615 results on '"Melvin B. Heyman"'
Search Results
2. Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response
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Yael Haberman, Rebekah Karns, Phillip J. Dexheimer, Melanie Schirmer, Judith Somekh, Ingrid Jurickova, Tzipi Braun, Elizabeth Novak, Laura Bauman, Margaret H. Collins, Angela Mo, Michael J. Rosen, Erin Bonkowski, Nathan Gotman, Alison Marquis, Mason Nistel, Paul A. Rufo, Susan S. Baker, Cary G. Sauer, James Markowitz, Marian D. Pfefferkorn, Joel R. Rosh, Brendan M. Boyle, David R. Mack, Robert N. Baldassano, Sapana Shah, Neal S. Leleiko, Melvin B. Heyman, Anne M. Grifiths, Ashish S. Patel, Joshua D. Noe, Bruce J. Aronow, Subra Kugathasan, Thomas D. Walters, Greg Gibson, Sonia Davis Thomas, Kevin Mollen, Shai Shen-Orr, Curtis Huttenhower, Ramnik J. Xavier, Jeffrey S. Hyams, and Lee A. Denson
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Science - Abstract
The severity of ulcerative colitis, and response to treatment, is highly variable. Here, the authors examine rectal gene expression signatures and faecal microbiomes of children and adults with the disease and provide new insights in to pathogenesis.
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- 2019
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3. Evaluating the Relationship Between Nutrition and Post-colectomy Pouchitis in Pediatric Patients with Ulcerative Colitis
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Perseus V. Patel, Emily Kao, Emily Stekol, Melvin B. Heyman, Lan Vu, and Sofia G. Verstraete
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Physiology ,Gastroenterology - Published
- 2023
4. Pediatric Medical Traumatic Stress in Inflammatory Bowel Disease, Pancreatitis, and Cystic Fibrosis
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Addison A. Cuneo, Maisam Abu-El-Haija, Meghan L. Marsac, Sofia Verstraete, Melvin B. Heyman, Ngoc Ly, and Emily R. Perito
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Pediatrics, Perinatology and Child Health ,Gastroenterology - Published
- 2022
5. Health-Related Quality of Life in Pediatric Acute Recurrent or Chronic Pancreatitis: Association With Biopsychosocial Risk Factors
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See Wan Tham, Fuchenchu Wang, Cheryl E. Gariepy, Gretchen A. Cress, Maisam A. Abu-El-Haija, Melena D. Bellin, Kate M. Ellery, Douglas S. Fishman, Tanja Gonska, Melvin B. Heyman, Tom K. Lin, Asim Maqbool, Brian A. McFerron, Veronique D. Morinville, Jaimie D. Nathan, Chee Y. Ooi, Emily R. Perito, Sarah Jane Schwarzenberg, Zachary M. Sellers, Uzma Shah, David M. Troendle, Michael Wilschanski, Yuhua Zheng, Ying Yuan, Mark E. Lowe, Aliye Uc, and Tonya M. Palermo
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Male ,Recurrence ,Risk Factors ,Pancreatitis, Chronic ,Pediatrics, Perinatology and Child Health ,Gastroenterology ,Quality of Life ,Humans ,Female ,Child ,Article ,Abdominal Pain - Abstract
OBJECTIVES: Abdominal pain, emergency department visits and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). However, data on health-related quality of life (HRQOL) in this population remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL. METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment. RESULTS: The sample included 368 children (54.3% females, mean age = 12.7 years, SD = 3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (M = 38.5, SD = 16.0) was demonstrated while psychosocial HRQOL (M = 49.5, SD = 10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (B =−10.28, p < .001), episodic and constant abdominal pain (B =−4.66, p =.03; B =−13.25, p
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- 2023
6. Medical traumatic stress in cystic fibrosis: A qualitative analysis
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Addison A. Cuneo, Simon Outram, Meghan L. Marsac, Siena Vendlinski, Melvin B. Heyman, Ngoc Ly, Emily von Scheven, and Emily R. Perito
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Pulmonary and Respiratory Medicine ,Pediatrics, Perinatology and Child Health - Published
- 2023
7. Personalised azithromycin+metronidazole (PAZAZ), in combination with standard induction therapy, to achieve a faecal microbiome community structure and metagenome changes associated with sustained remission in paediatric Crohn's disease (CD):protocol of a pilot study
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Charlotte M Verburgt, Katherine A Dunn, Anthony Otley, Melvin B Heyman, Sofia Verstraete, Withney Sunseri, Francisco Sylvester, Tim de Meij, Andre Comeau, Morgan Langille, Wouter J de Jonge, Marc A Benninga, Johan E Van Limbergen, Pediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Reproduction & Development (AR&D), Graduate School, Tytgat Institute for Liver and Intestinal Research, Gastroenterology and Hepatology, AII - Inflammatory diseases, Paediatric Gastroenterology, APH - Digital Health, and APH - Health Behaviors & Chronic Diseases
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clinical trials ,inflammatory bowel disease ,microbiology ,General Medicine ,paediatric gastroenterology - Abstract
IntroductionEarly relapse in Crohn’s disease (CD) is associated with a more severe disease course. The microbiome plays a crucial role, yet strategies targeting the microbiome are underrepresented in current guidelines. We hypothesise that early manipulation of the microbiome will improve clinical response to standard-of-care (SOC) induction therapy in patients with a relapse-associated microbiome profile. We describe the protocol of a pilot study assessing feasibility of treatment allocation based on baseline faecal microbiome profiles.Methods and analysisThis is a 52-week, multicentre, randomised, controlled, open-label, add-on pilot study to test the feasibility of a larger multicontinent trial evaluating the efficacy of adjuvant antibiotic therapy in 20 paediatric patients with mild-to-moderate-CD (10Ethics and disseminationThis study was approved by METC-AMC and CCMO (Netherlands) and IWK Health Centre (Canada). The first version of this protocol was approved by North Carolina Children’s Hospital (USA), Wolfson Medical Centre (Israel). The FDA (USA), Health Canada and Ministry of Health (Israel) have reviewed and approved the protocol. Results will be published in international peer-reviewed journals and summaries will be provided to the funders and participants.Trial registration numberNCT04186247.
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- 2023
8. Diagnosis and treatment of exocrine pancreatic insufficiency in chronic pancreatitis: An international expert survey and case vignette study
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Florence E.M. de Rijk, Charlotte L. van Veldhuisen, Marc G. Besselink, Jeanin E. van Hooft, Hjalmar C. van Santvoort, Erwin J.M. van Geenen, Peter Hegyi, J-Matthias Löhr, Juan E. Dominguez-Munoz, Pieter Jan F. de Jonge, Marco J. Bruno, Robert C. Verdonk, Massimo Falconi, Wen-Bin Zou, Trond Engjom, Chee Y. Ooi, Robert Sutton, Luca Frulloni, John Neoptolemos, Charles Wilcox, Vujasinovic Miroslav, Guru Trikudanathan, Zhuan Liao, Truls Hauge, Joachim Mössner, Chantal Hoge, Paul Fockens, Sven Mieog, Gabriele Capurso, Yunfeng Cui, Enrique de Madaria, Marius Distler, Ali Aghdassi, David C. Whitcomb, Kylie Russell, Georg Beyer, Lumír Kunovsky, Wilhelmus Kwanten, Andrea Kazemi Nava, Kevin Conlon, A.K. Siriwardena, Salvatore Paiella, Felipe Alconchel, Marco Vito Marino, Vincent E. de Meijer, Carlos Domingo, Jorg Kleeff, Aarti Lakshmanan, Michael Jen Lie Chu, Stefan Bouwense, Pueya Rashid Nashidengo, Perivoliotis Konstantinos, Edoardo Maria Muttillo, Garzali Ibrahim Umar, Maria Jesus Castro Santiago, Victor Lopez-Lopez, Francesco Torri, Moritz Schmelzle, Povilas Ignatavicius, Dennis Wicherts, Antonio Gomes, Nikolaos A. Machairas, Panagiotis I. Dorovinis, Alejandro Serrablo, Kjetil Soreide, Mohammad Rahbari, Michael Jen Jie Chu, Margarita Ptasnuka, Marius Petrulionis, Colin Byron Noel, Ernest Castro, Marcello Di Martino, Alfonso Recordare, Stefan Stättner, Fabio Ausania, Vera Hartman, Geert Roeyen, Viacheslav Egorov, Tomas Vanagas, Mohamed Ebrahim, Elena Arabadzhieva, Giuseppe Malleo, Liang Li, David Adams, Grzegorz Oracz, Reddy D. Nageshwar, Alexander Waldthaler, Atsushi Masamune, Asbjorn Mohr Drewes, Antonio Amodio, Temel Tirkes, Anshu Srivastava, Gregory J. Beilman, Zoltan Berger, Bjorn Lindkvist, Giulia Martina Cavestro, Cheryl Gariepy, Laszlo Czakó, Milena Di Leo, Vishal Sharma, Sundeep Lakhtakia, Surinder Singh Rana, Sinaed N. Duggan, Chang-Il Kwon, Anna Evans Phillips, Christopher E. Forsmark, Ferga C. Gleeson, Glen A. Lehman, William Greenhalf, Guido Costamagna, Christopher M. Halloran, Helmut Friess, Henrik Hojgaard Rasmussen, Tsukasa Ikeura, Ingfrid S. Haldorsen, Takao Itoi, Jacob R. Izbicki, John Windsor, Jakob Lykke Poulsen, Jens Brondum Frokjaer, Jose Larino-Noia, Dan Wang, Julio Iglesias Garcia, Evangelos Kalaitzakis, Kararzyna Wertheim-Tysarowska, Kensuke Kubota, Jessica Larusch, Markus M. Lerch, Liang-Hao Hu, Mert Erkan, Jorg D. Machicado, Marianna Arvanitakis, Markus W. Buchler, Marlon F. Levy, Melvin B. Heyman, Camilla Nojgaard, Mouen A. Khashab, Myriam Delhaye, Takeshi Ogura, Kazuichi Okazaki, Paula Ghaneh, Peter A. Banks, Pankaj Gupta, Georgios I. Papachristou, Patrick Michl, Philippe Levy, Aldis Pukitis, Raffaele Pezzilli, Ryan D. Baron, Stephen T. Amann, Sarah Jane Schwarzenberg, Shuiji Isaji, Soren Schou Olesen, Srdan Novovic, Steven J. Hughes, Steven L. Werlin, Tanja Gonska, Timothy B. Gardner, Mark D. Topazian, Frank Ulrich Weiss, Venakata S. Akshintala, Veronique D. Morinville, Vinciane Rebours, Aron Vincze, Vikesh K. Singh, Naiqiang Cui, Hong Zhang, Zhao-shen Li, Integrated Research on Energy, Environment & Socie, Molecular Active Systems, Gastroenterology and hepatology, Gastroenterology & Hepatology, Graduate School, Surgery, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology and Hepatology
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Pancreatic enzyme replacement therapy ,Hepatology ,Endocrinology, Diabetes and Metabolism ,Clinical Decision-Making ,Exocrine pancreatic insufficiency ,Gastroenterology ,Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] ,Steatorrhea ,SDG 3 - Good Health and Well-being ,Expert opinion ,Pancreatitis, Chronic ,Humans ,HaPanEU-guidelines ,Pancreas ,Chronic pancreatitis - Abstract
IntroductionDespite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency.MethodsAn online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years.ResultsOverall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency.ConclusionThis survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence. Introduction: Despite evidence-based guidelines, exocrine pancreatic insufficiency is frequently underdiagnosed and undertreated in patients with chronic pancreatitis. Therefore, the aim of this study is to provide insight into the current opinion and clinical decision-making of international pancreatologists regarding the management of exocrine pancreatic insufficiency. Methods: An online survey and case vignette study was sent to experts in chronic pancreatitis and members of various pancreatic associations: EPC, E-AHPBA and DPSG. Experts were selected based on publication record from the past 5 years. Results: Overall, 252 pancreatologists participated of whom 44% had ≥ 15 years of experience and 35% treated ≥ 50 patients with chronic pancreatitis per year. Screening for exocrine pancreatic insufficiency as part of the diagnostic work-up for chronic pancreatitis is performed by 69% and repeated annually by 21%. About 74% considers nutritional assessment to be part of the standard work-up. Patients are most frequently screened for deficiencies of calcium (47%), iron (42%), vitamin D (61%) and albumin (59%). In case of clinically steatorrhea, 71% prescribes enzyme supplementation. Of all pancreatologists, 40% refers more than half of their patients to a dietician. Despite existing guidelines, 97% supports the need for more specific and tailored instructions regarding the management of exocrine pancreatic insufficiency. Conclusion: This survey identified a lack of consensus and substantial practice variation among international pancreatologists regarding guidelines pertaining the management of exocrine pancreatic insufficiency. These results highlight the need for further adaptation of these guidelines according to current expert opinion and the level of available scientific evidence.
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- 2022
9. Detecting Microbial Dysbiosis Associated with Pediatric Crohn Disease Despite the High Variability of the Gut Microbiota
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Feng Wang, Jess L. Kaplan, Benjamin D. Gold, Manoj K. Bhasin, Naomi L. Ward, Richard Kellermayer, Barbara S. Kirschner, Melvin B. Heyman, Scot E. Dowd, Stephen B. Cox, Haluk Dogan, Blaire Steven, George D. Ferry, Stanley A. Cohen, Robert N. Baldassano, Christopher J. Moran, Elizabeth A. Garnett, Lauren Drake, Hasan H. Otu, Leonid A. Mirny, Towia A. Libermann, Harland S. Winter, and Kirill S. Korolev
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Biology (General) ,QH301-705.5 - Abstract
The relationship between the host and its microbiota is challenging to understand because both microbial communities and their environments are highly variable. We have developed a set of techniques based on population dynamics and information theory to address this challenge. These methods identify additional bacterial taxa associated with pediatric Crohn disease and can detect significant changes in microbial communities with fewer samples than previous statistical approaches required. We have also substantially improved the accuracy of the diagnosis based on the microbiota from stool samples, and we found that the ecological niche of a microbe predicts its role in Crohn disease. Bacteria typically residing in the lumen of healthy individuals decrease in disease, whereas bacteria typically residing on the mucosa of healthy individuals increase in disease. Our results also show that the associations with Crohn disease are evolutionarily conserved and provide a mutual information-based method to depict dysbiosis.
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- 2016
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10. Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression
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David R. Mack, Jarod Prince, Susan S. Baker, Brendan M. Boyle, Rebekah Karns, Suresh Venkateswaran, Subra Kugathasan, Talin Haritunians, Dermot P.B. McGovern, Mamta Giri, James Markowitz, Nai Yun Hsu, Melvin B. Heyman, Lee A. Denson, Ling-Shiang Chuang, Mayte Suárez-Fariñas, Greg Gibson, Jeffrey S. Hyams, Neal S. LeLeiko, Andrew Kasarskis, Kyle Gettler, Bruce J. Aronow, Cary G. Sauer, Yael Haberman, Carmen Argmann, Anne M. Griffiths, Joel R. Rosh, Nathan Gotman, Angela Mo, Dalia Arafat, Sapana Shah, Paul A. Rufo, Thomas D. Walters, Marian Pfefferkorn, Ashish S. Patel, Sonia Davis Thomas, Judy H. Cho, Robert N. Baldassano, Emebet Mengesha, Joshua D. Noe, and Sini Nagpal
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Oncology ,Multifactorial Inheritance ,medicine.medical_treatment ,Datasets as Topic ,Ulcerative ,Disease ,Medical and Health Sciences ,cell-type-specific gene expression ,Cohort Studies ,Crohn Disease ,Colectomy ,Genetics (clinical) ,Biological Specimen Banks ,Genetics & Heredity ,Framingham Risk Score ,eQTLs ,Biological Sciences ,Colitis ,Prognosis ,Ulcerative colitis ,transcriptome-wide association studies ,Disease Progression ,Patient Safety ,predicted polygenic transcriptional risk scores ,Biotechnology ,medicine.medical_specialty ,Colon ,Quantitative Trait Loci ,Quantitative trait locus ,Autoimmune Disease ,Risk Assessment ,Article ,Clinical Research ,Internal medicine ,Genetics ,medicine ,Humans ,Genetic association ,business.industry ,Prevention ,Gene Expression Profiling ,Human Genome ,Inflammatory Bowel Disease ,medicine.disease ,United Kingdom ,Gene expression profiling ,transcriptional risk scores ,prediction of disease progression ,Expression quantitative trait loci ,Colitis, Ulcerative ,Generic health relevance ,Digestive Diseases ,Transcriptome ,business ,Genome-Wide Association Study - Abstract
Summary An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.
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- 2021
11. Obesity at Age 6 Months Is Associated with Shorter Preschool Leukocyte Telomere Length Independent of Parental Telomere Length
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Janet M. Wojcicki, Melvin B. Heyman, Melanie J. Baskind, and Jessica Hawkins
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Male ,Pediatric Obesity ,medicine.medical_specialty ,Population ,Breastfeeding ,Childhood obesity ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Diabetes mellitus ,Internal medicine ,Leukocytes ,Humans ,Medicine ,030212 general & internal medicine ,education ,Prospective cohort study ,Telomere Shortening ,Sugar-Sweetened Beverages ,education.field_of_study ,business.industry ,Infant ,Hispanic or Latino ,medicine.disease ,Obesity ,Telomere ,Breast Feeding ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cohort ,Linear Models ,Female ,San Francisco ,business - Abstract
To assess whether early modifiable dietary factors and obesity measures are associated with leukocyte telomere length at 3-5 years of age after controlling for the heritability of leukocyte telomere length in a prospective cohort of low-income Latina mothers and their children in San Francisco.We analyzed data from the Latinx, Eating and Diabetes cohort, a prospective study of 97 woman-infant dyads. We used linear regression models to evaluate associations between early dietary factors and obesity measures and child leukocyte telomere length at 3-5 years of age. Multivariable models included child age at the time of telomere collection, breastfeeding at 6 months (yes/no), obesity at 6 months, maternal education, child sex, and maternal and paternal leukocyte telomere length.Data for 73 of the 97 children at 3-5 years of age were analyzed. Any breastfeeding at 6 months was positively associated (β = 0.14; P = .02) and obesity at 6 months was negatively associated (β = -0.21; P .001) with leukocyte telomere length in bivariate analyses. In multivariable models including parental leukocyte telomere length, obesity at 6 months was associated with a shorter leukocyte telomere length at 3-5 years of age (β = -0.15; P = .02). Analyses of dietary factors showed high flavored milk consumption at 3 years of age was associated with shorter leukocyte telomere length after adjustment for possible confounders.In a low-income Latinx population, obesity at 6 months of age is negatively associated with cellular health at 3-5 years of age after controlling for genetic factors (parental leukocyte telomere length) associated with leukocyte telomere length. Early life obesity may be more deleterious for cellular health than obesity later in childhood.
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- 2021
12. Perspectives from the Society for Pediatric Research: advice on sustaining science and mentoring during COVID-19
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Andrew J. Nowalk, Daniel J. Moore, Suong T Nguyen, Jordan S. Orange, Catherine S Forster, Kate G. Ackerman, Melvin B. Heyman, Margaret K. Hostetter, Rebecca Blankenburg, Weston T. Powell, Debra Boyer, Caroline E. Rassbach, Pnina Weiss, Audrea M. Burns, Tara L. Wenger, Fernando F. Gonzalez, and Jacqueline Ho
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Biomedical Research ,education ,Efficiency ,Pediatrics ,03 medical and health sciences ,Interpersonal relationship ,Special Article ,0302 clinical medicine ,Leverage (negotiation) ,030225 pediatrics ,Political science ,Pandemic ,Humans ,Interpersonal Relations ,Economic impact analysis ,Pediatrics, Perinatology, and Child Health ,Pediatricians ,Workgroup ,Productivity ,Societies, Medical ,Medical education ,Mentors ,COVID-19 ,Mental health ,Career Mobility ,Mental Health ,Education, Medical, Graduate ,Pediatrics, Perinatology and Child Health ,Futures contract ,030217 neurology & neurosurgery - Abstract
The COVID-19 pandemic will leave an indelible mark on the careers of current medical trainees. Given the disruptions to medical education, economic impact on institutions, and the uncertainties around future job prospects, trainees are facing unprecedented challenges. This situation is especially concerning for futures of pediatric physician-scientist trainees, where concerns regarding maintaining the pipeline were well documented prior to the emergence of COVID-19. In this Perspectives article, we leverage the unique expertise of our workgroup to address concerns of physician-scientist trainees and to provide suggestions on how to navigate career trajectories in the post-COVID-19 era. We identified and addressed four major areas of concern: lack of in-person conferences and the associated decrease access to mentors and networking activities, decreased academic productivity, diminished job prospects, and mental health challenges. We also suggest actions for trainees, mentors and educational leaders, and institutions to help support trainees during the pandemic, with a goal of maintaining the pediatric physician-scientist pipeline., Impact The advice in this article will provide guidance to pediatric physician-scientist trainees on sustaining and developing their career during the continued challenges presented by COVID-19.We also provide suggestions for mentors, educational leaders, institutions, and professional societies on ways to help support the pediatric physician-scientist pipeline.
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- 2021
13. Plasma Corticotropin-Releasing Factor Receptors and B7-2+ Extracellular Vesicles in Blood Correlate with Irritable Bowel Syndrome Disease Severity
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Shin-ichiro Hagiwara, Burcu Hasdemir, Melvin B. Heyman, Lin Chang, and Aditi Bhargava
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cell-to-cell ,B-cells ,dendritic cells ,EV cargo ,Cytology ,QH573-671 - Abstract
Extracellular vesicles (EVs) are composed of bilayer membranes that are released by different cell types and are present in bodily fluids, such as blood, urine, and bile. EVs are thought to play a key role in intracellular communication. Based on their size and density, EVs are classified into small, medium, or large EVs. Cargo composition in EVs reflects physiological changes in health and disease. Patients with irritable bowel syndrome (IBS) exhibit visceral hypersensitivity and mood disorders. Stressful episodes often precede disease symptoms in IBS patients. Stress-induced symptoms include, but are not limited to, abdominal pain and mood swings. Perceived stress responses are mediated by two known G protein-coupled receptors (GPCRs), corticotropin-releasing factor receptor 1 and 2 (CRFRs). CRFRs belong to the Class B secretin receptor family of GPCRs. Here, we show that CRFRs were present in human and murine plasma, and in EVs purified from mouse serum. CRFRs were present in plasma from IBS patients and healthy controls. EVs secreted from immune cells influence both adaptive and innate immune responses via exchange of EVs between different immune cell types. B7-2 (CD86), a plasma membrane antigen-presenting protein, is present on EVs secreted from dendritic, B-, and mast cells, whereas CD9 is present on EVs secreted from dendritic and intestinal epithelial cells. We found that plasma CRFR levels positively correlated with B7-2+ EVs (R = 0.8597, p < 0.0001), but no association was seen with CD9+ EVs. Plasma CRFRs expression negatively correlated with IBS severity scores. Our data suggests that plasma EVs from immune cells carry CRFRs as cargos and influence cell-cell communication in health and disease.
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- 2019
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14. Recommendations for Transgender and Gender Nonconforming Adolescents and Young Adults With Inflammatory Bowel Disease
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Melvin B. Heyman, Rachel B Schenker, Laura C. Cooke, Meredith Russell, Sofia G. Verstraete, and Erin C. Wilson
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Male ,medicine.medical_specialty ,Adolescent ,Population ,MEDLINE ,Transgender Persons ,Inflammatory bowel disease ,Young Adult ,Transgender ,Humans ,Medicine ,Young adult ,education ,education.field_of_study ,Gender identity ,business.industry ,Gastroenterology ,Gender Identity ,Gender nonconforming ,Inflammatory Bowel Diseases ,medicine.disease ,Mental health ,digestive system diseases ,Family medicine ,Pediatrics, Perinatology and Child Health ,Female ,business - Abstract
Transgender and gender nonconforming (TGNC) individuals have a different gender identity than the sex they were assigned at birth. Despite an increase in provider awareness of TGNC health over the past decade, no original research or societal guidelines exist on TGNC patients with inflammatory bowel disease (IBD). We review TGNC IBD cases in the University of California, San Francisco (UCSF) Pediatric IBD Program and in the literature. We then provide some recommendations for the provision of high-quality care to the TGNC IBD population, divided into 3 categories: medications, anatomy, and mental health.
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- 2020
15. Diabetes Mellitus in Children with Acute Recurrent and Chronic Pancreatitis: Data From the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE Cohort
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M. Bridget Zimmerman, Veronique D. Morinville, Douglas S. Fishman, Uzma Shah, Tanja Gonska, Cheryl E. Gariepy, Bradley A. Barth, Chee Y. Ooi, Melena D. Bellin, Matthew J. Giefer, Mark E. Lowe, Maisam Abu-El-Haija, Brian A. McFerron, Ryan Himes, Quin Liu, Michael Wilschanski, Tom K. Lin, Sarah Jane Schwarzenberg, Jaimie D. Nathan, Steven D. Freedman, David M. Troendle, John F. Pohl, Steven L. Werlin, Melvin B. Heyman, Aliye Uc, Sohail Z. Husain, Asim Maqbool, Emily R. Perito, and Maria R. Mascarenhas
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First episode ,Hereditary pancreatitis ,medicine.medical_specialty ,business.industry ,Hypertriglyceridemia ,Gastroenterology ,Odds ratio ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,030225 pediatrics ,Diabetes mellitus ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Cohort ,medicine ,Acute pancreatitis ,Pancreatitis ,030211 gastroenterology & hepatology ,business - Abstract
Objectives Adults with chronic pancreatitis (CP) have a high risk for developing pancreatogenic diabetes mellitus (DM), but little is known regarding potential risk factors for DM in children with acute recurrent pancreatitis (ARP) or CP. We compared demographic and clinical features of children with ARP or CP, with and without DM, in the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE) registry. Methods We reviewed the INSPPIRE database for the presence or absence of physician-diagnosed DM in 397 children, excluding those with total pancreatectomy with islet autotransplantation, enrolled from August 2012 to August 2017. Patient demographics, BMI percentile, age at disease onset, disease risk factors, disease burden, and treatments were compared between children with DM (n = 24) and without DM (n = 373). Results Twenty-four children (6% of the cohort) had a diagnosis of DM. Five of 13 tested were positive for beta cell autoantibodies. The DM group was 4.2 years [95% confidence interval (CI) 3-5.4] older at first episode of acute pancreatitis, and tended to more often have hypertriglyceridemia [odds ratio (OR) 5.21 (1.33-17.05)], coexisting autoimmune disease [OR 3.94 (0.88-13.65)] or pancreatic atrophy [OR 3.64 (1.13, 11.59)]. Conclusion Pancreatic atrophy may be more common among children with DM, suggesting more advanced exocrine disease. However, data in this exploratory cohort also suggest increased autoimmunity and hypertriglyceridemia in children with DM, suggesting that risk factors for type 1 and type 2 DM, respectively may play a role in mediating DM development in children with pancreatitis.
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- 2019
16. Experience Using Ustekinumab in Pediatric Patients With Medically Refractory Crohn Disease
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Melvin B. Heyman, Hassan Hamandi, Francis Kim, Sabina Ali, Perseus V Patel, Sofia G. Verstraete, and Emily Stekol
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Adult ,medicine.medical_specialty ,efficacy ,Crohn's Disease ,Hematocrit ,Autoimmune Disease ,Medical and Health Sciences ,Article ,Antibodies ,Vaccine Related ,Refractory ,Crohn Disease ,children ,Clinical Research ,inflammatory bowel disease ,Psoriasis ,Internal medicine ,Ustekinumab ,Monoclonal ,medicine ,dose adjustment ,Humans ,Adverse effect ,Child ,Retrospective Studies ,Pediatric ,medicine.diagnostic_test ,Gastroenterology & Hepatology ,business.industry ,Medical record ,Prevention ,Gastroenterology ,Antibodies, Monoclonal ,Evaluation of treatments and therapeutic interventions ,Retrospective cohort study ,medicine.disease ,6.1 Pharmaceuticals ,Pediatrics, Perinatology and Child Health ,Cohort ,Tumor Necrosis Factor Inhibitors ,Immunization ,Patient Safety ,business ,Digestive Diseases ,medicine.drug - Abstract
Introduction Ustekinumab (UST), a human monoclonal antibody against interleukin-12 and 23, is approved to treat adult patients with psoriasis or Crohn's Disease (CD). Outcomes data for off-label use in pediatric patients with CD are limited. Aim We conducted a retrospective cohort study to analyze the long-term efficacy of UST, including dose adjustments, in the treatment of pediatric patients with medically refractory CD. Adverse events were documented. Methods We identified 40 pediatric patients with CD treated with UST between January 1, 2016 and December 31, 2019. Electronic medical records were reviewed for demographics, Paris Classification, significant comorbidities, previous CD therapy, adverse events after initiation, and surveillance markers at the time of their first dose and most recent clinic visit. A validated abbreviated pediatric CD activity index (aPCDAI) was used to assess response to therapy. Results Thirty-eight pediatric patients with CD, including 34.2% with stricturing or penetrating disease, were analyzed after initiation of treatment with UST. Median age at diagnosis of CD was 12.5 years, and median age at UST induction was 17.2 years. No patients were anti-TNF naive, and 34.2% were previously exposed to two or more anti-TNF agents. At time of last follow-up, 84.2% of patients remained on UST for a median duration on UST of 62.1 weeks, and 60.5% achieved clinical remission. Patients had significant improvement in aPCDAI scores, clinical remission rates, albumin, and hematocrit, and 89.5% of patients had no significant adverse events. Similar results were observed among those who required dose adjustment, including 61.1% achieving clinical remission, and among those with perianal disease, including 38.5% achieving clinical remission. Conclusion Our data suggest that, within our cohort of pediatric patients with CD, UST has long-term efficacy with no observed safety concerns. Dose adjustment may be helpful in achieving clinical remission.
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- 2021
17. Current Fellowship Funding Limitations and Their Threat to the Pediatric Subspecialty Workforce
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Kathleen A. McGann, Linda M. Gerber, Christine E. Barron, Angela L. Myers, Elizabeth Mauer, Ann E. Klasner, Melvin B. Heyman, Pnina Weiss, Doria L. Weiss, Erika L. Abramson, Jennifer C. Kesselheim, and Katherine Mason
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Medical education ,business.industry ,Graduate medical education ,Internship and Residency ,Subspecialty ,United States ,Education, Medical, Graduate ,Pediatrics, Perinatology and Child Health ,Workforce ,Medicine ,Humans ,Current (fluid) ,Fellowships and Scholarships ,business ,Child - Published
- 2021
18. Infections Requiring Hospitalization as Predictors of Pediatric-Onset Crohn’s Disease and Ulcerative Colitis
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Susan Hutfless, Oren Abramson, Melvin B. Heyman, Theodore M. Bayless, De-Kun Li, Kevin Winthrop, and Lisa J. Herrinton
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Objectives. To assess the relationship between infections and the risk of pediatric-onset inflammatory bowel disease (IBD). Methods. We conducted a nested case-control study of 501 incident cases aged ≤17 years and 9,442 controls who were members of Kaiser Permanente Northern California for at least one consecutive year between 1996 and 2006. IBD was confirmed and the incidence date was adjudicated by pediatric gastroenterologists. Hospitalized infections were identified from the principal diagnosis code of electronic inpatient records. Medications to treat infections were identified during the hospitalization. Conditional logistic regression was used to assess the associations between hospitalized infections, medications, and Crohn’s disease and ulcerative colitis. Results. In the year prior to diagnosis, both hospitalized infection of any system (OR 6.3; 95% CI 1.6–23.9) and hospitalized intestinal infection (OR 19.4; 95% CI 2.6–143.2) were associated with CD. Hospitalized infections of any system were inversely associated with UC after excluding the year prior to diagnosis (OR 0.4; 95% CI 0.2–0.9). No UC case had a hospitalized gastrointestinal infection prior to diagnosis. Conclusion. Infections appear to play opposite roles prior to the diagnosis of CD and UC. Infections may be associated with an increased risk of CD and a decreased risk of UC.
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- 2015
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19. Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping.
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David J Cutler, Michael E Zwick, David T Okou, Sampath Prahalad, Thomas Walters, Stephen L Guthery, Marla Dubinsky, Robert Baldassano, Wallace V Crandall, Joel Rosh, James Markowitz, Michael Stephens, Richard Kellermayer, Marian Pfefferkorn, Melvin B Heyman, Neal LeLeiko, David Mack, Dedrick Moulton, Michael D Kappelman, Archana Kumar, Jarod Prince, Promita Bose, Kajari Mondal, Dhanya Ramachandran, John F Bohnsack, Anne M Griffiths, Yael Haberman, Jonah Essers, Susan D Thompson, Bruce Aronow, David J Keljo, Jeffrey S Hyams, Lee A Denson, PRO-KIIDS Research Group, and Subra Kugathasan
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Medicine ,Science - Abstract
The inflammatory bowel diseases (IBD) are common, complex disorders in which genetic and environmental factors are believed to interact leading to chronic inflammatory responses against the gut microbiota. Earlier genetic studies performed in mostly adult population of European descent identified 163 loci affecting IBD risk, but most have relatively modest effect sizes, and altogether explain only ~20% of the genetic susceptibility. Pediatric onset represents about 25% of overall incident cases in IBD, characterized by distinct disease physiology, course and risks. The goal of this study is to compare the allelic architecture of early onset IBD with adult onset in population of European descent.We performed a fine mapping association study of early onset IBD using high-density Immunochip genotyping on 1008 pediatric-onset IBD cases (801 Crohn's disease; 121 ulcerative colitis and 86 IBD undetermined) and 1633 healthy controls. Of the 158 SNP genotypes obtained (out of the 163 identified in adult onset), this study replicated 4% (5 SNPs out of 136) of the SNPs identified in the Crohn's disease (CD) cases and 0.8% (1 SNP out of 128) in the ulcerative colitis (UC) cases. Replicated SNPs implicated the well known NOD2 and IL23R. The point estimate for the odds ratio (ORs) for NOD2 was above and outside the confidence intervals reported in adult onset. A polygenic liability score weakly predicted the age of onset for a larger collection of CD cases (p< 0.03, R2= 0.007), but not for the smaller number of UC cases.The allelic architecture of common susceptibility variants for early onset IBD is similar to that of adult onset. This immunochip genotyping study failed to identify additional common variants that may explain the distinct phenotype that characterize early onset IBD. A comprehensive dissection of genetic loci is necessary to further characterize the genetic architecture of early onset IBD.
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- 2015
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20. Stratification of Risk of Progression to Colectomy in Ulcerative Colitis using Measured and Predicted Gene Expression
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Suresh Venkateswaran, Melvin B. Heyman, Neal S. LeLeiko, Judy H. Cho, Robert N. Baldassano, T Walters, Ashish S. Patel, Brendan M. Boyle, Andrew Kasarskis, Ling-Shiang Chuang, Emebet Mengesha, Greg Gibson, Talin Haritunians, Nai Yun Hsu, Joshua D. Noe, Cary G. Sauer, David R. Mack, Yael Haberman, Jarod Prince, Susan S. Baker, Marian Pfefferkorn, Sini Nagpal, Mayte Suárez-Fariñas, Subra Kugathasan, Lee A. Denson, Anne M. Griffiths, James Markowitz, Bruce J. Aronow, Dalia Arafat, Sonia Davis Thomas, Rebekah Karns, Joel R. Rosh, Nathan Gotman, Angela Mo, Sapana Shah, Paul A. Rufo, Mamta Giri, Kyle Gettler, Dermot P.B. McGovern, Jeffrey S. Hyams, and Carmen Argmann
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Oncology ,medicine.medical_specialty ,Framingham Risk Score ,business.industry ,medicine.medical_treatment ,Genome-wide association study ,Disease ,medicine.disease ,Ulcerative colitis ,Clinical trial ,Gene expression profiling ,Internal medicine ,medicine ,business ,Colectomy ,Genetic association - Abstract
SUMMARYAn important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of ulcerative colitis (UC) patients require colectomy within five years of diagnosis, but polygenic risk scores (PRS) utilizing findings from GWAS are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn’s disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a Transcriptional Risk Score (TRS). Here we demonstrate that both measured (TRS) and polygenic predicted gene expression (PPTRS) identify UC patients at 5-fold elevated risk of colectomy with data from the PROTECT clinical trial and UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with transcriptome-wide association studies to stratify risk of disease complications.
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- 2021
21. INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE Cohort Study
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Kate Ellery, Sarah Jane Schwarzenberg, Douglas S. Fishman, Ying Yuan, David M. Troendle, Matthew J. Giefer, Bradley A. Barth, Quin Y. Liu, Jose Serrano, Melena D. Bellin, John F. Pohl, Asim Maqbool, Emily R. Perito, Mark E. Lowe, Brian A. McFerron, Maria R. Mascarenhas, Sohail Z. Husain, Ryan Himes, Maisam Abu-El-Haija, Steven L. Werlin, Aliye Uc, Melvin B. Heyman, Veronique D. Morinville, Jaimie D. Nathan, Cheryl E. Gariepy, Tom K. Lin, Uzma Shah, Sue Rhee, Michael Wilschanski, Chee Y. Ooi, Tanja Gonska, Yuhua Zheng, and Zachary M. Sellers
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Research design ,medicine.medical_specialty ,Biomedical Research ,Endocrinology, Diabetes and Metabolism ,Article ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Quality of life ,Pancreatitis, Chronic ,Surveys and Questionnaires ,030225 pediatrics ,Internal medicine ,Diabetes Mellitus ,Internal Medicine ,medicine ,Humans ,Multicenter Studies as Topic ,Child ,Depression (differential diagnoses) ,Hepatology ,business.industry ,International Agencies ,medicine.disease ,Pancreatic Neoplasms ,Observational Studies as Topic ,Pancreatitis ,Research Design ,Social history (medicine) ,Child, Preschool ,Acute Disease ,Cohort ,030211 gastroenterology & hepatology ,business ,Psychosocial ,Cohort study - Abstract
We created the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE 2) cohort to study the risk factors, natural history, and outcomes of pediatric acute recurrent pancreatitis and chronic pancreatitis (CP). Patient and physician questionnaires collect information on demographics, clinical history, family and social history, and disease outcomes. Health-related quality of life, depression, and anxiety are measured using validated questionnaires. Information entered on paper questionnaires is transferred into a database managed by Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer's Coordinating and Data Management Center. Biosamples are collected for DNA isolation and analysis of most common pancreatitis-associated genes.Twenty-two sites (18 in the United States, 2 in Canada, and 1 each in Israel and Australia) are participating in the INSPPIRE 2 study. These sites have enrolled 211 subjects into the INSPPIRE 2 database toward our goal to recruit more than 800 patients in 2 years. The INSPPIRE 2 cohort study is an extension of the INSPPIRE cohort study with a larger and more diverse patient population. Our goals have expanded to include evaluating risk factors for CP, its sequelae, and psychosocial factors associated with pediatric acute recurrent pancreatitis and CP.
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- 2018
22. The Effect of Early-Life Environmental Exposures on Disease Phenotype and Clinical Course of Crohn's Disease in Children
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Marla Dubinsky, Melvin B. Heyman, Ashwin N. Ananthakrishnan, Scott B. Snapper, Anne M. Griffiths, Joel R. Rosh, James Markowitz, Livia Lindoso, Thomas D. Walters, Michael C. Stephens, Susan S. Baker, David R. Mack, Jeffrey S. Hyams, Dedrick E. Moulton, Ajay S. Gulati, Marian D. Pfefferkorn, Kajari Mondal, Maria Oliva-Hemker, Stephen L. Guthery, Suresh Venkateswaran, Anthony R. Otley, Cortney R. Ballengee, David J. Keljo, Jonathan Evans, Robert N. Baldassano, Ashish S. Patel, Lee A. Denson, Hari K. Somineni, Subra Kugathasan, Barbara S. Kirschner, Shervin Rabizadeh, Wallace Crandall, Joshua D. Noe, David Ziring, Stanley N. Cohen, Richard Kellermayer, and Neal S. LeLeiko
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Male ,0301 basic medicine ,Time Factors ,Adolescent ,Colon ,Constriction, Pathologic ,Disease ,Severity of Illness Index ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Crohn Disease ,Pregnancy ,Risk Factors ,Severity of illness ,medicine ,Humans ,Longitudinal Studies ,Prospective Studies ,Microbiome ,Child ,Immunologic Tolerance ,Crohn's disease ,Hepatology ,business.industry ,Smoking ,Infant, Newborn ,Gastroenterology ,Environmental Exposure ,medicine.disease ,Phenotype ,Hospitalization ,Breast Feeding ,030104 developmental biology ,Prenatal Exposure Delayed Effects ,North America ,Immunology ,Disease Progression ,Female ,Tobacco Smoke Pollution ,030211 gastroenterology & hepatology ,business ,Follow-Up Studies - Abstract
Environmental factors play an important role in the pathogenesis of Crohn's Disease (CD). In particular, by virtue of the instability of the microbiome and development of immunologic tolerance, early life factors may exert the strongest influence on disease risk and phenotype.We used data from 1119 CD subjects recruited from RISK inception cohort to examine the impact of early life environment on disease progression. Our primary exposures of interest were breastfeeding in infancy and exposure to maternal, active, or passive smoke. Our primary outcomes were development of complicated (stricturing or penetrating) disease, and need for CD-related hospitalization, and surgery. Multivariable logistic regression models were used to define independent associations, adjusting for relevant covariates.Our study cohort included 1119 patients with CD among whom 15% had stricturing (B2) or penetrating disease (B3) by 3 years. 331 patients (35%) and 95 patients (10.6%) required CD-related hospitalizations and surgery respectively. 74.5% were breastfed in infancy and 31% were exposed to smoking among whom 7% were exposed to maternal smoke. On multivariable analysis, a history of breastfeeding was inversely associated with complicated (B2/B3 disease) 0.65, CI 95% 0.44-96; P = 0.03) in pediatric CD. Maternal smoking during pregnancy was associated with increased risk of hospitalization during the 3-year follow-up period (OR 1.75, CI 95% 1.05-2.89; P = 0.03).Early life environmental factors influence the eventual phenotypes and disease course in CD.
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- 2018
23. Association of Baseline Luminal Narrowing With Ileal Microbial Shifts and Gene Expression Programs and Subsequent Transmural Healing in Pediatric Crohn Disease
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Scott B. Snapper, Anil G. Jegga, Nicholas J Ollberding, Marla Dubinsky, Marian D. Pfefferkorn, James Markowitz, Jason Shapiro, Robert Baldassano, Lee A. Denson, Jonathan R Dillman, Subra Kugathasan, Maria Oliva-Hemker, Adina Alazraki, David Hercules, Anthony R. Otley, Melvin B. Heyman, Ramnik J. Xavier, Allison Ta, Rebekah Karns, Yael Haberman, Jeffrey S. Hyams, Joshua D. Noe, Sandra C. Kim, Barbara S. Kirschner, Shervin Rabizadeh, and Richard Kellermayer
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medicine.medical_specialty ,16S ,Myeloid ,Aggregatibacter ,Clinical Sciences ,microbiome ,Gene Expression ,Constriction, Pathologic ,Gastroenterology ,transmural healing ,Autoimmune Disease ,Oral and gastrointestinal ,Serology ,Cohort Studies ,Crohn Disease ,Internal medicine ,RNA, Ribosomal, 16S ,Gene expression ,medicine ,Genetics ,Immunology and Allergy ,Humans ,Child ,Pathologic ,Ribosomal ,Pediatric ,Wound Healing ,magnetic resonance enterography ,biology ,Gastroenterology & Hepatology ,business.industry ,Lachnospiraceae ,Inflammatory Bowel Disease ,Area under the curve ,Odds ratio ,Gene signature ,biology.organism_classification ,Constriction ,medicine.anatomical_structure ,RNA ,luminal narrowing ,Leading Off ,business ,Digestive Diseases - Abstract
Background Transmural healing (TH) is associated with better long-term outcomes in Crohn disease (CD), whereas pretreatment ileal gene signatures encoding myeloid inflammatory responses and extracellular matrix production are associated with stricturing. We aimed to develop a predictive model for ileal TH and to identify ileal genes and microbes associated with baseline luminal narrowing (LN), a precursor to strictures. Materials and Methods Baseline small bowel imaging obtained in the RISK pediatric CD cohort study was graded for LN. Ileal gene expression was determined by RNASeq, and the ileal microbial community composition was characterized using 16S rRNA amplicon sequencing. Clinical, demographic, radiologic, and genomic variables were tested for association with baseline LN and future TH. Results After controlling for ileal location, baseline ileal LN (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.8), increasing serum albumin (OR, 4; 95% CI, 1.3-12.3), and anti-Saccharomyces cerevisiae antibodies IgG serology (OR, 0.97; 95% CI, 0.95-1) were associated with subsequent TH. A multivariable regression model including these factors had excellent discriminant power for TH (area under the curve, 0.86; positive predictive value, 80%; negative predictive value, 87%). Patients with baseline LN exhibited increased Enterobacteriaceae and inflammatory and extracellular matrix gene signatures, coupled with reduced levels of butyrate-producing commensals and a respiratory electron transport gene signature. Taxa including Lachnospiraceae and the genus Roseburia were associated with increased respiratory and decreased inflammatory gene signatures, and Aggregatibacter and Blautia bacteria were associated with reduced extracellular matrix gene expression. Conclusions Pediatric patients with CD with LN at diagnosis are less likely to achieve TH. The association between specific microbiota, wound healing gene programs, and LN may suggest future therapeutic targets.
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- 2021
24. Journal of Pediatric Gastroenterology and Nutrition Editor Comment: Progress, Transition, and Thank You!
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Melvin B. Heyman
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medicine.medical_specialty ,Gastroenterology & Hepatology ,business.industry ,Family medicine ,Pediatrics, Perinatology and Child Health ,Gastroenterology ,MEDLINE ,medicine ,business ,Medical and Health Sciences ,Pediatric gastroenterology - Published
- 2020
25. Physician-Scientist Training and Programming in Pediatric Residency Programs: A National Survey
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Caroline E. Rassbach, Heather McPhillips, Bobbi J. Byrne, Andrew J. Nowalk, Satid Thammasitboon, Pnina Weiss, Shelley Kumar, Daniel J. Moore, Weston T. Powell, Melvin B. Heyman, Anthony R. French, Margaret K. Hostetter, Donald W. Parsons, Jordan S. Orange, Kate G. Ackerman, Fernando F. Gonzalez, Debra Boyer, Audrea M. Burns, Jacqueline Ho, Mark A. Ward, Rebecca Blankenburg, Catherine S Forster, and Suong T Nguyen
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Medical education ,Biomedical Research ,business.industry ,Internship and Residency ,Resident education ,Pediatrics ,Training (civil) ,Pipeline (software) ,United States ,Surveys and Questionnaires ,Pediatrics, Perinatology and Child Health ,Humans ,Medicine ,Curriculum ,business - Published
- 2022
26. Maintenance Golimumab Treatment in Pediatric UC Patients With Moderately to Severely Active UC: PURSUIT PEDS PK Long-Term Study Results
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Joel R. Rosh, Anne M. Griffiths, Jeffrey S. Hyams, Geneviève Veereman, Melvin B. Heyman, Omoniyi J. Adedokun, Daphne Chan, Christopher D. O'Brien, Richard Strauss, Ghassan Wahbeh, Dan Turner, John P. Lynch, Lakshmi Padgett, Pediatrics, Clinical sciences, and Growth and Development
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medicine.medical_specialty ,Tuberculosis ,clinical response ,Autoimmune Disease ,030226 pharmacology & pharmacy ,Gastroenterology ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Pharmacokinetics ,Clinical Research ,Internal medicine ,Internal Medicine ,medicine ,Pediatrics, Perinatology, and Child Health ,ulcerative colitis ,Pediatric ,clinical remission ,business.industry ,Inflammatory Bowel Disease ,SERUM SICKNESS-LIKE REACTION ,Cancer ,medicine.disease ,Ulcerative colitis ,Golimumab ,Good Health and Well Being ,Long term learning ,Disease remission ,030211 gastroenterology & hepatology ,Digestive Diseases ,business ,medicine.drug - Abstract
Background Long-term safety, pharmacokinetics, and efficacy of open-label golimumab therapy in children with moderate–severe ulcerative colitis were evaluated. Methods Week-6 golimumab responders (Mayo score decrease of ≥30% and ≥3 points from baseline, rectal bleeding subscore of 0/1 or ≥1 decrease from baseline) entered the long-term extension at week 14 and received maintenance therapy (subcutaneous, q4w). Patients ≥45 kg could receive at-home treatments at week 18. Pharmacokinetic, safety, and efficacy results were summarized through week 126 (2 years). Results Among 35 enrolled children, 21 (60%) responded at week 6 and 20 entered the long-term extension (median age of 14.5 years and median weight of 46.1 kg). Eleven of 20 patients (55%) completed 2 years of treatment. No anaphylactic or serum sickness-like reactions, opportunistic infections, malignancies, tuberculosis, or deaths occurred. The safety profile of golimumab from weeks 14 through 126 and that observed through week 14 was generally consistent. Median trough golimumab concentrations in evaluable patients were consistent from weeks 14 (1.39, interquartile range 0.67–3.60) through 102 (1.18, 0.78–2.16), but higher at week 110 (4.10, 1.30–4.81). The incidence of antigolimumab antibodies increased from 10% (2/20) at week 30 to 25.0% (5/20) at week 126; 1 patient had neutralizing antibodies. At week 110, 50% (10/20) of patients were in remission (ie, Pediatric Ulcerative Colitis Activity Index Conclusions Among children with ulcerative colitis who initially responded to golimumab induction and received q4w maintenance treatment in the long-term extension, 50% showed continued clinical benefit through 2 years. No new safety signals were observed.
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- 2020
27. Mucosal Inflammatory and Wound Healing Gene Programs Reveal Targets for Stricturing Behavior in Pediatric Crohn's Disease
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Susan S. Baker, David R. Mack, Phillip Minar, Ashish S. Patel, Neal S. Leleiko, Jennifer L. Dotson, Bruce J. Aronow, Suresh Venkateswaran, Samuel Tegge, Marla Dubinsky, Brianne Shuler, Scott B. Snapper, Dedrick E. Moulton, Yael Haberman, Robert Baldassano, Jeffrey S. Hyams, Ajay S. Gulati, Daniel Shapiro, David Ziring, Michael C. Stephens, Rebekah Karns, Richard Kellermayer, Ranjana Gokhale, Stanley A. Cohen, Thomas D. Walters, Sudhir Ghandikota, Maria Oliva-Hemker, Anthony R. Otley, Joshua D. Noe, Sandra C. Kim, Lee A. Denson, Tzipi Braun, Jonathan R. Dillman, Joel R. Rosh, Subra Kugathasan, Greg Gibson, Anne M. Griffiths, Melvin B. Heyman, Allison Ta, Phillip J. Dexheimer, James Markowitz, Anil G. Jegga, Stephen L. Guthery, and Steven J. Steiner
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0301 basic medicine ,medicine.medical_specialty ,pediatric Crohn Disease ,Clinical Sciences ,small molecule ,Crohn's Disease ,Disease ,Gastroenterology ,Transcriptome ,surgery ,03 medical and health sciences ,0302 clinical medicine ,Paediatric Crohn disease ,Clinical Research ,Internal medicine ,Gene expression ,medicine ,Genetics ,Gene ,Pediatric ,Crohn's disease ,Gastroenterology & Hepatology ,business.industry ,Inflammatory Bowel Disease ,Mucous membrane ,Original Articles ,General Medicine ,Gene signature ,medicine.disease ,Gene expression profiling ,030104 developmental biology ,medicine.anatomical_structure ,030211 gastroenterology & hepatology ,ileum ,business ,Digestive Diseases ,transcriptome - Abstract
Background and Aims Ileal strictures are the major indication for resective surgery in Crohn’s disease [CD]. We aimed to define ileal gene programmes present at diagnosis and linked with future stricturing behaviour during 5-year follow-up, and to identify potential small molecules to reverse these gene signatures. Methods Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicentre paediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behaviour and for model testing to predict stricturing behaviour. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. Results A total of 19 of the 249 patients developed isolated B2 stricturing behaviour during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our previous report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix [ECM] gene expression, in those who developed stricturing complications. We further computationally prioritise small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by Year 5 after diagnosis {AUC (area under the curve) (95th CI [confidence interval]) = 0.82 [0.7–0.94)}. Conclusions An ileal gene programme for macrophage and fibroblast activation is linked to stricturing complications in treatment of naïve pediatric CD, and may inform novel small molecule therapeutic approaches.
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- 2020
28. Clinical and Practice Variations in Pediatric Acute Recurrent or Chronic Pancreatitis: Report From the INSPPIRE Study
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Brian A. McFerron, Steven L. Werlin, Maria R. Mascarenhas, Matthew J. Giefer, Asim Maqbool, Uzma Shah, Sarah Jane Schwarzenberg, A. Uc, David M. Troendle, Quin Liu, Michael Wilschanski, Tanja Gonska, Jaimie D. Nathan, Chee Y. Ooi, Sohail Z. Husain, Emily R. Perito, Mark E. Lowe, Yuhua Zheng, John F. Pohl, Douglas S. Fishman, Chinenye R. Dike, Cheryl E. Gariepy, Melena D. Bellin, Maisam Abu-El-Haija, Melvin B. Heyman, Bridget Zimmerman, Veronique D. Morinville, Bradley A. Barth, and Tom K. Lin
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medicine.medical_specialty ,Referral ,medicine.medical_treatment ,acute recurrent pancreatitis ,Medical and Health Sciences ,Oral and gastrointestinal ,chronic pancreatitis ,03 medical and health sciences ,0302 clinical medicine ,Endoscopic Retrograde ,Recurrence ,Clinical Research ,030225 pediatrics ,Internal medicine ,Pancreatitis, Chronic ,pediatric pancreatitis ,Medicine ,Humans ,pancreas ,Chronic ,Child ,Disease burden ,Cholangiopancreatography, Endoscopic Retrograde ,Pediatric ,Endoscopic retrograde cholangiopancreatography ,medicine.diagnostic_test ,Gastroenterology & Hepatology ,business.industry ,Gastroenterology ,Gallstones ,medicine.disease ,Autotransplantation ,Cholangiopancreatography ,Pancreatitis ,Pediatrics, Perinatology and Child Health ,Cohort ,Acute Disease ,Acute pancreatitis ,Biomedical Imaging ,030211 gastroenterology & hepatology ,business ,Digestive Diseases ,pancreatic disease - Abstract
ObjectiveThe aim of the study was to determine whether clinical characteristics and management of pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) differ across INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a cuRE) sites.Study designData were collected from INSPPIRE and analyzed per US regions and "non-US" sites. Between-group differences were compared by Pearson chi-square test. Differences in disease burden were compared by Kruskal-Wallis test.ResultsOut of the 479 subjects, 121 (25%) were enrolled in West, 151 (32%) Midwest, 45 Northeast (9%), 78 (16%) South, and 84 (18%) at non-US sites. Hispanic ethnicity was more common in South (P
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- 2020
29. Whither pediatric physician-scientist training in the COVID-19 era
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Melvin B. Heyman and Fernando F. Gonzalez
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Medical education ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Physician-scientist ,funding ,MEDLINE ,faculty development ,03 medical and health sciences ,0302 clinical medicine ,Quality of life (healthcare) ,030225 pediatrics ,Pediatrics, Perinatology and Child Health ,Workforce ,Treatment strategy ,Pediatrics, Perinatology, and Child Health ,Psychology ,030217 neurology & neurosurgery ,Disease burden - Abstract
Author(s): Gonzalez, Fernando F; Heyman, Melvin B | Abstract: Pediatric physician-scientists play a critical role in translating research findings from basic and clinical research into new paradigms and approaches pertinent to our care for children. The United States has long been a leader in biomedical research; however, this workforce has been diminishing over many years secondary to decreases in recruitment, limited funding and protected time, and attrition during training.1 This pipeline of pediatric physician-scientists is critical not only for discovery but also for contextualizing specific findings and extrapolating those findings to understanding development and treatment strategies that can reduce disease burden and improve quality of life.
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- 2020
30. Analysis of Using the Total White Blood Cell Count to Define Severe New-onset Ulcerative Colitis in Children
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Joel R. Rosh, Susan S. Baker, Alison Marquis, David R. Mack, Anne M. Griffiths, Melvin B. Heyman, Sonia M. Thomas, Brendan M. Boyle, Ashish S. Patel, Steve Steiner, Thomas D. Walters, Joshua D. Noe, Lee A. Denson, Robert Baldassano, David Keljo, Paul A. Rufo, Neal S. LeLeiko, Subra Kugathasan, James Markowitz, Cary G. Sauer, Bradley Saul, and Jeffrey S. Hyams
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Male ,medicine.medical_specialty ,Colonoscopy ,Disease ,macromolecular substances ,Blood Sedimentation ,Gastroenterology ,Severity of Illness Index ,Article ,03 medical and health sciences ,Leukocyte Count ,0302 clinical medicine ,030225 pediatrics ,White blood cell ,Internal medicine ,Severity of illness ,medicine ,Humans ,Colitis ,Child ,medicine.diagnostic_test ,business.industry ,medicine.disease ,Ulcerative colitis ,medicine.anatomical_structure ,Erythrocyte sedimentation rate ,Pediatrics, Perinatology and Child Health ,Cohort ,030211 gastroenterology & hepatology ,Colitis, Ulcerative ,Female ,business - Abstract
OBJECTIVES: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis. METHODS: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (
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- 2020
31. Whither pediatric physician-scientist training in the COVID-19 era
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Fernando F, Gonzalez and Melvin B, Heyman
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Biomedical Research ,SARS-CoV-2 ,Financing, Organized ,COVID-19 ,Efficiency ,Pediatrics ,Research Personnel ,United States ,Cost of Illness ,Research Support as Topic ,Humans ,Pediatricians ,Fellowships and Scholarships ,Social Change ,Personnel Selection ,Pandemics - Published
- 2020
32. Natural History of Very Early Onset Inflammatory Bowel Disease in North America: A Retrospective Cohort Study
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Ying Lu, Joel R. Rosh, Helen M. Pappa, Marisa G. Stahl, Joseph A. Galanko, Alka Goyal, Karoline Fiedler, Michael D. Kappelman, Jeffrey S. Hyams, Eileen Crowley, Michael C. Stephens, Jennifer A. Strople, Johan Van Limbergen, Melvin B Heyman, Ross M Maltz, A. Muise, Eric I Benchimol, Joshua D. Noe, Anthony L. Guerrerio, Mark Deneau, Lina Karam, Marian Pfefferkorn, Neal S. Leleiko, Raza Alkhouri, Judith R. Kelsen, Scott B. Snapper, Anne M. Griffiths, Leah Siebold, Dedrick Mouton, Keith J. Benkov, Basavaraj Kerur, Paediatric Gastroenterology, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, APH - Digital Health, and APH - Health Behaviors & Chronic Diseases
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Pancolitis ,medicine.medical_specialty ,Pediatrics ,medicine.medical_treatment ,Constriction, Pathologic ,Inflammatory bowel disease ,surgery ,Crohn Disease ,Interquartile range ,Epidemiology ,medicine ,Immunology and Allergy ,Humans ,Child ,VEOIBD ,Colectomy ,Retrospective Studies ,Crohn's disease ,business.industry ,Gastroenterology ,Retrospective cohort study ,medicine.disease ,Ulcerative colitis ,Child, Preschool ,Chronic Disease ,North America ,epidemiology ,Colitis, Ulcerative ,medicine.symptom ,Leading Off ,business - Abstract
Background The incidence of very early onset inflammatory bowel disease (VEOIBD) is increasing, yet the phenotype and natural history of VEOIBD are not well described. Methods We performed a retrospective cohort study of patients diagnosed with VEOIBD (6 years of age and younger) between 2008 and 2013 at 25 North American centers. Eligible patients at each center were randomly selected for chart review. We abstracted data at diagnosis and at 1, 3, and 5 years after diagnosis. We compared the clinical features and outcomes with VEOIBD diagnosed younger than 3 years of age with children diagnosed with VEOIBD at age 3 to 6 years. Results The study population included 269 children (105 [39%] Crohn’s disease, 106 [39%] ulcerative colitis, and 58 [22%] IBD unclassified). The median age of diagnosis was 4.2 years (interquartile range 2.9–5.2). Most (94%) Crohn’s disease patients had inflammatory disease behavior (B1). Isolated colitis (L2) was the most common disease location (70% of children diagnosed younger than 3 years vs 43% of children diagnosed 3 years and older; P = 0.10). By the end of follow-up, stricturing/penetrating occurred in 7 (6.6%) children. The risk of any bowel surgery in Crohn’s disease was 3% by 1 year, 12% by 3 years, and 15% by 5 years and did not differ by age at diagnosis. Most ulcerative colitis patients had pancolitis (57% of children diagnosed younger than 3 years vs 45% of children diagnosed 3 years and older; P = 0.18). The risk of colectomy in ulcerative colitis/IBD unclassified was 0% by 1 year, 3% by 3 years, and 14% by 5 years and did not differ by age of diagnosis. Conclusions Very early onset inflammatory bowel disease has a distinct phenotype with predominantly colonic involvement and infrequent stricturing/penetrating disease. The cumulative risk of bowel surgery in children with VEOIBD was approximately 14%–15% by 5 years. These data can be used to provide anticipatory guidance in this emerging patient population.
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- 2020
33. Pediatric chronic pancreatitis without prior acute or acute recurrent pancreatitis: A report from the INSPPIRE consortium
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Brian A. McFerron, Ryan Himes, Tanja Gonska, Bridget Zimmerman, Maria R. Mascarenhas, Cheryl E. Gariepy, Melena D. Bellin, Asim Maqbool, Jaimie D. Nathan, Tom K. Lin, Quin Liu, Maisam Abu-El-Haija, John F. Pohl, Douglas S. Fishman, Emily R. Perito, Steven L. Werlin, Mark E. Lowe, Matthew J. Giefer, Sohail Z. Husain, David M. Troendle, Uzma Shah, Veronique D. Morinville, Chee Y. Ooi, Bradley A. Barth, Michael Wilschanski, Steve Freedman, Melvin B. Heyman, Aliye Uc, and Sarah Jane Schwarzenberg
- Subjects
Male ,medicine.medical_specialty ,Hepatology ,Adolescent ,business.industry ,Endocrinology, Diabetes and Metabolism ,Gastroenterology ,MEDLINE ,Infant ,medicine.disease ,Article ,Pancreatitis ,Risk Factors ,Internal medicine ,Child, Preschool ,Pancreatitis, Chronic ,Acute recurrent pancreatitis ,Acute Disease ,medicine ,Humans ,Female ,business ,Child - Published
- 2020
34. Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease
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Scott B. Snapper, Anne Dodd, Anne M. Griffiths, Michael E. Zwick, Marla Dubinsky, Wallace Crandall, Ingrid Jurickova, Jeffrey S. Hyams, David T. Okou, Yael Haberman, Aaron Linn, Stephen L. Guthery, Melvin B. Heyman, Subra Kugathasan, Lee A. Denson, Christine Stevens, David J. Cutler, Robert N. Baldassano, Rebekah Karns, Ramnik J. Xavier, Bruce J. Aronow, Anthony R. Otley, Ramona Bezold, Neal S. Leleiko, Barbara S. Kirschner, Mark J. Daly, Kajari Mondal, Kathleen Lake, Kimberly Jackson, Kelly A Shaw, Thomas D. Walters, C. Alexander Valencia, Adam Price, and Joshua D. Noe
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Adult ,Male ,0301 basic medicine ,Macrophage colony-stimulating factor ,Adolescent ,Neutrophils ,Neutrophil granulocyte ,medicine.medical_treatment ,Mutation, Missense ,STAT5B ,Inflammatory bowel disease ,Cytokine Receptor Common beta Subunit ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Crohn Disease ,medicine ,Humans ,Immunology and Allergy ,Missense mutation ,Child ,STAT5 ,biology ,business.industry ,Gastroenterology ,Granulocyte-Macrophage Colony-Stimulating Factor ,Infant ,Prognosis ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Granulocyte macrophage colony-stimulating factor ,Cytokine ,Receptors, Granulocyte-Macrophage Colony-Stimulating Factor ,Case-Control Studies ,Child, Preschool ,Immunology ,biology.protein ,Female ,030211 gastroenterology & hepatology ,Original Clinical Articles ,Transcriptome ,business ,Follow-Up Studies ,medicine.drug - Abstract
Author(s): Denson, Lee A; Jurickova, Ingrid; Karns, Rebekah; Shaw, Kelly A; Cutler, David J; Okou, David; Valencia, C Alexander; Dodd, Anne; Mondal, Kajari; Aronow, Bruce J; Haberman, Yael; Linn, Aaron; Price, Adam; Bezold, Ramona; Lake, Kathleen; Jackson, Kimberly; Walters, Thomas D; Griffiths, Anne; Baldassano, Robert N; Noe, Joshua D; Hyams, Jeffrey S; Crandall, Wallace V; Kirschner, Barbara S; Heyman, Melvin B; Snapper, Scott; Guthery, Stephen L; Dubinsky, Marla C; Leleiko, Neal S; Otley, Anthony R; Xavier, Ramnik J; Stevens, Christine; Daly, Mark J; Zwick, Michael E; Kugathasan, Subra | Abstract: BACKGROUND:Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS:Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS:We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P l 0.0001). CONCLUSIONS:Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.
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- 2018
35. Recommendations for Diagnosis and Management of Autoimmune Pancreatitis in Childhood: Consensus From INSPPIRE
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Maria R. Mascarenhas, Bridget Zimmerman, Steven D. Freedman, Douglas S. Fishman, David A. Piccoli, Isabelle Scheers, Chee Y. Ooi, Mark E. Lowe, Steven L. Werlin, Tanja Gonska, Uzma Shah, Sarah Jane Schwarzenberg, John F. Pohl, Emily R. Perito, Ryan Himes, Matthew J. Giefer, David M. Troendle, Quin Liu, Maisam Abu-El-Haija, Melvin B. Heyman, Aliye Uc, Sohail Z. Husain, Cheryl E. Gariepy, Veronique D. Morinville, Tom K. Lin, Bradley A. Barth, Michael Wilschanski, and Joseph J. Palermo
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medicine.medical_specialty ,education ,pancreatitis ,MEDLINE ,lymphoplasmacytic sclerosing pancreatitis ,Medical and Health Sciences ,Article ,Autoimmune Diseases ,idiopathic duct-centric pancreatitis ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,children ,medicine ,Humans ,Child ,Intensive care medicine ,Autoimmune pancreatitis ,Pediatric ,Pancreas disorder ,Gastroenterology & Hepatology ,Extramural ,business.industry ,Gastroenterology ,medicine.disease ,autoimmune pancreatitis ,Pancreatitis ,030220 oncology & carcinogenesis ,recommendations ,Pediatrics, Perinatology and Child Health ,030211 gastroenterology & hepatology ,Digestive Diseases ,business - Abstract
OBJECTIVES:Autoimmune pancreatitis (AIP) represents a complex immune-mediated pancreas disorder. Pediatric AIP (P-AIP) is rare. We have recently summarized the characteristic features of P-AIP. We now aim to develop recommendation statements to standardize the diagnostic and therapeutic approach to P-AIP and facilitate future research in the field. METHODS:A panel of pediatric gastroenterologists participating in the International Study Group of Pediatric Pancreatitis: In search for a cuRE was formed to discuss and then vote on 15 recommendation statements. A consensus of at least 80% was obtained following 3 voting rounds and revision of the statements. RESULTS:We have now generated 15 statements to help standardize the approach to diagnosis and management of P-AIP. CONCLUSIONS:The first P-AIP recommendation statements developed by the International Study Group of Pediatric Pancreatitis: In search for a cuRE group are intended to bring standardization to the diagnosis and treatment of this rare childhood disorder. These statements may help guide a uniform approach to patient care and facilitate future research studies.
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- 2018
36. Depression Predicts Prolonged Length of Hospital Stay in Pediatric Inflammatory Bowel Disease
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Matthew S. Pantell, Melvin B. Heyman, Sofia G. Verstraete, and Perseus V Patel
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Male ,Parenteral Nutrition ,Databases, Factual ,Cross-sectional study ,Crohn's Disease ,Hospitalized ,Inflammatory bowel disease ,inpatient ,Medical and Health Sciences ,Oral and gastrointestinal ,0302 clinical medicine ,Medicine ,Child ,Depression (differential diagnoses) ,Cancer ,Pediatric ,education.field_of_study ,Depression ,Gastroenterology ,Crohn disease ,Ulcerative colitis ,Mental Health ,030211 gastroenterology & hepatology ,Female ,Patient Safety ,medicine.medical_specialty ,Psychometrics ,Adolescent ,Population ,Autoimmune Disease ,Article ,03 medical and health sciences ,Databases ,Clinical Research ,030225 pediatrics ,Internal medicine ,Humans ,education ,Factual ,Retrospective Studies ,ulcerative colitis ,Depressive Disorder ,Gastroenterology & Hepatology ,business.industry ,Inflammatory Bowel Disease ,Retrospective cohort study ,Odds ratio ,Length of Stay ,medicine.disease ,Inflammatory Bowel Diseases ,United States ,Parenteral nutrition ,Cross-Sectional Studies ,Pediatrics, Perinatology and Child Health ,business ,Digestive Diseases ,Child, Hospitalized - Abstract
Objective Few studies report the impact of depression on inflammatory bowel disease (IBD)-related hospitalizations. We evaluated the association between depression and pediatric IBD-related hospitalizations. Our primary aim was to test the hypothesis that depression is associated with hospital length of stay (LOS); our secondary goal was to evaluate if patients with depression are at higher risk for undergoing additional imaging and procedures. Methods Data were extracted from the 2012 Kids Inpatient Database (KID), the largest nationally representative publicly available all-payer pediatric inpatient cross-sectional database in the United States. Hospitalizations for patients less than 21 years with a primary diagnosis Crohn disease (CD) or ulcerative colitis (UC) by ICD-9 code were included. Multivariable logistic regression was used to predict long LOS controlling for patient- and hospital-level variables and for potential disease confounders. Results For primary IBD-related hospitalizations (N = 8222), depression was associated with prolonged LOS (odds ratio [OR] 1.50; 95% confidence interval [CI] 1.19-1.90) and total parenteral nutrition use (OR 1.54; 95% CI 1.04-2.27). Depression was not associated with increased likelihood of surgery (OR 0.97; 95% CI 0.72-1.30), endoscopy (OR 0.91; 95% CI 0.74-1.14), blood transfusion (OR 0.85; 95% CI 0.58-1.23), or abdominal imaging (OR 1.15; 95% CI 0.53-2.53). Conclusions Depression is associated with prolonged LOS in pediatric patients with IBD, even when controlling for gastrointestinal disease severity. Future research evaluating the efficacy of standardized depression screening and early intervention may be beneficial to improving inpatient outcomes in this population.
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- 2019
37. Factors Associated With Frequent Opioid Use in Children With Acute Recurrent and Chronic Pancreatitis
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Steven L. Werlin, Tonya M. Palermo, Matthew J. Giefer, Sarah Jane Schwarzenberg, Sohail Z. Husain, Tom K. Lin, Uzma Shah, David M. Troendle, Michael Wilschanski, Asim Maqbool, Emily R. Perito, Tanja Gonska, Cheryl E. Gariepy, Sue Rhee, Brian A. McFerron, Chee Y. Ooi, Maria R. Mascarenhas, Ryan Himes, Miriam B. Zimmerman, Veronique D. Morinville, Bradley A. Barth, Steven D. Freedman, Jaime D. Nathan, Quin Liu, Mark E. Lowe, Douglas S. Fishman, John F. Pohl, Melvin B. Heyman, Aliye Uc, Melena D. Bellin, Yuhua Zheng, and Maisam Abu-El-Haija
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Male ,Multivariate analysis ,pancreatitis ,Psychological intervention ,Medical and Health Sciences ,0302 clinical medicine ,Recurrence ,Odds Ratio ,Child ,Pediatric ,Analgesics ,Emergency Service ,Pain Research ,Gastroenterology ,Chronic pain ,Analgesics, Opioid ,Hospitalization ,Phenotype ,Cohort ,Acute Disease ,030211 gastroenterology & hepatology ,Female ,Chronic Pain ,Emergency Service, Hospital ,medicine.drug ,medicine.medical_specialty ,Adolescent ,Opioid ,Article ,Hospital ,03 medical and health sciences ,Clinical Research ,030225 pediatrics ,Internal medicine ,medicine ,Humans ,Pain Management ,Gastroenterology & Hepatology ,business.industry ,Prevention ,opioids ,Odds ratio ,Patient Acceptance of Health Care ,medicine.disease ,Confidence interval ,Abdominal Pain ,Good Health and Well Being ,Cross-Sectional Studies ,Pancreatitis ,pain medication ,Pediatrics, Perinatology and Child Health ,Chronic Disease ,business - Abstract
ObjectivesThe aim of the study was to understand the association of frequent opioid use with disease phenotype and pain pattern and burden in children and adolescents with acute recurrent (ARP) or chronic pancreatitis (CP).MethodsCross-sectional study of children
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- 2019
38. Clinical and Genomic Correlates of Neutrophil Reactive Oxygen Species Production in Pediatric Patients With Crohn’s Disease
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Ramona Bezold, Anne Dodd, Rebekah Karns, Yael Haberman, David J. Cutler, Ramnik J. Xavier, Scott B. Snapper, Neal S. Leleiko, Ingrid Jurickova, Michael E. Zwick, Christine Stevens, Anne M. Griffiths, Anthony R. Otley, Aaron Linn, Jeffrey S. Hyams, Robert N. Baldassano, David T. Okou, Kathleen Lake, Thomas D. Walters, Adam Price, Subra Kugathasan, Wallace Crandall, Marla Dubinsky, Joshua D. Noe, Stephen L. Guthery, Kathryn Quinn, Melvin B. Heyman, Kajari Mondal, Kimberly Jackson, Lee A. Denson, Kelly A Shaw, Barbara S. Kirschner, Mark J. Daly, and Bruce J. Aronow
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Male ,0301 basic medicine ,Neutrophils ,Crohn's Disease ,Gene mutation ,Inflammatory bowel disease ,Whole Exome Sequencing ,Cohort Studies ,Chronic granulomatous disease ,Crohn Disease ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Pediatric ,Crohn's disease ,NADPH oxidase ,biology ,Gastroenterology ,Up-Regulation ,Phenotype ,Child, Preschool ,Genetic Variant ,WES ,Female ,Tumor necrosis factor alpha ,Sequence Analysis ,Adolescent ,Neutrophil Oxidative Burst ,IBD ,Clinical Sciences ,Mutation, Missense ,Down-Regulation ,Autoimmune Disease ,Article ,Paediatrics and Reproductive Medicine ,03 medical and health sciences ,Clinical Research ,Exome Sequencing ,Genetics ,medicine ,Humans ,CYBB ,Preschool ,Gene ,Alleles ,Gastroenterology & Hepatology ,Hepatology ,Sequence Analysis, RNA ,business.industry ,Gene Expression Profiling ,Inflammatory Bowel Disease ,Neurosciences ,Infant ,NADPH Oxidases ,medicine.disease ,Glucose ,030104 developmental biology ,Mutation ,Immunology ,biology.protein ,RNA ,Missense ,Reactive Oxygen Species ,Digestive Diseases ,business - Abstract
Background & aimsIndividuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's disease (CD). We tested for associations between mutations in genes encoding reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, neutrophil function, and phenotypes of CD in pediatric patients.MethodsWe performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases. Blood samples were collected from an additional 129 pediatric patients with CD and 26 children without IBD (controls); we performed assays for neutrophil activation, reactive oxygen species (ROS) production, and bacteria uptake and killing. Whole-exome sequence analysis was performed using DNA from 46 of the children with CD to examine associations with NADPH gene mutations; RNA sequence analyses were performed using blood cells from 46 children with CD to test for variations in neutrophil gene expression associated with ROS production.ResultsWe identified 26 missense mutations in CYBA, CYBB, NCF1, NCF2, and NCF4. Patients with CD who carried mutations in these genes were 3-fold more likely to have perianal disease (P= .0008) and stricturing complications (P= .002) than children with CD without these mutations. Among patients withCD with none of these mutations, 9% had undergone abdominal surgery; among patients with mutations in these NADPH oxidase genes, 31% had undergone abdominal surgery (P=.0004). A higher proportion of neutrophils from children with CD had low ROS production (47%) than from controls (15%) among the 129 patients tested for ROS (P= .002). Minor alleles of the NADPH genes were detected in 7% of children with CD whose neutrophils produced normal levels of ROS vs 38% of children whose neutrophils produced low levels of ROS (P= .009). Neutrophils that produced low levels of ROS had specific alterations in genes that regulate glucose metabolism and antimicrobial responses.ConclusionsWe identified missense mutations in genes that encode NADPH oxidases in children with CD; these were associated with a more aggressive disease course and reduced ROS production by neutrophils from the patients.
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- 2018
39. Sphingosine-1-Phosphate Signaling and Metabolism Gene Signature in Pediatric Inflammatory Bowel Disease: A Matched-case Control Pilot Study
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Ginny Gildengorin, K.T. Park, Julie D. Saba, Melissa Irek, Ashish S. Patel, Melvin B. Heyman, Jung H. Suh, Mala Setty, Neil E. Hubbard, Alexis Rodriguez, Sofia G. Verstraete, Emilie Degagné, Alexander D. Borowsky, and Elizabeth E. Gleghorn
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Male ,0301 basic medicine ,Gene Expression ,Pilot Projects ,Crohn's Disease ,Disease ,Inflammatory bowel disease ,Gastroenterology ,Oral and gastrointestinal ,chemistry.chemical_compound ,0302 clinical medicine ,Sphingosine ,Tandem Mass Spectrometry ,2.1 Biological and endogenous factors ,Immunology and Allergy ,Aetiology ,Child ,S1PR1 ,Pediatric ,Chromatography ,Liquid ,education.field_of_study ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,lipids (amino acids, peptides, and proteins) ,Signal Transduction ,medicine.medical_specialty ,Adolescent ,Colon ,Clinical Sciences ,Population ,Ceramides ,Autoimmune Disease ,Young Adult ,03 medical and health sciences ,Clinical Research ,inflammatory bowel disease ,Internal medicine ,Genetics ,medicine ,Animals ,Humans ,Sphingosine-1-phosphate ,Preschool ,education ,sphingolipids ,Gastroenterology & Hepatology ,business.industry ,Case-control study ,Infant ,Gene signature ,Inflammatory Bowel Diseases ,medicine.disease ,Sphingolipid ,digestive system diseases ,030104 developmental biology ,chemistry ,Case-Control Studies ,sphingosine-1-phosphate ,Lysophospholipids ,Original Clinical Articles ,Digestive Diseases ,business ,Chromatography, Liquid - Abstract
Goal The aim of this study was to investigate gene expression levels of proteins involved in sphingosine-1-phosphate (S1P) metabolism and signaling in a pediatric inflammatory bowel disease (IBD) patient population. Background IBD is a debilitating disease affecting 0.4% of the US population. The incidence of IBD in childhood is rising. Identifying effective targeted therapies that can be used safely in young patients and developing tools for selecting specific candidates for targeted therapies are important goals. Clinical IBD trials now underway target S1PR1, a receptor for the pro-inflammatory sphingolipid S1P. However, circulating and tissue sphingolipid levels and S1P-related gene expression have not been characterized in pediatric IBD. Methods Pediatric IBD patients and controls were recruited in a four-site study. Patients received a clinical score using PUCAI or PCDAI evaluation. Colon biopsies were collected during endoscopy. Gene expression was measured by qRT-PCR. Plasma and gut tissue sphingolipids were measured by LC-MS/MS. Results Genes of S1P synthesis (SPHK1, SPHK2), degradation (SGPL1), and signaling (S1PR1, S1PR2, and S1PR4) were significantly upregulated in colon biopsies of IBD patients with moderate/severe symptoms compared with controls or patients in remission. Tissue ceramide, dihydroceramide, and ceramide-1-phosphate (C1P) levels were significantly elevated in IBD patients compared with controls. Conclusions A signature of elevated S1P-related gene expression in colon tissues of pediatric IBD patients correlates with active disease and normalizes in remission. Biopsied gut tissue from symptomatic IBD patients contains high levels of pro-apoptotic and pro-inflammatory sphingolipids. A combined analysis of gut tissue sphingolipid profiles with this S1P-related gene signature may be useful for monitoring response to conventional therapy.
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- 2018
40. Maternal Obesity and Risk of Preterm Birth and Low Birthweight in Hawaii PRAMS, 2000–2011
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Janet M. Wojcicki, Andrea K. Garber, Alana C. Ju, and Melvin B. Heyman
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Adult ,medicine.medical_specialty ,Native Hawaiian or Other Pacific Islander ,Adolescent ,Epidemiology ,Maternal Health ,Population ,Hawaii ,Cohort Studies ,03 medical and health sciences ,0302 clinical medicine ,Pregnancy ,Risk Factors ,Prevalence ,Birth Weight ,Humans ,Medicine ,Obesity ,030212 general & internal medicine ,Risk factor ,education ,Socioeconomic status ,Retrospective Studies ,education.field_of_study ,030219 obstetrics & reproductive medicine ,business.industry ,Obstetrics ,Confounding ,Infant, Newborn ,Public Health, Environmental and Occupational Health ,Obstetrics and Gynecology ,Retrospective cohort study ,Infant, Low Birth Weight ,medicine.disease ,Low birth weight ,Cross-Sectional Studies ,Pediatrics, Perinatology and Child Health ,Premature Birth ,Pacific islanders ,Female ,medicine.symptom ,business - Abstract
Objective Maternal obesity is a risk factor for preterm birth, a leading cause of infant morbidity and mortality. Native Hawaiian and other Pacific Islanders (NHOPI) have high rates of poor birth outcomes. Despite the high rates of obesity in NHOPI in Hawaii, the association with preterm birth has not been examined in this population. Methods We performed a retrospective cohort study of 20,061 women using data collected by Hawaii’s Pregnancy Risk Assessment Monitoring System (PRAMS) from 2000 to 2011. We investigated the contribution of maternal age, pre-pregnancy BMI, gestational diabetes, hypertension, race, socioeconomic status, and smoking to our primary outcomes of preterm birth and low birthweight using multivariable logistic regression, stratified by NHOPI versus non-NHOPI race. Results Pre-pregnancy obesity was more common in NHOPI than non-NHOPI women (23.9 and 10.5%, respectively; p
- Published
- 2018
41. Aspiration of a Video Capsule Placed Endoscopically Into the Duodenum Under General Anesthesia
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Marjorie McCracken, Sagar Pathak, and Melvin B. Heyman
- Published
- 2021
42. Chronic maternal depression is associated with reduced weight gain in latino infants from birth to 2 years of age.
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Janet M Wojcicki, Katherine Holbrook, Robert H Lustig, Elissa Epel, Aaron B Caughey, Ricardo F Muñoz, Stephen C Shiboski, and Melvin B Heyman
- Subjects
Medicine ,Science - Abstract
Latino children are at increased risk for mirconutrient deficiencies and problems of overweight and obesity. Exposures in pregnancy and early postpartum may impact future growth trajectories.To evaluate the relationship between prenatal and postnatal maternal depressive symptoms experienced in pregnancy and infant growth from birth to 2 years of age in a cohort of Latino infants.We recruited pregnant Latina mothers at two San Francisco hospitals and followed their healthy infants to 24 months of age. At 6, 12 and 24 months of age, infants were weighed and measured. Maternal depressive symptoms were assessed prenatally and at 4-6 weeks postpartum. Women who had high depressive symptoms at both time periods were defined as having chronic depression. Logistic mixed models were applied to compare growth curves and risk for overweight and underweight based on exposure to maternal depression.We followed 181 infants to 24 months. At 12 and 24 months, respectively, 27.4% and 40.5% were overweight, and 5.6% and 2.2% were underweight. Exposure to chronic maternal depression was associated with underweight (OR = 12.12, 95%CI 1.86-78.78) and with reduced weight gain in the first 2 years of life (Coef = -0.48, 95% CI -0.94-0.01) compared with unexposed infants or infants exposed to episodic depression (depression at one time point). Exposure to chronic depression was also associated with reduced risk for overweight in the first 2 years of life (OR 0.28, 95%CI 0.03-0.92).Exposure to chronic maternal depression in the pre- and postnatal period was associated with reduced weight gain in the first two years of life and greater risk for failure to thrive, in comparison with unexposed infants or those exposed episodically. The infants of mothers with chronic depression may need additional nutritional monitoring and intervention.
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- 2011
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43. Subcutaneous Golimumab in Pediatric Ulcerative Colitis
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Geneviève Veereman, Richard Strauss, Anne M. Griffiths, Daphne Chan, Omoniyi J. Adedokun, Dan Turner, Lakshmi Padgett, Jeffrey S. Hyams, Melvin B. Heyman, Ghassan Wahbeh, Joel R. Rosh, Clinical sciences, and Growth and Development
- Subjects
Male ,medicine.medical_specialty ,Pancolitis ,Adolescent ,Injections, Subcutaneous ,Population ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Refractory ,Interquartile range ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,Tissue Distribution ,Child ,education ,Adverse effect ,education.field_of_study ,business.industry ,Remission Induction ,Antibodies, Monoclonal ,Golimumab ,Clinical trial ,Treatment Outcome ,Child, Preschool ,030220 oncology & carcinogenesis ,Colitis, Ulcerative ,Female ,030211 gastroenterology & hepatology ,medicine.symptom ,business ,Follow-Up Studies ,medicine.drug - Abstract
BACKGROUND: Current treatments for pediatric ulcerative colitis (UC) are limited. We evaluated the pharmacokinetics and clinical benefits of subcutaneous golimumab, an anti-tumor necrosis factor agent, in moderately-to-severely active pediatric patients with UC refractory to conventional therapy. METHODS: We report a multicenter, open-label study of golimumab with a pharmacokinetics phase (week 0-14). Patients had moderately-to-severely active UC and were naive to anti-tumor necrosis factor treatment. At weeks 0 and 2, patients received golimumab induction dosed by weight (
- Published
- 2017
44. MACHINE LEARNING FOR CROHN’S DISEASE PHENOTYPE MODELING USING BIOPSY IMAGES
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Scott B. Snapper, Joel R. Rosh, Shervin Rabizadeh, Ashish S. Patel, Christopher A. Moskaluk, Anne M. Griffiths, Stanley N. Cohen, Erin Bonkowski, Maria Oliva-Hemker, Joshua D. Noe, Dedrick E. Moulton, Richard Kellermayer, Jeffrey S. Hyams, Barbara S. Kirschner, Susan S. Baker, David R. Mack, David Ziring, Lee A. Denson, Sandra C. Kim, Ajay S. Gulati, Lubaina Ehsan, Anthony R. Otley, Subra Kugathasan, Thomas D. Walters, Jennifer L. Dotson, Marian D. Pfefferkorn, Jason Shapiro, Robert N. Baldassano, Saurav Sengupta, Stephen L. Guthery, James Markowitz, Melvin B. Heyman, and Sana Syed
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Crohn's disease ,Pathology ,medicine.medical_specialty ,Hepatology ,medicine.diagnostic_test ,business.industry ,Biopsy ,Gastroenterology ,Medicine ,Immunology and Allergy ,business ,medicine.disease ,Phenotype - Abstract
Background Predicting Crohn’s disease (CD) phenotype development has proven challenging due to difficulties in biopsy image interpretation of histologically similar yet biologically distinct phenotypes. At initial diagnosis, mostly CD patients are classified as B1 (inflammatory behavior), they typically either retain B1 phenotype or develop more complicated B2 (stricturing), B3 (internal penetrating), or B2/B3 phenotypes (defined by Montreal Classification). Prediction of phenotype development based on baseline biopsies can radically improve our clinical care by altering disease management. Biopsy-based image analysis via Convolutional Neural Networks (CNNs) has been successful in cancer detection, but investigation into its utility for CD phenotypes is lacking. We applied a machine learning CNN model to classify CD phenotypes and histologically normal ileal controls. Methods Baseline hematoxylin & eosin (H&E) stained ileal biopsy slides were obtained from the Cincinnati Children’s Hospital Medical Center’s RISK validation sub cohort. At University of Virginia, biopsy slides were digitized, and a ResNet101 CNN model was trained. High resolution images were patched into 1000x1000 pixels with a 50% overlap and then resized to 256x256 pixels for training (80-20 split was kept between training and testing sets to ensure same patient patches were not mixed). Gradient Weighted Activating Mappings (GradCAMs) were used to visualize the model’s decision making process. Results We initially trained the model for CD vs. controls where it achieved 97% accuracy in detecting controls. We further trained it for classifying CD phenotypes (n=16 B1, n=16 B2, n=4 B3, n=13 B2/B3; phenotype decision at 5 year). It displayed a higher accuracy in detecting B2 (85%) while there were overlaps in the detection of other phenotypes (Figure 1). For B2, Grad-CAM heatmaps highlighted central pink areas within the lamina propria as the model’s regions of interests which were present when other phenotypes were misclassified as B2 (Figure 2). Conclusions: Here we highlight the potential utility of a machine learning image analysis model for describing CD phenotypes using H&E stained biopsies. Previous studies have shown B2 to be associated with increased activation for extracellular matrix genes (connective tissue component). Our GradCAM results support this finding as the pink central areas utilized by the model for classifying B2 could be connective tissue. Further confirmation via molecular phenotyping including Sirius Red immunohistochemistry is underway. Our work supports prediction of CD phenotypes using baseline biopsies at diagnosis and has potential to influence individualized care for children with CD.
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- 2021
45. Early Antibiotic Exposure and Risk of Childhood Obesity in Latinos
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Janet M. Wojcicki, Rosalinda Medrano, Melvin B. Heyman, and Annette P. Ville
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Leptin ,Male ,Pediatric Obesity ,Pediatrics ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Cardiovascular ,Weight Gain ,Oral and gastrointestinal ,0302 clinical medicine ,Pregnancy ,Risk Factors ,Surveys and Questionnaires ,Odds Ratio ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Insulin ,Aetiology ,Child ,Cancer ,Pediatric ,Nutrition and Dietetics ,Dietary intake ,Hispanic or Latino ,Fetal Blood ,Anti-Bacterial Agents ,Stroke ,Child, Preschool ,Cord blood ,Cohort ,Female ,social and economic factors ,medicine.medical_specialty ,rapid infant weight gain ,030209 endocrinology & metabolism ,Nursing ,Childhood obesity ,Paediatrics and Reproductive Medicine ,Endocrinology & Metabolism ,03 medical and health sciences ,Clinical Research ,2.3 Psychological ,030225 pediatrics ,medicine ,Humans ,Obesity ,infancy ,Preschool ,Poverty ,Metabolic and endocrine ,Nutrition ,business.industry ,Prevention ,Antibiotic exposure ,Infant ,Original Articles ,medicine.disease ,Diet ,Logistic Models ,Pediatrics, Perinatology and Child Health ,business - Abstract
We investigated the relationship between early antibiotic exposure before 6 months age and risk for obesity at 2 years in a high-risk, low-income, urban Latino cohort (n = 97), with the hypothesis that antibiotic exposure would increase risk for obesity by 2 years. Data were collected through maternal report of infant 24-hour dietary intake at 4-6 weeks, 6 months, 1, and 2 years; and food frequency questionnaires at 4-6 weeks, 6 months, 1, and 2 years. Antibiotic use data, including type and frequency, were collected through maternal self-report at 6 months and 1 year. Cord blood levels of leptin and insulin were measured at birth. Chi-squared tests were used to assess the relationship between obesity and dichotomous predictors and Student's t-tests for continuous predictors. Multivariable logistic models were used to ascertain independent predictors of obesity at age 2. We found that early antibiotic exposure before 6 months was independently associated with increased risk for rapid infant weight gain [odds ratio (OR) 6.42, 95% confidence interval (CI, defined as the range in which sample will fall with 95% confidence: 1.17-35.06)] and obesity at age 2 [OR 6.15, 95% CI (1.03-36.70)]. These findings provide evidence promoting antibiotic stewardship in pediatric practices to minimize exposure in the first 6 months of life.
- Published
- 2017
46. Causal Evaluation of Acute Recurrent and Chronic Pancreatitis in Children: Consensus From the INSPPIRE Group
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Tanja Gonska, Michael Wilschanski, Bradley A. Barth, Ryan Himes, Mark E. Lowe, Steven D. Freedman, Melvin B. Heyman, John F. Pohl, Aliye Uc, Sarah Jane Schwarzenberg, Veronique D. Morinville, Steven L. Werlin, Douglas S. Fishman, Elizabeth H. Yen, Sohail Z. Husain, Chee Y. Ooi, David M. Troendle, Cheryl E. Gariepy, and Matthew J. Giefer
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Pediatrics ,medicine.medical_specialty ,Consensus ,Delphi Technique ,Medical and Health Sciences ,Article ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Clinical Research ,Pancreatitis, Chronic ,medicine ,Humans ,PRSS1 ,Chronic ,CFTR ,Child ,Autoimmune pancreatitis ,Pediatric ,Hereditary pancreatitis ,hereditary pancreatitis ,Gastroenterology & Hepatology ,business.industry ,Gastroenterology ,pancreatic insufficiency ,medicine.disease ,autoimmune pancreatitis ,Pancreatitis ,030220 oncology & carcinogenesis ,Acute Disease ,Pediatrics, Perinatology and Child Health ,Acute recurrent pancreatitis ,030211 gastroenterology & hepatology ,Digestive Diseases ,business - Abstract
ObjectivesAcute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) have been diagnosed in children at increasing rates during the past decade. As pediatric ARP and CP are still relatively rare conditions, little quality evidence is available on which to base the diagnosis and determination of etiology. The aim of the study was to review the current state of the literature regarding the etiology of these disorders and to developed a consensus among a panel of clinically active specialists caring for children with these disorders to help guide the diagnostic evaluation and identify areas most in need of future research.MethodsA systematic review of the literature was performed and scored for quality, followed by consensus statements developed and scored by each individual in the group for level of agreement and strength of the supporting data using a modified Delphi method. Scores were analyzed for the level of consensus achieved by the group.ResultsThe panel reached consensus on 27 statements covering the definitions of pediatric ARP and CP, evaluation for potential etiologies of these disorders, and long-term monitoring. Statements for which the group reached consensus to make no recommendation or could not reach consensus are discussed.ConclusionsThis consensus helps define the minimal diagnostic evaluation and monitoring of children with ARP and CP. Even in areas in which we reached consensus, the quality of the evidence is weak, highlighting the need for further research. Improved understanding of the underlying cause will facilitate treatment development and targeting.
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- 2017
47. Risk Factors for Rapid Progression From Acute Recurrent to Chronic Pancreatitis in Children: Report From INSPPIRE
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Brian A. McFerron, Veronique D. Morinville, Michael Wilschanski, Chee Y. Ooi, Ryan Himes, John F. Pohl, Steven L. Werlin, Tom K. Lin, M. Bridget Zimmerman, David M. Troendle, Mark E. Lowe, Bradley A. Barth, Maisam Abu-El-Haija, Matthew J. Giefer, Melvin B. Heyman, Aliye Uc, Sohail Z. Husain, Emily R. Perito, Jaimie D. Nathan, Asim Maqbool, Maria R. Mascarenhas, Douglas S. Fishman, Cheryl E. Gariepy, Sarah Jane Schwarzenberg, Uzma Shah, Sue Rhee, Quin Y. Liu, Steven D. Freedman, Tanja Gonska, and Melena D. Bellin
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Male ,Medical and Health Sciences ,Cohort Studies ,0302 clinical medicine ,Recurrence ,Risk Factors ,PRSS1 ,Chronic ,Israel ,Child ,Pediatric ,screening and diagnosis ,Diabetes ,Gastroenterology ,Age Factors ,Natural history ,Detection ,natural history ,Child, Preschool ,diabetes mellitus ,Disease Progression ,Regression Analysis ,030211 gastroenterology & hepatology ,Female ,Cohort study ,medicine.medical_specialty ,Canada ,Article ,03 medical and health sciences ,Clinical Research ,030225 pediatrics ,Diabetes mellitus ,Internal medicine ,Pancreatitis, Chronic ,pediatric pancreatitis ,medicine ,Humans ,Preschool ,Survival analysis ,Proportional Hazards Models ,Gastroenterology & Hepatology ,business.industry ,Proportional hazards model ,Prevention ,Australia ,pancreatic insufficiency ,medicine.disease ,Survival Analysis ,United States ,4.1 Discovery and preclinical testing of markers and technologies ,Multicenter study ,Pancreatitis ,Pediatrics, Perinatology and Child Health ,Acute recurrent pancreatitis ,business ,Digestive Diseases - Abstract
ObjectiveThe aim of the study was to determine the rate of progression from acute recurrent pancreatitis (ARP) to chronic pancreatitis (CP) in children and assess risk factors.Study designData were collected from the INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE) cohort. Kaplan-Meier curves were constructed to calculate duration of progression from initial attack of acute pancreatitis (AP) to CP. Log-rank test was used to compare survival (nonprogression) probability distribution between groups. Cox proportional hazard regression models were fitted to obtain hazard ratio (with 95% confidence interval [CI]) of progression for each risk variable.ResultsOf 442 children, 251 had ARP and 191 had CP. The median time of progression from initial attack of AP to CP was 3.79 years. The progression was faster in those ages 6 years or older at the first episode of AP compared to those younger than 6 years (median time to CP: 2.91 vs 4.92 years; P = 0.01). Children with pathogenic PRSS1 variants progressed more rapidly to CP compared to children without PRSS1 variants (median time to CP: 2.52 vs 4.48 years; P = 0.003). Within 6 years after the initial AP attack, cumulative proportion with exocrine pancreatic insufficiency was 18.0% (95% CI: 12.4%, 25.6%); diabetes mellitus was 7.7% (95% CI: 4.2%, 14.1%).ConclusionsChildren with ARP rapidly progress to CP, exocrine pancreatic insufficiency, and diabetes. The progression to CP is faster in children who were 6 years or older at the first episode of AP or with pathogenic PRSS1 variants. The factors that affect the aggressive disease course in childhood warrant further investigation.
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- 2019
48. Designing clinical trials in paediatric inflammatory bowel diseases:a PIBDnet commentary
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Lissy de Ridder, Robert N. Baldassano, William A. Faubion, Marla Dubinsky, Diane R. Mould, Frank M. Ruemmele, Sibylle Koletzko, Athos Bousvaros, Dan Turner, Laurie S. Conklin, David C. Wilson, Anne M. Griffiths, Javier Martín de Carpi, Richard K. Russell, Jeffrey S. Hyams, Melvin B. Heyman, and Pediatrics
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medicine.medical_specialty ,education ,Placebo ,Severity of Illness Index ,Gastrointestinal Agents ,Drug approval ,medicine ,Humans ,Dosing ,Child ,Intensive care medicine ,Drug Approval ,Biological Products ,Clinical Trials as Topic ,Dose-Response Relationship, Drug ,business.industry ,Patient Selection ,Age Factors ,Gastroenterology ,Inflammatory Bowel Diseases ,Viewpoints ,Clinical trial ,Treatment Outcome ,Clinical research ,Research Design ,Position paper ,business - Abstract
IntroductionThe optimal trial design for assessing novel therapies in paediatric IBD (PIBD) is a subject of intense ongoing global discussions and debate among the different stakeholders. However, there is a consensus that the current situation in which most medications used in children with IBD are prescribed as off-label without sufficient paediatric data is unacceptable. Shortening the time lag between adult and paediatric approval of drugs is of the upmost importance. In this position paper we aimed to provide guidance from the global clinical research network (Pediatric Inflammatory Bowel Disease Network, PIBDnet) for designing clinical trials in PIBD in order to facilitate drug approval for children.MethodsA writing group has been established by PIBDnet and topics were assigned to different members. After an iterative process of revisions among the writing group and one face-to-face meeting, all statements have reached consensus of >80% as defined a priori. Next, all core members of PIBDnet voted on the statements, reaching consensus of >80% on all statements. Comments from the members were incorporated in the text.ResultsThe commentary includes 18 statements for guiding data extrapolation from adults, eligibility criteria to PIBD trials, use of placebo, dosing, endpoints and recommendations for feasible trials. Controversial issues have been highlighted in the text.ConclusionThe viewpoints expressed in this paper could assist planning clinical trials in PIBD which are both of high quality and ethical, while remaining pragmatic.
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- 2019
49. Chronic Pancreatitis: Pediatric and Adult Cohorts Show Similarities in Disease Progress Despite Different Risk Factors
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Mark E. Lowe, David C Whitcomb, Matthew J. Giefer, Chris E. Forsmark, Judah Abberbock, Michelle A. Anderson, Bimaljit S. Sandhu, Maria R. Mascarenhas, Stuart Sherman, Brian A. McFerron, Melena D. Bellin, Jaimie D. Nathan, Tom K. Lin, Uzma Shah, Thiruvengadam Muniraj, Maisam Abu-El-Haija, Gregory A. Cote, Douglas S. Fishman, Melvin B. Heyman, Aliye Uc, Sue Rhee, Adam Slivka, Asim Maqbool, C. Mel Wilcox, Sarah Jane Schwarzenberg, Gong Tang, Vikesh K. Singh, Bradley A. Barth, Emily R. Perito, Veronique D. Morinville, Bridget Zimmerman, Andres Gelrud, John F. Pohl, Sohail Z. Husain, Steven D. Freedman, Ryan Himes, Stephen T. Amann, Tanja Gonska, Michael Wilschanski, Timothy B. Gardner, Randall E. Brand, Cheryl E. Gariepy, Samer Alkaade, Darwin L. Conwell, Steven L. Werlin, Peter A. Banks, Joseph Romagnuolo, Michele D. Lewis, Chee Y. Ooi, Dhiraj Yadav, David M. Troendle, Nalini M. Guda, and Quin Liu
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Male ,Pediatrics ,Cross-sectional study ,Disease ,Medical and Health Sciences ,Oral and gastrointestinal ,environmental ,Cohort Studies ,0302 clinical medicine ,Risk Factors ,Surveys and Questionnaires ,Medicine ,2.1 Biological and endogenous factors ,pain ,Chronic ,Aetiology ,Child ,Pediatric ,diabetes ,Gastroenterology ,Middle Aged ,Natural history ,6.1 Pharmaceuticals ,Disease Progression ,030211 gastroenterology & hepatology ,Female ,Cohort study ,Adult ,medicine.medical_specialty ,Alcohol Drinking ,Adolescent ,MEDLINE ,Article ,03 medical and health sciences ,children ,Clinical Research ,Pancreatitis, Chronic ,030225 pediatrics ,Tobacco Smoking ,Humans ,Genetic Predisposition to Disease ,endoscopy ,Demography ,Gastroenterology & Hepatology ,business.industry ,Prevention ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,Cross-Sectional Studies ,Good Health and Well Being ,Socioeconomic Factors ,Pancreatitis ,Pediatrics, Perinatology and Child Health ,North America ,Age of onset ,Disease progress ,genetic ,business ,Digestive Diseases - Abstract
ObjectivesThe aim of the present study was to investigate the natural history of chronic pancreatitis (CP); patients in the North American Pancreatitis Study2 (NAPS2, adults) and INternational Study group of Pediatric Pancreatitis: In search for a cuRE (INSPPIRE, pediatric) were compared.MethodsDemographics, risk factors, disease duration, management and outcomes of 224 children and 1063 adults were compared using appropriate statistical tests for categorical and continuous variables.ResultsAlcohol was a risk in 53% of adults and 1% of children (P
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- 2019
50. Age-of-diagnosis dependent ileal immune intensification and reduced alpha-defensin in older versus younger pediatric Crohn Disease patients despite already established dysbiosis
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David Ziring, Stanley N. Cohen, Scott B. Snapper, Melvin B. Heyman, David J. Keljo, Jonathan Evans, Bruce J. Aronow, Richard Kellermayer, Dedrick E. Moulton, Steven J. Steiner, Mi-Ok Kim, Susan S. Baker, David R. Mack, Melanie Schirmer, Thomas D. Walters, Curtis Huttenhower, Joshua D. Noe, Barbara S. Kirschner, Phillip Dexheimer, Maria Oliva-Hemker, Lee A. Denson, Wallace Crandall, Ajay S. Gulati, Joel R. Rosh, James Markowitz, Yael Haberman, Robert N. Baldassano, Tzipi Braun, Stephen L. Guthery, Anne M. Griffiths, Ramnik J. Xavier, Jeffrey S. Hyams, Neal S. Leleiko, Marla Dubinsky, Subramaniam Kugathasan, Rebekah Karns, Anthony Otley, and Ashish S. Patel
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0301 basic medicine ,Male ,Aging ,Disease ,Medical and Health Sciences ,Alpha defensin ,immune response ,Pathogenesis ,Cohort Studies ,Peyer's Patches ,0302 clinical medicine ,Crohn Disease ,Immunology and Allergy ,2.1 Biological and endogenous factors ,Aetiology ,Child ,Pediatric ,Age Factors ,Biological Sciences ,medicine.anatomical_structure ,Pediatric age-of-diagnosis ,Child, Preschool ,mucosal microbial profile and transcriptome ,Female ,Risk ,alpha-Defensins ,Adolescent ,Immunology ,digestive system ,Article ,03 medical and health sciences ,Immune system ,Ileum ,Clinical Research ,medicine ,Genetics ,Humans ,Preschool ,business.industry ,Prevention ,Lachnospiraceae ,Puberty ,Inflammatory Bowel Disease ,Gene signature ,Th1 Cells ,medicine.disease ,030104 developmental biology ,Gene Expression Regulation ,Paneth cell ,Dysbiosis ,business ,Digestive Diseases ,030215 immunology - Abstract
Age-of-diagnosis associated variation in disease location and antimicrobial sero-reactivity has suggested fundamental differences in pediatric Crohn Disease (CD) pathogenesis. This variation may be related to pubertal peak incidence of ileal involvement and Peyer’s patches maturation, represented by IFNγ-expressing Th1 cells. However, direct mucosal evidence is lacking. We characterize the global pattern of ileal gene expression and microbial communities in 525 treatment-naive pediatric CD patients and controls (Ctl), stratifying samples by their age-of-diagnosis. We show a robust ileal gene signature notable for higher expression of specific immune genes including GM-CSF and INFγ, and reduced expression of antimicrobial Paneth cell α-defensins, in older compared to younger patients. Reduced α-defensin expression in older patients was associated with higher IFNγ expression. By comparison, the CD-associated ileal dysbiosis, characterized by expansion of Enterobacteriaceae and contraction of Lachnospiraceae and Ruminococcaceae, was already established within the younger group and did not vary systematically with increasing age-of-diagnosis. Multivariate analysis considering individual taxa, however did demonstrate negative associations between Lachnospiraceae and IFNγ, and positive associations between Bacteroides and α-defensin expression. These data provide evidence for maturation of mucosal Th1 immune responses and loss of epithelial antimicrobial α-defensins which are associated with specific taxa with increasing age-of-diagnosis in pediatric CD.
- Published
- 2019
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