Publications by authors named "Raanan Shamir"

334 Publications

Children with Intestinal Failure Maintain Their Renal Function on Long-Term Parenteral Nutrition.

Nutrients 2021 Oct 18;13(10). Epub 2021 Oct 18.

Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva 4920235, Israel.

Background: Long-term parenteral nutrition (PN) has been associated with renal complications, including hypercalciuria, nephrocalcinosis, proteinuria and reduced glomerular filtration rate (GFR). Pediatric data are scarce and mostly short-term. Our study aimed to evaluate renal complications in children with intestinal failure (IF) receiving long-term PN.

Methods: A cross-sectional study was performed in a tertiary pediatric IF clinic of patients receiving home-PN treatment for more than 1 year. Data regarding medical background, anthropometrics, laboratory investigations and abdominal sonography were retrieved.

Results: Complete data were available for 15 children (67% males), with a median age of 6 (range 1.5-15) years and a median (IQR) PN duration of 4 (1.5-6) years. Low-grade proteinuria was identified in 61% and microalbuminuria in 30% of the cohort. Hypercalciuria and hyperoxaluria were present in 50% and 46%, respectively. One patient had nephrocalcinosis. The estimated GFR was normal in all but one patient who had pre-existing kidney disease.

Conclusions: Pediatric IF patients can present with preserved kidney function after years of PN treatment. Despite the high prevalence of hypercalciuria, nephrocalcinosis was not common. Base line and long-term monitoring of various aspects of renal function would be essential to characterize the effects of prolonged PN on kidney functions in pediatric patients.
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http://dx.doi.org/10.3390/nu13103647DOI Listing
October 2021

Is fundoplication mandatory in children with neurological impairment undergoing gastrostomy?

J Paediatr Child Health 2021 Oct 11. Epub 2021 Oct 11.

Department of Pediatric and Adolescent Surgery, Schneider Children's Medical Center of Israel, Petah-Tiqva, Israel.

Aim: Percutaneous endoscopic gastrostomy (PEG) and surgical gastrostomy (SG) are common procedures in children with neurological impairment (NI) with swallowing difficulties. Pulmonary aspirations are a major concern and performing concomitant or delayed fundoplication is still controversial, especially among these patients. The aim of our study was to review our experience with fundoplication performed concomitantly with gastrostomy or later and to evaluate patient outcomes.

Methods: This is a retrospective, cohort study including all paediatric patients who underwent SG or PEG with or without Nissen fundoplication at Schneider Children's Medical Center of Israel between the years 2007 and 2018. Patients' clinical and surgical data were recorded and analysed.

Results: Between 2007 and 2018, 345 patients underwent SG or PEG. Of these, 89 patients underwent fundoplication. Of the patients who underwent PEG/SG, 158 (45.8%) were neurologically impaired. Most of the patients who underwent fundoplication (n = 69, 77.5%) were NI patients (P = 0.0001). NI patients with refractory seizures showed almost no improvement in terms of relief of gastro-oesophageal reflux disease symptoms following fundoplication (P = 0.0001) compared to NI patients without refractory seizures.

Conclusion: Our findings suggest that in NI patients a concomitant fundoplication is not mandatory and is not efficacious in preventing gastro-oesophageal reflux disease in patients with refractory seizures.
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http://dx.doi.org/10.1111/jpc.15767DOI Listing
October 2021

Reply to: Postbiotics - when simplification fails to clarify.

Nat Rev Gastroenterol Hepatol 2021 Sep 23. Epub 2021 Sep 23.

Instituto de Lactología Industrial (CONICET-UNL), Faculty of Chemical Engineering, National University of Litoral, Santa Fe, Argentina.

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http://dx.doi.org/10.1038/s41575-021-00522-5DOI Listing
September 2021

Research priorities in pediatric parenteral nutrition: a consensus and perspective from ESPGHAN/ESPEN/ESPR/CSPEN.

Pediatr Res 2021 Sep 2. Epub 2021 Sep 2.

Department of Neonatology, La Paz University Hospital, Red De Salud Materno Infantil Y Desarrollo E Samid, Universidad Autonoma De Madrid, Madrid, Spain.

Parenteral nutrition is used to treat children that cannot be fully fed by the enteral route. While the revised ESPGHAN/ESPEN/ESPR/CSPEN pediatric parenteral nutrition guidelines provide clear guidance on the use of parenteral nutrition in neonates, infants, and children based on current available evidence, they have helped to crystallize areas where research is lacking or more studies are needed in order to refine recommendations. This paper collates and discusses the research gaps identified by the authors of each section of the guidelines and considers each nutrient or group of nutrients in turn, together with aspects around delivery and organization. The 99 research priorities identified were then ranked in order of importance by clinicians and researchers working in the field using a survey methodology. The highest ranked priority was the need to understand the relationship between total energy intake, rapid catch-up growth, later metabolic function, and neurocognitive outcomes. Research into the optimal intakes of macronutrients needed in order to achieve optimal outcomes also featured prominently. Identifying research priorities in PN should enable research to be focussed on addressing key issues. Multicentre trials, better definition of exposure and outcome variables, and long-term metabolic and developmental follow-up will be key to achieving this. IMPACT: The recent ESPGHAN/ESPEN/ESPR/CSPEN guidelines for pediatric parenteral nutrition provided updated guidance for providing parenteral nutrition to infants and children, including recommendations for practice. However, in several areas there was a lack of evidence to guide practice, or research questions that remained unanswered. This paper summarizes the key priorities for research in pediatric parenteral nutrition, and ranks them in order of importance according to expert opinion.
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http://dx.doi.org/10.1038/s41390-021-01670-9DOI Listing
September 2021

Efficacy and Safety of Enteral Recombinant Human Insulin for Reduction of Time-to-Full Enteral Feeding in Preterm Infants: A Randomized, Double-blind, Placebo-Controlled Trial.

Isr Med Assoc J 2021 Sep;23(9):563-568

Institute for Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Petah Tikva, Israel.

Background: Infants born very prematurely have functionally and structurally immature gastrointestinal tracts.

Objectives: To assess the safety and tolerability of administration of enteral recombinant human (rh) insulin on formula fed preterm infants and to assess whether enteral administration of rh-insulin enhances gastrointestinal tract maturation by reducing the time to reach full enteral feeding.

Methods: A phase 2, multicenter, double-blind, placebo-controlled, randomized study was conducted. Premature infants (26-33 weeks gestation) were randomized 1:1 to receive insulin 400 μU/ml mixed with enteral feeding or placebo added to their formula. The primary efficacy outcome measure was the number of days required to achieve full enteral feeding. Safety outcomes included adverse events and blood glucose levels.

Results: The study consisted of 33 infants randomized for the safety population and 31 for efficacy analysis. The mean time to full enteral feeding was 6.37 days (95% confidence interval [95%CI] 4.59-8.15) in the enteral rh-insulin treatment group (n=16) and 8.00 days (95%CI 6.20-9.80) in the placebo group (n=15), which represents a statistically significant reduction of 1.63 days (95%CI 0.29-2.97; P = 0.023). There was no difference in blood glucose levels between the groups and none of the participants experienced hypoglycemia. Adverse events occurred in 9/17 (53%) infants in the enteral rh-insulin group and 12/16 (75%) in the placebo group.

Conclusions: Our trial demonstrated that administration of enteral rh-insulin as supplement to enteral nutrition significantly reduced time to achieve full enteral feeding in preterm infants with a gestational age of 26-33 weeks.
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September 2021

Overall Impact of COVID-19 Outbreak in Children with Functional Abdominal Pain Disorders: Results From the First Pandemic Phase.

J Pediatr Gastroenterol Nutr 2021 Aug 19. Epub 2021 Aug 19.

Department of Woman, Child and General and Specialistic Surgery, University of Campania "Luigi Vanvitelli", Napoli, Italy Department of Translational Medical Science, Section of Pediatrics, University of Naples "Federico II" Division of Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA Institute of Pediatric Gastroenterology, Nutrition, and Liver Diseases, Schneider Children's Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel Boston Children's Hospital, Harvard medical School, Boston, MA, USA Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital/Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Objective: We aimed to assess how the first phase of COVID-19 pandemic influenced symptoms in children with functional abdominal pain disorders (FAPDs) and to characterize their quality of life (QoL), anxiety and global health.

Methods: This was a multicenter, observational, international study conducted between April and July 2020 at 6 different referral centers. Children diagnosed with FAPDs between October 2019 and February 2020 were enrolled and prospectively interviewed at 4 months of follow-up during the first pandemic phase (Quarantine group). Patients were asked to complete PedsQL 4.0 Generic Core Scale and PROMIS Anxiety and Global Health questionnaires. A cohort of children diagnosed with FAPDs between October 2018 and February 2019 was used as a Control group.

Results: Three-hundred-fifty-six children were enrolled of whom 180 (Mean age at diagnosis: 14  ±  2.8 years) in the Quarantine group and 176 (Mean age at diagnosis: 13  ±  2.8 years) in the Control group. At 4 months of follow-up, we observed a significant reduction of children reporting ≥5 episodes of abdominal pain per month when compared to baseline, in both groups (Quarantine group: 63.9% vs 42.2%, p < 0.001; Control group: 83.5% vs 50%, p < 0.001). The Quarantine group had median QoL values of 84.8 with 16.6% of children showing high anxiety values and 55% having decreased global health score.

Conclusions: We demonstrated symptoms' improvement at 4 months of follow-up in both cohorts. During the first months of the COVID-19 quarantine children with FAPDs showed satisfactory QoL and anxiety scores, suggesting positive effects of school closure and increased parental attention.
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http://dx.doi.org/10.1097/MPG.0000000000003286DOI Listing
August 2021

Nutrition and Growth in Chronic Disease.

World Rev Nutr Diet 2021 5;123:108-121. Epub 2021 Aug 5.

Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.

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http://dx.doi.org/10.1159/000516457DOI Listing
August 2021

Preface.

World Rev Nutr Diet 2021 5;123:IX-X. Epub 2021 Aug 5.

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http://dx.doi.org/10.1159/000516451DOI Listing
August 2021

Effect of a nutritional supplementation on growth and body composition in short and lean preadolescent boys: A randomised, double-blind, placebo-controlled study.

Acta Paediatr 2021 Aug 4. Epub 2021 Aug 4.

National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, Petah Tikva, Israel.

Aim: To evaluate the effect of nutritional supplementation on height, weight and body composition in short and lean male preadolescents.

Methods: A randomised, double-blinded, placebo-controlled trial of nutritional supplementation of short and lean prepubertal 10-14.5-year-old boys. Primary outcomes included Δheight-SDS and Δweight-SDS. Secondary outcomes included changes in body composition and BMI-SDS.

Results: Of 160 boys enrolled, 126 (80%) completed 6 months' intervention. Baseline age, height-SDS, weight-SDS, BMI-SDS, body composition and dietary intake were similar in the formula and placebo groups. 'Good' formula consumers (intake of ≥50% of the recommended dose, n = 30) gained significantly more in weight-SDS, BMI-SDS, fat-free-mass and muscle mass (p < 0.05) than did 'poor' consumers (n = 35) and the placebo group (n = 61). Only in the formula group, positive dose-response correlations were found between consumption of the formula and changes in the outcome parameters examined, including Δheight-SDS (r = 0.301, p = 0.015). Boys aged >11.4 years who were 'good' formula consumers maintained their Δheight-SDS, while Δheight-SDS declined in 'poor' consumers and the placebo group of the same age (p = 0.033).

Conclusion: Intervention with a multi-nutrient, protein-rich formula was effective in increasing weight-SDS, fat-free-mass, muscle mass and BMI-SDS in short and lean prepubertal male adolescents. Good consumption of the formula prevented Δheight-SDS decline in the older participants.
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http://dx.doi.org/10.1111/apa.16054DOI Listing
August 2021

High anti-TNFα Concentrations are Not Associated With More Adverse Events in Pediatric Inflammatory Bowel Disease.

J Pediatr Gastroenterol Nutr 2021 Jul 20. Epub 2021 Jul 20.

The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv Israel The institute of Gastroenterology, Nutrition and Liver diseases, Schneider Children's Hospital, Petach-Tikva, Israel The Ben-Gurion University of the Negev, Beer Sheva, Israel.

Abstract: Anti-tumor necrosis factor alpha (anti-TNFα) therapy is commonly used to treat refractory pediatric inflammatory bowel disease (IBD) and carry risks for adverse events. We aimed to assess the relationship between anti-TNFα trough concentrations (TC) and adverse events rate among pediatric patients with IBD. The medical records of pediatric patients with IBD who were treated with anti-TNFα agents from 2015 to 2020 and had sequential monitoring of TC were reviewed retrospectively for the presence of adverse events. The study cohort included 135 eligible patients, [59 (43.7%) female, mean age at diagnosis 12.9 (±3) years, 111 (82.2%) Crohn's disease] who had 1589 measurements of TCs [1037 (63%) infliximab]. During a median follow-up period of 1.7 years (IQR 1.1-2.7), we recorded 156 adverse events in 50 patients (37%). Higher TCs were not associated with higher rate of anti-TNFα related adverse events whereas these events (excluding increase in liver transaminases) were associated with younger age.
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http://dx.doi.org/10.1097/MPG.0000000000003240DOI Listing
July 2021

Joint Effort towards Preventing Nutritional Deficiencies at the Extremes of Life during COVID-19.

Nutrients 2021 May 12;13(5). Epub 2021 May 12.

Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy.

The COVID-19 (Coronavirus disease 2019) pandemic is posing a threat to communities and healthcare systems worldwide. Malnutrition, in all its forms, may negatively impact the susceptibility and severity of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) infection in both children and older adults. Both undernutrition and obesity have been evoked as conditions associated with a higher susceptibility to the infection and poor prognosis. In turn, the COVID-19 infection may worsen the nutritional status through highly catabolic conditions, exposing individuals to the risk of malnutrition, muscle wasting, and nutritional deficiencies. Accordingly, the relationship between malnutrition and COVID-19 is likely to be bidirectional. Furthermore, the modification of nutritional behaviors and physical activity, required to limit the spread of the virus, are posing a challenge to health at both the extremes of life. Thus far, even the most advanced healthcare systems have failed to address the alarming consequences of malnutrition posed by this pandemic. If not properly addressed, we may run the risk that new and old generations will experience the consequences of COVID-19 related malnutrition.
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http://dx.doi.org/10.3390/nu13051616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150599PMC
May 2021

The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics.

Nat Rev Gastroenterol Hepatol 2021 09 4;18(9):649-667. Epub 2021 May 4.

Instituto de Lactología Industrial (CONICET-UNL), Faculty of Chemical Engineering, National University of Litoral, Santa Fe, Argentina.

In 2019, the International Scientific Association for Probiotics and Prebiotics (ISAPP) convened a panel of experts specializing in nutrition, microbial physiology, gastroenterology, paediatrics, food science and microbiology to review the definition and scope of postbiotics. The term 'postbiotics' is increasingly found in the scientific literature and on commercial products, yet is inconsistently used and lacks a clear definition. The purpose of this panel was to consider the scientific, commercial and regulatory parameters encompassing this emerging term, propose a useful definition and thereby establish a foundation for future developments. The panel defined a postbiotic as a "preparation of inanimate microorganisms and/or their components that confers a health benefit on the host". Effective postbiotics must contain inactivated microbial cells or cell components, with or without metabolites, that contribute to observed health benefits. The panel also discussed existing evidence of health-promoting effects of postbiotics, potential mechanisms of action, levels of evidence required to meet the stated definition, safety and implications for stakeholders. The panel determined that a definition of postbiotics is useful so that scientists, clinical triallists, industry, regulators and consumers have common ground for future activity in this area. A generally accepted definition will hopefully lead to regulatory clarity and promote innovation and the development of new postbiotic products.
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http://dx.doi.org/10.1038/s41575-021-00440-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387231PMC
September 2021

Age-Dependent Trends in the Celiac Disease: A Tertiary Center Experience.

J Pediatr Gastroenterol Nutr 2021 06;72(6):894-899

Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel.

Objectives: Celiac disease (CD) is a common intestinal autoimmune disorder with diverse presenting features. We aimed to determine age-dependent patterns in CD presentation, diagnosis and management at a large tertiary referral center.

Methods: A retrospective review of electronic medical records of pediatric patients diagnosed with CD between January 1999 and December 2018 at Schneider Children's Medical Center of Israel. We compared demographics, clinical and laboratory parameters between four age groups at CD presentation.

Results: A cohort of 932 children was divided into four groups by age (in years) at diagnosis: 0-3 (17.9%), 3-6 (31.8%), 6-12 (34.5%), 12-18 (15.8%). The youngest age group presented more frequently with diarrhea, weight loss, abdominal distention, vomiting and lower weight z scores, P < 0.01. Hypoalbuminemia and zinc deficiency were also more frequent in this age group, compared to older patients (P < 0.05, each). Rates of anemia were higher in younger age groups (0-3 and 3-6 years), compared to older age groups, P < 0.05. Patients in the younger age groups (0-3 and 3-6 years) presented more frequently with tissue transglutaminase (TTG) levels above 10 times the upper limit of normal (ULN; P < 0.05), and more often normalized their CD serologies by 24 months of gluten-free diets (GFD) compared to older age groups (P < 0.05).

Conclusion: There is an age-dependent variation in CD presentation during childhood. Younger patients present more often with malabsorptive features, and higher TTG levels, yet normalize TTG while on GFD more rapidly than older patients. Clinicians should be aware of the diversity in CD presentation and course at the various presentation age.
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http://dx.doi.org/10.1097/MPG.0000000000003130DOI Listing
June 2021

Letter: increased incidence of tissue transglutaminase antibody in Israel-is it always related to coeliac disease? Authors' reply.

Aliment Pharmacol Ther 2021 05;53(9):1053-1054

Institute of Pediatric Gastroenterology, Nutrition, and Liver Diseases, Schneider Children's Medical Center, Petach Tikva, Israel.

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http://dx.doi.org/10.1111/apt.16343DOI Listing
May 2021

Clinical and Esophagogastroduodenoscopy Findings in Pediatric Patients With Severe Obesity Evaluated Before Bariatric Surgery.

J Pediatr Gastroenterol Nutr 2021 06;72(6):854-858

Pediatric Gastroenterology, Nutrition, and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva.

Objectives: Severe obesity in the pediatric population has lifelong consequences. Bariatric surgery has been suggested for selected adolescents with severe obesity after careful evaluation. The indications for preoperative esophagogastroduodenoscopy (EGD) in this age group are not clear, despite its established usefulness in adults. We aimed to assess the usefulness of EGD before bariatric surgery in pediatric patients with severe obesity and metabolic comorbidities.

Methods: We conducted a retrospective chart review in a single tertiary pediatric medical center of adolescents treated during 2011 to 2018. Data collected from electronic medical records included patient demographics, endoscopic findings, and laboratory parameters.

Results: A total of 80 patients (40 boys) underwent evaluation. Macroscopic abnormalities were detected in 54% of the endoscopies, including gastritis, esophagitis, and duodenitis in 46%, 16%, and 13%, respectively. Forty-nine percentage of the biopsies showed histological abnormalities; in 35 (44%) patients, Helicobacter pylori was detected. Thirty-three patients (41%) received medical treatment and 2 (2.5%) required a second EGD. Metabolic comorbidities included hypertriglyceridemia (38% of the patients), low high-density lipoprotein (23%), and prediabetic (16%) or diabetic levels of HbA1C (4%). Fifty-five percentage of the cohort had elevated alanine aminotransferase (ALT), suggestive of nonalcoholic fatty liver disease (NAFLD).

Conclusions: Endoscopies performed before bariatric surgeries suggest a higher prevalence of clinically significant findings, many of which required treatment. These findings support incorporating an EGD into the preoperative evaluation of this patient population.
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http://dx.doi.org/10.1097/MPG.0000000000003109DOI Listing
June 2021

Increased incidence of coeliac disease autoimmunity rate in Israel: a 9-year analysis of population-based data.

Aliment Pharmacol Ther 2021 03 5;53(6):696-703. Epub 2021 Feb 5.

Maccabi Institute for Research & Innovation, Maccabi Healthcare Services, Tel Aviv, Israel.

Background: Incidence rate and temporal trends in coeliac disease and coeliac disease autoimmunity incidence vary worldwide with most data available from North American and European countries.

Aims: To explore temporal trends in incidence of coeliac disease autoimmunity and their relation to increase in screening tests in Israel.

Methods: A large retrospective population-based study was conducted in Maccabi Healthcare Services, a 2.3-million-member health maintenance organisation operating in Israel. The cohort included all patients with newly diagnosed coeliac disease autoimmunity based on first positive anti-tissue transglutaminase type 2 IgA antibodies. Data were analysed for the years 2007-2015.

Results: During the study period (17.3 million person-years), a total of 403 283 patients were tested for coeliac disease autoimmunity, of whom 6444 were positive, representing an average incidence rate of 36.64 per 100 000 person-years (95% CI: 35.74-37.55). Incidence of coeliac disease autoimmunity increased from 25.4 per 100 000 in 2007 to 52.3 per 100 000 person-years in 2015 (Incidence rate ratio of 2.06, 95% CI 1.81-2.26). Coeliac disease autoimmunity incidence was highest in the paediatric age groups, especially in children aged 0-5, and was 4 times higher than the incidence in adults aged 26-55 (Incidence rate ratio of 0.24, 95% CI (0.22-0.26). The increase in incidence surpassed the increase in testing for new patients. Positive trends in incidence were highest in small children, whereas the incidence in adults was stable over the years.

Conclusions: There was a steady increase in coeliac disease autoimmunity incidence in our cohort between the years 2007-2015. The paediatric population was the only contributor to this trend.
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http://dx.doi.org/10.1111/apt.16282DOI Listing
March 2021

Pediatric inflammatory bowel disease and the effect of COVID-19 pandemic on treatment adherence and patients' behavior.

Pediatr Res 2021 Sep 14;90(3):637-641. Epub 2021 Jan 14.

Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center, Petach Tikva, Israel.

Background: The coronavirus disease (COVID-19) pandemic affects medical care worldwide, including patients with inflammatory bowel disease (IBD). Thus, we aimed to assess its impact on health care provision, fear of infection, adherence to medical treatment, and compliance with preventative instructions in children and adolescents with IBD.

Methods: A cross-sectional telephonic survey using a Likert scale-based questionnaire was conducted among all pediatric patients with IBD from a single tertiary medical center.

Results: A total of 244 pediatric patients with IBD were included in the study, reporting a high rate of fear of severe COVID-19 infection due to IBD or IBD medications (198, 81.1%). Most of the patients obeyed the Ministry of Health instructions (228, 93.4%), while almost 50% took additional protective measures including avoidance of school and complete lockdown. Concerns regarding the attendance of regular clinics (116, 47.5%) and emergency room in case of IBD exacerbation (178, 73%) were frequently reported. Only 7 patients (2.9%) changed or discontinued their IBD treatment due to COVID-19.

Conclusion: We noted several distinct features of the COVID-19 pandemic effect on pediatric patients with IBD including a high rate of fear of severe COVID-19 infection, fear of attending necessary medical facilities, and high rate of avoidance of social activities.

Impact: Pediatric patients with IBD have a high rate of fear of severe COVID-19 infection, fear of attending necessary medical facilities, and a high rate of avoidance of social activities. Medication adherence rate in pediatric patients with IBD during the pandemic is similar to the adherence rate among adults with IBD. Almost 50% of pediatric patients with IBD took additional protective measures including avoidance of school and voluntary lockdown during the COVID-19 pandemic.
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http://dx.doi.org/10.1038/s41390-020-01312-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807409PMC
September 2021

Response to Letter: 'Serological exclusion of coeliac disease: an audit of anti-tissue transglutaminase and immunoglobulin A testing'.

Eur J Gastroenterol Hepatol 2021 02;32(2):300

Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Israel.

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http://dx.doi.org/10.1097/MEG.0000000000001770DOI Listing
February 2021

The role of milk feeds and other dietary supplementary interventions in preventing allergic disease in infants: Fact or fiction?

Clin Nutr 2021 02 20;40(2):358-371. Epub 2020 Oct 20.

The University of Western Australia, Perth, Australia.

Exclusive breastfeeding ideally up to 6 months of life is the feed of choice for infants and should be promoted by healthcare professionals. However, when human milk is not sufficient or not available, infant formula, generally cow's milk-based, meeting strictly regulated nutritional and safety requirements, are recommended. Human breastmilk feeding has a positive health impact for both mother and child, but there is limited evidence that it has a long-term protective effect on the development of allergic disease. Some studies have found an association of an increased risk to develop cow's milk allergy with early exposure to cow's milk protein in formula milk. As a result, over the last 30 years, partially hydrolyzed formulas (pHF) have gained popularity and, more recently, become embroiled in a debate about their role in the primary prevention of allergic outcomes. Similar debates exist in regards to the potential preventative effects of pre-, pro- and synbiotics as well as nutritional factors, notably vitamin D and omega-3 fatty acids. This paper aims to critically address these aspects, drawing information from published data interpreted by an international expert group in paediatrics, allergy, gastro-intestinal diseases and nutrition. This group of experts emphasize that human milk is the optimal source of infant nutrition. With regards to pHFs, whilst no harm has been shown with their use and some studies have suggested potential benefit preventing atopic dermatitis in at risk infants, there is insufficient evidence for or against their routine recommendation for primary allergy prevention. The method of hydrolysation differs for every formula. There is insufficient evidence to recommend supplementation with vitamin D, omega-3 LCPUFA, specific prebiotic oligosaccharides or specific probiotic strains during pregnancy, lactation and early life to prevent the development of allergic disease in children. There remains a need for well-designed trials with the currently commercialised pHFs and supplements to allow for better clarity and evidence-based recommendations.
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http://dx.doi.org/10.1016/j.clnu.2020.10.025DOI Listing
February 2021

Positivity of Stool Pathogen Sampling in Pediatric Inflammatory Bowel Disease Flares and Its Association With Disease Course.

J Pediatr Gastroenterol Nutr 2021 01;72(1):61-66

Institute of Gastroenterology, Nutrition and Liver Disease, Schneider Children's Medical Center, Petach Tikva.

Objectives: Acute exacerbations of inflammatory bowel disease (IBD) may involve enteric pathogen. We aimed to assess the frequency and outcomes of Clostridium difficille toxin (CDT) and non-CDT enteric infections in symptomatic pediatric patients with IBD.

Methods: Patients' records were retrospectively searched for disease flares in which stool samples were collected for enteric pathogens. Each patient with a positive sample was matched with a patient with IBD flare and negative samples for analyzing 1-year outcomes following sampling.

Results: A total of 618 pediatric patients with IBD [Crohn's disease, n = 439 (71%), mean age at diagnosis 13.0 ± 3.4 years, girls, n = 264 (42.7%)] had 1048 stool samples during the study period (2001-2018). Of 914 bacterial cultures, 40 (4.3%) were positive, 30 (75%) of which, positive for Campylobacter jejuni. Of 393 samples for CDT, 28 (7.1%) were positive while parasitic infection rate was 21/529 (3.9%).Overall, 19 positive C jejuni cases and 19 positive CDT cases with matching controls were examined. During 12 months of follow-up, the mean number of disease flares and emergency room visits was higher among patients with positive CDT (1.5 ± 1.4 vs 0.5 ± 0.9, P = 0.019, 1.3 ± 1.5 vs 0.4 ± 0.8, P = 0.05, respectively) with a numeric increase of surgical interventions (3 vs 0, P = 0.08). There were no significant differences in disease outcomes between patients with C jejuni infections and matched controls.

Conclusions: C difficile and C jejuni are the most common enteric infections among pediatric patients with IBD but only clostridial infection was associated with a more severe disease course within 12 months.
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http://dx.doi.org/10.1097/MPG.0000000000002895DOI Listing
January 2021

Anti-tissue transglutaminase titers are associated with endoscopic findings and severity of mucosal damage in children with celiac disease.

Eur J Pediatr 2021 Jan 8;180(1):263-269. Epub 2020 Aug 8.

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

We aimed to assess the correlation between clinical findings, serology, endoscopic findings, and histology in children diagnosed with celiac disease. Medical records of children diagnosed with celiac disease (2010-2017) at the Schneider Children's Hospital were reviewed retrospectively. Correlation between serologic measures anti-tissue transglutaminase (anti-tTG)/anti-endomysial antibodies (EMA) and other variables including mucosal damage, endoscopic findings (scalloping of duodenal folds), and clinical findings (abdominal pain, diarrhea, and anemia) was assessed. Out of 686 patients, 432 patients fulfilled the inclusion criteria (females 262, 61%; median age 6.0; interquartile range 4.0-9.0 years). Distribution of histopathology findings was Marsh IIIa 4%, Marsh IIIb 25%, and Marsh IIIc 71% with 313 (73%) patients having anti-tTG titer of ≥ 10 times the upper normal limit. Anti-tTG titer (but not EMA) positively correlated with Marsh grades, scalloping of duodenal folds and anemia. Anti-tTG ≥ 10 times the upper normal limit was associated with Marsh IIIc changes with an adjusted odds ratio of 4.5 (95% confidence interval, 1.7-12.1). Diarrhea and abdominal pain were not associated with serologic, endoscopic, or histologic markers of disease severity.Conclusion: Anti-tTG titers correlated with macroscopic and microscopic mucosal damage, with anemia but not with diarrhea or abdominal pain in children with celiac disease. What is Known: • Tissue transglutaminase antibody titers were shown to correlate with the degree of mucosal damage in patients with celiac disease. • There is a limited evidence regarding the association of celiac serologies with endoscopic and clinical measures. What is New: • Higher titers of tissue transglutaminase but not anti-endomysial antibodies are associated with more severe histologic and endoscopic damage and with the presence of anemia. • Symptoms do not correlate with the severity of mucosal damage such as scalloping of duodenal folds and histopathology changes according to Marsh classification or with serologic markers.
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http://dx.doi.org/10.1007/s00431-020-03770-wDOI Listing
January 2021

Anti-TNF-α Therapy Exerts Intestinal Anti-inflammatory and Anti-apoptotic Effects After Massive Bowel Resection in a Rat.

J Pediatr Gastroenterol Nutr 2021 01;72(1):49-55

Sackler Faculty of Medicine, Tel Aviv University.

Objectives: The aim of this study was to examine the effect of massive small bowel resection on proinflammatory cytokine intestinal expression and the effect of anti-TNF-α antibodies (ATA) on intestinal inflammation, epithelial cell turnover, and intestinal adaptation after bowel resection in rats.

Methods: Male Sprague-Dawley rats were divided into 4 experimental groups: Sham-rats underwent bowel transection; Sham-ATA rats underwent bowel transection and were treated with ATA; SBS-animals underwent 75% bowel resection; and SBS-ATA rats underwent bowel resection and were treated with ATA similarly to Group B. Parameters of intestinal adaptation, enterocyte proliferation, and apoptosis were determined at sacrifice. TNF-α and apoptosis-related gene and protein levels were determined by Illumina's Digital Gene Expression (DGE) analysis, Real Time PCR, Western blotting, and immunohistochemistry.

Results: From 25 genes related to TNF-α signalling that were investigated, 8 genes in the jejunum and 10 genes in the ileum were found to be up-regulated in resected versus sham animals. SBS rats demonstrated a significant increase in tissue and plasma TNF-α, IL-6 levels, intestinal mucosal TNF-α related gene expression, and microscopic parameters of inflammation. Treatment of resected animals with ATA resulted in a significant decrease in TNF-α levels, intestinal mucosal TNF-α-related gene expression, decreased number of intraepithelial lymphocytes and macrophages, and lower apoptotic index compared with SBS animals.

Conclusions: In a rat model of SBS, ATA decreased plasma and tissue TNF-α levels, diminished mucosal inflammation, and inhibited cell apoptosis. Anti-apoptotic effects of ATA appear to be associated with an inhibited extrinsic apoptotic pathway.
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http://dx.doi.org/10.1097/MPG.0000000000002876DOI Listing
January 2021

Therapeutic Drug Monitoring-guided High-dose Infliximab for Infantile-onset Inflammatory Bowel Disease: A Case Series.

J Pediatr Gastroenterol Nutr 2020 10;71(4):516-520

Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv.

Very early-onset inflammatory bowel disease (IBD) and specifically infantile-onset IBD patients, are characterized by high rates of extensive colonic involvement and decreased response rate to standard therapeutic regimens, including infliximab (IFX). We present a case series of 4 patients with infantile-onset IBD achieving clinical and biologic remission, after treatment with therapeutic drug monitoring (TDM)-guided accelerated high-dose IFX therapy. All patients were treated with accelerated high-dose IFX induction of up to 22 mg/kg. In 3 of these patients, accelerated high-dose IFX was used following failure of intensified standard dose induction. All patients achieved remission following re-induction.We suggest that children with infantile-onset IBD may require a TDM-guided accelerated high-dose IFX induction and maintenance treatment in order to achieve and maintain remission. Personalized approach in these patients is essential in order to prevent underdosing and to avoid inappropriate interpretation of treatment failure.
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http://dx.doi.org/10.1097/MPG.0000000000002832DOI Listing
October 2020

Coronavirus Disease 2019 and the Pediatric Gastroenterologist.

J Pediatr Gastroenterol Nutr 2020 06;70(6):720-726

Division of Gastroenterology, Department of Pediatrics, Children's Hospital Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.

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http://dx.doi.org/10.1097/MPG.0000000000002730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273939PMC
June 2020

Extrahepatic cholangiocyte obstruction is mediated by decreased glutathione, Wnt and Notch signaling pathways in a toxic model of biliary atresia.

Sci Rep 2020 05 5;10(1):7599. Epub 2020 May 5.

Institute for Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.

Biliary atresia is a neonatal liver disease with extrahepatic bile duct obstruction and progressive liver fibrosis. The etiology and pathogenesis of the disease are unknown. We previously identified a plant toxin, biliatresone, responsible for biliary atresia in naturally-occurring animal models, that causes cholangiocyte destruction in in-vitro models. Decreases in reduced glutathione (GSH) mimic the effects of biliatresone, and agents that replenish cellular GSH ameliorate the effects of the toxin. The goals of this study were to define signaling pathways downstream of biliatresone that lead to cholangiocyte destruction and to determine their relationship to GSH. Using cholangiocyte culture and 3D cholangiocyte spheroid cultures, we found that biliatresone and decreases in GSH upregulated RhoU/Wrch1, a Wnt signaling family member, which then mediated an increase in Hey2 in the NOTCH signaling pathway, causing downregulation of the transcription factor Sox17. When these genes were up- or down-regulated, the biliatresone effect on spheroids was phenocopied, resulting in lumen obstruction. Biopsies of patients with biliary atresia demonstrated increased RhoU/Wrch1 and Hey2 expression in cholangiocytes. We present a novel pathway of cholangiocyte injury in a model of biliary atresia, which is relevant to human BA and may suggest potential future therapeutics.
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http://dx.doi.org/10.1038/s41598-020-64503-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200694PMC
May 2020

Growth rate of coeliac children is compromised before the onset of the disease.

Arch Dis Child 2020 10 30;105(10):964-968. Epub 2020 Apr 30.

Department of Translational Medical Science, University of Naples Federico II, Napoli, Italy.

Introduction: Growth impairment has often been described in children who develop coeliac disease (CD). Based on data from the multicentre, longitudinal PreventCD study, we analysed the growth patterns of infants at genetic risk of CD, comparing those who developed CD by 6 years of age (CD 'cases', 113 infants) versus those who did not develop CD by 6 years (no CD 'controls', 831 infants).

Methods: Weight and length/height were measured using a longitudinal protocol. Raw measurements were standardised, computing z-scores for length/height and weight; a linear mixed model was fitted to the data in order to compare the rate of growth in the two cohorts.

Results: Neither cases nor controls had significant growth failure. However, when the mean z-scores for weight and height were analysed, there was a difference between the two groups starting at fourth month of life. When the growth pattern in the first year was analysed longitudinally using mixed models, it emerged that children who develop CD had a significantly lower growth rate in weight z-score (-0.028/month; 95% CI -0.038 to -0.017; p<0.001) and in length/height z-score (-0.018/month; 95% CI -0.031 to -0.005; p=0.008) than those who do not develop CD. When the whole follow-up period was analysed (0-6 years), differences between groups in both weight and length/height z-scores were confirmed.

Conclusion: The growth of children at risk of CD rarely fell below 'clinical standards'. However, growth rate was significantly lower in cases than in controls. Our data suggest that peculiar pathways of growth are present in children who develop CD, long before any clinical or serological signs of the disease appear.
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http://dx.doi.org/10.1136/archdischild-2019-317976DOI Listing
October 2020

Use of Probiotics for the Management of Acute Gastroenteritis in Children: An Update.

J Pediatr Gastroenterol Nutr 2020 08;71(2):261-269

Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland.

Since the publication of the 2014 European Society for Paediatric Gastroenterology, Hepatology, and Nutrition Working Group (WG) on Probiotics and Prebiotics guidelines for the management of acute gastroenteritis (AGE), new evidence concerning the efficacy of probiotics has become available. This document provides updated recommendations on the use of probiotics for the treatment of AGE in previously presumed healthy infants and children. A systematic literature search was performed. All pooled analyses were explicitly performed for the current report. The WG graded the recommendations and assessed the certainty of the supporting evidence using the Grading of Recommendations, Assessment Development, and Evaluations tool. The recommendations were formulated if at least 2 randomized controlled trials that used a given probiotic were available. Despite the large number of identified trials, the WG could not identify 2 randomized controlled trial of high quality for any strain that provided benefit when used for treating AGE. The WG made weak recommendations for (in descending order in terms of the number of trials evaluating any given strain): Saccharomyces boulardii (low to very low certainty of evidence); Lactobacillus rhamnosus GG (very low certainty of evidence); L reuteri DSM 17938 (low to very low certainty of evidence); and L rhamnosus 19070-2 and L reuteri DSM 12246 (very low certainty of evidence). The WG made a strong recommendation against L helveticus R0052 and L rhamnosus R0011 (moderate certainty of evidence) and a weak recommendation against Bacillus clausii strains O/C, SIN, N/R, and T (very low certainty of evidence).
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http://dx.doi.org/10.1097/MPG.0000000000002751DOI Listing
August 2020

Probiotics and Preterm Infants: A Position Paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics.

J Pediatr Gastroenterol Nutr 2020 05;70(5):664-680

Department of Paediatrics, The Medical University of Warsaw, Poland.

More than 10,000 preterm infants have participated in randomised controlled trials on probiotics worldwide, suggesting that probiotics in general could reduce rates of necrotising enterocolitis (NEC), sepsis, and mortality. Answers to relevant clinical questions as to which strain to use, at what dosage, and how long to supplement are, however, not available. On the other hand, an increasing number of commercial products containing probiotics are available from sometimes suboptimal quality. Also, a large number of units around the world are routinely offering probiotic supplementation as the standard of care despite lacking solid evidence. Our recent network meta-analysis identified probiotic strains with greatest efficacy regarding relevant clinical outcomes for preterm neonates. Efficacy in reducing mortality and morbidity was found for only a minority of the studied strains or combinations. In the present position paper, we aim to provide advice, which specific strains might potentially be used and which strains should not be used. In addition, we aim to address safety issues of probiotic supplementation to preterm infants, who have reduced immunological capacities and occasional indwelling catheters. For example, quality reassurance of the probiotic product is essential, probiotic strains should be devoid of transferable antibiotic resistance genes, and local microbiologists should be able to routinely detect probiotic sepsis. Provided all safety issues are met, there is currently a conditional recommendation (with low certainty of evidence) to provide either Lactobacillus rhamnosus GG ATCC53103 or the combination of Bifidobacterium infantis Bb-02, Bifidobacterium lactis Bb-12, and Streptococcus thermophilus TH-4 in order to reduce NEC rates.
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http://dx.doi.org/10.1097/MPG.0000000000002655DOI Listing
May 2020
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