Publications by authors named "Babette S Zemel"

263 Publications

Visceral fat and arterial stiffness in youth with healthy weight, obesity, and type 2 diabetes.

Pediatr Obes 2021 Oct 19:e12865. Epub 2021 Oct 19.

Department of Nutritional Sciences, University of Georgia, Athens, Georgia, USA.

Background And Objectives: Visceral fat is associated with increased cardiovascular risk in adults, but studies in youth are limited. We assessed associations between visceral fat and arterial stiffness in youth with healthy weight, obesity and type 2 diabetes and determined whether relationships were independent of clinical estimates of body fatness.

Methods: This cross-sectional sample included youth ages 10-23 years (67% female, 56% non-black) with healthy weight (body mass index [BMI] = 5th-85th percentile, n = 236), obesity (BMI ≥ 95th percentile, n = 224) and type 2 diabetes (BMI ≥ 95th percentile, n = 145). Visceral fat was assessed via dual-energy X-ray absorptiometry. Carotid-femoral pulse wave velocity (PWV) was assessed via applanation tonometry. Obesity and type 2 diabetes groups were combined for final analyses. Analyses accounted for age, sex, ancestry and mean arterial pressure.

Results: Visceral fat and PWV were greater in youth with obesity versus healthy weight (p < 0.001). In youth with obesity, but not healthy weight, visceral fat was positively associated with PWV (p < 0.001) and was predictive of PWV beyond BMI and waist circumference.

Conclusions: Visceral fat likely contributes to subclinical cardiovascular complications in youth. Since cardiovascular health tracks from adolescence to adulthood, longitudinal studies in youth with obesity are required to define the role of visceral fat in lifelong cardiovascular disease risk.
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http://dx.doi.org/10.1111/ijpo.12865DOI Listing
October 2021

Diet Quality and Bone Density in Youth with Healthy Weight, Obesity, and Type 2 Diabetes.

Nutrients 2021 Sep 21;13(9). Epub 2021 Sep 21.

Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA 9146, USA.

Purpose: To assess relationships between diet quality and areal bone mineral density (aBMD) in youth with healthy weight, obesity, and type 2 diabetes (T2D).

Methods: We performed a secondary analysis of cross-sectional data from youth (55% African American, 70% female) ages 10-23 years with T2D (n = 90), obesity (BMI > 95th; n = 128), or healthy weight (BMI < 85th; n = 197). Whole body (less head) areal bone mineral density (aBMD) was assessed by dual-energy X-ray absorptiometry (DXA). aBMD was expressed as age-, sex-, and ancestry-specific standard deviation scores (Z-scores). Whole body aBMD Z-scores were adjusted for height-for-age Z-score. Diet was assessed via three-day diaries, and the Healthy Eating Index (HEI) was computed. Total HEI score and HEI subcomponent scores were compared across groups, and associations with aBMD Z-scores were assessed via linear regression adjusted for group, age, sex, and ancestry.

Results: Mean HEI was similar between the healthy weight, obesity, and T2D groups. Several HEI sub-components differed between groups, including meats and beans, total vegetables, milk, saturated fat, sodium, oils, and empty calories. The obesity and T2D group had significantly greater aBMD Z-scores compared to the healthy weight group. Multiple linear regression analyses revealed a significant positive association between HEI and aBMD Z-score ( < 0.05). The HEI sub-components for whole grains ( = 0.052) and empty calories ( < 0.05) were positively associated with aBMD Z-score.

Conclusions: Individuals that followed a dietary pattern more closely aligned with the Dietary Guidelines for Americans had greater bone density. Since few studies have investigated the role of diet on bone in youth with obesity-related conditions, additional research is required among these populations.
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http://dx.doi.org/10.3390/nu13093288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8472061PMC
September 2021

Sarcopenic Obesity in Rheumatoid Arthritis: Prevalence and Impact on Physical Functioning.

Rheumatology (Oxford) 2021 Sep 24. Epub 2021 Sep 24.

University of California San Francisco, San Francisco, CA, USA.

Objective: We determined the prevalence of sarcopenic obesity in patients with rheumatoid arthritis (RA) using multiple methods and assessed associations with physical functioning.

Methods: This study evaluated data from three RA cohorts. Whole-body dual-energy absorptiometry (DXA) measures of appendicular lean mass index (ALMI, kg/m2) and fat mass index (FMI) were converted to age, sex, and race-specific Z-Scores and categorized using a recently validated method and compared it to a widely-used existing method. The prevalence of body composition abnormalities in RA was compared with two reference populations. In the RA cohorts, associations between body composition and change in the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB) in follow-up were assessed using linear and logistic regression, adjusting for age, sex, race, and study.

Results: The prevalence of low lean mass and sarcopenic obesity were higher in patients with RA (14.2; 12.6%, respectively) compared with the reference population cohorts (7-10%; 4-4.5%, respectively, all p< 0.05). There was only moderate agreement among methods of sarcopenic obesity categorization (Kappa 0.45). The recently validated method categorized fewer subjects as obese, and many of these were categorized as low lean mass only. Low lean mass, obesity, and sarcopenic obesity were each associated with higher HAQ and lower SPPB at baseline and numerically greater worsening.

Conclusion: RA patients had higher rates of low lean mass and sarcopenic obesity than the general population. The recently validated methods characterized body composition changes differently from traditional methods and were more strongly associated with physical function.
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http://dx.doi.org/10.1093/rheumatology/keab710DOI Listing
September 2021

Adipocytokines and Associations with Abnormal Body Composition in Rheumatoid Arthritis.

Arthritis Care Res (Hoboken) 2021 Sep 24. Epub 2021 Sep 24.

Columbia University, New York, NY, USA.

Purpose: We determined associations between adipokines and abnormal body composition in patients with rheumatoid arthritis (RA).

Methods: Combining data from three RA cohorts, whole-body dual-energy absorptiometry measures of appendicular lean mass and fat mass indices were converted to age, sex, and race-specific Z-Scores. Lean mass relative to fat mass was determined based on prior methods. Independent associations between body composition profiles and circulating levels of adiponectin, leptin, and fibroblast growth factor(FGF)-21 were assessed using linear and logistic regression models adjusting for demographics and study cohort. We also determined the improvement in the area-under-the-curve (AUC) for prediction of low lean mass when adipokines were added to predictive models that included clinical factors such as demographics, study, and body mass index (BMI).

Results: Among 419 participants, older age was associated with higher levels of all adipokines while higher C-reactive protein was associated with lower adiponectin levels and higher FGF-21 levels. Greater fat mass was strongly associated with lower adiponectin levels and higher leptin and FGF-21 levels. Higher levels of adiponectin, leptin, and FGF-21 were independently associated with low lean mass. The addition of adiponectin and leptin levels to regression models improved prediction of low lean mass when combined with demographics, study, and BMI (AUC 0.75 v. 0.66).

Conclusions: Adipokines are associated with both excess adiposity and low lean mass in patients with RA. Improvements in the prediction of body composition abnormalities suggest that laboratory screening could help identify patients with altered body composition who may be at greater risk of adverse outcomes.
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http://dx.doi.org/10.1002/acr.24790DOI Listing
September 2021

Lower dietary intake of magnesium is associated with more callous-unemotional traits in children.

Nutr Neurosci 2021 Sep 3:1-10. Epub 2021 Sep 3.

School of Nursing, University of Pennsylvania, Philadelphia, PA, USA.

Background: Although researchers increasingly recognize the role of nutrition in mental health, little research has examined specific micronutrient intake in relation to antisocial behavior and callous-unemotional (CU) traits in children. Vitamin B and magnesium are involved in neurochemical processes implicated in modulating antisocial behavior and CU traits. The current study examined dietary intakes of magnesium and vitamin B in relation to antisocial behavior and CU traits.

Method: We enrolled 11-12 year old children ( = 446, mean age = 11.9 years) participating in the Healthy Brains and Behavior Study. Magnesium and vitamin B dietary intake were assessed with three 24-hour dietary recall interviews in children. CU traits and antisocial behavior were assessed by caregiver-reported questionnaires. We controlled for age, sex, race, total energy intake, body mass index, social adversity, ADHD or learning disability diagnosis, and internalizing behavior in all regression analyses.

Results: Children with lower magnesium intake had higher levels of CU traits, controlling for covariates (β= -0.18,  = -0.0066,  = 0.0027,  < 0.05). Vitamin B intake was not significantly associated with CU traits (β= 0.061,  = 0.19,  = 0.20,  > 0.05). Neither magnesium (β= 0.014,  = 0.0020,  = 0.0093,  > 0.05) nor vitamin B (β= 0.025,  = 0.33,  = 0.70,  > 0.05) were significantly associated with antisocial behavior.

Conclusions: Findings suggest that low dietary intake of magnesium may play a role in the etiology of CU traits but not general antisocial behavior. More studies are needed to determine if magnesium supplementation or diets higher in magnesium could improve CU traits in children.
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http://dx.doi.org/10.1080/1028415X.2021.1963064DOI Listing
September 2021

Changes in Body Composition, Muscle Strength, and Fat Distribution Following Kidney Transplantation.

Am J Kidney Dis 2021 Aug 2. Epub 2021 Aug 2.

Department of Medicine, Stanford University School of Medicine, Stanford, California; Department of Pediatrics, Stanford University School of Medicine, Stanford, California.

Rationale & Objective: Low muscle mass relative to fat mass (relative sarcopenia) has been associated with mortality and disability but has not been examined after kidney transplantation. We studied how measures of body composition change after receipt of a kidney allograft.

Study Design: Prospective longitudinal cohort study.

Setting & Participants: 60 kidney transplant recipients, aged 20-60 years, at the University of Pennsylvania.

Exposure: Kidney transplantation.

Outcome: Dual-energy x-ray absorptiometry measures of fat mass index (FMI) and appendicular lean mass index (ALMI, representing muscle mass), computed tomography measures of muscle density (low density represents increased intramuscular adipose tissue), dynamometer measures of leg muscle strength, and physical activity. ALMI relative to FMI (ALM) is an established index of relative sarcopenia.

Analytical Approach: Measures expressed as age, sex, and race-specific z scores for transplant recipients were compared with 327 healthy controls. Regression models were used to identify correlates of change in outcome z scores and compare transplant recipients with controls.

Results: At transplantation, ALMI, ALMI, muscle strength, and muscle density z scores were lower versus controls (all P≤0.001). Transplant recipients received glucocorticoids throughout. The prevalence of obesity increased from 18% to 45%. Although ALMI increased after transplantation (P<0.001) and was comparable with the controls from 6 months onward, gains were outpaced by increases in FMI, resulting in persistent ALMI deficits (mean z score of-0.31 at 24 months; P=0.02 vs controls). Muscle density improved after transplantation despite gains in FMI (P=0.02). Muscle strength relative to ALMI also improved (P=0.04) but remained low compared with controls (P=0.01). Exercise increased in the early months after transplantation (P<0.05) but remained lower than controls (P = 0.02).

Limitations: Lack of muscle biopsies precluded assessment of muscle histology and metabolism.

Conclusions: The 2-year interval after kidney transplantation was characterized by gains in muscle mass and strength that were outpaced by gains in fat mass, resulting in persistent relative sarcopenia.
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http://dx.doi.org/10.1053/j.ajkd.2020.11.032DOI Listing
August 2021

Stress gets into the belly: Early life stress and the gut microbiome.

Behav Brain Res 2021 Sep 16;414:113474. Epub 2021 Jul 16.

Roberts Center for Pediatric Research, 2716 South Street, Philadelphia, PA 19146, USA.

Research has established that stress "gets under the skin," impacting neuroendocrine and neuroimmune pathways to influence risk for physical and mental health outcomes. These effects can be particularly significant for early life stress (ELS), or adverse childhood experiences (ACEs). In this review, we explore whether stress gets "into the belly," that is, whether psychosocial stress affects the gut microbiome. We review animal and human research utilizing a variety of stress paradigms (acute laboratory stressors, chronic stress, stressful life events, perceived stress, ELS, in utero stress) and their impacts on the gut microbiota, with a particular focus on ELS. We also review data on dietary interventions to moderate impact of stress on the gut microbiome. Our review suggests strong evidence that acute laboratory stress, chronic stress, and ELS affect the gut microbiota in rodents, and growing evidence that perceived stress and ELS may impact the gut microbiota in humans. Emerging data also suggests, particularly in rodents, that dietary interventions such as omega-3 fatty acids and pre- and pro-biotics may buffer against the effects of stress on the gut microbiome, but more research is needed. In sum, growing evidence suggests that stress impacts not only the neuroendocrine and neuroimmune axes, but also the microbiota-gut-brain-axis, providing a pathway by which stress may get "into the belly" to influence health risk.
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http://dx.doi.org/10.1016/j.bbr.2021.113474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380711PMC
September 2021

Deficits in the Functional Muscle-Bone Unit in Youths with Fontan Physiology.

J Pediatr 2021 Jun 30. Epub 2021 Jun 30.

Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA. Electronic address:

Objective: To determine whether dual energy X-ray absorptiometry (DXA), a clinically available tool, mirrors the magnitude of deficits in trabecular and cortical bone mineral density (BMD) demonstrated on peripheral quantitative computed tomography in youth with Fontan physiology.

Study Design: We aimed to describe DXA-derived BMD at multiple sites and to investigate the relationship between BMD and leg lean mass, a surrogate for skeletal muscle loading. Subjects with Fontan (n = 46; aged 5-20 years) underwent DXA in a cross-sectional study of growth and bone and muscle health as described previously. Data from the Bone Mineral Density in Childhood Study were used to calculate age-, sex-, and race-specific BMD z-scores of the whole body, lumbar spine, hip, femoral neck, distal one-third radius, ultradistal radius, and leg lean mass z-score (LLMZ).

Results: Fontan BMD z-scores were significantly lower than reference at all sites-whole body, -0.34 ± 0.85 (P = .01); spine, -0.41 ± 0.96 (P = .008); hip, -0.75 ± 1.1 (P < .001); femoral neck, -0.73 ± 1.0 (P < .001); distal one-third radius, -0.87 ± 1.1 (P < .001); and ultradistal radius. -0.92 ± 1.03 (P < .001)-as was LLMZ (-0.93 ± 1.1; P < .001). Lower LLMZ was associated with lower BMD of the whole body (R = 0.40; P < .001), lumbar spine (R = 0.16; P = .005), total hip (R = 0.32; P < .001), femoral neck (R = 0.47; P < .001), and ultradistal radius (R = 0.35; P < .001).

Conclusions: Patients with Fontan have marked deficits in both cortical (hip, distal one-third radius) and trabecular (lumbar spine, femoral neck, ultradistal radius) BMD. Lower LLMZ is associated with lower BMD and may reflect inadequate skeletal muscle loading. Interventions to increase muscle mass may improve bone accrual.
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http://dx.doi.org/10.1016/j.jpeds.2021.06.068DOI Listing
June 2021

Sarcopenia and preserved bone mineral density in paediatric survivors of high-risk neuroblastoma with growth failure.

J Cachexia Sarcopenia Muscle 2021 08 29;12(4):1024-1033. Epub 2021 Jun 29.

Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Background: Survival from paediatric high-risk neuroblastoma (HR-NBL) has increased, but cis-retinoic acid (cis-RA), the cornerstone of HR-NBL therapy, can cause osteoporosis and premature physeal closure and is a potential threat to skeletal structure in HR-NBL survivors. Sarcopenia is associated with increased morbidity in survivors of paediatric malignancies. Low muscle mass may be associated with poor prognosis in HR-NBL patients but has not been studied in these survivors. The study objective was to assess bone density, body composition and muscle strength in HR-NBL survivors compared with controls.

Methods: This prospective cross-sectional study assessed areal bone mineral density (aBMD) of the whole body, lumbar spine, total hip, femoral neck, distal 1/3 and ultradistal radius and body composition (muscle and fat mass) using dual-energy X-ray absorptiometry (DXA) and lower leg muscle strength using a dynamometer. Measures expressed as sex-specific standard deviation scores (Z-scores) included aBMD (adjusted for height Z-score), bone mineral apparent density (BMAD), leg lean mass (adjusted for leg length), whole-body fat mass index (FMI) and ankle dorsiflexion peak torque adjusted for leg length (strength-Z). Muscle-specific force was assessed as strength relative to leg lean mass. Outcomes were compared between HR-NBL survivors and controls using Student's t-test or Mann-Whitney U test. Linear regression models examined correlations between DXA and dynamometer outcomes.

Results: We enrolled 20 survivors of HR-NBL treated with cis-RA [13 male; mean age: 12.4 ± 1.6 years; median (range) age at therapy initiation: 2.6 (0.3-9.1) years] and 20 age-, sex- and race-matched controls. Height-Z was significantly lower in HR-NBL survivors compared with controls (-1.73 ± 1.38 vs. 0.34 ± 1.12, P < 0.001). Areal BMD-Z, BMAD-Z, FMI-Z, visceral adipose tissue and subcutaneous adipose tissue were not significantly different in HR-NBL survivors compared with controls. Compared with controls, HR-NBL survivors had lower leg lean mass-Z (-1.46 ± 1.35 vs. - 0.17 ± 0.84, P < 0.001) and strength-Z (-1.13 ± 0.86 vs. - 0.15 ± 0.71, P < 0.001). Muscle-specific force was lower in HR-NBL survivors compared with controls (P < 0.05).

Conclusions: Bone mineral density and adiposity are not severely impacted in HR-NBL survivors with growth failure, but significant sarcopenia persists years after treatment. Future studies are needed to determine if sarcopenia improves with muscle-specific interventions in this population of cancer survivors.
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http://dx.doi.org/10.1002/jcsm.12734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350210PMC
August 2021

Reproductive Hormone Concentrations and Associated Anatomical Responses: Does Soy Formula Affect Minipuberty in Boys?

J Clin Endocrinol Metab 2021 Aug;106(9):2635-2645

Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.

Context: Soy formula feeding is common in infancy and is a source of high exposure to phytoestrogens, documented to influence vaginal cytology in female infants. Its influence on minipuberty in males has not been established.

Objective: To assess the association between infant feeding practice and longitudinally measured reproductive hormones and hormone-responsive tissues in infant boys.

Methods: The Infant Feeding and Early Development study was a prospective cohort of maternal-infant dyads requiring exclusive soy formula, cow milk formula, or breast milk feeding during study follow-up. In the 147 infant boy participants, serum testosterone, luteinizing hormone, stretched penile length, anogenital distance, and testis volume were longitudinally assessed from birth to 28 weeks. We examined feeding-group differences in age trajectories for these outcomes using mixed-effects regression splines.

Results: Median serum testosterone was at pubertal levels at 2 weeks (176 ng/dL [quartiles: 124, 232]) and remained in this range until 12 weeks in all feeding groups. We did not observe differences in trajectories of hormone concentrations or anatomical measures between boys fed soy formula (n = 55) and boys fed cow milk formula (n = 54). Compared with breastfed boys (n = 38), soy formula-fed boys had a more rapid increase in penile length (P = .004) and slower initial lengthening of anogenital distance (P = .03), but no differences in hormone trajectories.

Conclusion: Reproductive hormone concentrations and anatomical responses followed similar trajectories in soy and cow milk formula-fed infant boys. Our findings suggest that these measures of early male reproductive development do not respond to phytoestrogen exposure during infancy.
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http://dx.doi.org/10.1210/clinem/dgab354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372659PMC
August 2021

Engineering a mobile platform to promote sleep in the pediatric primary care setting.

Sleep Adv 2021 15;2(1):zpab006. Epub 2021 Apr 15.

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Study Objectives: Pediatricians lack tools to support families at home for the promotion of childhood sleep. We are using the Multiphase Optimization Strategy (MOST) framework to guide the development of a mobile health platform for childhood sleep promotion. The objective of this study is to demonstrate feasibility of a mobile health platform towards treating children with insufficient sleep.

Methods: Children aged 10-12 years were enrolled (Study #1: = 30; Study #2: = 43). Participants wore a sleep tracker to measure sleep duration. Data were retrieved by a mobile health platform, programmed to send introductory messages during run-in (2 weeks) and goal achievement messages during intervention (7 weeks) periods. In study #1, participants were randomized to control, gain-framed incentive or loss-framed incentive arms. In study #2, participants were randomized to control, loss-framed incentive, normative feedback or loss-framed incentive plus normative feedback arms.

Results: In study #1, 1514 nights of data were captured (69%) and sleep duration during the intervention was higher by an average of 21 (95% CI: -8, 51) and 34 (95% CI: 7, 61) minutes per night for the gain-framed and loss-framed arms, respectively, compared to controls. In study #2, 2,689 nights of data were captured (81%), with no major differences in average sleep duration between the control and the loss-framed or normative feedback arms.

Conclusions: We have developed and deployed a mobile health platform that can capture sleep data and remotely communicate with families. Promising candidate intervention components will be further investigated under the of the MOST framework.

Clinical Trials: Both studies included in this manuscript were registered at clinicaltrials.gov:-Study #1: NCT03263338-Study #2: NCT03426644.
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http://dx.doi.org/10.1093/sleepadvances/zpab006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101485PMC
April 2021

The Challenges of Interpreting Body Mass Index in Children with Obesity.

Authors:
Babette S Zemel

J Pediatr 2021 Aug 13;235:21-22. Epub 2021 Apr 13.

Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA. Electronic address:

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http://dx.doi.org/10.1016/j.jpeds.2021.04.011DOI Listing
August 2021

Discovery and fine-mapping of height loci via high-density imputation of GWASs in individuals of African ancestry.

Am J Hum Genet 2021 04 12;108(4):564-582. Epub 2021 Mar 12.

The Charles R. Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.
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http://dx.doi.org/10.1016/j.ajhg.2021.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059339PMC
April 2021

Marked skeletal muscle deficits are associated with 6-minute walk distance in paediatric pulmonary hypertension.

Cardiol Young 2021 Sep 11;31(9):1426-1433. Epub 2021 Feb 11.

Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Background: Poor growth is common in children with pulmonary hypertension; however, skeletal muscle deficits have not been described and the association between muscle deficits and functional status is unknown.

Methods: Patients aged 8-18 years with pulmonary hypertension (diagnostic Groups 1, 2, or 3) and World Health Organization functional class I or II underwent dual-energy absorptiometry to measure leg lean mass Z-score (a surrogate for skeletal muscle). Muscle strength was assessed using dynamometry. Physical activity questionnaires were administered. Clinical data, including 6-minute walk distance, were reviewed. Relationships between skeletal muscle, physical activity score, and 6-minute walk distance were assessed by correlations and linear regression.

Results: Sixteen patients (12.1 ± 3.2 years, 50% female, 56% Group 1, 56% functional class II) were enrolled. Leg lean mass Z-score was significantly less than reference data (-1.40 ± 1.12 versus 0.0 ± 0.9, p < 0.001) and worse in those with functional class II versus I (-2.10 ± 0.83 versus -0.50 ± 0.73, p < 0.01). Leg lean mass Z-score was positively associated with right ventricular systolic function by tricuspid annular plane systolic Z-score (r = 0.54, p = 0.03) and negatively associated with indexed pulmonary vascular resistance (r = -0.78, p < 0.001). Leg lean mass Z-score and forearm strength were positively associated with physical activity score. When physical activity score was held constant, leg lean mass Z-score independently predicted 6-minute walk distance (R2 = 0.39, p = 0.03).

Conclusions: Youth with pulmonary hypertension demonstrate marked skeletal muscle deficits in association with exercise intolerance. Future studies should investigate whether low leg lean mass is a marker of disease severity or an independent target that can be improved.
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http://dx.doi.org/10.1017/S1047951121000342DOI Listing
September 2021

Associations of the residential built environment with adolescent sleep outcomes.

Sleep 2021 06;44(6)

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Study Objectives: Over 75% of US high school students obtain insufficient sleep, placing them at risk for adverse health outcomes. Identification of modifiable determinants of adolescent sleep is needed to inform prevention strategies, yet little is known about the influence of the built environment on adolescent sleep.

Methods: In this prospective study, actigraphy was used to assess sleep outcomes among 110 adolescents for 14 days each in eighth and ninth grades: duration (hours/night), onset and offset, and sleeping ≥8 hours. Home addresses were linked to built environment exposures: sound levels, tree canopy cover, street density, intersection density, population density, and housing density. Mixed-effects regression estimated associations of built environment measures with sleep outcomes, adjusting for sex, race, parent education, household income, household size, grade, weeknight status, and neighborhood poverty.

Results: A 1-standard deviation (SD) increase in neighborhood sound was associated with 16 minutes later sleep onset (β = 0.28; 95% confidence interval (CI): 0.06, 0.49) and 25% lower odds of sleeping for ≥8 hours (odds ratio (OR) = 0.75, 95% CI: 0.59, 0.96). A 1-SD increase in neighborhood tree canopy was associated with 18 minutes earlier sleep onset (β = -0.31, 95% CI: -0.49, -0.13) and 10 minutes earlier sleep offset (β= -0.17, 95% CI: -0.28, -0.05). No associations were observed for density-based exposures.

Conclusions: Higher neighborhood sound level was associated with lower odds of sufficient sleep, while higher tree canopy cover was associated with more favorable sleep timing. Neighborhood sound levels and tree canopy cover are potential targets for policies and interventions to support healthier sleep among adolescents.
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http://dx.doi.org/10.1093/sleep/zsaa276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193550PMC
June 2021

Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual.

Genome Biol 2021 01 4;22(1). Epub 2021 Jan 4.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: Bone accrual impacts lifelong skeletal health, but genetic discovery has been primarily limited to cross-sectional study designs and hampered by uncertainty about target effector genes. Here, we capture this dynamic phenotype by modeling longitudinal bone accrual across 11,000 bone scans in a cohort of healthy children and adolescents, followed by genome-wide association studies (GWAS) and variant-to-gene mapping with functional follow-up.

Results: We identify 40 loci, 35 not previously reported, with various degrees of supportive evidence, half residing in topological associated domains harboring known bone genes. Of several loci potentially associated with later-life fracture risk, a candidate SNP lookup provides the most compelling evidence for rs11195210 (SMC3). Variant-to-gene mapping combining ATAC-seq to assay open chromatin with high-resolution promoter-focused Capture C identifies contacts between GWAS loci and nearby gene promoters. siRNA knockdown of gene expression supports the putative effector gene at three specific loci in two osteoblast cell models. Finally, using CRISPR-Cas9 genome editing, we confirm that the immediate genomic region harboring the putative causal SNP influences PRPF38A expression, a location which is predicted to coincide with a set of binding sites for relevant transcription factors.

Conclusions: Using a new longitudinal approach, we expand the number of genetic loci putatively associated with pediatric bone gain. Functional follow-up in appropriate cell models finds novel candidate genes impacting bone accrual. Our data also raise the possibility that the cell fate decision between osteogenic and adipogenic lineages is important in normal bone accrual.
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http://dx.doi.org/10.1186/s13059-020-02207-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780623PMC
January 2021

Gut Microbiome Profile After Pancreatectomy in Infants With Congenital Hyperinsulinism.

Pancreas 2021 01;50(1):89-92

From the Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia.

Objectives: The objective of this study was to characterize gut microbiome profiles of infants with congenital hyperinsulinism (HI) who underwent near-total or partial pancreatectomy for hypoglycemia management, as compared with healthy controls.

Methods: A prospective observational cohort study was performed. Subjects were infants (0-6 months) with HI who underwent removal of pancreatic tissue for management of intractable hypoglycemia from February 2017 to February 2018 at the Children's Hospital of Philadelphia. Fecal samples were collected postoperatively, on full enteral nutrition. The gut microbiome of HI subjects was analyzed and compared with age-matched samples from healthy infants.

Results: Seven subjects with ≥50% pancreatectomy and 6 with <50% pancreatectomy were included. α (within-sample) diversity was lowest among infants with ≥50% pancreatectomy (richness: false discovery rate, 0.003; Shannon index: false discovery rate, 0.01). β (between-sample) diversity (Bray-Curtis dissimilarity, P = 0.02; Jaccard distance, P = 0.001) differed across groups (≥ or <50% pancreatectomy, controls). Bifidobacteria and Klebsiella species were least abundant among infants with ≥50% pancreatectomy but did not differ between infants with <50% pancreatectomy and historical controls.

Conclusions: Infants with HI who underwent ≥50% pancreatectomy differed from age-matched infants in gut microbiome profile, whereas those with <50% pancreatectomy more closely resembled control profiles. The durability of this difference should be investigated.
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http://dx.doi.org/10.1097/MPA.0000000000001708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783597PMC
January 2021

A Meta-Analysis of the Transferability of Bone Mineral Density Genetic Loci Associations From European to African Ancestry Populations.

J Bone Miner Res 2021 03 18;36(3):469-479. Epub 2020 Dec 18.

Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.

Genetic studies of bone mineral density (BMD) largely have been conducted in European populations. We therefore conducted a meta-analysis of six independent African ancestry cohorts to determine whether previously reported BMD loci identified in European populations were transferable to African ancestry populations. We included nearly 5000 individuals with both genetic data and assessments of BMD. Genotype imputation was conducted using the 1000G reference panel. We assessed single-nucleotide polymorphism (SNP) associations with femoral neck and lumbar spine BMD in each cohort separately, then combined results in fixed effects (or random effects if study heterogeneity was high, I index >60) inverse variance weighted meta-analyses. In secondary analyses, we conducted locus-based analyses of rare variants using SKAT-O. Mean age ranged from 12 to 68 years. One cohort included only men and another cohort included only women; the proportion of women in the other four cohorts ranged from 52% to 63%. Of 56 BMD loci tested, one locus, 6q25 (C6orf97, p = 8.87 × 10 ), was associated with lumbar spine BMD and two loci, 7q21 (SLC25A13, p = 2.84 × 10 ) and 7q31 (WNT16, p = 2.96 × 10 ), were associated with femoral neck BMD. Effects were in the same direction as previously reported in European ancestry studies and met a Bonferroni-adjusted p value threshold, the criteria for transferability to African ancestry populations. We also found associations that met locus-specific Bonferroni-adjusted p value thresholds in 11q13 (LRP5, p < 2.23 × 10 ), 11q14 (DCDC5, p < 5.35 × 10 ), and 17p13 (SMG6, p < 6.78 × 10 ) that were not tagged by European ancestry index SNPs. Rare single-nucleotide variants in AKAP11 (p = 2.32 × 10 ), MBL2 (p = 4.09 × 10 ), MEPE (p = 3.15 × 10 ), SLC25A13 (p = 3.03 × 10 ), STARD3NL (p = 3.35 × 10 ), and TNFRSF11A (p = 3.18 × 10 ) were also associated with BMD. The majority of known BMD loci were not transferable. Larger genetic studies of BMD in African ancestry populations will be needed to overcome limitations in statistical power and to identify both other loci that are transferable across populations and novel population-specific variants. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353846PMC
March 2021

"COVID-19 and the epistemology of epidemiological models at the dawn of AI": comment from the editors.

Ann Hum Biol 2020 09;47(6):505

Full Professor of Molecular Anthropology, Department of Biology, University of Rome "Tor Vergata", Italy.

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http://dx.doi.org/10.1080/03014460.2020.1841383DOI Listing
September 2020

Engineering a Mobile Platform to Promote Sleep in the Pediatric Primary Care Setting.

medRxiv 2020 Nov 7. Epub 2020 Nov 7.

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Background: Pediatricians lack tools to support families at home for the promotion of childhood sleep. We are using the Multiphase Optimization Strategy (MOST) framework to guide the development of a mobile health platform for childhood sleep promotion.

Purpose: Under the preparation phase of the MOST framework, to demonstrate feasibility of a mobile health platform towards treating children with insufficient sleep.

Methods: Children aged 10-12y were enrolled (Study #1: N=30; Study #2: N=43). Participants wore a sleep tracker to measure sleep duration. Data were retrieved by a mobile health platform, programmed to send introductory messages during run-in (2 weeks) and goal achievement messages during intervention (7 weeks) periods. In study #1, participants were randomized to control, gain-framed incentive or loss-framed incentive arms. In study #2, participants were randomized to control, loss-framed incentive, normative feedback or loss-framed incentive plus normative feedback arms.

Results: In study #1, 1,514 nights of data were captured (69%) and sleep duration during the intervention was higher by an average of 21 (95% CI: -8, 51) and 34 (95% CI: 7, 61) minutes per night for the gain-framed and loss-framed arms, respectively, compared to controls. In study #2, 2,689 nights of data were captured (81%), with no major differences in average sleep duration between the control and the loss-framed or normative feedback arms.

Conclusion: We have developed and deployed a mobile health platform that can capture sleep data and remotely communicate with families. Promising candidate intervention components will be further investigated under the optimization phase of the MOST framework.
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http://dx.doi.org/10.1101/2020.11.06.20223719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7654877PMC
November 2020

Circulating Fibroblast Growth Factor-21 Levels in Rheumatoid Arthritis: Associations With Disease Characteristics, Body Composition, and Physical Functioning.

J Rheumatol 2021 04 1;48(4):504-512. Epub 2020 Nov 1.

J.F. Baker, MD, MSCE, Perelman School of Medicine, University of Pennsylvania, Philadelphia VA Medical Center, Division of Rheumatology, University of Pennsylvania, and Department of Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Objective: This study evaluated associations between fibroblast growth factor (FGF)-21, an adipokine associated with metabolic stress, and adverse longitudinal changes in body composition and physical functioning in patients with rheumatoid arthritis (RA).

Methods: At baseline and follow-up, patients with RA aged 18-70 years completed whole-body dual-energy X-ray absorptiometry and peripheral quantitative computed tomography to quantify lean mass, fat mass, and muscle density. Dynamometry assessed muscle strength at the hand and knee, and physical functioning was measured with the Health Assessment Questionnaire (HAQ) and the Short Physical Performance Battery (SPPB). FGF-21 and inflammatory cytokines were measured at baseline. Linear and logistic regression analyses assessed associations between FGF-21 levels and both body composition and physical functioning over time.

Results: There were 113 patients with RA enrolled, and 84 (74%) returned for follow-up at a median of 2.68 years. At baseline, FGF-21 was associated with age, smoking, methotrexate use, adiposity, and inflammatory cytokines: tumor necrosis factor receptor type I, YKL-40, vascular endothelial growth factor (VEGF), and resistin. The highest FGF-21 quartile was associated with worse SPPB and HAQ. Higher baseline FGF-21 levels (per 1 SD) were associated with worsening in muscle density and area Z-scores (β -0.06, 95% CI -0.12 to 0.008, = 0.08; and β -0.05, 95% CI -0.10 to 0.006, = 0.08, respectively) and a greater probability of a clinically meaningful worsening of HAQ (OR 2.37, 95% CI 1.21-4.64, = 0.01). The fourth FGF-21 quartile was associated with worsening of SPPB (β -0.57, 95% CI -1.04 to -0.09, = 0.02).

Conclusion: FGF-21 levels are associated with obesity and inflammatory cytokines, and with worsening in physical functioning in RA. These data support the hypothesis that FGF-21 can identify patients at risk of functional decline.
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http://dx.doi.org/10.3899/jrheum.200673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087721PMC
April 2021

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
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http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

Leg length and sitting height reference data and charts for children in the United States.

Data Brief 2020 Oct 5;32:106131. Epub 2020 Aug 5.

Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, USA.

Population-specific reference data are required to interpret growth measurements in children. Sitting height and leg length (standing height minus sitting height) measurements are indicators of proportionality and can be used to evaluate children with disordered growth. NHANES III recorded sitting height and standing height measurements in a strategic random sample of the United States population from 1988 to 1994, and we have previously published reference charts for sitting height to standing height ratio in this population. In this study, we have developed separate sitting height and leg length reference charts for Non-Hispanic Black, Non-Hispanic White, and Mexican-American children in the United States. In addition, we provide mean (SD) and LMS data to support the use of these reference charts in clinical care.
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http://dx.doi.org/10.1016/j.dib.2020.106131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452688PMC
October 2020

Intermachine differences in DXA measurements vary by skeletal site, and impact the assessment of low bone density in children.

Bone 2020 12 11;141:115581. Epub 2020 Aug 11.

Department of Pediatrics, University of Cincinnati College of Medicine, United States of America; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, United States of America.

Background: Bone mineral content (BMC) and areal-bone mineral density (aBMD) measurements of the lumbar spine (LS) and whole body less head (WBLH) by dual energy X-ray absorptiometry (DXA) are recommended for bone health assessment in children. Intermachine differences were not considered previously in formulating these recommendations.

Methodology: DXA measurements of the LS, WBLH, total hip, femoral neck and distal 1/3 radius from the Bone Mineral Density in Childhood Study were examined. Healthy children, ages 6 to 16 years, from five clinical centers participated. The same spine, whole body, and femur phantoms were measured on each Center's DXA machine. Percentage of individuals with low BMC or aBMD (Z-score < -1.5) was determined. Clinical center differences were evaluated by analysis of covariance adjusting for height and BMI Z-score, calcium intake, physical activity, Tanner stage and bone age. Logistic regression assessed odds of low BMC or aBMD across clinical centers.

Results: Significant differences among Clinical Centers (p < 0.05) were evident in adjusted mean BMC and aBMD Z-scores (n = 1503) for all skeletal sites. WBLH BMC and aBMD Z-scores had the greatest range across centers (-0.13 to 0.24, and -0.17 to 0.56, respectively). The percentage of children with Z-scores less than -1.5 varied among Clinical Centers from 1.9 [95%CI 0.8, 4.5] to 8.1 [95%CI 5.7, 11.3] for WBLH BMC, 1.1 [95%CI 0.4, 3.5] to 6.3 [95%CI 3.8, 10.1] for WBLH aBMD, and from 4.4 [95%CI 2.8, 7.0] to 12.6 [95%CI 9.3, 16.9] for distal 1/3 radius aBMD. For each skeletal site except total hip aBMD and femoral neck BMC, at least one center had significantly lower odds of low bone density.

Conclusions: By design, our reference ranges capture intermachine variability. Most clinical centers don't know where their machine falls within the range of intermachine variability, and this may affect diagnosis of children evaluated for conditions that threaten bone health. Total hip scans showed the least, and whole body scans showed the most intermachine variability. Pediatric bone health assessment recommendations should recognize intermachine differences and address this important issue.
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http://dx.doi.org/10.1016/j.bone.2020.115581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680379PMC
December 2020

Bone geometry and microarchitecture deficits in children with Alagille syndrome.

Bone 2020 12 11;141:115576. Epub 2020 Aug 11.

Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, United States of America; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States of America. Electronic address:

Alagille syndrome (ALGS) is an autosomal dominant disorder attributed to mutations in the Notch signaling pathway. Children with ALGS are at increased risk for fragility fracture of unknown etiology. Our objective was to characterize bone mass, geometry, and microarchitecture in children with ALGS. This was a cross-sectional study of 10 children (9 females), ages 8-18 years, with a clinical diagnosis of ALGS. Bone density was assessed via DXA (Hologic Discovery A) at several skeletal regions. Tibia trabecular and cortical bone was assessed via pQCT (Stratec XCT 2000) at the distal 3% and 38% sites, respectively. Tibia bone microarchitecture was assessed via HR-pQCT (Scanco XtremeCT II) at an ultradistal site located at 4% of tibia length and a cortical site at 30% of tibia length. Z-scores were calculated for DXA and pQCT measures. In the absence of XtremeCT II HR-pQCT reference data, these outcome measures were descriptively compared to a sample of healthy children ages 5-20 years (n = 247). Anthropometrics and labs were also collected. Based on one-sample t-tests, mean Z-scores for height and weight (both p < .05), were significantly less than zero. DXA bone Z-scores were not significantly different from zero, but were highly variable. For pQCT bone measures, Z-scores for total bone mineral content at the distal 3% site and cortical bone mineral content, cortical area, and cortical thickness at the distal 38% site were significantly less than zero (all p < .05). There was good correspondence between pQCT measures of cortical thickness Z-scores and DXA Z-scores for aBMD at the whole body less head, 1/3 radius, and femoral neck (all p < .05). Compared to healthy children, those with ALGS generally had lower trabecular number and greater trabecular separation despite having greater trabecular thickness (measured via HR-pQCT). Bilirubin and bile acids, markers of hepatic cholestasis, were associated with poorer bone measures. For example, greater bilirubin was associated with lower trabecular number (Spearman's rho [ρ] = -0.82, p = .023) and greater trabecular separation (ρ = 0.82, p = .023) measured via HR-pQCT, and greater bile acids were associated with lower cortical area measured via pQCT (ρ = -0.78, p = .041) and lower serum insulin-like growth factor-1 (ρ = -0.86, p = .002). In summary, deficits in cortical bone size and trabecular bone microarchitecture were evident in children with ALGS. Further investigation is needed to understand the factors contributing to these skeletal inadequacies, and the manner in which these deficits contribute to increased fracture risk.
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http://dx.doi.org/10.1016/j.bone.2020.115576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680312PMC
December 2020

Bone Mass and Density in Youth With Type 2 Diabetes, Obesity, and Healthy Weight.

Diabetes Care 2020 10 10;43(10):2544-2552. Epub 2020 Aug 10.

Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA

Objective: Youth-onset type 2 diabetes is an aggressive condition with increasing incidence. Adults with type 2 diabetes have increased fracture risk despite normal areal bone mineral density (aBMD), but the influence of diabetes on the growing skeleton is unknown. We compared bone health in youth with type 2 diabetes to control patients with obesity or healthy weight.

Research Design And Methods: Cross-sectional study of youth (56% African American, 67% female) ages 10-23 years with type 2 diabetes ( = 180), obesity (BMI >95th; = 226), or healthy weight (BMI <85th; = 238). Whole-body (less head) aBMD and lean mass as well as abdominal visceral fat were assessed via DXA. Lean BMI (LBMI) and aBMD SD scores ( scores) were computed using published reference data.

Results: We observed age-dependent differences in aBMD and LBMI scores between the healthy weight, obese, and type 2 diabetes groups. In children, aBMD and LBMI scores were greater in the type 2 diabetes group versus the obese group, but in adolescents and young adults, aBMD and LBMI scores were lower in the type 2 diabetes group versus the obese group (age interactions < 0.05). In the type 2 diabetes group and the obese group, aBMD was about 0.5 SDs lower for a given LBMI score compared with healthy weight control patients ( < 0.05). Further, aBMD was lower in those with greater visceral fat (β = -0.121, = 0.047).

Conclusions: These results suggest that type 2 diabetes may be detrimental to bone density around the age of peak bone mass. Given the increased fracture risk in adults with type 2 diabetes, there is a pressing need for longitudinal studies aimed at understanding the influence of diabetes on the growing skeleton.
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http://dx.doi.org/10.2337/dc19-2164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510020PMC
October 2020

Sitting Height to Standing Height Ratio Reference Charts for Children in the United States.

J Pediatr 2020 Jun 21. Epub 2020 Jun 21.

Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, PA; Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, PA.

Objective: To create reference charts for sitting height to standing height ratio (SitHt/Ht) for children in the US, and to describe the trajectory of SitHt/Ht during puberty.

Study Design: This was a cross-sectional study using data from the 1988-1994 National Health and Nutrition Examination Survey III, a strategic random sample of the US population. Comparison between non-Hispanic White (NHW), non-Hispanic Black (NHB) and Mexican American groups was performed by ANOVA to determine if a single population reference chart could be used. ANOVA was used to compare SitHt/Ht in pre-, early, and late puberty.

Results: NHANES III recorded sitting height and standing height measurements in 9569 children aged 2-18 years of NHW (n = 2715), NHB (n = 3336), and Mexican American (n = 3518) ancestry. NHB children had lower SitHt/Ht than NHW and Mexican American children throughout childhood (P < .001). In both sexes, the SitHt/Ht decreased from prepuberty to early puberty and increased in late puberty. Sex-specific percentile charts of SitHt/Ht vs age were generated for NHB and for NHW and Mexican American youth combined.

Conclusions: SitHt/Ht assessment can detect disproportionate short stature in children with skeletal dysplasia, but age-, sex-, and population-specific reference charts are required to interpret this measurement. NHB children in the US have significantly lower SitHt/Ht than other children, which adds complexity to interpretation. We recommend the use of standardized ancestry-specific reference charts in screening for skeletal dysplasias and have developed such charts in this study.
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http://dx.doi.org/10.1016/j.jpeds.2020.06.051DOI Listing
June 2020

Pediatric Reference Ranges for Ultradistal Radius Bone Density: Results from the Bone Mineral Density in Childhood Study.

J Clin Endocrinol Metab 2020 10;105(10)

Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

Context: The ultradistal (UD) radius is rich in trabecular bone and is easily measured by dual energy X-ray absorptiometry (DXA). UD radius areal bone mineral density (aBMD) may help identify trabecular bone deficits, but reference data are needed for research and clinical interpretation of this measure.

Objective: We developed age-, sex-, and population ancestry-specific reference ranges for UD radius aBMD assessed by DXA and calculated Z-scores. We examined tracking of UD radius aBMD Z-scores over 6 years and determined associations between UD radius aBMD Z-scores and other bone measures by DXA and peripheral quantitative computed tomography.

Design: Multicenter longitudinal study.

Participants: A total of 2014 (922 males, 22% African American) children ages 5 to 19 years at enrollment who participated in the Bone Mineral Density in Childhood Study.

Main Outcome Measure: UD radius aBMD.

Results: UD radius aBMD increased nonlinearly with age (P < 0.001) and tended to be greater in males versus females (P = 0.054). Age-, sex-, and ancestry-specific UD radius aBMD reference curves were constructed. UD radius aBMD Z-scores positively associated with Z-scores at other skeletal sites (r = 0.54-0.64, all P < 0.001) and peripheral quantitative computed tomography measures of distal radius total volumetric BMD (r = 0.68, P < 0.001) and trabecular volumetric BMD (r = 0.70, P < 0.001), and was weakly associated with height Z-score (r = 0.09, P = 0.015). UD radius aBMD Z-scores tracked strongly over 6 years, regardless of pubertal stage (r = 0.66-0.69; all P < 0.05).

Conclusion: UD radius aBMD Z-scores strongly associated with distal radius trabecular bone density, with marginal confounding by stature. These reference data may provide a valuable resource for bone health assessment in children.
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http://dx.doi.org/10.1210/clinem/dgaa380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465545PMC
October 2020

The stepwise assembly of the neonatal virome is modulated by breastfeeding.

Nature 2020 05 15;581(7809):470-474. Epub 2020 Apr 15.

Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

The gut of healthy human neonates is usually devoid of viruses at birth, but quickly becomes colonized, which-in some cases-leads to gastrointestinal disorders. Here we show that the assembly of the viral community in neonates takes place in distinct steps. Fluorescent staining of virus-like particles purified from infant meconium or early stool samples shows few or no particles, but by one month of life particle numbers increase to 10 per gram, and these numbers seem to persist throughout life. We investigated the origin of these viral populations using shotgun metagenomic sequencing of virus-enriched preparations and whole microbial communities, followed by targeted microbiological analyses. Results indicate that, early after birth, pioneer bacteria colonize the infant gut and by one month prophages induced from these bacteria provide the predominant population of virus-like particles. By four months of life, identifiable viruses that replicate in human cells become more prominent. Multiple human viruses were more abundant in stool samples from babies who were exclusively fed on formula milk compared with those fed partially or fully on breast milk, paralleling reports that breast milk can be protective against viral infections. Bacteriophage populations also differed depending on whether or not the infant was breastfed. We show that the colonization of the infant gut is stepwise, first mainly by temperate bacteriophages induced from pioneer bacteria, and later by viruses that replicate in human cells; this second phase is modulated by breastfeeding.
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http://dx.doi.org/10.1038/s41586-020-2192-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263352PMC
May 2020
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