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Lisa Schaaf,1 Sanita Ley,2 Allen Riegler,1 Amy Poetker,1 Stavra Xanthakos,3 Jennifer Sizemore,1 Nancy Crimmins,4 Michael Helmrath,5 Rebekah Tracy,6 Ana Catalina Arce-Clachar,3 Jennifer Crail,1 Nancy Morwessel,1 Kelsey Frenck,1 Fatima Tariq,1 Amy Sanghavi Shah4 1Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; 2Department of Pediatrics, Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA; 3Department of Pediatrics, Division of Gastroenterology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Department of Pediatrics, Cincinnati, OH, USA; 4Department of Pediatrics, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA; 5Department of Surgery, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA; 6Center for Better Health and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USACorrespondence: Lisa Schaaf, Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, OH, 45229, USA, Tel +1 610 291 6981, Fax +1 513 636 9677, Email lisa.schaaf@cchmc.orgIntroduction: Diabetes self-management education and lifestyle interventions are the cornerstones of type 2 diabetes (T2D) care; however, the higher risk of comorbidities among youth with T2D requires a comprehensive care model. Traditionally, sub-specialty care relies on a referral model placing the burden on patients/families. In response, we developed a pediatric T2D multidisciplinary clinic (MDC)-A single physical location where patients can access various sub-specialists. The goals of the MDC are to aid with lifestyle modifications and provide referral/access to sub-specialists within the MDC, as determined through screening labs and assessment tools.Methods: We conducted a retrospective chart review of youth seen in the T2D MDC clinic at Cincinnati Children’s Hospital from 1/2020 to 12/2021. We evaluated the frequency that youth met with each specialist and completion rates of annual screening labs.Results: The cohort consisted of 227 youth with T2D (mean age 17.6 years, mean BMI 40.9kg/m2, 64% female, 50% Black or African American, 65% public insurance). All patients met with a diabetes provider and 81.2% met with a registered dietitian/certified diabetes education specialist. Exercise physiology met with 51.5% of patients, gastroenterology met with 34.8% of patients, social work met with 44.1% of patients, clinical psychology met with 27.3% of patients, and bariatric surgery met with 9.7% of patients. Percent completion of annual labs were: 98.2% for HbA1c, 84.6% for urine microalbumin, 83.7% for lipids, 90% for liver function, 59.5% for retinopathy, and 45.4% for the Patient Health Questionnaire-9.Conclusion: The majority of patients received diabetes and nutrition education and annual screening labs. Exercise counseling and sub-specialty care remain below 60% in part due to services not being available at every MDC. Our goals are to increase access to subspecialty care within the MDC’s and consider additional care delivery methods to provide comprehensive care to youth with T2D.Keywords: pediatrics, type 2 diabetes, multidisciplinary, adolescent, comorbidities

Background: The goal of intestinal rehabilitation in children is to wean from parenteral nutrition (PN). The aim of this study was to identify factors associated with accelerated weaning and to evaluate long-term outcomes of children receiving long-term PN., Methods: This was a retrospective study of children managed by the Intestinal Rehabilitation Center at Cincinnati Children's Hospital. Medical history data were retrieved. The outcomes of children receiving long-term chronic PN (>2 years) were compared with those of children receiving short-term chronic PN regimen (<2 years)., Results: The cohort consisted of 112 children (58% boys, median [IQR] age of 6.0 [3.7-9.5] years). The group treated with a long-term PN regimen had significantly shorter residual small bowel and large bowel compared with the group treated with a short-term PN regimen (20% vs 60% and 75% vs 100%, respectively; P < 0.05). The lapse of time between PN and enteral feed initiation was longer in the group undergoing long-term PN regimen than in the short-term group (71 vs 32.5 days; P = 0.012). More episodes of central line-associated bloodstream infection (CLABSI) and a higher percentage of feeding aversion was demonstrated in the long-term PN group (2 [1-3] vs 1 [0-2] episodes and 36% vs 0%, respectively)., Conclusion: Small bowel, colon length, enteral feed initiation, and frequency of CLABSI are factors associated with duration of PN regimen. A long-term chronic PN regimen is associated with a higher risk of food aversion., (© 2024 The Author(s). Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Human induced pluripotent stem cells (hiPSCs) can give rise to multiple lineages derived from three germ layers, endoderm, mesoderm and ectoderm. Definitive endoderm (DE) cell types and tissues have great potential for regenerative medicine applications. Current hiPSC differentiation protocols focus on the addition of soluble factors; however, extracellular matrix properties are known to also play a role in dictating cell fate. Matrigel™ is the gold standard for DE differentiation, but this xenogeneic, poorly defined basement membrane extract limits the clinical translatability of DE-derived tissues. Here we present a fully defined PEG-based hydrogel substrate to support hiPSC-derived DE differentiation. We screened hydrogel formulations presenting different adhesive peptides and matrix stiffness. Our results demonstrate that presenting a short peptide, cyclic RGD, on the engineered PEG hydrogel supports the transition from undifferentiated hiPSCs to DE using a serum-free, commercially available kit. We show that increasing substrate stiffness (G' = 1.0-4.0 kPa) results in an increased linear response in DE differentiation efficiency. We also include a temporal analysis of the expression of integrin and syndecan receptors as the hiPSCs undergo specification towards DE lineage. Finally, we show that focal adhesion kinase activity regulates hiPSC growth and DE differentiation efficiency. Overall, we present a fully defined matrix as a synthetic alternative for Matrigel™ supporting DE differentiation., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: Weight loss following vertical sleeve gastrectomy (VSG) in youth can range from 10% to 50%. We examined whether there are differences in demographic or metabolic parameters before VSG in youth who achieve above-average weight loss (AAWL) versus below-average weight loss (BAWL) at 1 year post VSG and if youth with BAWL still achieve metabolic health improvements at 1 year post VSG., Methods: Demographic, anthropometric, and clinical lab data were collected before VSG and at 1, 3, 6, and 12 months after VSG., Results: Forty-three youth with a mean age of 16.9 (SD 1.7) years before VSG were studied; 70% were female, 19% non-Hispanic Black, 58% non-Hispanic White, and 23% mixed/other race. Mean baseline BMI was 51.1 (SD 10.5) kg/m 2 . Average weight loss was 25.8%. The AAWL group lost 18.6 kg/m 2 (35.3%) versus the BAWL group, who lost 8.8 kg/m 2 (17.5%). BMI, age, race, sex, and socioeconomic status at baseline were similar between AAWL and BAWL groups; however, the BAWL group had a higher frequency of pre-VSG dysglycemia, steatotic liver disease, and dyslipidemia. At 1 year post VSG, fewer youth in the BAWL group achieved ideal health parameters, and they had less resolution of comorbidities., Conclusions: The presence of comorbidities before VSG is associated with less weight loss and reduced resolution of metabolic conditions at 1 year post VSG., (© 2024 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Background & Aims: Humans with WNT2B deficiency have severe intestinal disease, including significant inflammatory injury, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis., Methods: We investigated the intestinal health of Wnt2b knock out (KO) mice. We assessed the baseline histology and health of the small intestine and colon, and the impact of inflammatory challenge using dextran sodium sulfate (DSS). We also evaluated human intestinal tissue., Results: Mice with WNT2B deficiency had normal baseline histology but enhanced susceptibility to DSS colitis because of an increased early injury response. Although intestinal stem cells markers were decreased, epithelial proliferation was similar to control subjects. Wnt2b KO mice showed an enhanced inflammatory signature after DSS treatment. Wnt2b KO colon and human WNT2B-deficient organoids had increased levels of CXCR4 and IL6, and biopsy tissue from humans showed increased neutrophils., Conclusions: WNT2B is important for regulation of inflammation in the intestine. Absence of WNT2B leads to increased expression of inflammatory cytokines and increased susceptibility to gastrointestinal inflammation, particularly in the colon., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Autosomal Recessive Renal Tubular Dysgenesis (AR-RTD) is a fatal genetic disorder characterized by complete absence or severe depletion of proximal tubules (PT) in patients harboring pathogenic variants in genes involved in the Renin-Angiotensin-Aldosterone System. To uncover the pathomechanism of AR-RTD, differentiation of ACE-/- and AGTR1-/- induced pluripotent stem cells (iPSCs) and AR-RTD patient-derived iPSCs into kidney organoids is leveraged. Comprehensive marker analyses show that both mutant and control organoids generate indistinguishable PT in vitro under normoxic (21% O2) or hypoxic (2% O2) conditions. Fully differentiated (d24) AGTR1-/- and control organoids transplanted under the kidney capsule of immunodeficient mice engraft and mature well, as do renal vesicle stage (d14) control organoids. By contrast, d14 AGTR1-/- organoids fail to engraft due to insufficient pro-angiogenic VEGF-A expression. Notably, growth under hypoxic conditions induces VEGF-A expression and rescues engraftment of AGTR1-/- organoids at d14, as does ectopic expression of VEGF-A. We propose that PT dysgenesis in AR-RTD is primarily a non-autonomous consequence of delayed angiogenesis, starving PT at a critical time in their development., (© 2023. The Author(s).)

Importance: Although most ovarian masses in children and adolescents are benign, many are managed with oophorectomy, which may be unnecessary and can have lifelong negative effects on health., Objective: To evaluate the ability of a consensus-based preoperative risk stratification algorithm to discriminate between benign and malignant ovarian pathology and decrease unnecessary oophorectomies., Design, Setting, and Participants: Pre/post interventional study of a risk stratification algorithm in patients aged 6 to 21 years undergoing surgery for an ovarian mass in an inpatient setting in 11 children's hospitals in the United States between August 2018 and January 2021, with 1-year follow-up., Intervention: Implementation of a consensus-based, preoperative risk stratification algorithm with 6 months of preintervention assessment, 6 months of intervention adoption, and 18 months of intervention. The intervention adoption cohort was excluded from statistical comparisons., Main Outcomes and Measures: Unnecessary oophorectomies, defined as oophorectomy for a benign ovarian neoplasm based on final pathology or mass resolution., Results: A total of 519 patients with a median age of 15.1 (IQR, 13.0-16.8) years were included in 3 phases: 96 in the preintervention phase (median age, 15.4 [IQR, 13.4-17.2] years; 11.5% non-Hispanic Black; 68.8% non-Hispanic White); 105 in the adoption phase; and 318 in the intervention phase (median age, 15.0 [IQR, 12.9-16.6)] years; 13.8% non-Hispanic Black; 53.5% non-Hispanic White). Benign disease was present in 93 (96.9%) in the preintervention cohort and 298 (93.7%) in the intervention cohort. The percentage of unnecessary oophorectomies decreased from 16.1% (15/93) preintervention to 8.4% (25/298) during the intervention (absolute reduction, 7.7% [95% CI, 0.4%-15.9%]; P = .03). Algorithm test performance for identifying benign lesions in the intervention cohort resulted in a sensitivity of 91.6% (95% CI, 88.5%-94.8%), a specificity of 90.0% (95% CI, 76.9%-100%), a positive predictive value of 99.3% (95% CI, 98.3%-100%), and a negative predictive value of 41.9% (95% CI, 27.1%-56.6%). The proportion of misclassification in the intervention phase (malignant disease treated with ovary-sparing surgery) was 0.7%. Algorithm adherence during the intervention phase was 95.0%, with fidelity of 81.8%., Conclusions and Relevance: Unnecessary oophorectomies decreased with use of a preoperative risk stratification algorithm to identify lesions with a high likelihood of benign pathology that are appropriate for ovary-sparing surgery. Adoption of this algorithm might prevent unnecessary oophorectomy during adolescence and its lifelong consequences. Further studies are needed to determine barriers to algorithm adherence.

Introduction/objectives: As intestinal failure (IF) management improves and long-term survival rate increases, its physiological complications have become more apparent. The development of chronic intestinal inflammation resembling inflammatory bowel disease (IBD) in this population has been reported, but the literature describing it in detail is sparse. The present study was designed to characterize children with IF who developed chronic intestinal inflammation and identify the potential predisposing clinical factors., Methods: This retrospective study was based on the electronic medical records of pediatric patients seen at the Cincinnati Children's Hospital Medical Center between January 2000 and July 2022. Demographic and medical history data were collected and compared between children with IF that developed chronic intestinal inflammation and children with IF that did not develop chronic intestinal inflammation., Results: During the follow-up period, 23 children were diagnosed with chronic intestinal inflammation. Of these, 12 (52%) were males, with a median age of 4.5 (3-7) years at diagnosis. Nearly one-third of the patients had gastroschisis (31%), followed by necrotizing enterocolitis (26%), and malrotation and volvulus (21.7%). More children in the chronic intestinal inflammation group lacked an ileocecal valve (ICV) and adjoining distal ileum as compared to the short bowel syndrome (SBS)-IF control group (15 patients, 65% vs 8 patients, 33%). Moreover, more children in the chronic intestinal inflammation group had undergone a prior lengthening procedure than the SBS-IF control group (5 patients, 21.7% vs. 0, respectively)., Discussion: SBS patients are at risk of relatively early onset chronic intestinal inflammation. The absence of an ICV (and adjoin ileum) and prior lengthening procedures emerge as factors associated with the risk of IBD in these patients., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by European Society for European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Background and Aims: WNT2B is a canonical Wnt ligand previously thought to be fully redundant with other Wnts in the intestinal epithelium. However, humans with WNT2B deficiency have severe intestinal disease, highlighting a critical role for WNT2B. We sought to understand how WNT2B contributes to intestinal homeostasis., Methods: We investigated the intestinal health of Wnt2b knock out (KO) mice. We assessed the impact of inflammatory challenge to the small intestine, using anti-CD3χ antibody, and to the colon, using dextran sodium sulfate (DSS). In addition, we generated human intestinal organoids (HIOs) from WNT2B-deficient human iPSCs for transcriptional and histological analyses., Results: Mice with WNT2B deficiency had significantly decreased Lgr5 expression in the small intestine and profoundly decreased expression in the colon, but normal baseline histology. The small intestinal response to anti-CD3χ antibody was similar in Wnt2b KO and wild type (WT) mice. In contrast, the colonic response to DSS in Wnt2b KO mice showed an accelerated rate of injury, featuring earlier immune cell infiltration and loss of differentiated epithelium compared to WT. WNT2B-deficient HIOs showed abnormal epithelial organization and an increased mesenchymal gene signature., Conclusion: WNT2B contributes to maintenance of the intestinal stem cell pool in mice and humans. WNT2B deficient mice, which do not have a developmental phenotype, show increased susceptibility to colonic injury but not small intestinal injury, potentially due to a higher reliance on WNT2B in the colon compared to the small intestine.WNT2B deficiency causes a developmental phenotype in human intestine with HIOs showing a decrease in their mesenchymal component and WNT2B-deficient patients showing epithelial disorganization., Data Transparency Statement: All RNA-Seq data will be available through online repository as indicated in Transcript profiling. Any other data will be made available upon request by emailing the study authors.

Introduction: We evaluate the incidence, outcomes, and management of peri‑umbilical hernias after sutured or sutureless gastroschisis closure., Methods: A retrospective, longitudinal follow-up of neonates with gastroschisis who underwent closure at 11 children's hospitals from 2013 to 2016 was performed. Patient encounters were reviewed through 2019 to identify the presence of a peri‑umbilical hernia, time to spontaneous closure or repair, and associated complications., Results: Of 397 patients, 375 had follow-up data. Sutured closure was performed in 305 (81.3%). A total of 310 (82.7%) infants had uncomplicated gastroschisis. Peri-umbilical hernia incidence after gastroschisis closure was 22.7% overall within a median follow-up of 2.5 years [IQR 1.3,3.9], and higher in those with uncomplicated gastroschisis who underwent primary vs. silo assisted closure (53.0% vs. 17.2%, p< 0.001). At follow-up, 50.0% of sutureless closures had a persistent hernia, while 16.4% of sutured closures had a postoperative hernia of the fascial defect (50.0% vs. 16.4%, p< 0.001). Spontaneous closure was observed in 38.8% of patients within a median of 17 months [9,26] and most frequently observed in those who underwent a sutureless primary closure (52.2%). Twenty-seven patients (31.8%) underwent operative repair within a median of 13 months [7,23.5]. Rate and interval of spontaneous closure or repair were similar between the sutured and sutureless closure groups, with no difference between those who underwent primary vs. silo assisted closure., Conclusion: Peri-umbilical hernias after sutured or sutureless gastroschisis closure may be safely observed similar to congenital umbilical hernias as spontaneous closure occurs, with minimal complications and no additional risk with either closure approach., Levels of Evidence: Level II., Competing Interests: Declarations of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction:  Gastroschisis feeding practices vary. Standardized neonatal feeding protocols have been demonstrated to improve nutritional outcomes. We report outcomes of infants with gastroschisis that were fed with and without a protocol., Materials and Methods:  A retrospective study of neonates with uncomplicated gastroschisis at 11 children's hospitals from 2013 to 2016 was performed.Outcomes of infants fed via institutional-specific protocols were compared with those fed without a protocol. Subgroup analyses of protocol use with immediate versus delayed closure and with sutured versus sutureless closure were conducted., Results:  Among 315 neonates, protocol-based feeding was utilized in 204 (65%) while no feeding protocol was used in 111 (35%). There were less surgical site infections (SSI) in those fed with a protocol (7 vs. 16%, p  = 0.019). There were no differences in TPN duration, time to initial oral intake, time to goal feeds, ventilator use, peripherally inserted central catheter line deep venous thromboses, or length of stay. Of those fed via protocol, less SSIs occurred in those who underwent sutured closure (9 vs. 19%, p  = 0.026). Further analyses based on closure timing or closure method did not demonstrate any significant differences., Conclusion:  Across this multi-institutional cohort of infants with uncomplicated gastroschisis, there were more SSIs in those fed without an institutional-based feeding protocol but no differences in other outcomes., Competing Interests: None declared., (Thieme. All rights reserved.)

Pluripotent-stem-cell-derived human intestinal organoids (HIOs) model some aspects of intestinal development and disease, but current culture methods do not fully recapitulate the diverse cell types and complex organization of the human intestine and are reliant on 3D extracellular matrix or hydrogel systems, which limit experimental control and translational potential for regenerative medicine. We describe suspension culture as a simple, low-maintenance method for culturing HIOs and for promoting in vitro differentiation of an organized serosal mesothelial layer that is similar to primary human intestinal serosal mesothelium based on single-cell RNA sequencing and histological analysis. Functionally, HIO serosal mesothelium has the capacity to differentiate into smooth-muscle-like cells and exhibits fibrinolytic activity. An inhibitor screen identifies Hedgehog and WNT signaling as regulators of human serosal mesothelial differentiation. Collectively, suspension HIOs represent a three-dimensional model to study the human serosal mesothelium., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Abstract: Infants born with congenital gastroschisis are at risk for intrauterine growth restriction, small for gestational size at birth, and growth failure during the newborn period despite advanced care. Body composition provides a more complete picture of proportional growth than weight and length alone. Fat-free mass (FFM) represents organ growth, and in preterm infants without gastroschisis, improved FFM deposition is associated with improved neurodevelopmental outcomes. There is limited literature regarding the body composition of infants with gastroschisis. This case series describes the body composition of 10 infants with gastroschisis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Introduction: This study examined problematic eating and eating-related psychopathology among young adults who underwent adolescent bariatric surgery including concurrent and prospective associations with psychosocial factors and weight change., Methods: VIEW point is a 6-year follow-up study within a prospective observational study series observing adolescents with severe obesity who had bariatric surgery ( n  = 139) or who presented to nonsurgical lifestyle modification programs ( n  = 83). Participants completed height/weight measurements, questionnaires, and diagnostic interviews. Regression analyses compared problematic eating across groups and examined Year 6 correlates (i.e., psychosocial factors and weight change) and baseline predictors (i.e., psychosocial factors) of eating-related psychopathology., Results: Compared to the nonsurgical group, the surgical group reported lower eating-related psychopathology, objective binge eating, and grazing at Year 6. While chewing/spitting out and vomiting for weight/shape-related reasons were very infrequent for the surgical group, self-induced vomiting for other reasons (e.g., avoid plugging) was more common. For the surgical group, lower self-worth, greater internalizing symptoms, and higher weight-related teasing in adolescence predicted increased eating-related psychopathology in young adulthood. Year 6 eating-related psychopathology was concurrently associated with lower percent weight loss for the surgical group and greater percent weight gain for the nonsurgical group., Conclusion: Undergoing adolescent bariatric surgery appears to afford benefit for problematic eating and eating-related psychopathology. Current findings suggest that the clinical intervention related to problematic eating and associated psychosocial concerns may be needed for young adults with obesity, regardless of surgical status., Competing Interests: Andrea B. Goldschmidt has served as a consultant for Sunovion Pharmaceuticals and has received royalties from Routledge Publishing. All other authors declare no competing interests. During the conduct of this study, the following authors report grant funding from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): Kristina M. Decker (T32‐DK063929), Carolina M. Bejarano (T32‐DK063929), Meg H. Zeller (R01DK080020), Jennifer Reiter‐Purtill (R01DK080020), Thomas H. Inge (U01DK072493, UM1DK072493, and UM1DK095710), and Todd M. Jenkins (UM1DK095710)., (© 2022 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Background: Severe fecal incontinence (FI) is common in patients both with and without anorectal malformations. Whether a formal bowel management program (BMP) has significant effects on FI, psychosocial development of the child, and caregiver stress is poorly understood. We hypothesize that BMP participation results in long-term clinical and quality of life (QOL) improvements for patients and caregivers., Methods: Using a prospective cohort study over three years, 342 children (age 3-12 years) and caregivers were followed for one year after attending a week-long BMP, during which a regimen was tailored to promote daily stool evacuation.FI QOL was measured with the validated Cincinnati Fecal Incontinence Scale (CINCY-FIS), evaluating multiple subscales, including parental stress. Scores were obtained at multiple timepoints following BMP (baseline, 2 weeks, 3 months, 1 year)., Results: Within 2 weeks, BMP participation significantly improved FI with increased frequency of daily daytime voluntary bowel movements (20%-70%, p < 0.001) and decreased daily daytime and nighttimeinvoluntary bowel movements (60%-20%, p < 0.001; 30%-10%, p < 0.05). Marked improvements in CINCY-FIS were observed across multiple QOL subscales, with the greatest in parental stress, and sustained through one year., Conclusions: BMP results in significant and sustained improvement in FI and QOL for patients and caregivers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: To provide generalizable estimates for expected outcomes of simple gastroschisis (SG) and complex gastroschisis (CG) patients from a large multi-institutional cohort for use during counseling., Study Design: A retrospective study of 394 neonates with gastroschisis at 11 children's hospitals from January 2013 to March 2017 was performed. Analysis by Fisher's exact tests and Wilcoxon rank sum tests were performed. Outcomes of complex and simple gastroschisis are reported., Result: There were 315 (80%) SG and 79 (20%) CG. CG had increased time from birth to closure (6 vs 4.4 days), closure to goal feeds (69 vs 23 days), ventilator use (90% vs 73%), SSIs (31% vs 11%), NEC (14% vs 6%), PN use (71 vs 24 days), LOS (104.5 vs 33 days), and mortality (11% vs 0%)., Conclusion: This study provides generalizable estimates for expected outcomes of patients with both SG and CG that can be utilized during counseling. CG has significantly worse in-hospital outcomes., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Cystic fibrosis is a deadly multiorgan disorder caused by loss of function mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride/bicarbonate ion channel. More than 1,700 CFTR genetic variants exist that can cause CF, and majority of these are extremely rare. Because of genetic and environmental influences, CF patients exhibit large phenotypic variation. These factors make clinical trials difficult and largely impractical due to limited and heterogeneous patient pools. Also, the benefit of approved small-molecule CF modulators in a large number of rare mutation patients remains unknown. The goal of this study is to perform a comprehensive bench-side study using in vitro patient enteroids and in vivo mice implanted human intestinal organoids (HIOs) to test CF modulator-Ivacaftor response for a rare CF mutation patient. Based on the positive Ivacaftor response in the enteroids, the patient was enrolled in a ( N = 1) clinical trial and showed improved clinical outcomes upon Ivacaftor treatment. HIO implantation model allowed in vivo modulator dosing and provided an elegant human organ-based demonstration of bench-to-bedside testing of modulator effects. Additionally, using the CF HIO model the role of CFTR function in the maturation of human intestine was reported for the first time. In all, we demonstrate that these models effectively serve to translate data from the lab to the clinic and back so that patient-specific therapies could be easily identified and disease-relevant developmental abnormalities in CF organs could be studied and addressed. NEW & NOTEWORTHY In this study, we report an example of laboratory models informing clinical care for rare CF mutation patient, with subsequent recapitulation of clinical benefit in a unique and disease relevant, human-derived in vivo model, effectively translating data from the lab to the clinic and back. This extensive work outlines a potential platform to identify patient-specific therapies and to understand relevant developmental abnormalities associated with CF disease.

The impact of immune mediators on weight homeostasis remains underdefined. Interrogation of resistance to diet-induced obesity in mice lacking a negative regulator of Toll-like receptor signaling serendipitously uncovered a role for B cell activating factor (BAFF). Here we show that overexpression of BAFF in multiple mouse models associates with protection from weight gain, approximating a log-linear dose response relation to BAFF concentrations. Gene expression analysis of BAFF-stimulated subcutaneous white adipocytes unveils upregulation of lipid metabolism pathways, with BAFF inducing white adipose tissue (WAT) lipolysis. Brown adipose tissue (BAT) from BAFF-overexpressing mice exhibits increased Ucp1 expression and BAFF promotes brown adipocyte respiration and in vivo energy expenditure. A proliferation-inducing ligand (APRIL), a BAFF homolog, similarly modulates WAT and BAT lipid handling. Genetic deletion of both BAFF and APRIL augments diet-induced obesity. Lastly, BAFF/APRIL effects are conserved in human adipocytes and higher BAFF/APRIL levels correlate with greater BMI decrease after bariatric surgery. Together, the BAFF/APRIL axis is a multifaceted immune regulator of weight gain and adipose tissue function.

Objective: To understand the nutritional intake and growth outcomes of very low birth weight infants with surgical necrotizing enterocolitis (NEC)., Study Design: In a retrospective cohort study, linear mixed models were used to compare growth outcomes from birth to 24 months corrected age for very low birth weight (VLBW) infants with surgical NEC to those with spontaneous intestinal perforation (SIP). Kaplan-Meier curves were developed to demonstrate the duration of parenteral nutrition (PN) use., Result: Height differed by surgical NEC and SIP over time (interaction p = 0.03). Surviving infants with surgical NEC had lower head circumference z-scores at 24 months. Of infants surviving surgical NEC, 71% received PN for >60 days after diagnosis., Conclusion: The majority of infants with surgical NEC have a delay in achieving enteral autonomy. There was a difference in linear catch-up growth over time between infants with SIP and surgical NEC at 24 months.

Background: Advances in untargeted metabolomic technologies have great potential for insight into adverse metabolic effects underlying exposure to environmental chemicals. However, important challenges need to be addressed, including how biological response corresponds to the environmental chemical burden in different target tissues., Aim: We performed a pilot study using state-of-the-art ultra-high-resolution mass spectrometry (UHRMS) to characterize the burden of lipophilic persistent organic pollutants (POPs) in metabolic tissues and associated alterations in the plasma metabolome., Methods: We studied 11 adolescents with severe obesity at the time of bariatric surgery. We measured 18 POPs that can act as endocrine and metabolic disruptors (i.e. 2 dioxins, 11 organochlorine compounds [OCs] and 5 polybrominated diphenyl ethers [PBDEs]) in visceral and subcutaneous abdominal adipose tissue (vAT and sAT), and liver samples using gas chromatography with UHRMS. Biological pathways were evaluated by measuring the plasma metabolome using high-resolution metabolomics. Network and pathway enrichment analysis assessed correlations between the tissue-specific burden of three frequently detected POPs (i.e. p,p'-dichlorodiphenyldichloroethene [DDE], hexachlorobenzene [HCB] and PBDE-47) and plasma metabolic pathways., Results: Concentrations of 4 OCs and 3 PBDEs were quantifiable in at least one metabolic tissue for > 80% of participants. All POPs had the highest median concentrations in adipose tissue, especially sAT, except for PBDE-154, which had comparable average concentrations across all tissues. Pathway analysis showed high correlations between tissue-specific POPs and metabolic alterations in pathways of amino acid metabolism, lipid and fatty acid metabolism, and carbohydrate metabolism., Conclusions: Most of the measured POPs appear to accumulate preferentially in adipose tissue compared to liver. Findings of plasma metabolic pathways potentially associated with tissue-specific POPs concentrations merit further investigation in larger populations., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: This prospective cohort analysis describes changes in weight, cardiometabolic health, and weight-related quality of life (WRQOL) following adolescent LAGB., Methods: Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) collected demographic, anthropometric, micronutrient, cardiometabolic risk, and WRQOL data for 242 adolescents. Data through 5 years were analyzed for 14 participants who underwent LAGB with 2 patients lost to follow-up., Results: Participants (mean age 18.2 ± 0.4 years) were mostly female (86%) and white (71%) with a median body mass index (BMI) of 48.7 kg/m 2 (45.5-54.1). Preoperatively, 100%(13/13), 62%(8/13), 57%(8/14), and 7%(1/14) had elevated high sensitivity C-reactive protein (hs-CRP), dyslipidemia, elevated blood pressure (EBP), and type 2 diabetes (T2D), respectively. At 5 years, mean BMI decreased by 3.3% (51.0 vs. 49.3 kg/m 2 , p = 0.6), 43%(6/14) had BMI values exceeding baseline and 21% (3/14) underwent band removal. Postoperative prevalence of hs-CRP, dyslipidemia, EBP, and T2D was 45% (4/11), 36% (5/11), 33% (4/12), and 0% (0/11), respectively., Conclusion: Adolescents undergoing LAGB experienced modest initial weight loss and improvements in cardiovascular risk factors with later weight regain and frequent need for band removal. Despite the small sample size, this prospective study highlights long-term outcomes with high rates of participant retention over time., Clinical Trial Registration: NCT00465829.

Over the past decade, outcomes data have demonstrated the benefit of bariatric surgery in achieving both sustained weight loss and reversal of co-morbidities. Comparing these data to contemporary known risks of adolescent bariatric surgery informs the patients and providers considering bariatric procedures and provides insight into potential ways to reduce and manage complications. The goal of this article is to review the common surgical and postoperative complications following bariatric procedures and discuss approaches to improve their safety. A systematic review identifying bariatric surgery complications in adolescents was conducted. The review focused on the data relevant to adolescent bariatric surgery. However, when necessary, adult studies were used to address the gaps in available pediatric information. The data pertaining to the intraoperative, short term, and long term surgically related and nutritional related complications show that complication are declining with increasing experience. Specific recommendations and strategies to avoid major complications of bariatric surgery in adolescents are offered., Competing Interests: Declaration of Competing Interest Nothing to be disclosed., (Copyright © 2020.)

Helicobacter pylori infection is a proven carcinogen for gastric cancer. Its virulence factor vacuolating cytotoxin A (VacA) promotes more severe disease and gastric colonization. VacA, by an unknown mechanism, usurps lysosomal and autophagy pathways to generate a protected reservoir for H. pylori that confers bacterial survival in vitro. Here, we show the existence of a VacA-generated intracellular niche in vivo that protects the bacteria from antibiotic treatment and leads to infection recrudescence after therapy. Furthermore, we report that VacA targets the lysosomal calcium channel TRPML1 to disrupt endolysosomal trafficking and mediate these effects. Remarkably, H. pylori that lack toxigenic VacA colonize enlarged dysfunctional lysosomes in the gastric epithelium of trpml1-null mice, where they are protected from eradication therapy. Furthermore, a small molecule agonist directed against TRPML1 reversed the toxic effects of VacA on endolysosomal trafficking, culminating in the clearance of intracellular bacteria. These results suggest that TRPML1 may represent a therapeutic target for chronic H. pylori infection.

Clostridium difficile impairs Paneth cells, driving intestinal inflammation that exaggerates colitis. Besides secreting bactericidal products to restrain C. difficile , Paneth cells act as guardians that constitute a niche for intestinal epithelial stem cell (IESC) regeneration. However, how IESCs are sustained to specify Paneth-like cells as their niche remains unclear. Cytokine-JAK-STATs are required for IESC regeneration. We investigated how constitutive STAT5 activation (Ca-pYSTAT5) restricts IESC differentiation towards niche cells to restrain C. difficile infection. We generated inducible transgenic mice and organoids to determine the effects of Ca-pYSTAT5-induced IESC lineages on C. difficile colitis. We found that STAT5 absence reduced Paneth cells and predisposed mice to C. difficile ileocolitis. In contrast, Ca-pYSTAT5 enhanced Paneth cell lineage tracing and restricted Lgr5 IESC differentiation towards pYSTAT5 + Lgr5 - CD24 + Lyso + or cKit + niche cells, which imprinted Lgr5 hi Ki67 + IESCs. Mechanistically, pYSTAT5 activated Wnt/β-catenin signaling to determine Paneth cell fate. In conclusion, Ca-pYSTAT5 gradients control niche differentiation. Lack of pYSTAT5 reduces the niche cells to sustain IESC regeneration and induces C. difficile ileocolitis. STAT5 may be a transcription factor that regulates Paneth cells to maintain niche regeneration., (© 2019 Liu et al.)

Human intestinal organoids (HIOs) represent a powerful system to study human development and are promising candidates for clinical translation as drug-screening tools or engineered tissue. Experimental control and clinical use of HIOs is limited by growth in expensive and poorly defined tumor-cell-derived extracellular matrices, prompting investigation of synthetic ECM-mimetics for HIO culture. Since HIOs possess an inner epithelium and outer mesenchyme, we hypothesized that adhesive cues provided by the matrix may be dispensable for HIO culture. Here, we demonstrate that alginate, a minimally supportive hydrogel with no inherent cell instructive properties, supports HIO growth in vitro and leads to HIO epithelial differentiation that is virtually indistinguishable from Matrigel-grown HIOs. In addition, alginate-grown HIOs mature to a similar degree as Matrigel-grown HIOs when transplanted in vivo, both resembling human fetal intestine. This work demonstrates that purely mechanical support from a simple-to-use and inexpensive hydrogel is sufficient to promote HIO survival and development., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Helicobacter pylori (H. pylori) is the major risk factor for the development of gastric cancer. Our laboratory has reported that the Sonic Hedgehog (Shh) signaling pathway is an early response to infection that is fundamental to the initiation of H. pylori-induced gastritis. H. pylori also induces programmed death ligand 1 (PD-L1) expression on gastric epithelial cells, yet the mechanism is unknown. We hypothesize that H. pylori-induced PD-L1 expression within the gastric epithelium is mediated by the Shh signaling pathway during infection. To identify the role of Shh signaling as a mediator of H. pylori-induced PD-L1 expression, human gastric organoids generated from either induced pluripotent stem cells (HGOs) or tissue (huFGOs) were microinjected with bacteria and treated with Hedgehog/Gli inhibitor GANT61. Gastric epithelial monolayers generated from the huFGOs were also infected with H. pylori and treated with GANT61 to study the role of Hedgehog signaling as a mediator of induced PD-1 expression. A patient-derived organoid/autologous immune cell co-culture system infected with H. pylori and treated with PD-1 inhibitor (PD-1Inh) was developed to study the protective mechanism of PD-L1 in response to bacterial infection. H. pylori significantly increased PD-L1 expression in organoid cultures 48 hours post-infection when compared to uninfected controls. The mechanism was cytotoxic associated gene A (CagA) dependent. This response was blocked by pretreatment with GANT61. Anti-PD-L1 treatment of H. pylori infected huFGOs, co-cultured with autologous patient cytotoxic T lymphocytes and dendritic cells, induced organoid death. H. pylori-induced PD-L1 expression is mediated by the Shh signaling pathway within the gastric epithelium. Cells infected with H. pylori that express PD-L1 may be protected from the immune response, creating premalignant lesions progressing to gastric cancer., Competing Interests: The authors have declared that no competing interests exist.

Background & Aims: Our goal was to develop an initial study for the proof of concept whereby gastric cancer organoids are used as an approach to predict the tumor response in individual patients., Methods: Organoids were derived from resected gastric cancer tumors (huTGOs) or normal stomach tissue collected from sleeve gastrectomies (huFGOs). Organoid cultures were treated with standard-of-care chemotherapeutic drugs corresponding to patient treatment: epirubicin, oxaliplatin, and 5-fluorouracil. Organoid response to chemotherapeutic treatment was correlated with the tumor response in each patient from whom the huTGOs were derived. HuTGOs were orthotopically transplanted into the gastric mucosa of NOD scid gamma mice., Results: Whereas huFGOs exhibited a half maximal inhibitory concentration that was similar among organoid lines, divergent responses and varying half maximal inhibitory concentration values among the huTGO lines were observed in response to chemotherapeutic drugs. HuTGOs that were sensitive to treatment were derived from a patient with a near complete tumor response to chemotherapy. However, organoids resistant to treatment were derived from patients who exhibited no response to chemotherapy. Orthotropic transplantation of organoids resulted in the engraftment and development of human adenocarcinoma. RNA sequencing revealed that huTGOs closely resembled the patient's native tumor tissue and not commonly used gastric cancer cell lines and cell lines derived from the organoid cultures., Conclusions: The treatment of patient-derived organoids alongside patients from whom cultures were derived will ultimately test their usefulness to predict individual therapy response and patient outcome., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Altered response to the intestinal microbiota strongly associates with inflammatory bowel disease (IBD); however, how commensal microbial cues are integrated by the host during the pathogenesis of IBD is not understood. Epigenetics represents a potential mechanism that could enable intestinal microbes to modulate transcriptional output during the development of IBD. Here, we reveal a histone methylation signature of intestinal epithelial cells isolated from the terminal ilea of newly diagnosed pediatric IBD patients. Genes characterized by significant alterations in histone H3-lysine 4 trimethylation (H3K4me3) showed differential enrichment in pathways involving immunoregulation, cell survival and signaling, and metabolism. Interestingly, a large subset of these genes was epigenetically regulated by microbiota in mice and several microbiota-sensitive epigenetic targets demonstrated altered expression in IBD patients. Remarkably though, a substantial proportion of these genes exhibited H3K4me3 levels that correlated with the severity of intestinal inflammation in IBD, despite lacking significant differential expression. Collectively, these data uncover a previously unrecognized epigenetic profile of IBD that can be primed by commensal microbes and indicate sensitive targets in the epithelium that may underlie how microbiota predispose to subsequent intestinal inflammation and disease.

Background: Factors contributing to adolescents' non-completion of bariatric surgery, defined as self-withdrawal during the preoperative phase of care, independent of program or insurance denial, are largely unknown. Recent adolescent and adult bariatric surgery literature indicate that psychological factors and treatment withdrawal play a role; however, for adolescents, additional age-salient (family/caregiver) variables might also influence progression to surgery., Objectives: The present study examined demographic, psychological, and family/caregiver variables as predictors of whether adolescents completed surgery ("completers") or withdrew from treatment ("non-completers")., Setting: Adolescents were from a bariatric surgery program within a pediatric tertiary care hospital., Methods: A retrospective chart review was conducted of consecutive patients who completed bariatric surgery psychological intake evaluations from September 2009 to April 2013. Data involving completer (n = 61) versus non-completer (n = 65) status were analyzed using two-tailed independent t tests, Chi-squared tests, and logistic regressions., Results: Forty-three percent of adolescents completed surgery, similar to adult bariatric samples. Significantly more males were non-completers (p < .05), and there was a trend towards non-completion for older adolescents (p = 0.06). No other demographic, psychological, or caregiver/family variables were significant predictors of non-completion., Conclusions: These findings indicate that demographic variables, rather than psychological or family factors, were associated with the progression to or withdrawal from surgery. Further assessment is needed to determine specific reasons for completing or withdrawing from treatment, particularly for males and older adolescents, to improve clinical care and reduce attrition.

Background/purpose: Fecal incontinence is a prevalent pediatric condition with psychosocial impacts on both children and their caregivers. We sought to develop and validate the Cincinnati Fecal Incontinence Scale (CINCY-FIS) as a psychometrically valid measure to assess the quality of life and caregiver impacts of pediatric fecal incontinence., Methods: Items were generated through review of previous measures, expert consensus, and pilot testing with feedback from 8 families. Initial study measures were completed by 222 caregivers. Following item reduction, 18 items were subjected to confirmatory factor analysis. Convergent and criterion validity were assessed using correlation. Reliability was established using internal consistency statistics and test-retest reliability at baseline and 2-week follow-up., Results: A five factor first-order structure with two higher-order factors demonstrated acceptable fit to the data, was consistent with a priori hypotheses, and was more parsimonious than the alternative model. Convergent validity and criterion-related validity were established for all of the CINCY-FIS scales. Reliability was high and consistent across both measurement occasions., Conclusions: The CINCY-FIS is a reliable and valid assessment of pediatric fecal incontinence-specific quality of life and parenting stress. The score is highly sensitive to patient changes making it suitable for both clinical and research purposes., Type of Study: Prospective observational., Level of Evidence: Study of Diagnostic Test Level II., (Copyright © 2018. Published by Elsevier Inc.)

Background and Objectives: Severely obese adolescents harbor numerous cardiovascular disease risk factors (CVD-RFs), which improve after metabolic and bariatric surgery (MBS). However, predictors of change in CVD-RFs among adolescents have not yet been reported., Methods: The Teen-Longitudinal Assessment of Bariatric Surgery study (NCT00474318) prospectively collected anthropometric and health status data on 242 adolescents undergoing MBS at 5 centers. Predictors of change in CVD-RFs (blood pressure, lipids, glucose homeostasis, and inflammation) 3 years after Roux-en-Y gastric bypass and vertical sleeve gastrectomy were examined., Results: The mean (±SD) age of participants at baseline was 17 ± 1.6 years; 76% were girls, and 72% were white, with a median BMI of 51. Participants underwent Roux-en-Y gastric bypass ( n = 161), vertical sleeve gastrectomy ( n = 67), or adjustable gastric banding ( n = 14). Increasing weight loss was an independent predictor of normalization in dyslipidemia, elevated blood pressure (EBP), hyperinsulinemia, diabetes, and elevated high-sensitivity C-reactive protein. Older participants at time of surgery were less likely to resolve dyslipidemia compared with younger participants, whereas girls were more likely than boys to demonstrate improvements in EBP. Even those participants without frank dyslipidemia or EBP at baseline showed significant improvements in lipid and blood pressure values over time., Conclusions: Numerous CVD-RFs improve among adolescents undergoing MBS. Increased weight loss, female sex, and younger age predict a higher probability of resolution of specific CVD-RFs. The elucidation of predictors of change in CVD-RFs may lead to refinements in patient selection and optimal timing of adolescent bariatric surgery designed to improve clinical outcomes., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Inge serves as a consultant for Standard Bariatrics, UpToDate Inc, and Independent Medical Expert Consulting Services, all of which are unrelated to this project. Dr Harmon served on an advisory panel for the Stryker Corporation from 1998 to 2015, which was unrelated to this project. Dr Dixon has consulted for Apollo Endosurgery, Medtronic Minimally Invasive Therapies (formerly Covidien), Bariatric Advantage, Nestle Health Science, Inova, and Novo Nordisk; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Cystic fibrosis (CF) is a genetic disorder in which epithelium-generated fluid flow from the lung, intestine, and pancreas is impaired due to mutations disrupting CF transmembrane conductance regulator (CFTR) channel function. CF manifestations of the pancreas and lung are present in the vast majority of CF patients, and 15% of CF infants are born with obstructed gut or meconium ileus. However, constipation is a significantly underreported outcome of CF disease, affecting 47% of the CF patients, and management becomes critical in the wake of increasing life span of CF patients. In this study, we unraveled a potentially novel molecular role of a membrane-bound cyclic guanosine monophosphate-synthesizing (cGMP-synthesizing) intestinal enzyme, guanylate cyclase 2C (GCC) that could be targeted to ameliorate CF-associated intestinal fluid deficit. We demonstrated that GCC agonism results in functional rescue of murine F508del/F508del and R117H/R117H Cftr and CFTR mutants in CF patient-derived intestinal spheres. GCC coexpression and activation facilitated processing and ER exit of F508del CFTR and presented a potentially novel rescue modality in the intestine, similar to the CF corrector VX-809. Our findings identify GCC as a biological CFTR corrector and potentiator in the intestine.

Background: Multicenter clinical research studies in pediatric surgery have been largely limited to relatively small case-series and retrospective reviews because of the rarity of many of the diseases we treat and difficulty coordinating and executing multi-institutional studies. Creation of a collaborative research network can provide the needed patient population and infrastructure to perform high quality multi-institutional studies., Methods: In 2013, eleven academic pediatric surgery centers within the United States formed a research consortium to develop and conduct multicenter clinical research projects to advance the practice of pediatric surgery., Results: We present our process for creating, developing, and maintaining this consortium including initial regional geographic limitation, charter development with by-laws and procedures for adopting studies, and research infrastructure including a central website for study monitoring and central reliance institutional review board process., Conclusion: Our model could be reproduced or adapted by other institutions to develop or strengthen other research collaboratives., Level of Evidence: Type of study: retrospective, IV., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A self-organizing organoid model provides a new approach to study the mechanism of human liver organogenesis. Previous animal models documented that simultaneous paracrine signaling and cell-to-cell surface contact regulate hepatocyte differentiation. To dissect the relative contributions of the paracrine effects, we first established a liver organoid using human induced pluripotent stem cells (iPSCs), mesenchymal stem cells (MSCs) and human umbilical vein endothelial cells (HUVECs) as previously reported. Time-lapse imaging showed that hepatic-specified endoderm iPSCs (HE-iPSCs) self-assembled into three-dimensional organoids, resulting in hepatic gene induction. Progressive differentiation was demonstrated by hepatic protein production after in vivo organoid transplantation. To assess the paracrine contributions, we employed a Transwell system in which HE-iPSCs were separately co-cultured with MSCs and/or HUVECs. Although the three-dimensional structure did not form, their soluble factors induced a hepatocyte-like phenotype in HE-iPSCs, resulting in the expression of bile salt export pump. In conclusion, the mesoderm-derived paracrine signals promote hepatocyte maturation in liver organoids, but organoid self-organization requires cell-to-cell surface contact. Our in vitro model demonstrates a novel approach to identify developmental paracrine signals regulating the differentiation of human hepatocytes., (© 2017. Published by The Company of Biologists Ltd.)

Objective: The aim of the present study was to describe the quality of life and parenting stress associated with a child with fecal incontinence (FI)., Methods: Female caregivers (n = 170) of children of 3 to 12 years age with FI completed a broad and general measure of quality of life and a measure of parenting stress. Results were compared with proxy reports for a normative sample of healthy children., Results: Caregivers of children with FI reported significantly impaired quality of life for their children and increased parenting stress in all of the respective domains relative to healthy controls. Impairments reported by caregivers were large in magnitude. Similarly, rates of parenting stress were at or greater than the 98th percentile for caregivers of children with FI., Conclusions: Children with fecal incontinence and their families are in need of interventions targeting their quality of life and the stress associated with caregiving. FI appears to be particularly stressful for caregivers who may be in need of support beyond medical management of their child's bowel. Moreover, additional refinements in disease-specific quality of life assessment are needed in this population. Such refinement would allow for more precise measurement of the quality of life processes that are unique to FI.

Intestinal adaptation to small-bowel resection (SBR) after necrotizing enterocolitis expands absorptive surface areas and promotes enteral autonomy. Survivin increases proliferation and blunts apoptosis. The current study examines survivin in intestinal epithelial cells after ileocecal resection. Wild-type and epithelial Pik3r1 (p85α)-deficient mice underwent sham surgery or 30% resection. RNA and protein were isolated from small bowel to determine levels of β-catenin target gene expression, activated caspase-3, survivin, p85α, and Trp53. Healthy and post-resection human infant small-bowel sections were analyzed for survivin, Ki-67, and TP53 by immunohistochemistry. Five days after ileocecal resection, epithelial levels of survivin increased relative to sham-operated on mice, which correlated with reduced cleaved caspase-3, p85α, and Trp53. At baseline, p85α-deficient intestinal epithelial cells had less Trp53 and more survivin, and relative responses to resection were blunted compared with wild-type. In infant small bowel, survivin in transit amplifying cells increased 71% after SBR. Resection increased proliferation and decreased numbers of TP53-positive epithelial cells. Data suggest that ileocecal resection reduces p85α, which lowers TP53 activation and releases survivin promoter repression. The subsequent increase in survivin among transit amplifying cells promotes epithelial cell proliferation and lengthens crypts. These findings suggest that SBR reduces p85α and TP53, which increases survivin and intestinal epithelial cell expansion during therapeutic adaptation in patients with short bowel syndrome., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Importance: Obesity is associated with chronic musculoskeletal pain and is a risk factor for disability and osteoarthritis., Objectives: To describe the prevalence, sites, and intensity of musculoskeletal pain in adolescents with severe obesity; to evaluate associations between musculoskeletal pain and self-reported physical function as well as weight-related quality of life; and to evaluate the association between musculoskeletal pain and high-sensitivity C-reactive protein level., Design, Setting, and Participants: Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) is a prospective, observational study that collects standardized data on adolescents undergoing weight loss surgery at 5 US centers. We examined baseline data from this cohort between February 28, 2007, and December 30, 2011. We excluded adolescents with Blount disease and slipped capital femoral epiphyses. A total of 233 participants were included in these analyses., Main Outcomes and Measures: We assessed musculoskeletal pain and pain intensity of the lower back, hips, knees, and ankles/feet using the visual analog scale, categorizing musculoskeletal pain into lower back pain, lower extremity (hips, knees, and feet/ankles combined) pain, and no pain. We assessed self-reported physical function status with the Health Assessment Questionnaire Disability Index and assessed weight-related quality of life with the Impact of Weight on Quality of Life-Kids measure. We adjusted for sex, race, age at surgery, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and clinical depressive symptoms in regression analyses., Results: Among the 233 participants, the mean (SD) age at surgery was 17.1 (1.56) years and the median BMI was 50.4. Participants were predominantly female (77%), white (73%), and non-Hispanic (93%). Among the participants, 49% had poor functional status and 76% had musculoskeletal pain. Lower back pain was prevalent (63%), followed by ankle/foot (53%), knee (49%), and hip (31%) pain; 26% had pain at all 4 sites. In adjusted analyses, compared with pain-free participants, those reporting lower extremity pain had greater odds of having poor physical function according to scores on the Health Assessment Questionnaire Disability Index (odds ratio = 2.82; 95% CI, 1.35 to 5.88; P < .01). Compared with pain-free participants, those reporting lower extremity pain had significantly lower Impact of Weight on Quality of Life-Kids total scores (β = -9.42; 95% CI, -14.15 to -4.69; P < .01) and physical comfort scores (β = -17.29; 95% CI, -23.32 to -11.25; P < .01). After adjustment, no significant relationship was observed between musculoskeletal pain and high-sensitivity C-reactive protein level., Conclusions and Relevance: Adolescents with severe obesity have musculoskeletal pain that limits their physical function and quality of life. Longitudinal follow-up will reveal whether weight loss surgery reverses pain and physical functional limitations and improves quality of life.

Importance: Severe obesity is increasingly common in the adolescent population but, as of yet, very little information exists regarding cardiovascular disease (CVD) risks in this group., Objective: To assess the baseline prevalence and predictors of CVD risks among severely obese adolescents undergoing weight-loss surgery., Design, Setting, and Participants: A prospective cohort study was conducted from February 28, 2007, to December 30, 2011, at the following 5 adolescent weight-loss surgery centers in the United States: Nationwide Children's Hospital in Columbus, Ohio; Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio; Texas Children's Hospital in Houston; University of Pittsburgh Medical Center in Pittsburgh, Pennsylvania; and Children's Hospital of Alabama in Birmingham. Consecutive patients aged 19 years or younger were offered enrollment in a long-term outcome study; the final analysis cohort consisted of 242 participants., Main Outcomes and Measures: This report examined the preoperative prevalence of CVD risk factors (ie, fasting hyperinsulinemia, elevated high-sensitivity C-reactive protein levels, impaired fasting glucose levels, dyslipidemia, elevated blood pressure, and diabetes mellitus) and associations between risk factors and body mass index (calculated as weight in kilograms divided by height in meters squared), age, sex, and race/ethnicity. Preoperative data were collected within 30 days preceding bariatric surgery., Results: The mean (SD) age was 17 (1.6) years and median body mass index was 50.5. Cardiovascular disease risk factor prevalence was fasting hyperinsulinemia (74%), elevated high-sensitivity C-reactive protein levels (75%), dyslipidemia (50%), elevated blood pressure (49%), impaired fasting glucose levels (26%), and diabetes mellitus (14%). The risk of impaired fasting glucose levels, elevated blood pressure, and elevated high-sensitivity C-reactive protein levels increased by 15%, 10%, and 6%, respectively, per 5-unit increase in body mass index (P < .01). Dyslipidemia (adjusted relative risk = 1.60 [95% CI, 1.26-2.03]; P < .01) and elevated blood pressure (adjusted relative risk = 1.48 [95% CI, 1.16-1.89]; P < .01) were more likely in adolescent boys compared with adolescent girls. White individuals were at greater risk of having elevated triglyceride levels (adjusted relative risk = 1.76 [95% CI, 1.14-2.72]; P = .01) but were less likely to have impaired fasting glucose levels (adjusted relative risk = 0.58 [95% CI, 0.38-0.89]; P = .01)., Conclusions and Relevance: Numerous CVD risk factors are apparent in adolescents undergoing weight-loss surgery. Increasing body mass index and male sex increase the relative risk of specific CVD risk factors. These data suggest that even among severely obese adolescents, recognition and treatment of CVD risk factors is important to help limit further progression of disease.

Objectives: To assess links between comorbid health status, severe excess weight, and weight-related quality of life (WRQOL) in adolescents with severe obesity and undergoing weight-loss surgery (WLS) to inform clinical care., Study Design: Baseline (preoperative) data from Teen Longitudinal Assessment of Bariatric Surgery, a prospective multicenter observational study of 242 adolescents with severe obesity (MedianBMI = 50.5 kg/m(2); Meanage = 17.1; 75.6% female; 71.9% white) undergoing WLS, were used to examine the impact of demographics, body mass index (BMI), presence/absence of 16 comorbid conditions, and a cumulative comorbidity load (CLoad) index on WRQOL scores (Impact of Weight on Quality of Life-Kids)., Results: WRQOL was significantly lower than reference samples of healthy weight, overweight, and obese samples. Of 16 comorbid conditions, the most prevalent were dyslipidemia (74.4%), chronic pain (58.3%), and obstructive sleep apnea (56.6%). Male subjects had a greater CLoad (P = .01) and BMI (P = .01), yet less impairment in total WRQOL (P < .01) than females. CLoad was a significant predictor of male WRQOL. For females, psychosocial (vs physical) comorbidities, BMI, and white race were significant predictors of WRQOL impairment. Less prevalent conditions (eg, stress urinary incontinence) also emerged as contributors to lower WRQOL., Conclusions: WRQOL impairment is substantial for adolescents with severe obesity undergoing WLS, with predictors varying by sex. These patient-data highlight targets for education, support, and adjunctive care referrals before WLS. Furthermore, they provide a comprehensive empirical base for understanding heterogeneity in adolescent WRQOL outcomes after WLS, as weight and comorbidity profiles change over time., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Intestinal epithelial stem cells (IESCs) control the intestinal homeostatic response to inflammation and regeneration. The underlying mechanisms are unclear. Cytokine-STAT5 signaling regulates intestinal epithelial homeostasis and responses to injury. We link STAT5 signaling to IESC replenishment upon injury by depletion or activation of Stat5 transcription factor. We found that depletion of Stat5 led to deregulation of IESC marker expression and decreased LGR5(+) IESC proliferation. STAT5-deficient mice exhibited worse intestinal histology and impaired crypt regeneration after γ-irradiation. We generated a transgenic mouse model with inducible expression of constitutively active Stat5. In contrast to Stat5 depletion, activation of STAT5 increased IESC proliferation, accelerated crypt regeneration, and conferred resistance to intestinal injury. Furthermore, ectopic activation of STAT5 in mouse or human stem cells promoted LGR5(+) IESC self-renewal. Accordingly, STAT5 promotes IESC proliferation and regeneration to mitigate intestinal inflammation. STAT5 is a functional therapeutic target to improve the IESC regenerative response to gut injury., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Adolescents seeking weight loss surgery (WLS) frequently encounter obstacles obtaining treatment authorization from insurance carriers. This study identified factors influencing authorization for adolescents with clinical indications for WLS., Methods: A retrospective review was conducted for adolescents with clinical indications for WLS at five adolescent centers. This cohort represented a consecutive series of adolescents with insurance benefits for WLS for whom insurance authorization was sought between 2009 and 2011. Outcomes included number and timing of insurance authorizations for surgery, denials, and appeals., Results: Records from 57 adolescents (74% female; mean age 16 (range: 12-17) years; mean BMI 51.3 kg/m(2) ) were reviewed. Of these, only 47% were approved with the original request. Eighty percent of those denied were approved on appeal, while 11% never obtained authorization for surgery. Age less than 18 years and proposed procedure were the most common reasons for denial., Conclusions: Less than half of adolescents with clinical indications for surgery received approval for the procedure on the first request. The appeal process typically resulted in overturning of denials, so that surgical care could be delivered., (© 2014 The Obesity Society.)

The number of adolescents undergoing weight loss surgery (WLS) has increased in response to the increasing prevalence of severe childhood obesity. Adolescents undergoing WLS require unique support, which may differ from adult programs. The aim of this study was to describe institutional and programmatic characteristics of centers participating in Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS), a prospective study investigating safety and efficacy of adolescent WLS. Data were obtained from the Teen-LABS database, and site survey completed by Teen-LABS investigators. The survey queried (1) institutional characteristics, (2) multidisciplinary team composition, (3) clinical program characteristics, and (4) clinical research infrastructure. All centers had extensive multidisciplinary involvement in the assessment, pre-operative education, and post-operative management of adolescents undergoing WLS. Eligibility criteria and pre-operative clinical and diagnostic evaluations were similar between programs. All programs have well-developed clinical research infrastructure, use adolescent-specific educational resources, and maintain specialty equipment, including high weight capacity diagnostic imaging equipment. The composition of clinical team and institutional resources is consistent with current clinical practice guidelines. These characteristics, coupled with dedicated research staff, have facilitated enrollment of 242 participants into Teen-LABS., (© 2013 Published by Elsevier Inc.)