Publications by authors named "M A Benninga"

536 Publications

Lubiprostone for Pediatric Functional Constipation: Randomized, Controlled, Double-blind Study With Long-term Extension.

Clin Gastroenterol Hepatol 2021 Apr 7. Epub 2021 Apr 7.

Pediatric Gastroenterologist, Division of Pediatric Gastroenterology, Nationwide Children's Hospital, Columbus, OH, USA. Electronic address:

Background & Aims: Pediatric functional constipation (PFC) is a common problem in children that causes distress and presents treatment challenges to healthcare professionals. We conducted a randomized, placebo-controlled trial (Study 1) in patients with PFC (aged 6-17 years) to evaluate the efficacy and safety of lubiprostone, followed by an open-label extension for those who completed the placebo-controlled phase (Study 2).

Methods: Study 1 (NCT02042183) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 12-week study evaluating the efficacy and safety of lubiprostone 12 mcg twice-daily (BID) and 24 mcg BID. Study 2 (NCT02138136) was a phase 3, long-term, open-label extension of Study 1. In both studies, lubiprostone doses were based on patients' weight. Efficacy was assessed solely based on Study 1, with a primary endpoint of overall spontaneous bowel movement (SBM) response (increase of ≥1 SBM/week vs baseline and ≥3 SBMs/week for ≥9 weeks, including 3 of the final 4 weeks).

Results: 606 patients were randomized to treatment (placebo: n=202; lubiprostone: n=404) in Study 1. No statistically significant difference in overall SBM response rate was observed between the lubiprostone and placebo groups (18.5% vs 14.4%; P=.2245). Both the 12-mcg BID and 24-mcg BID doses of lubiprostone were well tolerated in the double-blind and extension phases, with a safety profile consistent with that seen in adult studies.

Conclusions: Lubiprostone did not demonstrate statistically significant effectiveness over placebo in children and adolescents with PFC, but did demonstrate a safety profile similar to that in adults.
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http://dx.doi.org/10.1016/j.cgh.2021.04.005DOI Listing
April 2021

Non-radiologist-performed abdominal point-of-care ultrasonography in paediatrics - a scoping review.

Pediatr Radiol 2021 Apr 10. Epub 2021 Apr 10.

Amsterdam UMC, Radiology, University of Amsterdam, Amsterdam, The Netherlands.

Background: Historically, US in the paediatric setting has mostly been the domain of radiologists. However, in the last decade, there has been an uptake of non-radiologist point-of-care US.

Objective: To gain an overview of abdominal non-radiologist point-of-care US in paediatrics.

Materials And Methods: We conducted a scoping review regarding the uses of abdominal non-radiologist point-of-care US, quality of examinations and training, patient perspective, financial costs and legal consequences following the use of non-radiologist point-of-care US. We conducted an advanced search of the following databases: Medline, Embase and Web of Science Conference Proceedings. We included published original research studies describing abdominal non-radiologist point-of-care US in children. We limited studies to English-language articles from Western countries.

Results: We found a total of 5,092 publications and selected 106 publications for inclusion: 39 studies and 51 case reports or case series on the state-of-art of abdominal non-radiologist point-of-care US, 14 on training of non-radiologists, and 1 each on possible harms following non-radiologist point-of-care US and patient satisfaction. According to included studies, non-radiologist point-of-care US is increasingly used, but no standardised training guidelines exist. We found no studies regarding the financial consequences of non-radiologist point-of-care US.

Conclusion: This scoping review supports the further development of non-radiologist point-of-care US and underlines the need for consensus on who can do which examination after which level of training among US performers. More research is needed on training non-radiologists and on the costs-to-benefits of non-radiologist point-of-care US.
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http://dx.doi.org/10.1007/s00247-021-04997-xDOI Listing
April 2021

Functional gastrointestinal disorders in children: agreement between Rome III and Rome IV diagnoses.

Eur J Pediatr 2021 Mar 18. Epub 2021 Mar 18.

Department of Pediatrics, University of Miami, Miami, FL, USA.

To evaluate the agreement between the Rome III and Rome IV criteria in diagnosing pediatric functional gastrointestinal disorders (FGIDs), we conducted a prospective cohort study in a public school in Cali, Colombia. Children and adolescents between 11 and 18 years of age were given the Spanish version of the Questionnaire on Pediatric Functional Gastrointestinal Disorders Rome III version on day 0 and Rome IV version on day 2 (48 h later). The study protocol was completed by 135 children. Thirty-nine (28.9%) children were excluded because of not following the instructions of the questionnaire. The final analysis included data of 96 children (mean 15.2 years old, SD ± 1.7, 54% girls). Less children fulfilled the criteria for an FGID according to Rome IV compared to Rome III (40.6% vs 29.2%, p=0.063) resulting in a minimal agreement between the two criteria in diagnosing an FGID (kappa 0.34, agreement of 70%). The prevalence of functional constipation according to Rome IV was significantly lower compared to Rome III (13.5% vs 31.3%, p<0.001), whereas functional dyspepsia had a higher prevalence according to Rome IV than Rome III (11.5% vs 0%).Conclusion: We found an overall minimal agreement in diagnosing FGIDs according to Rome III and Rome IV criteria. This may be partly explained by the differences in diagnostic criteria. However, limitations with the use of questionnaires to measure prevalence have to be taken into account. What is Known: • The Rome IV criteria replaced the previous Rome III criteria providing updated criteria to diagnose functional gastrointestinal disorders (FGIDs). • Differences found between Rome IV and historic Rome III FGID prevalence may have been affected by changes in prevalence over time or differences in sample characteristics. What is New: • We found a minimal agreement between Rome III and Rome IV FGID diagnosis, especially in the diagnoses of functional constipation, irritable bowel syndrome, and functional dyspepsia. • The minimal agreement may be partly explained by changes in diagnostic criteria, but limitations with the use of questionnaires to measure prevalence have to be taken into account.
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http://dx.doi.org/10.1007/s00431-021-04013-2DOI Listing
March 2021

Prevalence of functional gastrointestinal disorders in infants and young children in China.

BMC Pediatr 2021 Mar 17;21(1):131. Epub 2021 Mar 17.

Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Academic Medical Center, Amsterdam, 1105, AZ, The Netherlands.

Background: The prevalence of functional gastrointestinal disorders (FGIDs) in children, particularly from Asia, is largely unknown. There are not many studies done in Asia especially using the Rome IV criteria. The aim of this study is to assess the prevalence of FGIDs in infants and young children in a representative sample in China.

Methods: A prospective, cross-sectional, community-based survey was conducted among healthy infants and young children between the ages of 0-4 years in Jinhua and Shanghai, China. A total of 2604 subjects (1300 subjects from Jinhua and 1304 subjects from Shanghai) completed a validated questionnaire on pediatric gastrointestinal symptoms. FGIDs in infants and young children were diagnosed using the Rome IV criteria.

Results: According to the Rome IV criteria, the prevalence of having a FGID in Chinese infants and young children is 27.3%. Infant regurgitation (33.9%) was the most common FGID among the 0-6 months old while functional constipation (7.0%) was the most common among the 1-4 years old. Risk factor analysis revealed that prevalence of infantile colic was higher with better maternal education and low birth weight. Prevalence of infantile regurgitation was significantly greater in males, living in a rural area, being exclusively breast fed at least up to 4 months and starting formula feeds within the first month. The risk of functional constipation was lower for infants who were delivered vaginally.

Conclusions: Infantile regurgitation was the most common FGID in Chinese infants while functional constipation was most prevalent among young Chinese children.

Trial Registration: Netherlands Trial Registry Identifier: NL6973/NTR7161 .
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http://dx.doi.org/10.1186/s12887-021-02610-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968152PMC
March 2021

The Use of Fecal Calprotectin Testing in Paediatric Disorders: A Position Paper of the European Society for Paediatric Gastroenterology and Nutrition Gastroenterology Committee.

J Pediatr Gastroenterol Nutr 2021 Apr;72(4):617-640

Neurogastroenterology and Motility, UCL Great Ormond Street Institute of Child Health and Department of Gastroenterology, Great Ormond Street Hospital, London, UK.

Objectives: The aim of the study was to review the evidence regarding the clinical use and value of fecal calprotectin (FC) measurements in different gastrointestinal disorders in children.

Methods: A literature search was conducted in the PubMed, MEDLINE, EMBASE, and Cochrane databases until October 31, 2019. Subtopics were identified and each assigned to individual authors.

Results: A total of 28 recommendations were voted on using the nominal voting technique. Recommendations are given related to sampling, measurement methods, and results interpretation. The 14 authors anonymously voted on each recommendation using a 9-point scale (1 strongly disagree to 9 fully agree). Consensus was considered achieved if at least 75% of the authors voted 6, 7, 8, or 9.

Conclusions: Consensus was reached for all recommendations. Limitations for the use of FC in clinical practice include variability in extraction methodology, performance of test kits as well as the need to establish local reference ranges because of the influence of individual factors, such as age, diet, microbiota, and drugs. The main utility of FC measurement at present is in the diagnosis and monitoring of inflammatory bowel disease (IBD) as well as to differentiate it from functional gastrointestinal disorders (FAPDs). FC, however, has neither utility in the diagnosis of infantile colic nor to differentiate between functional and organic constipation. A rise in FC concentration, may alert to the risk of developing necrotizing enterocolitis and help identifying gastrointestinal involvement in children with Henoch-Schönlein purpura. FC measurement is of little value in Cow's Milk Protein Allergy, coeliac disease (CD), and cystic fibrosis. FC does neither help to distinguish bacterial from viral acute gastroenteritis (AGE), nor to diagnose Helicobacter Pylori infection, small intestinal bacterial overgrowth (SIBO), acute appendicitis (AA), or intestinal polyps.
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http://dx.doi.org/10.1097/MPG.0000000000003046DOI Listing
April 2021

Bowel Lengthening Procedures in Children with Short Bowel Syndrome: A Systematic Review.

Eur J Pediatr Surg 2021 Mar 4. Epub 2021 Mar 4.

Pediatric Surgical Centre, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Vrije Universiteit, Amsterdam, The Netherlands.

Introduction:  The aims of the study are to systematically assess and critically appraise the evidence concerning two surgical techniques to lengthen the bowel in children with short bowel syndrome (SBS), namely, the longitudinal intestinal lengthening and tailoring (LILT) and serial transverse enteroplasty (STEP), and to identify patient characteristics associated with a favorable outcome.

Materials And Methods:  MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched from inception till December 2019. No language restriction was used.

Results:  In all, 2,390 articles were found, of which 40 were included, discussing 782 patients. The median age of the patients at the primary bowel lengthening procedure was 16 months (range: 1-84 months). Meta-analysis could not be performed due to the incomparability of the groups, due to heterogeneous definitions and outcome reporting. After STEP, 46% of patients weaned off parenteral nutrition (PN) versus 52% after LILT. Mortality was 7% for STEP and 26% for LILT. Patient characteristics predictive for success (weaning or survival) were discussed in nine studies showing differing results. Quality of reporting was considered poor to fair.

Conclusion:  LILT and STEP are both valuable treatment strategies used in the management of pediatric SBS. However, currently it is not possible to advise surgeons on accurate patient selection and to predict the result of either intervention. Homogenous, prospective, outcome reporting is necessary, for which an international network is needed.
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http://dx.doi.org/10.1055/s-0041-1725187DOI Listing
March 2021

Simultaneous assessment of colon motility in children with functional constipation by cine-MRI and colonic manometry: a feasibility study.

Eur Radiol Exp 2021 Feb 10;5(1). Epub 2021 Feb 10.

Division of Gastroenterology, Hepatology and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA.

Background: Colonic manometry is the current reference standard for assessing colonic neuromuscular function in children with intractable functional constipation (FC). Recently, cine magnetic resonance imaging (cine-MRI) has been proposed as a non-invasive alternative. We compared colonic motility patterns on cine-MRI with those obtained by manometry in children, by stimulating high-amplitude propagating contractions (HAPCs) with bisacodyl under manometric control while simultaneously acquiring cine-MRI.

Methods: After Institutional Review Board approval, adolescents with FC scheduled to undergo colonic manometry were included. A water-perfused 8-lumen catheter was used for colonic manometry recordings. After an intraluminal bisacodyl infusion, cine-MRI sequences of the descending colon were acquired for about 30 min simultaneously with colonic manometry. Manometry recordings were analysed for HAPCs. MRI images were processed with spatiotemporal motility MRI techniques. The anonymised motility results of both techniques were visually compared for the identification of HAPCs in the descending colon.

Results: Data regarding six patients (three males) were analysed (median age 14 years, range 12-17). After bisacodyl infusion, three patients showed a total of eleven HAPCs with colonic manometry. Corresponding cine-MRI recorded high colonic activity during two of these HAPCs, minimal activity during seven HAPCs, while two HAPCs were not recorded. In two of three patients with absent HAPCs on manometry, colonic activity was recorded with cine-MRI.

Conclusions: Simultaneous acquisition of colonic cine-MRI and manometry in children with FC is feasible. Their motility results did not completely overlap in the identification of HAPCs. Research is needed to unravel the role of cine-MRI in this setting.
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http://dx.doi.org/10.1186/s41747-021-00205-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873179PMC
February 2021

Profound pathogen-specific alterations in intestinal microbiota composition precede late onset sepsis in preterm infants: A longitudinal multicenter case-control study.

Clin Infect Dis 2021 Feb 9. Epub 2021 Feb 9.

Department of Pediatric Gastroenterology, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands.

Background: The role of intestinal microbiota in the pathogenesis of late onset sepsis (LOS) in preterm infants is largely unexplored, but could provide opportunities for microbiota-targeted preventive and therapeutic strategies. We hypothesized that microbiota composition changes before the onset of sepsis with causative bacteria that are isolated later in blood culture.

Methods: In this multicenter case-control study preterm infants born under 30 weeks of gestation were included. Fecal samples collected from the five days preceding LOS diagnosis, were analyzed by a molecular microbiota detection technique. LOS cases were subdivided into three groups: Gram-negative, Gram-positive and Coagulase negative Staphylococci (CoNS).

Results: Totally, 40 LOS cases and 40 matched controls were included. In Gram-negative LOS, the causative pathogen could be identified in at least one of the fecal samples collected three days prior LOS onset in all cases, whereas in all matched controls this pathogen was absent (p-value 0.015). The abundance of these pathogens increased from three days towards clinical onset. In Gram-negative and -positive LOS (except CoNS) combined, the causative pathogen could be identified in at least one fecal sample collected three days prior to LOS onset in 92% of the fecal samples of cases, whereas these pathogens were present in 33% of the control samples (p-value 0.004). Overall, LOS (expect CoNS) could be predicted one day prior clinical onset with an AUC of 0.78.

Conclusions: Profound preclinical microbial alterations underline that gut microbiota is involved in the pathogenesis of LOS and has the potential as early non-invasive biomarker.
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http://dx.doi.org/10.1093/cid/ciaa1635DOI Listing
February 2021

Antidepressants for functional abdominal pain disorders in children and adolescents.

Cochrane Database Syst Rev 2021 02 9;2:CD008013. Epub 2021 Feb 9.

Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Background: Functional Abdominal Pain Disorders (FAPDs) present a considerable burden to paediatric patients, impacting quality of life, school attendance and causing higher rates of anxiety and depression disorders. There are no international guidelines for the management of this condition. A previous Cochrane Review in 2011 found no evidence to support the use of antidepressants in this context.

Objectives: To evaluate the current evidence for the efficacy and safety of antidepressants for FAPDs in children and adolescents.

Search Methods: In this updated review, we searched the Cochrane Library, PubMed, MEDLINE, Embase, PsycINFO and two clinical trial registers from inception until 03 February 2020. We also updated our search of databases of ongoing research, reference lists and 'grey literature' from inception to 03 February 2020.

Selection Criteria: We included randomised controlled trials (RCTs) comparing antidepressants to placebo, to no treatment or to any other intervention, in children aged 4 to 18 years with a FAPD diagnosis as per the Rome or any other defined criteria (as defined by the authors). The primary outcomes of interest included treatment success (as defined by the authors), pain severity, pain frequency and withdrawal due to adverse events.

Data Collection And Analysis: Two review authors checked all citations independently, resolving disagreement with a third-party arbiter. We reviewed all potential studies in full text, and once again made independent decisions, with disagreements resolved by consensus. We conducted data extraction and 'Risk of bias' assessments independently, following Cochrane methods. Where homogeneous data were available, we performed meta-analysis using a random-effects model. We conducted GRADE analysis.

Main Results: We found one new study in this updated search, making a total of three trials (223 participants) eligible for inclusion: two using amitriptyline (AMI) and one using citalopram. For the primary outcome of treatment success, two studies used reports of success on a symptom-based Likert scale, with either a two-point reduction or the two lowest levels defined as success. The third study defined success as a 15% improvement in quality of life (QOL) ratings scales. Therefore, meta-analysis did not include this final study due to the heterogeneity of the outcome measure. There is low-certainty evidence that there may be no difference when antidepressants are compared with placebo (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.87 to 1.56; 2 studies, 205 participants; I = 0%). We downgraded the evidence for significant imprecision due to extremely sparse data (see Summary of findings table 1). The third study reported that participants receiving antidepressants were significantly more likely than those receiving placebo to experience at least a 15% improvement in overall QOL score at 10 and 13 weeks (P = 0.007 and P = 0.002, respectively (absolute figures were not given)). The analysis found no difference in withdrawals due to adverse events between antidepressants and placebo: RR 3.17 (95% CI 0.65 to 15.33), with very low certainty due to high risk of bias in studies and imprecision due to low event and participant numbers. Sensitivity analysis using a fixed-effect model and analysing just for AMI found no change in this result. Due to heterogeneous and limited reporting, no further meta-analysis was possible.

Authors' Conclusions: There may be no difference between antidepressants and placebo for treatment success of FAPDs in childhood. There may be no difference in withdrawals due to adverse events, but this is also of low certainty. There is currently no evidence to support clinical decision making regarding the use of these medications. Further studies must consider sample size, homogenous and relevant outcome measures and longer follow up.
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http://dx.doi.org/10.1002/14651858.CD008013.pub3DOI Listing
February 2021

Diagnosis, Management, and Prevention of Button Battery Ingestion in Childhood: An ESPGHAN Position Paper.

J Pediatr Gastroenterol Nutr 2021 Jan 14. Epub 2021 Jan 14.

*Department of Pediatric Gastroenterology, University Medical Center Utrecht, Utrecht, The Netherlands †Emma Children's Hospital, Amsterdam University Medical Center, Amsterdam, The Netherlands ‡Department of Paediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany §Paediatric Gastroenterology, Hepatology and Nutrition Unit, Department of Paediatrics, UMC Maribor, Slovenia ||Department of Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, University Children's Hospital, University of Ljubljana, Ljubljana, Slovenia ¶Unité de Gastroentérologie, Hépatologie, Nutrition et Maladies Héréditaires du Métabolisme, Hôpital des Enfants, CHU de Toulouse, F-31300, France et IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France #Department of Translational Medical Science, Section of Paediatrics, University of Naples "Federico II", Naples, Italy **Victor Babes University of Medicine and Pharmacy, Timisoara, Romania ††Department of Paediatric Gastroenterology, Great Ormond Street Hospital, London, United Kingdom ‡‡Department of Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia §§Centre for Paediatric Gastroenterology and International Academy of Paediatric Endoscopy Training, Sheffield Children's Hospital, Sheffield, United Kingdom ||||Department of Pediatric Gastroenterology, Al Jalila Children's Specialty Hospital, Dubai, United Arab Emirates ¶¶Department of Pediatric Gastroenterology, Sophia Children's Hospital/Erasmus Medical Center, Rotterdam, The Netherlands.

Button batteries (BB) remain a health hazard to children as ingestion might lead to life-threatening complications, especially if the battery is impacted in the esophagus. Worldwide initiatives have been set up in order to prevent and also timely diagnose and manage button battery (BB) ingestions. An European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) task force for BB ingestions has been founded which aimed to contribute to reducing the health risks related to this event. It is important to focus on the European setting, next to other worldwide initiatives, to develop and implement effective management strategies. As one of the first initiatives of the ESPGHAN task force, this ESPGHAN position paper has been written. The literature is summarized, and prevention strategies are discussed focusing on some controversial topics. An algorithm for the diagnosis and management of BB ingestions is presented and compared to previous guidelines (NASPGHAN, National Poison Center). In agreement with earlier guidelines, immediate localization of the BB is important and in case of esophageal impaction the BB should be removed instantly (preferably < 2 hours). Honey and sucralfate can be considered in ingestions ≤12 hours while waiting for endoscopic removal but should not delay it. In case of delayed diagnosis (first confirmation of the BB on x-ray >12 hours after ingestion or time point of removal >12 hours after ingestion) and esophageal impaction the guideline suggests to perform a CT scan in order to evaluate for vascular injury before removing the battery. In delayed diagnosis, even if the battery has passed the esophagus, endoscopy to screen for esophageal damage and a CT scan to rule out vascular injury should be considered even in asymptomatic children. In asymptomatic patients with early diagnosis (≤12 hours after ingestion) and position of the BB beyond the esophagus one can monitor with repeat x-ray (if not already evacuated in stool) in 7-14 days which is different from previous guidelines where repeat x-ray and removal is recommended after 2-4 days and is also based on age. Finally, prevention strategies are discussed in this paper.
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http://dx.doi.org/10.1097/MPG.0000000000003048DOI Listing
January 2021

Brazilian Portuguese version of the Amsterdam infant stool scale: a valid and reliable scale for evaluation of stool from children up to 120 days old.

BMC Pediatr 2021 Feb 4;21(1):64. Epub 2021 Feb 4.

Department of Surgery and Orthopedics - Division of Pediatric Surgery, Botucatu Medical School, São Paulo State University (UNESP), São Paulo, Brazil.

Background: For newborns and infants wearing diapers the difficulties in characterizing the appearance of the stool are significant, since the changes in consistency, quantity, and color of the stool are higher than in other age groups. The Amsterdam Infant Stool Scale (AISS) was created and validated in 2009, providing a specific tool for the evaluation of the stool of children up to 120 days old. However, to be used in clinical practice and scientific investigations in Brazil, it is mandatory to perform the translation and cross-cultural adaptation process for Brazilian Portuguese language. Thus, we aim to perform the translation and cross-cultural adaptation of AISS into Brazilian Portuguese and to evaluate the psychometric properties of the translated version.

Methods: The process of translation and cross-cultural adaptation was performed according to the internationally accepted methodology, including: translation, summary of translations, backtranslation, preparation of the pre-final version, application of the pre-test and determination of the final version. The evaluation of the psychometric properties was performed through the application of Brazilian Portuguese AISS, by five examiners (including child health field specialists and a literate adult lay on the subject), analyzing 238 stool photographs of children under 120 days old. The intra and inter-examiner agreement values were determined using kappa statistic. The validity of the criterion was investigated through correlation analysis (Kendall's coefficient) between the classifications determined by the non-specialist examiner and the expert examiners.

Results: In all 30 tests performed between different examiners, there was an agreement considered as at least moderate (kappa values above 0.40). The intra-examiner reliability was considered as substantial (kappa> 0.6). There was a statistically significant correlation (p <  0.05) between the classifications determined by the examiners considered as specialists and the examiner considered as non-specialist.

Conclusion: The Brazilian Portuguese AISS version proved to be valid and reliable to be used by healthcare professionals and the general public in the evaluation of stool from children up to 120 days old.
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http://dx.doi.org/10.1186/s12887-021-02527-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860020PMC
February 2021

Functional Fecal Incontinence in Children: Epidemiology, Pathophysiology, Evaluation, and Management.

J Pediatr Gastroenterol Nutr 2021 Jan 28. Epub 2021 Jan 28.

Department of Pediatrics, Faculty of Medicine, University of Colombo, Colombo 8, Western Province, Sri Lanka Department of Physiology, Faculty of Medicine, University of Kelaniya, Ragama, Western Province, Sri Lanka Department of Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Abstract: Functional fecal incontinence (FI) is a worldwide problem in children and comprises constipation-associated fecal incontinence and nonretentive fecal incontinence. Irrespective of pathophysiology, both disorders impact negatively on the psychological well-being and quality of life of affected children. A thorough clinical history and physical examination using the Rome IV criteria is usually sufficient to diagnose these conditions in most children. Evolving investigations such as high resolution anorectal and colonic manometry have shed new light on the pathophysiology of functional FI. Although conventional interventions such as toilet training and laxatives successfully treat most children with constipation associated FI, children with nonretentive fecal incontinence need more psychologically based therapeutic options. Intrasphincteric injection of botulinum toxin, transanal irrigation and, in select cases, surgical interventions have been used in more resistant children with constipation associated FI.
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http://dx.doi.org/10.1097/MPG.0000000000003056DOI Listing
January 2021

Adverse Events of Thiopurine Therapy in Pediatric Inflammatory Bowel Disease and Correlations with Metabolites: A Cohort Study.

Dig Dis Sci 2021 Feb 3. Epub 2021 Feb 3.

Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam, UMC, Vrije Universiteit Amsterdam, 1105 AZ, Amsterdam, The Netherlands.

Background: In the recent era of growing availability of biological agents, the role of thiopurines needs to be reassessed with the focus on toxicity.

Aims: We assessed the incidence and predictive factors of thiopurine-induced adverse events (AE) resulting in therapy cessation in pediatric inflammatory bowel disease (IBD), related to thiopurine metabolites and biochemical abnormalities, and determined overall drug survival.

Methods: We performed a retrospective, single-center study of children diagnosed with IBD between 2000 and 2019 and treated with thiopurine therapy. The incidence of AE and overall drug survival of thiopurines were evaluated using the Kaplan-Meier method. Correlations between thiopurine metabolites and biochemical tests were computed using Spearman's correlation coefficient.

Results: Of 391 patients with IBD, 233 patients (162 Crohn's disease, 62 ulcerative colitis, and 9 IBD-unclassified) were prescribed thiopurines (230 azathioprine and 3 mercaptopurine), of whom 50 patients (22%) discontinued treatment, at least temporary, due to thiopurine-induced AE (median follow-up 20.7 months). Twenty-six patients (52%) were rechallenged and 18 of them (70%) tolerated this. Sixteen patients (6%) switched to a second thiopurine agent after azathioprine intolerance and 10 of them (63%) tolerated this. No predictive factors for development of AE could be identified. Concentrations of 6-thioguanine nucleotides (6-TGN) were significantly correlated with white blood cell and neutrophil count, 6-methylmercaptopurine (6-MMP) concentrations with alanine aminotransferase and gamma-glutamyltranspeptidase.

Conclusions: Approximately 20% of pediatric patients with IBD discontinued thiopurine treatment due to AE. A rechallenge or switch to mercaptopurine is an effective strategy after development of AE. Concentrations of 6-TGN and 6-MMP are associated with biochemical abnormalities.
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http://dx.doi.org/10.1007/s10620-021-06836-3DOI Listing
February 2021

Nutritional Therapy Strategies in Pediatric Crohn's Disease.

Nutrients 2021 Jan 13;13(1). Epub 2021 Jan 13.

Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands.

The increase in incidences of pediatric Crohn's Disease (CD) worldwide has been strongly linked with dietary shifts towards a Westernized diet, ultimately leading to altered gut microbiota and disturbance in intestinal immunity and the metabolome. Multiple clinical studies in children with CD have demonstrated the high efficacy of nutritional therapy with exclusive enteral nutrition (EEN) to induce remission with an excellent safety profile. However, EEN is poorly tolerated, limiting its compliance and clinical application. This has spiked an interest in the development of alternative and better-tolerated nutritional therapy strategies. Several nutritional therapies have now been designed not only to treat the nutritional deficiencies seen in children with active CD but also to correct dysbiosis and reduce intestinal inflammation. In this review, we report the most recent insights regarding nutritional strategies in children with active CD: EEN, partial enteral nutrition (PEN), Crohn's disease exclusive diet (CDED), and CD treatment-with-eating diet (CD-TREAT). We describe their setup, efficacy, safety, and (dis)advantages as well as some of their potential mechanisms of action and perspectives. A better understanding of different nutritional therapeutic options and their mechanisms will yield better and safer management strategies for children with CD and may address the barriers and limitations of current strategies in children.
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http://dx.doi.org/10.3390/nu13010212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828385PMC
January 2021

The not-so-rare absent RAIR: Internal anal sphincter achalasia in a review of 1072 children with constipation undergoing high-resolution anorectal manometry.

Neurogastroenterol Motil 2021 Apr 10;33(4):e14028. Epub 2020 Dec 10.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, USA.

Background: Our objective is to describe the prevalence of patients with internal anal sphincter achalasia (IASA) without Hirschsprung disease (HD) among children undergoing anorectal manometry (ARM) and their clinical characteristics.

Methods: We performed a retrospective review of high-resolution ARM studies performed at our institution and identified patients with an absent rectoanal inhibitory reflex (RAIR). Clinical presentation, medical history, treatment outcomes, and results of ARM and other diagnostic tests were collected. We compared data between IASA patients, HD patients, and a matched control group of patients with functional constipation (FC).

Key Results: We reviewed 1,072 ARMs and identified 109 patients with an absent RAIR, of whom 28 were diagnosed with IASA. Compared to patients with FC, patients with IASA had an earlier onset of symptoms and were more likely to have abnormal contrast enema studies. Compared to patients with HD, patients with IASA were more likely to have had a normal timing of meconium passage, a later onset of symptoms, and were diagnosed at an older age. At the latest follow-up, the majority of patients diagnosed with IASA (54%) were only using oral laxatives. Over half of patients with IASA had been treated with anal sphincter botulinum toxin injection, and 55% reported a positive response.

Conclusions And Inferences: Patients diagnosed with IASA may represent a more severe patient population compared to patients with FC, but have a later onset of symptoms compared to patients with HD. They may require different treatments for their constipation and deserve further study.
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http://dx.doi.org/10.1111/nmo.14028DOI Listing
April 2021

Predictive factors for surgical treatment in preterm neonates with necrotizing enterocolitis: a multicenter case-control study.

Eur J Pediatr 2021 Feb 2;180(2):617-625. Epub 2020 Dec 2.

Department of Pediatric Gastroenterology, Amsterdam UMC, VU University Medical Center, Amsterdam, the Netherlands.

Necrotizing enterocolitis (NEC) is one of the most common and lethal gastrointestinal diseases in preterm infants. Early recognition of infants in need for surgical intervention might enable early intervention. In this multicenter case-control study, performed in nine neonatal intensive care units, preterm born infants (< 30 weeks of gestation) diagnosed with NEC (stage ≥ IIA) between October 2014 and August 2017 were divided into two groups: (1) medical (conservative treatment) and (2) surgical NEC (sNEC). Perinatal, clinical, and laboratory parameters were collected daily up to clinical onset of NEC. Univariate and multivariate logistic regression analyses were applied to identify potential predictors for sNEC. In total, 73 preterm infants with NEC (41 surgical and 32 medical NEC) were included. A low gestational age (p value, adjusted odds ratio [95%CI]; 0.001, 0.91 [0.86-0.96]), no maternal corticosteroid administration (0.025, 0.19 [0.04-0.82]), early onset of NEC (0.003, 0.85 [0.77-0.95]), low serum bicarbonate (0.009, 0.85 [0.76-0.96]), and a hemodynamically significant patent ductus arteriosus for which ibuprofen was administered (0.003, 7.60 [2.03-28.47]) were identified as independent risk factors for sNEC.Conclusions: Our findings may support the clinician to identify infants with increased risk for sNEC, which may facilitate early decisive management and consequently could result in improved prognosis. What is Known: • In 27-52% of the infants with NEC, a surgical intervention is indicated during its disease course. • Absolute indication for surgical intervention is bowel perforation, whereas fixed bowel loop or clinical deterioration highly suggestive of bowel perforation or necrosi, is a relative indication. What is New: • Lower gestational age, early clinical onset, and no maternal corticosteroids administration are predictors for surgical NEC. • Low serum bicarbonate in the 3 days prior clinical onset and patent ductus arteriosus for which ibuprofen was administered predict surgical NEC.
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http://dx.doi.org/10.1007/s00431-020-03892-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813726PMC
February 2021

Chronic constipation in adults: Contemporary perspectives and clinical challenges. 1: Epidemiology, diagnosis, clinical associations, pathophysiology and investigation.

Neurogastroenterol Motil 2020 Dec 2:e14050. Epub 2020 Dec 2.

NIHR Nottingham Biomedical Research Centre (BRC), Hospitals NHS Trust and the University of Nottingham, Nottingham University, Nottingham, UK.

Background: Chronic constipation is a prevalent disorder that affects patients' quality of life and consumes resources in healthcare systems worldwide. In clinical practice, it is still considered a challenge as clinicians frequently are unsure as to which treatments to use and when. Over a decade ago, a Neurogastroenterology & Motility journal supplement devoted to the investigation and management of constipation was published (2009; 21 (Suppl.2)). This included seven articles, disseminating all themes covered during a preceding 2-day meeting held in London, entitled "Current perspectives in chronic constipation: a scientific and clinical symposium." In October 2018, the 3rd London Masterclass, entitled "Contemporary management of constipation" was held, again over 2 days. All faculty members were invited to author two new review articles, which represent a collective synthesis of talks presented and discussions held during this meeting.

Purpose: This article represents the first of these reviews, addressing epidemiology, diagnosis, clinical associations, pathophysiology, and investigation. Clearly, not all aspects of the condition can be covered in adequate detail; hence, there is a focus on particular "hot topics" and themes that are of contemporary interest. The second review addresses management of chronic constipation, covering behavioral, conservative, medical, and surgical therapies.
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http://dx.doi.org/10.1111/nmo.14050DOI Listing
December 2020

Hypnotherapy for irritable bowel syndrome-type symptoms in patients with quiescent inflammatory bowel disease: a randomized, controlled trial.

J Crohns Colitis 2020 Nov 27. Epub 2020 Nov 27.

Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Center, Amsterdam, the Netherlands.

Background And Aims: Many inflammatory bowel disease (IBD) patients in remission have persisting symptoms, compatible with irritable bowel syndrome (IBS-type symptoms). We aimed to compare the effectiveness of gut-directed hypnotherapy versus standard medical treatment (SMT) for IBS-type symptoms in IBD patients.

Methods: In this multicenter, randomized, controlled, open label trial, patients aged 12-65 years with IBD in clinical remission (global assessment) and biochemical remission (fecal calprotectin ≤100 µg/g, or ≤200 µg/g without inflammation at endoscopy) with IBS according to Rome III criteria, were randomized to hypnotherapy or SMT. Primary outcome was the proportion with ≥50% reduction on a visual analogue scale for symptom severity, as measured with the Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) at week 40 (i.e. 6 months after finishing the intervention), compared to baseline. Secondary outcomes included total IBS-SSS score, quality of life, adequate relief, IBS-related cognitions and depression and anxiety scores.

Results: Eighty patients were included, of whom 70 received at least one session of the allocated treatment and were included in the modified intention-to-treat-population. Seven patients were excluded because of missing baseline data required for the primary outcome. The primary outcome was met in 9 (27%) of 33 patients randomized to SMT and 9 (30%) of 30 patients randomized to hypnotherapy (p=0.81). Adequate relief was reported in respectively 60% and 40% of subjects. Exploratory analyses of secondary outcomes revealed no apparent differences between both treatment groups.

Conclusions: Hypnotherapy was not superior to SMT in the treatment of IBS-type symptoms IBD patients. Both treatment strategies are reasonable options from a clinical perspective.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa241DOI Listing
November 2020

Reply to "Rapid Infliximab Infusions in Paediatric Inflammatory Bowel Disease Patients, a Single Hospital Experience".

J Pediatr Gastroenterol Nutr 2021 Feb;72(2):e56

Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam Reproduction and Development; Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1097/MPG.0000000000002998DOI Listing
February 2021

Clinical Experience With Performing Esophageal Function Testing in Children.

J Pediatr Gastroenterol Nutr 2021 Feb;72(2):226-231

Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Gastroenterology.

Objectives: Pediatric high-resolution manometry (HRM) and 24-hour pH-impedance with/without ambulatory manometry (pH-MII+/-mano) tests are generally performed using adult-derived protocols. We aimed to assess the feasibility of these protocols in children, the occurrence of patient-related imperfections and their influence on test interpretability.

Methods: Esophageal function tests performed between 2015 and 2018 were retrospectively analyzed. All tests were subcategorized into uninterpretable or interpretable tests (regardless of occurrence of patient-related imperfections). For HRM, the following patient-related imperfections were scored: patient-related artefacts, multiple swallowing and/or inability to establish baseline characteristics. For pH-MII(+/-mano), incorrect symptom registration and/or premature catheter removal were scored. Results were compared between age-groups (0-3, 4-12, and >12 years).

Results: In total 106 HRM, 60 pH-MII, and 23 pH-MII-mano could be fully analyzed. Of these, 94.8% HRM, 91.9% pH-MII, and 95.7% pH-MII-mano were interpretable. Overall, HRM contained imperfections in 78.3% overall and in 8/8 (100%) in the youngest age group, 36/42 (85.7%) in 4 to 12 years and in 37/56 (66.1%) in children above 12 years; P = 0.011. These imperfections led to uninterpretable results in 4 HRM (3.8%), of which 3 were in the youngest age group (3/8, 37.5%). Imperfections were found in 10% of pH-MII and 17.4% of pH-MII-mano. These led to uninterpretable results in 5.0% and 4.3%, respectively. No age-effect was found.

Conclusions: Esophageal function tests in children are interpretable in more than 90% overall. In children under the age of 4 years, all patients had imperfect HRM and 3/8 tests were uninterpretable. HRM in older children and pH-MII+/-mano were interpretable in the vast majority.
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http://dx.doi.org/10.1097/MPG.0000000000003000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815250PMC
February 2021

Intestinal Microbiota in Children With Symptomatic Dientamoeba fragilis Infection: A Case-control Study.

Pediatr Infect Dis J 2021 Apr;40(4):279-283

Department of Pediatric Gastroenterology, Emma Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands.

Background: Dientamoeba fragilis in children has been associated with gastrointestinal symptoms, like abdominal pain and diarrhea. The mechanism underlying these symptoms in children with D. fragilis remains unclear. We hypothesized that concomitant microbial alterations, which have been described in other parasitic infections, may be associated with gastrointestinal symptoms in D. fragilis.

Methods: In this case-control study performed in 2 centers, 19 children referred to a pediatrician because of gastrointestinal symptoms and with a positive fecal PCR for D. fragilis were included as cases. We included 19 healthy children as controls and matched for age and gender, selected from an existing cohort of 63 children. A PCR for D. fragilis was performed on fecal samples of the 19 controls to assess D. fragilis carriership in this asymptomatic group. Microbiota was analyzed with the IS-pro technique, and the intestinal microbiota composition and diversity were compared between the 2 groups.

Results: Microbiota of children with D. fragilis and gastrointestinal symptoms did not significantly differ in terms of composition and diversity compared with controls, both on phylum and species level. In the asymptomatic controls, a positive fecal PCR for D. fragilis was found in 16 of 19 (84.2%).

Conclusion: Intestinal microbiota does not seem to play a key role in the presence of clinical symptoms in children with D. fragilis. The pathogenicity of D. fragilis and pathophysiologic pathways underlying the development of gastrointestinal symptoms remains yet to be clarified.
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http://dx.doi.org/10.1097/INF.0000000000002975DOI Listing
April 2021

The Dutch Incidence of Infantile Hypertrophic Pyloric Stenosis and the Influence of Seasons.

Eur J Pediatr Surg 2020 Nov 10. Epub 2020 Nov 10.

Department of Pediatric Surgery, University of Amsterdam and Vrije Universiteit, Emma Children's Hospital, Amsterdam UMC, Amsterdam, The Netherlands.

Introduction:  Studies report contradicting results on the incidence of infantile hypertrophic pyloric stenosis (IHPS) and its association with seasons. We aim to assess the IHPS incidence in the Netherlands and to determine whether seasonal variation is present in a nationwide cohort.

Materials And Methods:  All infants with IHPS hospitalized in the Netherlands between 2007 and 2017 were included in this retrospective cohort study. Incidence rates per 1,000 livebirths (LB) were calculated using total number of LB during the matched month, season, or year, respectively. Seasonal variation based on month of birth and month of surgery was analyzed using linear mixed model and one-way ANOVA, respectively.

Results:  A total of 2,479 infants were included, of which the majority was male (75.9%). Median (interquartile range) age at surgery was 34 (18) days. The average IHPS incidence rate was 1.28 per 1,000 LB (variation: 1.09-1.47 per 1,000 LB). We did not find a conclusive trend over time in IHPS incidence. Differences in incidence between season of birth and season of surgery were not significant ( = 0.677 and  = 0.206, respectively).

Conclusion:  We found an average IHPS incidence of 1.28 per 1,000 LB in the Netherlands. Our results showed no changing trend in incidence and no seasonal variation.
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http://dx.doi.org/10.1055/s-0040-1721055DOI Listing
November 2020

Evaluation of the "3 Good Questions" program for shared decision-making in pediatric medicine: a feasibility study.

Eur J Pediatr 2021 Apr 9;180(4):1235-1242. Epub 2020 Nov 9.

Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Pediatric Gastroenterology, Room C2-312, PO Box 22700, 1100, DD, Amsterdam, The Netherlands.

The "3 Good Questions" program was developed to increase shared decision making. The current pilot-study determined the feasibility of these questions to increase shared decision-making in Dutch pediatric medicine. Pre-/postintervention surveys were used to include children (10-18 years) at pediatric outpatient clinics of four hospitals in the Netherlands. After their appointment, two different groups of children completed the questionnaires. Group 1 filled in the survey before the intervention; group 2 completed the survey after active implementation of the "3 Good Questions" program. The primary outcome was to determine the feasibility (reach, applicability). Secondary outcomes were related to patient involvement in healthcare and treatment decisions and decision-making process between child and healthcare professional. In total, 168 and 114 children in groups 1 and 2 (61 vs 63% female, P = 0.68; age 13.3 ± 2.4 vs 13.8 ± 2.4 years, P = 0.72), respectively, completed the questionnaire. In group 2, 44% of children were aware of the "3 Good Questions", of whom 18% posed ≥ 1 of the "3 Good Questions" during their appointment (feasibility). The "3 Good Questions" program led to more shared decision-making (SDM-Q-9: P = < 0.001;95%CI: - 2.43 to - 1.17). The majority of children who have read or heard of the "3 Good Questions" would recommend this program to other children.Conclusion: Implementation of the "3 Good Questions" program seemed feasible, although it is necessary to further explore the implementation of this program at national level as a simple way for children and healthcare professionals to share decisions in practice. What is known • Children have the right to be included in decision-making, and inclusion can improve patient satisfaction and quality of care, and reduce costs. • The "3 Good Questions" program was successfully implemented in adult healthcare to increase shared decision making, and therefore these "3 Good Questions" have been adapted to a child version. What is new • In this pilot study, we found that the implementation of the "3 Good Questions" program to increase shared decision-making in pediatric medicine seemed feasible. Although it is necessary to further explore the implementation of the "3 Good Questions" program at national level as a simple way for children and healthcare professionals to share decisions in practice.
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http://dx.doi.org/10.1007/s00431-020-03868-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940148PMC
April 2021

Paediatric functional abdominal pain disorders.

Nat Rev Dis Primers 2020 11 5;6(1):89. Epub 2020 Nov 5.

University Hospital Tübingen, Department of Internal Medicine VI: Psychosomatic Medicine and Psychotherapy, Tübingen, Germany.

Paediatric functional abdominal pain disorders, currently referred to as disorders of gut-brain interaction, comprise irritable bowel syndrome, functional dyspepsia, abdominal migraine and functional abdominal pain not otherwise specified, as defined by the Rome IV diagnostic criteria. Functional abdominal pain disorders are common disorders with a prevalence of 3-16% depending on country, age and sex. A greater understanding of aetiopathogenesis and pathophysiology is emerging and includes intestinal components (inflammation, motility and the microbiota), central factors (psychological aspects, sensitization and/or differences in connectivity or activity of certain brain regions) as well as extrinsic factors (infections). In particular, the timing of disruption of the microbiota-gut-brain axis seems to be important. Diagnosis is challenging but is primarily based on clinical symptoms and exclusion of other organic causes, with an emphasis on avoiding unnecessary invasive diagnostic procedures. The available pharmacological interventions are limited in children and, therefore, management has focused on combined approaches, including mind-targeted interventions (hypnotherapy and cognitive behavioural therapy), diet (probiotics) and percutaneous electrical nerve field stimulation. The evidence for their clinical efficacy, although limited, is favourable, with positive impacts on symptoms and overall quality of life. The coming decades hold promise for improved understanding and management of these enigmatic disorders.
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http://dx.doi.org/10.1038/s41572-020-00222-5DOI Listing
November 2020

Exclusive enteral nutrition mediates gut microbial and metabolic changes that are associated with remission in children with Crohn's disease.

Sci Rep 2020 11 3;10(1):18879. Epub 2020 Nov 3.

Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Location AMC, Meibergdreef 69, 1105BK, Amsterdam, The Netherlands.

A nutritional intervention, exclusive enteral nutrition (EEN) can induce remission in patients with pediatric Crohn's disease (CD). We characterized changes in the fecal microbiota and metabolome to identify the mechanism of EEN. Feces of 43 children were collected prior, during and after EEN. Microbiota and metabolites were analyzed by 16S rRNA gene amplicon sequencing and NMR. Selected metabolites were evaluated in relevant model systems. Microbiota and metabolome of patients with CD and controls were different at all time points. Amino acids, primary bile salts, trimethylamine and cadaverine were elevated in patients with CD. Microbiota and metabolome differed between responders and non-responders prior to EEN. EEN decreased microbiota diversity and reduced amino acids, trimethylamine and cadaverine towards control levels. Patients with CD had reduced microbial metabolism of bile acids that partially normalized during EEN. Trimethylamine and cadaverine inhibited intestinal cell growth. TMA and cadaverine inhibited LPS-stimulated TNF-alpha and IL-6 secretion by primary human monocytes. A diet rich in free amino acids worsened inflammation in the DSS model of intestinal inflammation. Trimethylamine, cadaverine, bile salts and amino acids could play a role in the mechanism by which EEN induces remission. Prior to EEN, microbiota and metabolome are different between responders and non-responders.
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http://dx.doi.org/10.1038/s41598-020-75306-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609694PMC
November 2020

Can 2 Different Fecal Calprotectin Assays be Used Interchangeably in IBD Treatment?

J Clin Gastroenterol 2020 Oct 27. Epub 2020 Oct 27.

Departments of Pediatric Gastroenterology, Emma Children's Hospital.

Background: Fecal calprotectin (FC) is a biomarker for inflammation in inflammatory bowel disease (IBD). Interpretation of results can be complicated because of the use of different assays to determine FC.

Goals: To assess the agreement between 2 different assays for determining FC in patients with IBD.

Methods: Samples from adults and children with IBD were tested with 2 assays: (1) EliA 2 Calprotectin and (2) EK-Cal. Samples were uniformly tested on the same day. Interassay variability was displayed in a Bland-Altman plot. The difference in categorization of the FC result (1: 0 to 250 mg/kg, 2: 250 to 500 mg/kg, 3: >500 mg/kg) was assessed with the linear weighted κ for adults and children separately.

Results: A total of 171 patients [mean age: 33 (range: 7 to 81); 92 (54%) female; 117 (68%) Crohn's disease; 53 (31%) ulcerative colitis] were included. Median (interquartile ranges) FC levels were 281 mg/kg (70 to 971) (EK-Cal) and 159 mg/kg (31 to 778) (EliA 2), and the mean delta FC was 89 mg/kg. In the adult population, there was substantial agreement between the 2 assays (κ: 0.72; SE: 0.06; 95% confidence interval, 0.60-0.83) and for pediatric patients, the agreement was almost perfect (κ: 0.83; SE: 0.06; 95% confidence interval: 0.70-0.95). Five of 171 patients (all aged ≥17 y and all with colonic disease) had a difference of 2 categories (1 vs. 3) between assays. Interassay variability was the highest in category 3.

Conclusions: The agreement between the EliA 2 and EK-Cal assay in this cohort of IBD patients is substantial to almost perfect. Interassay variability is higher in the highest FC category.
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http://dx.doi.org/10.1097/MCG.0000000000001460DOI Listing
October 2020

Behavioral and emotional problems in adolescents with constipation and their association with quality of life.

PLoS One 2020 12;15(10):e0239092. Epub 2020 Oct 12.

Faculty of Medicine, Department of Physiology, University of Kelaniya, Ragama, Western Province, Sri Lanka.

Objectives: To assess behavioral and emotional problems in children and adolescents with functional constipation and their relationship with psychological maladjustment and health-related quality of life (HRQoL).

Design: A school-based cross-sectional survey conducted in 8 randomly selected schools from 4 randomly selected districts in Sri Lanka. A previously validated questionnaire was used for data collection. Behavioral and emotional problems were assessed using the Sinhala version of the Child Behavior Check List (CBCL-S/4-18). Constipation was diagnosed by applying the Rome III criteria.

Results: A total of 1000 questionnaires were distributed, and 913 completed questionnaires were included in the analysis. Sixty adolescents (6.5%) had functional constipation. Scores obtained for isolated psychological problems such as withdrawal (3.1 [3.1] vs. 1.9 [2.4], p<0.001), somatic complaints (3.2 [2.8] vs. 2.3 [2.5], p<0.05) anxiety/depression (5.8 [2.5] vs. 3.9 [3.6], p<0.001), social problems (3.0 [2.7] vs. 2.2 [1.9] p<0.001) and attention problems (5.4 [4.1] vs. 3.9 [3.4], p<0.001), and broadband scale of internalization (12.1 [8.4] vs. 8.3 [7.2], p<0.05) and mean total CBCL-S/4-18 score (29.4 [19.5] vs. 23.2 [17.0], p<0.001) were higher in adolescents with functional constipation. Clinical characteristics, socio-demographic and family factors and psychological maladjustment had no relationship with externalization, internalization and total CBCL-S/4-18 score. Internalization (-0.49, p<0.0001), externalization (-0.30, p<0.05), and total CBCL-S/4-18 (-0.44, p<0.001) scores had a negative impact on HRQoL of adolescents with functional constipation.

Conclusions: Adolescents with functional constipation are suffering from significant behavioral and emotional problems. These problems negatively affect their HRQoL.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0239092PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549826PMC
November 2020

Optimized sample preparation for fecal volatile organic compound analysis by gas chromatography-mass spectrometry.

Metabolomics 2020 10 10;16(10):112. Epub 2020 Oct 10.

EurofinsEAG, Eurofins Materials Science Netherlands B.V., Eindhoven, The Netherlands.

Introduction: Headspace gas chromatography-mass spectrometry (HS-GC-MS) is widely considered the gold standard of quantitative fecal VOC analysis. However, guidelines providing general recommendations for bioanalytical method application in research and clinical setting are lacking.

Objectives: To propose an evidence-based research protocol for fecal VOC analysis by HS-GC-MS, based on extensive testing of instrumental and sampling conditions on detection and quantification limits, linearity, accuracy and repeatability of VOC outcome.

Methods: The influence of the following variables were assessed: addition of different salt solutions, injection temperature, injection speed, injection volume, septum use, use of calibration curves and fecal sample mass. Ultimately, the optimal sample preparation was assessed using fecal samples from healthy preterm infants. Fecal VOC analysis in this specific population has potential as diagnostic biomarkers, but available amount of feces is limited here, so optimization of VOC extraction is of importance.

Results: We demonstrated that addition of lithium chloride enhanced the release of polar compounds (e.g. small alcohols) into the headspace. Second, a linear relationship between injection volume, speed and temperature, and fecal sample mass on the abundance of VOC was demonstrated. Furthermore, the use of a septum preserved 90% of the non-polar compounds. By application of optimal instrumental and sampling conditions, a maximum of 320 unique compounds consisting of 14 different chemical classes could be detected.

Conclusions: These findings may contribute to standardized analysis of fecal VOC by HS-GC-MS, facilitating future application of fecal VOC in clinical practice.
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http://dx.doi.org/10.1007/s11306-020-01735-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547966PMC
October 2020

Aerophagia Study in Indonesia: Prevalence and Association With Family-related Stress.

J Clin Gastroenterol 2020 Oct 1. Epub 2020 Oct 1.

Department of Paediatrics, University of Colombo, Colombo, Sri Lanka.

Background: Aerophagia is a functional gastrointestinal disorder characterized by repeated air swallowing leading to chronic abdominal distension. Symptoms can be long lasting, lead to frustration, and distress. This study describes prevalence, related factors, and symptomatology of aerophagia, together with its relationship with emotional stress.

Materials And Methods: Cross-sectional study. Adolescents aged 10 to 17 years from selected state schools by convenient sampling from Jakarta, Indonesia, were recruited. Rome III self-administered questionnaire was used to compile data on gastrointestinal symptoms. Data on sociodemographic characteristics, intestinal and extraintestinal symptoms, and stressful life events were collected using a separate questionnaire.

Results: A total of 1796 questionnaires were included in the analysis [males 732 (40.8%), mean age 13.58 (SD 0.992) years]. There were 81 (4.5%) subjects diagnosed with aerophagia. When the criterion of belching was removed from the diagnosis of aerophagia, the prevalence drops to only 2 (0.1%).

Subjects: Bivariate analysis showed that sociodemographic factors have no correlation with aerophagia. In subjects with aerophagia, among the intestinal-related and extraintestinal symptoms, only loss of appetite was significantly more common in the aerophagia population (33.3%) when compared with controls (22.8%). Death of a close family member [adjusted odds ratio (OR), 2.78; 95% confidence interval (CI), 1.46-5.31; P=0.002], divorce or separation of parents (adjusted OR, 2.54; 95% CI, 1.38-4.66; P=0.003), and divorce followed by separate individual remarriage of parents (adjusted OR, 2.01; 95% CI, 1.01-3.98; P=0.046) were found to be significantly associated with aerophagia by multivariate analysis.

Conclusions: The prevalence of aerophagia was found in 4.5% of Indonesian school-aged children according to Rome III criteria, but the prevalence was found only 0.1% if the belching is removed from the criteria. Besides the main symptoms, only loss of appetite was significantly more common in aerophagia among intestinal-related and extraintestinal symptoms. Family-related stress showed a significant correlation with aerophagia.
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http://dx.doi.org/10.1097/MCG.0000000000001434DOI Listing
October 2020

Nutritional Therapy to Modulate Tryptophan Metabolism and Aryl Hydrocarbon-Receptor Signaling Activation in Human Diseases.

Nutrients 2020 Sep 17;12(9). Epub 2020 Sep 17.

Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers, Emma Children's Hospital, 1105 AZ Amsterdam, The Netherlands.

The aryl hydrocarbon receptor (AhR) is a nuclear protein which, upon association with certain endogenous and exogenous ligands, translocates into the nucleus, binds DNA and regulates gene expression. Tryptophan (Trp) metabolites are one of the most important endogenous AhR ligands. The intestinal microbiota is a critical player in human intestinal homeostasis. Many of its effects are mediated by an assembly of metabolites, including Trp metabolites. In the intestine, Trp is metabolized by three main routes, leading to kynurenine, serotonin, and indole derivative synthesis under the direct or indirect involvement of the microbiota. Disturbance in Trp metabolism and/or AhR activation is strongly associated with multiple gastrointestinal, neurological and metabolic disorders, suggesting Trp metabolites/AhR signaling modulation as an interesting therapeutic perspective. In this review, we describe the most recent advances concerning Trp metabolism and AhR signaling in human health and disease, with a focus on nutrition as a potential therapy to modulate Trp metabolites acting on AhR. A better understanding of the complex balance between these pathways in human health and disease will yield therapeutic opportunities.
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http://dx.doi.org/10.3390/nu12092846DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551725PMC
September 2020