but there is a need for a universal standard. WHO BMIz may be useful for clinicians and researchers from countries that recommend using the WHO growth reference. What is Known: • Severe obesity in pediatrics is a global health issue. • Few reports have evaluated body mass index (BMI)-derived metrics based on the World Health Organization growth reference. What is New: • Our analyses showed that the Centers for Disease Control and Prevention BMI percent of the 95th percentile and World Health Organization (WHO) BMI z-score (BMIz) performed similarly as measures of severe obesity in pediatrics. • WHO BMIz should be a useful metric to measure severe obesity for clinicians and researchers from countries that recommend using the WHO growth reference.

Increased gut serotonin production in response to bisphenol A structural analogs may contribute to their obesogenic effects.

Obesogens are synthetic, environmental chemicals that can disrupt endocrine control of metabolism and contribute to the risk of obesity and metabolic disease. Bisphenol A (BPA) is one of the most studied obesogens. There is considerable evidence that BPA exposure is associated with weight gain, increased adiposity, poor blood glucose control, and nonalcoholic fatty liver disease in animal models and human populations. Increased usage of structural analogs of BPA has occurred in response to legislation banning their use in some commercial products. However, BPA analogs may also cause some of the same metabolic impairments because of common mechanisms of action. One key effector that is altered by BPA and its analogs is serotonin, however, it is unknown if BPA-induced changes in peripheral serotonin pathways underlie metabolic perturbations seen with BPA exposure. Upon ingestion, BPA and its analogs act as endocrine-disrupting chemicals in the gastrointestinal tract to influence serotonin production by the gut, where over 95% of serotonin is produced. The purpose of this review is to evaluate how BPA and its analogs alter gut serotonin regulation and then discuss how disruption of serotonergic networks influences host metabolism. We also provide evidence that BPA and its analogs enhance serotonin production in gut enterochromaffin cells. Taken together, we propose that BPA and many BPA analogs represent endocrine-disrupting chemicals that can influence host metabolism through the endogenous production of gut-derived factors, such as serotonin.

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.

Metabolic-endocrine disruption due to preterm birth impacts growth, body composition, and neonatal outcome.

Despite optimized nutrition, preterm-born infants grow slowly and tend to over-accrete body fat. We hypothesize that the premature dissociation of the maternal-placental-fetal unit disrupts the maintenance of physiological endocrine function in the fetus, which has severe consequences for postnatal development. This review highlights the endocrine interactions of the maternal-placental-fetal unit and the early perinatal period in both preterm and term infants. We report on hormonal levels (including tissue, thyroid, adrenal, pancreatic, pituitary, and placental hormones) and nutritional supply and their impact on infant body composition. The data suggest that the premature dissociation of the maternal-placental-fetal unit leads to a clinical picture similar to panhypopituitarism. Further, we describe how the premature withdrawal of the maternal-placental unit, neonatal morbidities, and perinatal stress can cause differences in the levels of growth-promoting hormones, particularly insulin-like growth factors (IGF). In combination with the endocrine disruption that occurs following dissociation of the maternal-placental-fetal unit, the premature adaptation to the extrauterine environment leads to early and fast accretion of fat mass in an immature body. In addition, we report on interventional studies that have aimed to compensate for hormonal deficiencies in infants born preterm through IGF therapy, resulting in improved neonatal morbidity and growth. IMPACT: Preterm birth prematurely dissociates the maternal-placental-fetal unit and disrupts the metabolic-endocrine maintenance of the immature fetus with serious consequences for growth, body composition, and neonatal outcomes. The preterm metabolic-endocrine disruption induces symptoms resembling anterior pituitary failure (panhypopituitarism) with low levels of IGF-1, excessive postnatal fat mass accretion, poor longitudinal growth, and failure to thrive. Appropriate gestational age-adapted nutrition alone seems insufficient for the achievement of optimal growth of preterm infants. Preliminary results from interventional studies show promising effects of early IGF-1 supplementation on postnatal development and neonatal outcomes.

Growth and body composition trajectories in infants meeting the WHO growth standards study requirements.

BACKGROUND: While the World Health Organization (WHO) developed postnatal growth standards for infants, corresponding body composition data remains scarce. This study explores growth and body composition trajectories in infants meeting the WHO Multicentre Growth Reference Study (MGRS) eligibility criteria. STUDY DESIGN: Infants enrolled in this longitudinal cohort underwent anthropometric and body composition measurement by air displacement plethysmography (ADP) at 6 weeks, 12 weeks, and 5 months postnatally. Age and sex-specific growth and body composition percentiles were generated using GAMLSS, with extrapolated data at 5 months for those exceeding ADP weight limits. We evaluated which anthropometric measure (body mass index (BMI), weight for length or mid upper arm circumference) was most closely related to adiposity. RESULTS: Of the 225 infants with body composition measures, 187 met the WHO MGRS criteria. Their length and weight curves were comparable with WHO growth curves. Trajectory curves for fat and fat-free mass were developed. Of the anthropometric measures, BMI z score was most closely related to fat mass index z score at all timepoints. CONCLUSION: This study presents body composition trajectories for infants meeting the WHO growth standard criteria. BMI z score is the best anthropometric metric to estimate adiposity in infants. IMPACT: While postnatal growth standards derived from the WHO Multicentre Growth Reference Study (MGRS) exist for the routine clinical assessment of infant growth, this study fills the previous gap in the availability of corresponding body composition data for term-born, healthy, breastfed infants meeting the MGRS criteria. Extrapolation was used to obtain body composition values for infants exceeding the weight limit of the ADP device, to avoid construction of biased body composition curves. Sex-specific growth curves for fat mass, fat-free mass, fat mass index, and fat-free mass index are presented for a population meeting the World Health Organization growth standard criteria.

DNA methylation profiles in adults born at extremely low birth weight.

Effects of stresses associated with extremely preterm birth may be biologically "recorded" in the genomes of individuals born preterm via changes in DNA methylation (DNAm) patterns. Genome-wide DNAm profiles were examined in buccal epithelial cells from 45 adults born at extremely low birth weight (ELBW; ≤1000 g) in the oldest known cohort of prospectively followed ELBW survivors (Mage = 32.35 years, 17 male), and 47 normal birth weight (NBW; ≥2500 g) control adults (Mage = 32.43 years, 20 male). Sex differences in DNAm profiles were found in both birth weight groups, but they were greatly enhanced in the ELBW group (77,895 loci) versus the NBW group (3,424 loci), suggesting synergistic effects of extreme prenatal adversity and sex on adult DNAm profiles. In men, DNAm profiles differed by birth weight group at 1,354 loci on 694 unique genes. Only two loci on two genes distinguished between ELBW and NBW women. Gene ontology (GO) and network analyses indicated that loci differentiating between ELBW and NBW men were abundant in genes within biological pathways related to neuronal development, synaptic transportation, metabolic regulation, and cellular regulation. Findings suggest increased sensitivity of males to long-term epigenetic effects of extremely preterm birth. Group differences are discussed in relation to particular gene functions.

The Aim2Be mHealth Intervention for Children With Overweight or Obesity and Their Parents: Person-Centered Analyses to Uncover Digital Phenotypes.

BACKGROUND: Despite the growing number of mobile health (mHealth) interventions targeting childhood obesity, few studies have characterized user typologies derived from individuals' patterns of interactions with specific app features (digital phenotypes). OBJECTIVE: This study aims to identify digital phenotypes among 214 parent-child dyads who used the Aim2Be mHealth app as part of a randomized controlled trial conducted between 2019 and 2020, and explores whether participants' characteristics and health outcomes differed across phenotypes. METHODS: Latent class analysis was used to identify distinct parent and child phenotypes based on their use of the app's behavioral, gamified, and social features over 3 months. Multinomial logistic regression models were used to assess whether the phenotypes differed by demographic characteristics. Covariate-adjusted mixed-effect models evaluated changes in BMI z scores (zBMI), diet, physical activity, and screen time across phenotypes. RESULTS: Among parents, 5 digital phenotypes were identified: socially engaged (35/214, 16.3%), independently engaged (18/214, 8.4%) (socially and independently engaged parents are those who used mainly the social or the behavioral features of the app, respectively), fully engaged (26/214, 12.1%), partially engaged (32/214, 15%), and unengaged (103/214, 48.1%) users. Married parents were more likely to be fullyengaged than independently engaged (P=.02) or unengaged (P=.01) users. Socially engaged parents were older than fullyengaged (P=.02) and unengaged (P=.01) parents. The latent class analysis revealed 4 phenotypes among children: fully engaged (32/214, 15%), partially engaged (61/214, 28.5%), dabblers (42/214, 19.6%), and unengaged (79/214, 36.9%) users. Fully engaged children were younger than dabblers (P=.04) and unengaged (P=.003) children. Dabblers lived in higher-income households than fully and partiallyengaged children (P=.03 and P=.047, respectively). Fully engaged children were more likely to have fully engaged (P<.001) and partiallyengaged (P<.001) parents than unengaged children. Compared with unengaged children, fully and partiallyengaged children had decreased total sugar (P=.006 and P=.004, respectively) and energy intake (P=.03 and P=.04, respectively) after 3 months of app use. Partially engaged children also had decreased sugary beverage intake compared with unengaged children (P=.03). Similarly, children with fully engaged parents had decreased zBMI, whereas children with unengaged parents had increased zBMI over time (P=.005). Finally, children with independently engaged parents had decreased caloric intake, whereas children with unengaged parents had increased caloric intake over time (P=.02). CONCLUSIONS: Full parent-child engagement is critical for the success of mHealth interventions. Further research is needed to understand program design elements that can affect participants' engagement in supporting behavior change. TRIAL REGISTRATION: ClinicalTrials.gov NCT03651284; https://clinicaltrials.gov/ct2/show/NCT03651284. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s13063-020-4080-2.

Impact of SARS-CoV-2 pandemic on the mental and physical health of children enrolled in a paediatric weight management clinic.

Background: Obesity is a global public health concern. Given the widespread disruption caused by the SARS-CoV-2 pandemic, it is important to evaluate its impact on children with chronic health conditions. This study examines the health of paediatric patients with obesity enrolled in a tertiary hospital weight management program, before and 1 year into the COVID-19 pandemic. Methods: This is a retrospective chart review of patients aged 2 to 17 years enrolled in a paediatric weight management clinic. Mental health outcomes (i.e., new referrals to psychologist, social work, eating disorder program, incidence of dysregulated eating, suicidal ideation, and/or self-harm) and physical health (anthropometric measures) were compared before and 1 year into the pandemic. Results: Among the 334 children seen in either period, there was an increase in referrals to psychologist (12.4% versus 26.5%; P=0.002) and the composite mental health outcome (17.2% versus 30.2%; P=0.005) during the pandemic compared with pre-pandemic. In a subset of children (n=30) with anthropometric measures in both periods, there was a lower rate of decline in BMIz score (-1.5 [2.00] versus -0.3 [0.73]/year; P=0.002) and an increase in adiposity (-0.8 [4.64] versus 2.7 [5.54]%/year; P=0.043) during the pandemic. Discussion: The pandemic has impacted the mental and physical health of children with obesity engaged in a weight management clinic. While our study provides evidence of a negative impact on mental health outcomes and less improvement in anthropometric measures, future research when patients return to in-person care will enable further examination of our findings with additional objective measures.

Metabolite profiles and the risk of metabolic syndrome in early childhood: a case-control study.

BACKGROUND: Defining the metabolic syndrome (MetS) in children remains challenging. Furthermore, a dichotomous MetS diagnosis can limit the power to study associations. We sought to characterize the serum metabolite signature of the MetS in early childhood using high-throughput metabolomic technologies that allow comprehensive profiling of metabolic status from a biospecimen. METHODS: In the Family Atherosclerosis Monitoring In earLY life (FAMILY) prospective birth cohort study, we selected 228 cases of MetS and 228 matched controls among children age 5 years. In addition, a continuous MetS risk score was calculated for all 456 participants. Comprehensive metabolite profiling was performed on fasting serum samples using multisegment injection-capillary electrophoresis-mass spectrometry. Multivariable regression models were applied to test metabolite associations with MetS adjusting for covariates of screen time, diet quality, physical activity, night sleep, socioeconomic status, age, and sex. RESULTS: Compared to controls, thirteen serum metabolites were identified in MetS cases when using multivariable regression models, and using the quantitative MetS score, an additional eight metabolites were identified. These included metabolites associated with gluconeogenesis (glucose (odds ratio (OR) 1.55 [95% CI 1.25-1.93]) and glutamine/glutamate ratio (OR 0.82 [95% CI 0.67-1.00])) and the alanine-glucose cycle (alanine (OR 1.41 [95% CI 1.16-1.73])), amino acids metabolism (tyrosine (OR 1.33 [95% CI 1.10-1.63]), threonine (OR 1.24 [95% CI 1.02-1.51]), monomethylarginine (OR 1.33 [95% CI 1.09-1.64]) and lysine (OR 1.23 [95% CI 1.01-1.50])), tryptophan metabolism (tryptophan (OR 0.78 [95% CI 0.64-0.95])), and fatty acids metabolism (carnitine (OR 1.24 [95% CI 1.02-1.51])). The quantitative MetS risk score was more powerful than the dichotomous outcome in consistently detecting this metabolite signature. CONCLUSIONS: A distinct metabolite signature of pediatric MetS is detectable in children as young as 5 years old and may improve risk assessment at early stages of development.

Grip strength is lower in adults born with extremely low birth weight compared to term-born controls.

BACKGROUND: Grip strength predicts long-term morbidity and mortality in adults. We compared grip strength in adults born with extremely low birth weight (ELBW; under 1 kg) and a normal birth weight control group (NBW) and describe change in grip strength over a 10-year period in a longitudinal cohort study of preterm birth. METHODS: Grip strength, body composition, and device-measured physical activity were assessed in 95 mature adults (MA) born ELBW (age 31.6 (1.6) mean (SD) years, 59 females) and 88 born NBW (age 31.9 (1.4) years, 52 females). Regression models were used to examine the effect of perinatal factors, body composition, physical activity, and physical self-efficacy on grip strength. RESULTS: Grip strength was lower in MA born ELBW compared to NBW (31.8 (10.0) vs. 39.8 (11.2) kg; p < 0.001). Birth weight group was associated with grip strength independent of sex, height, and lean mass index, but device-measured physical activity was not. The change in grip strength from mid-20s to MA was similar in ELBW and NBW participants. DISCUSSION: Grip strength in MA born ELBW is low and is similar to a reference group 25-30 years older, suggesting higher risk for cardiovascular and all-cause mortality. IMPACT: Adults born extremely preterm have reduced grip strength compared to control participants born at full term. Reduced grip strength is a predictor of frailty and increased cardiovascular disease risk. Change in grip strength from age in mid-20s to mid-30s is similar in those born preterm and full-term-born controls. Grip strength is related to lean mass and not to device-measured physical activity-and correlates of grip strength are similar in those born preterm and term-born controls. Grip strength is a simple measure that may provide information about the health of adults born preterm.

Adiposity in Survivors of Cancer in Childhood: How is it Measured and Why Does it Matter?

Survival of cancer in childhood is increasingly common with modern therapeutic protocols but leads frequently to adverse long-term impacts on health, including metabolic and cardiovascular disease. Changes in body composition, especially an increase in fat mass and a decrease in muscle mass, are found early in patients with pediatric cancer, persist long after treatment has been completed and seem to contribute to the development of chronic disease. This review details the effects of such changes in body composition and reviews the underlying pathophysiology of the development of sarcopenic obesity and its adverse metabolic impact. The authors discuss the particular challenges in identifying obesity accurately in survivors of pediatric cancer using available measurement techniques, given that common measures, such as body mass index, do not distinguish between muscle and adipose tissue or assess their distribution. The authors highlight the importance of a harmonized approach to the assessment of body composition in pediatric cancer survivors and early identification of risk using "gold-standard" measurements. This will improve our understanding of the significance of adiposity and sarcopenia in this population, help identify thresholds predictive of metabolic risk, and ultimately prevent or ameliorate the long-term metabolic and cardiovascular impacts on health experienced by survivors of cancer in childhood.

Cumulative risks predict epigenetic age in adult survivors of extremely low birth weight.

Long-term sequelae of extremely low birth weight (ELBW; ≤1000 g) may contribute to accelerated biological aging. This hypothesis was examined by analyzing a range of risk factors with a molecular age marker in adults born at ELBW or normal birth weight (NBW; ≥2500 g). DNAm age-the weighted average of DNA methylation at 353 cytosine-phosphate-guanine (CpG) sites from across the genome-was derived from a sample of 45 ELBW (Mage  = 32.35 years) and 47 NBW control (Mage  = 32.44 years) adults, using the Illumina 850k BeadChip Array. At two assessments undertaken 9 years apart (at 23 and 32 years), cumulative risks were summed from six domains with potential to affect physiological and psychological health: resting respiratory sinus arrhythmia, blood pressure, basal cortisol, grip strength, body mass index, and self-esteem. At age 32 years, cumulative risks were differentially associated with epigenetic age in ELBW survivors (interaction, p < 0.01). For each additional risk factor they possessed, ELBW survivors (B = 1.43) were biologically 2.16 years older than NBW adults (B = -0.73), by the fourth decade of life. Developmental change, epigenetic maintenance, and intervention targets are discussed.

Publisher Correction: Pathways to eating in children and adolescents with obesity.

In the original version of this Article the following were listed as authors; however, they should have only been referred to in the Acknowledgments section and not listed in this way.

Pathways to eating in children and adolescents with obesity.

BACKGROUND: Paediatric obesity management remains generalised to dietary and exercise modifications with an underappreciation for the contributions of eating behaviours and appetitive traits in the development of obesity. OBJECTIVES: To determine whether treatment-seeking children and adolescents with obesity cluster into phenotypes based on known eating behaviours and appetitive traits ("eating correlates") and how socio-demographic and clinical characteristics associate with different phenotypes. METHODS: A cross-sectional, multi-centre questionnaire was administered between November 2015 and March 2017 examining correlates of eating in children and adolescents attending weight-management programmes in Canada. Latent profile analysis was used to cluster participants based on seven eating correlate scores obtained from questionnaires. Analysis of variance (ANOVA) was used to determine phenotype differences on socio-demographic and clinical characteristics. Multinomial logistic regression models assessed relative risk of specific characteristics associating with a disordered eating phenotype. RESULTS: Participants were 247 children and adolescents (45.3% male, mean BMI z-score = 3.4 ± 1.0 kg/m2) from six paediatric weight management centres in Canada. Seven eating correlates clustered into three distinct phenotypes: (1) loss of control eating, emotional eating, external eating, hyperphagia, impulsivity ("Mixed-Severe"; n = 42, 17%), (2) loss of control eating, emotional eating, external eating, hyperphagia ("Mixed-Moderate"; n = 138, 55.9%), and (3) impulsivity ("Impulsive"; n = 67; 27.1%). Social functioning scores and body esteem were significantly different across groups, with the Mixed-Severe participants having the poorest social functioning and lowest body esteem. Low body esteem indicated a greater risk of being in a multi-correlate group compared to the Impulsive group, while poor social function had a greater risk of clustering in the Mixed-Severe than Impulsive phenotype. CONCLUSIONS: Distinct eating phenotypes were found in treatment-seeking children and adolescents with obesity. Empirical evidence is needed, but these data suggest that tailored treatment approaches could be informed by these classifications to improve weight-management outcomes.

Exposure to antenatal corticosteroids and reduced respiratory sinus arrhythmia in adult survivors of extremely low birth weight.

Purpose/aim: Antenatal corticosteroid (ACS) therapy has dramatically increased survival rates among extremely low birth weight (ELBW) infants. However, the long-term effects of ACS on autonomic nervous system function have not been explored. Using the world's oldest longitudinally followed cohort of ELBW infants we compared respiratory sinus arrhythmia (RSA) among ELBW survivors whose mothers received ACS (ELBW-S), those who did not (ELBW-NS) and normal birth weight (NBW) controls in their 20 and 30 s. Methods: Resting electrocardiogram (ECG) was recorded from ELBW-S (n = 28), ELBW-NS (n = 36), and matched NBW controls (n = 79) at 22-26 and 29-36 years. Resting RSA was compared across groups via analyses of covariance (ANCOVA), adjusting for sex, medication use, postnatal steroid exposure and the presence of chronic health conditions. RSA was also compared across assessments for each group. Results: At 29-36 years, resting RSA in ELBW-S was significantly lower than in NBW controls. RSA in the ELBW-NS group was intermediate between ELBW-S and NBW groups. Although the ELBW-S group also showed nominally reduced RSA compared to NBW controls at the 22-26-year visit, this difference was not statistically significant. Conclusions: ELBW survivors exposed to ACS had lower RSA than NBW controls during their 30 s, suggestive of a decline in parasympathetic input to heart. ELBW survivors who received ACS may be particularly vulnerable to cardiovascular problems in later life.

Effect of Rosuvastatin on Carotid Intima-Media Thickness in Children With Heterozygous Familial Hypercholesterolemia: The CHARON Study (Hypercholesterolemia in Children and Adolescents Taking Rosuvastatin Open Label).

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is an autosomal dominant disorder leading to premature atherosclerosis. Children with HeFH exhibit early signs of atherosclerosis manifested by increased carotid intima-media thickness (IMT). In this study, we assessed the effect of 2-year treatment with rosuvastatin on carotid IMT in children with HeFH. METHODS: Children with HeFH (age, 6-<18 years) and low-density lipoprotein cholesterol >4.9 mmol/L or >4.1 mmol/L in combination with other risk factors received rosuvastatin for 2 years, starting at 5 mg once daily, with uptitration to 10 mg (age, 6-<10 years) or 20 mg (age, 10-<18 years). Carotid IMT was assessed by ultrasonography at baseline and 12 and 24 months in all patients and in age-matched unaffected siblings. Carotid IMT was measured at 3 locations (common carotid artery, carotid bulb, internal carotid artery) in both the left and right carotid arteries. A linear mixed-effects model was used to evaluate differences in carotid IMT between children with HeFH and the unaffected siblings. P values were adjusted for age, sex, carotid artery site, and family relations. RESULTS: At baseline, mean±SD carotid IMT was significantly greater for the 197 children with HeFH compared with the 65 unaffected siblings (0.397±0.049 and 0.377±0.045 mm, respectively; P=0.001). During 2 years of follow-up, the change in carotid IMT was 0.0054 mm/y (95% confidence interval, 0.0030-0.0082) in children with HeFH and 0.0143 mm/y (95% confidence interval, 0.0095-0.0192) in unaffected siblings (P=0.002). The end-of-study difference in mean carotid IMT between children with HeFH and unaffected siblings after 2 years was no longer significant (0.408±0.043 and 0.402±0.042 mm, respectively; P=0.2). CONCLUSIONS: In children with HeFH who were ≥6 years of age, carotid IMT was significantly greater at baseline compared with unaffected siblings. Rosuvastatin treatment for 2 years resulted in significantly less progression of increased carotid IMT in children with HeFH than untreated unaffected siblings. As a result, no difference in carotid IMT could be detected between the 2 groups after 2 years of rosuvastatin. These findings support the value of early initiation of statin treatment for low-density lipoprotein cholesterol reduction in children with HeFH. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01078675.

Parent Recommendations to Enhance Enrollment in Multidisciplinary Clinical Care for Pediatric Weight Management.

OBJECTIVE: To explore parents' recommendations to enhance enrollment in multidisciplinary clinical care for managing pediatric obesity. STUDY DESIGN: Data for this interpretative description study were collected through individual, semistructured interviews that were audiorecorded, transcribed verbatim, and analyzed thematically. Parents (n = 79) were recruited from 4 multidisciplinary weight management clinics in Canada located in Edmonton, Hamilton, Montreal, and Vancouver. RESULTS: Most interviewed parents had children with obesity (body mass index ≥95th percentile; 84.2%), were female (87.3%), had postsecondary education (69.6%), and were white (75.9%). Parents' recommendations referred to enrollment opportunities, information about obesity services, motivation for treatment, and accessibility to obesity services. Specifically, parents recommended to increase referral options and follow-up contacts with families during the enrollment process, inform referring physicians and families about the availability and characteristics of obesity services, enhance families' motivation for treatment, prevent families from getting discouraged, make services more appealing to families, and address accessibility issues (eg, offering multiple options for appointment times, providing support for transportation). CONCLUSIONS: Parents' recommendations support the need for family-centered approaches to enhance enrollment; however, their feasibility, acceptability, and effectiveness remain to be tested empirically.