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BACKGROUND: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.METHODS: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.RESULTS: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.CONCLUSIONS: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).

Background: Coeliac disease is one of the most prevalent immune-mediated gastrointestinal disorders in children. Aim: To review the incidence and prevalence of paediatric coeliac disease, and their trends, regionally across Europe, overall and according to age at diagnosis. Methods: Systematic review and meta-analysis from January 1, 1950 to December 31, 2019, based on PubMed, CINAHL and the Cochrane Library, searches of grey literature and websites and hand searching of reference lists. A total of 127 eligible studies were included. Results: The prevalence of previously undiagnosed coeliac disease from screening surveys (histology based) ranged from 0.10% to 3.03% (median = 0.70%), with a significantly increasing annual trend (P = 0.029). Prevalence since 2000 was significantly higher in northern Europe (1.60%) than in eastern (0.98%), southern (0.69%) and western (0.60%) Europe. Large increases in the incidence of diagnosed coeliac disease across Europe have reached 50 per 100 000 person-years in Scandinavia, Finland and Spain. The median age at diagnosis increased from 1.9 years before 1990 to 7.6 since 2000. Larger increases in incidence were found in older age groups than in infants and ages

INTRODUCTION: 13 C-breath tests are valuable, noninvasive diagnostic tests that can be widely applied for the assessment of gastroenterological symptoms and diseases. Currently, the potential of these tests is compromised by a lack of standardization regarding performance and interpretation among expert centers. METHODS: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of 13 C-breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 43 experts from 18 European countries. Consensus on individual statements and recommendations was established if ≥ 80% of reviewers agreed and

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-Schonlein 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.

Proton pump inhibitors (PPIs) are amongst the most commonly prescribed drugs in infants and children with the last decades witnessing a dramatic rise in their utilization. Although PPIs are clearly effective when used appropriately and have been regarded as safe drugs, there is growing evidence regarding their potential adverse effects. Although, largely based on adult data it is clear that many of these are also relevant to pediatrics. PPI use potentially affects gastrointestinal microbiota composition and function, decreases defence against pathogens resulting in increased risk for infections, interferes with absorption of minerals and vitamins leading to specific deficiencies and increased risk for bone fractures as well as interferes with protein digestion resulting in increased risk of sensitization to allergens and development of allergic diseases and eosinophilic esophagitis. An association with gastric, liver and pancreatic cancer has also been inferred from adult data but is tenuous and causation is not proven. Overall, evidence for these adverse events is patchy and not always compelling. Overall, the use of PPIs, for selected indications with a good evidence base, has significant potential benefit but carries more caution in infants and children. Pediatricians should be aware of the concerns regarding the potential adverse events associated with their use.

Functional fecal incontinence (FI) is a worldwide problem in children and comprises constipation-associated FI and nonretentive FI. 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 are 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 FI 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.

Background Spinal cord injury (SCI) presents a significant challenge for the field of neurotherapeutics. Stem cells have shown promise in replenishing the cells lost to the injury process, but the release of axon growth-inhibitory molecules such as chondroitin sulfate proteoglycans (CSPGs) by activated cells within the injury site hinders the integration of transplanted cells. We hypothesised that simultaneous application of enteric neural stem cells (ENSCs) isolated from the gastrointestinal tract, with a lentivirus (LV) containing the enzyme chondroitinase ABC (ChABC), would enhance the regenerative potential of ENSCs after transplantation into the injured spinal cord. Methods ENSCs were harvested from the GI tract of p7 rats, expanded in vitro and characterised. Adult rats bearing a contusion injury were randomly assigned to one of four groups: no treatment, LV-ChABC injection only, ENSC transplantation only or ENSC transplantation+LV-ChABC injection. After 16 weeks, rats were sacrificed and the harvested spinal cords examined for evidence of repair. Results ENSC cultures contained a variety of neuronal subtypes suitable for replenishing cells lost through SCI. Following injury, transplanted ENSC-derived cells survived and ChABC successfully degraded CSPGs. We observed significant reductions in the injured tissue and cavity area, with the greatest improvements seen in the combined treatment group. ENSC-derived cells extended projections across the injury site into both the rostral and caudal host spinal cord, and ENSC transplantation significantly increased the number of cells extending axons across the injury site. Furthermore, the combined treatment resulted in a modest, but significant functional improvement by week 16, and we found no evidence of the spread of transplanted cells to ectopic locations or formation of tumours. Conclusions Regenerative effects of a combined treatment with ENSCs and ChABC surpassed either treatment alone, highlighting the importance of further research into combinatorial therapies for SCI. Our work provides evidence that stem cells taken from the adult gastrointestinal tract, an easily accessible source for autologous transplantation, could be strongly considered for the repair of central nervous system disorders.

International audience; Thiopurines, alone or in combination with other agents, have a pivotal role in the treatment of specific gastrointestinal and hepatological disorders. In inflammatory bowel disease and autoimmune hepatitis thiopurines have proven their value as steroid sparing agents for the maintenance of remission and may be considered for preventing postoperative Crohn disease recurrence where there is moderate risk of this occurring. Their use with infliximab therapy reduces antibody formation and increases biologic drug levels. The routine clinical use of thiopurines has, however, been questioned due to a number of potential adverse effects. The aim of this article is to provide information regarding the use, and in particular, safety of these agents in clinical practice in the light of such potentially severe, albeit rare, effects.

Exclusive breast feeding is recommended in all guidelines as the first choice feeding. Cow milk allergy (CMA) can be diagnosed by a diagnostic elimination diet for 2 to 4 weeks with a hypo-allergenic formula, followed by a challenge test with intact cow milk protein. The most often used hypo-allergenic formula for the diagnostic elimination diet and the therapeutic diet is a CM based extensive hydrolysate. CM-based partial hydrolysates cannot be recommended in the management of CMA because of insufficient efficacy and possible reactions, but about half of the infants with CMA may tolerate a partial hydrolysate. The pros and cons of other dietary options are discussed in this paper. The use of an amino acid-based formula and/or rice based hydrolysate formula during the diagnostic elimination and therapeutic diet is debated. When available, there is sufficient evidence to consider rice hydrolysates as an adequate alternative to CM-based hydrolysates, since some infants will still react to the CM hydrolysate. The pros and cons of dietary options such as soy formula, buckwheat, almond, pea or other plant based dietary products are discussed. Although the majority of the plant-based beverages are nutritionally inadequate, some are nutritionally adapted for toddlers. However, accessibility and content vary by country and, thus far there is insufficient evidence on the efficacy and tolerance of these plant-based drinks (except for soy formula and rice hydrolysates) to provide an opinion on them. Conclusion: A diagnostic elimination diet, followed by a challenge remains the diagnostic standard. The use of an awareness tool may result in a decrease of delayed diagnosis. Breastmilk remains the ideal source of nutrition and when not available a CM extensively hydrolyzed formula, rice hydrolysate or amino acid formula should be recommended. More evidence is needed regarding plant-based drinks.

BACKGROUND Antroduodenal manometry (ADM) and histopathology are currently employed to aid the diagnosis of pediatric intestinal pseudo-obstruction (PIPO). Limited data are available on the reliability of ADM analysis and its correlation with histopathology. We aimed to develop a protocol for enhanced analysis of ADM contractile patterns, including a scoring system, and explore whether this provided better correlation with histopathology. METHODS Children referred with suspected PIPO between April 2012-December 2019 who underwent both ADM and full-thickness biopsies were included. ADM tracings were analyzed using both standard (conventional ADM) and novel (enhanced ADM) motility parameters. A novel ADM score (GLASS score) was generated based on the enhanced ADM analysis. Conventional and enhanced ADM analyses were then correlated with histopathology. RESULTS Forty patients were included. Using conventional clinical criteria, 29 of these were diagnosed with PIPO and the other 11 with non-PIPO diagnoses. Twenty-three of the PIPO patients had abnormal histopathology: 6 myopathy, 4 neuropathy, 3 neuro-myopathy, and 10 non-specific changes. No agreement in diagnosis was found between conventional ADM analysis and histopathology (ϰ = 0.068; p = 0.197), whereas the latter significantly correlated with enhanced ADM analysis (ϰ = 0.191; p = 0.003). The enhanced ADM score was significantly higher in PIPO versus non-PIPO (16.0 vs. 8.0; p

Hirschsprung disease (HSCR) and Paediatric Intestinal Pseudo-obstruction (PIPO) comprise two of the most recognized and severe disorders of gastrointestinal (GI) motility. HSCR is a developmental disorder of the enteric nervous system invariably affecting the large intestine, whereas the majority of PIPO conditions represent congenital disorders of one or more components of the neuromusculature and more diffusely affect the GI tract. Histopathology is deemed the gold standard for the diagnosis of HSCR and, arguably, of PIPO, but, other diagnostic modalities such as manometric and genetic studies have seen recent advances that may increase their utility. Especially for PIPO, management is multidisciplinary and best performed in specialist referral centres. Surgery remains the only viable treatment for HSCR and appears essential to optimize and sustain feeding and viability of intestinal function in PIPO patients. Novel therapies such as neural stem cell transplants show promise for the future.

International audience; 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 BB ingestions. A 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 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 (

International audience; Acute diarrhoea is a leading cause of morbidity and mortality in the paediatric population. Racecadotril is an antisecretory drug recommended as an adjuvant anti-diarrhoeal treatment.In the small bowel, the enzyme neutral endopeptidase (NEP) inhibits the action of enkephalins, which prevent water and electrolyte hypersecretion. By inhibiting NEP, racecadotril allows enkephalins to exhibit their antisecretory effects. Consequently, racecadotril reduces the secretion of water and electrolytes in the small intestine, without having an effect on intestinal motility. No serious adverse events related to racecadotril have been reported.Racecadotril has proven its efficacy as an adjuvant anti-diarrhoeal drug with a good safety profile. Its addition to oral rehydration solution (ORS) appears clinically beneficial and potentially leads to health care savings.

To evaluate clinical, endoscopic, and pH-impedance measures in a cohort of children with esophageal atresia and concomitant eosinophilic esophagitis (EoE) and compared it with disease-matched controls, to identify predictive factors for the development of EoE and esophageal stricture.We reviewed 63 patients with esophageal atresia assessed for refractory upper gastrointestinal symptoms between January 2015 and September 2017 at 2 tertiary referral centers. All patients underwent upper gastrointestinal endoscopy and pH-impedance monitoring. Based on esophageal histology, patients were classified as (1) esophageal atresia without evidence of esophagitis; (2) esophageal atresia with evidence of esophagitis (including esophageal eosinophilia not meeting the criteria for EoE); (3) esophageal atresia with concomitant EoE. Age and sex matched patients with gastroesophageal reflux disease were used as disease controls.The presence of atopy and peripheral eosinophilia at baseline were significantly associated with EoE (P .05). Although there was a tendency toward an increased number of strictures in patients with esophageal atresia-EoE, this did not reach statistical significance (P = .06). Higher esophageal acid exposure time and lower baseline impedance values were significantly associated with eosinophilic infiltration (P .05 and P .01, respectively). Using logistic regression analysis, the presence of mucosal eosinophilia was the most predictive factor for stricture formation (P .05).A history of atopy and the presence of peripheral eosinophilia in patients with esophageal atresia are predictive factors for the development of EoE, which in turn is a predictive factor for stricture occurrence. Higher esophageal acid exposure time and lower baseline impedance are associated with esophageal eosinophilic infiltration, suggesting their value in selecting which patients with esophageal atresia should undergo endoscopic examination.

Objectives To critically appraise ileocolonoscopy (IC) practice in a large tertiary center, where IC is exclusively performed by experienced pediatric colonoscopists, particularly focusing on indications for the procedure; bowel preparation efficacy; IC completion rates and timings; diagnostic yield; and complications. Patients and methods We prospectively evaluated all patients referred to our clinic between July 2015 and June 2016. Data on age, height and weight, sex, surgical history, indications for colonoscopy, bowel preparation given, and bowel cleansing efficacy were collected. The following were calculated: percentage of terminal ileal (TI) intubation; time to terminal ileum; total duration of each procedure. In addition, we evaluated the number and the type of complications encountered and the number of patients readmitted within 30 days from the elective procedure. Endoscopic diagnostic yield, stratified for indication, was calculated. Results A total of 1392 patients were referred; 181 required an endoscopic evaluation of the lower gastrointestinal (GI) tract (Outpatient Department conversion rate: 13%). Main indications for IC were: recurrent abdominal pain 38.1%; unexplained chronic diarrhea 16%; suspected inflammatory bowel disease (IBD) 24.9%; isolated rectal bleeding 13.2%; occult GI bleeding 1.6%; unexplained faltering growth 1.6%; IBD restaging 2.6%; and miscellaneous 1.6%. Terminal ileum was reached in all the patients (TI intubation rate = 100%). Median time to TI was 9.8 minutes (1-50 minutes). Time to TI was lower in younger patients compared to older ones (P = 0.005). Bowel cleansing was judged as grade 1 in 49.2%; grade 2 in 33.7%; grade 3 in 13.3%; and grade 4 in 3.9%. A significant statistical correlation was recorded between bowel cleansing and time to TI. The positive diagnostic yield was: 11.6% in patients with abdominal pain; 37.9% in patients with chronic diarrhea; 51.1% in patients with suspected IBD; 29.2% in patients with isolated rectal bleeding; 33.3% in patients with occult GI bleeding; 0% in patients with faltering growth; and 33% in the miscellaneous group. Conclusions In conclusion, appropriately targeted IC in the management of children with GI symptoms is a safe, fast, and useful investigation. TI intubation rates of 100% are achievable and desirable and can be conducted quickly. Poor bowel preparation impacts negatively on this and IC duration may be faster in younger children. High diagnostic yields have been recorded in patients with a clinical suspicion of IBD. Diagnostic yield in isolated recurrent abdominal pain is low. Training to excellence in pediatric IC should be a persistent goal.

Pediatric functional gastrointestinal disorders including irritable bowel syndrome with constipation and functional constipation are common conditions in childhood, but no drugs are U.S. Food and Drug Administration (FDA) approved for chronic use in pediatric patients with these disorders. Despite efforts to better standardize the diagnosis of these conditions in children (including recent modifications to the Rome criteria), conducting pediatric clinical trials to support drug approval remains a challenge. In March 2018, FDA, in collaboration with the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, American Gastroenterological Association, and American College of Gastroenterology, convened a public workshop to discuss the challenges and opportunities in conducting pediatric clinical trials in functional gastrointestinal conditions. The workshop assembled gastroenterologists, psychologists, patients, patient advocates, regulators, and industry representatives to discuss trial design and conduct including alternative designs, eligibility criteria, instruments for patient- and observer-reported outcomes, and optimal primary endpoints to support regulatory approval. This report summarizes the workshop, key challenges and knowledge gaps identified, and outlines areas where further research efforts are needed to overcome barriers to developing drugs to treat these conditions.

Background and Aim: There have been no large-scale epidemiological study of functional constipation of pediatric gastroenterology services. This survey was undertaken to investigate the prevalence of functional constipation and magnitude of related problems in hospital settings of various countries as well as the practice of pediatric gastroenterologists in management of these conditions. Methods: The survey was conducted by sending questionnaires to members of Societies for Pediatric Gastroenterology Hepatology and Nutrition of various continents. Results: A total of 274 pediatric gastroenterologists from 41 countries participated in this study. Functional constipation accounted for overall 30% of patients attending pediatric gastroenterology outpatient clinics. In comparison with non-western countries, respondents from western countries reported significantly higher median annual numbers of new patients with intractable functional constipation (10 [4,25] vs 5 [2,10], P < 0.001), dyssynergic defecation (3 [0,15] vs 1 [0,4], P < 0.001), and colonic inertia (2 [0,5] vs 0 [0,1], P < 0.001). The use of high dose polyethylene glycol for fecal disimpaction was significantly more commonly among respondents from western countries, whereas rectal enema was significantly more favored in non-western countries. Respondents from different continents reported significant discrepancies in choices of investigations and management of patients with dyssynergic defecation and colonic inertia. Conclusions: Functional constipation is a major problem for pediatric gastroenterology outpatient services worldwide. There were significant variations in the investigations of choice and therapeutic management of functional constipation, intractable functional constipation, and related problems among pediatric gastroenterologists of different geographic regions.

Background The main aim of the study was to assess the association between joint hypermobility (JH) and gastrointestinal (GI) disorders in children. Methods All children aged 4-17 years attending the clinics of the participating Pediatric Gastroenterology Centres for functional GI disorders (FGIDs) and inflammatory bowel disease (IBD) were screened for joint laxity. JH diagnosis was inferred using the Beighton Score. JHS diagnosis was inferred based on the Brighton Criteria. Rome III Diagnostic Criteria were used to diagnose possible FGIDs. Ulcerative colitis and Crohn`s disease diagnoses were made according to the Porto Criteria. Age and sex- matched healthy children were enrolled as controls. Results One-hundred-seventy children with GI disorders (70 with FGIDs, 50 with Crohn`s disease, and 50 with ulcerative colitis) and 100 healthy controls were enrolled in the study. JH was reported in 7/70 (10%) children with FGIDs (p=0.26 compared to controls), 4/50 (8%) children with Crohn`s disease (p=0.21 compared to controls) and 15/50 (30%) children with ulcerative colitis (p=0.09 compared to controls; p=0.01 compared to FGIDs; p=0.01 compared to Crohn`s). Conclusions JH is more prevalent in patients suffering from ulcerative colitis compared to the healthy general population, yet the difference did not reach statistical significance. Likely, a proportion of children with ulcerative colitis and JH may show connective tissue abnormalities. However, whether JH can be considered a possible feature of pediatric GI disorders deserves further investigation.

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.

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.

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global public health emergency. COVID-19 typically manifests as a respiratory illness but an increasing number of clinical reports describe gastrointestinal (GI) symptoms. This is particularly true in children in whom GI symptoms are frequent and viral shedding outlasts viral clearance from the respiratory system. By contrast, fetuses seem to be rarely affected by COVID-19, although the virus has been detected in placentas of affected women. These observations raise the question of whether the virus can infect and replicate within the stomach once ingested. Moreover, it is not yet clear whether active replication of SARS-CoV-2 is possible in the stomach of children or in fetuses at different developmental stages. Here we show the novel derivation of fetal gastric organoids from 8-21 post-conception week (PCW) fetuses, and from pediatric biopsies, to be used as an in vitro model for SARS-CoV-2 gastric infection. Gastric organoids recapitulate human stomach with linear increase of gastric mucin 5AC along developmental stages, and expression of gastric markers pepsinogen, somatostatin, gastrin and chromogranin A. In order to investigate SARS-CoV-2 infection with minimal perturbation and under steady-state conditions, we induced a reversed polarity in the gastric organoids (RP-GOs) in suspension. In this condition of exposed apical polarity, the virus can easily access viral receptor angiotensin-converting enzyme 2 (ACE2). The pediatric RP-GOs are fully susceptible to infection with SARS-CoV-2, where viral nucleoprotein is expressed in cells undergoing programmed cell death, while the efficiency of infection is significantly lower in fetal organoids. The RP-GOs derived from pediatric patients show sustained robust viral replication of SARS-CoV-2, compared with organoids derived from fetal stomachs. Transcriptomic analysis shows a moderate innate antiviral response and the lack of differentially expressed genes belonging to the interferon family. Collectively, we established the first expandable human gastric organoid culture across fetal developmental stages, and we support the hypothesis that fetal tissue seems to be less susceptible to SARS-CoV-2 infection, especially in early stages of development. However, the virus can efficiently infect gastric epithelium in pediatric patients, suggesting that the stomach might have an active role in fecal-oral transmission of SARS-CoV-2.

Background: Colonic manometry with intraluminal bisacodyl infusion can be used to assess colonic neuromuscular function in children with treatment-refractory constipation. If bisacodyl does not induce high-amplitude propagating contractions (HAPCs), this can be an indication for surgical intervention. A detailed characterization of the colonic response to intraluminal bisacodyl in children with constipation may help to inform clinical interpretation of colonic manometry studies. Methods: Studies were performed in five pediatric hospitals. Analysis included identification of HAPCs, reporting HAPCs characteristics, and an area under the curve (AUC) analysis. Comparisons were performed between hospitals, catheter type, placement techniques, and site of bisacodyl infusion. Results: One hundred and sixty-five children were included (median age 10, range 1-17 years; n = 96 girls). One thousand eight hundred and ninety-three HAPCs were identified in 154 children (12.3 ± 8.8 HAPCs per child, 0.32 ± 0.21 HAPCs per min; amplitude 113.6 ± 31.5 mm Hg; velocity 8.6 ± 3.8 mm/s, propagation length 368 ± 175 mm). The mean time to first HAPC following bisacodyl was 553 ± 669 s. Prior to the first HAPC, there was no change in AUC when comparing pre- vs post-bisacodyl (Z = −0.53, P =.60). The majority of HAPCs terminated in a synchronous pressurization in the rectosigmoid. Defecation was associated with HAPCs (χ 2(1)=7.04, P

Background Hirschsprung’s disease (HSCR) is a serious congenital bowel disorder with a prevalence of 1/5000. Currently, there is a lack of systematically developed guidelines to assist clinical decision-making regarding diagnostics and management. Aims This guideline aims to cover the diagnostics and management of rectosigmoid HSCR up to adulthood. It aims to describe the preferred approach of ERNICA, the European Reference Network for rare inherited and congenital digestive disorders. Methods Recommendations within key topics covering the care pathway for rectosigmoid HSCR were developed by an international workgroup of experts from 8 European countries within ERNICA European Reference Network from the disciplines of surgery, medicine, histopathology, microbiology, genetics, and patient organization representatives. Recommendation statements were based on a comprehensive review of the available literature and expert consensus. AGREE II and GRADE approaches were used during development. Evidence levels and levels of agreement are noted. Results Thirty-three statements within 9 key areas were generated. Most recommendations were based on expert opinion. Conclusion In rare or low-prevalence diseases such as HSCR, there remains limited availability of high-quality clinical evidence. Consensus-based guidelines for care are presented.

Motility of the gastrointestinal tract plays a critical role in the maintenance of its many physiological functions. These motility patterns, which vary along the gastrointestinal tract, are achieved by highly coordinated interactions between the neuromusculature of the gut (smooth muscle layers, enteric nervous system, interstitial cells of Cajal), central nervous system, autonomic nervous system, hormones, peptides and the microbiome. Other external factors such as diet, and age related changes in the gastrointestinal tract also, ultimately, affect gastrointestinal motility. A subtle change in any of the above factors could significantly impact on gastrointestinal function leading to pediatric gastrointestinal motility disorders. Here, we review common motility disorders in children and provide an indepth understanding of the pathophysiology and management of these problem.

Background and AimsInflammatory bowel disease [IBD] is often one of the most devastating and debilitating chronic gastrointestinal disorders in children and adolescents. The main objectives here were to systematically review the incidence and prevalence of paediatric IBD across all 51 European states.MethodsWe undertook a systematic review and meta-analysis based on PubMed, CINAHL, the Cochrane Library, searches of reference lists, grey literature and websites, covering the period from 1970 to 2018.ResultsIncidence rates for both paediatric Crohn’s disease [CD] and ulcerative colitis [UC] were higher in northern Europe than in other European regions. There have been large increases in the incidence of both paediatric CD and UC over the last 50 years, which appear widespread across Europe. The largest increases for CD have been reported from Sweden, Wales, England, the Czech Republic, Denmark and Hungary, and for UC from the Czech Republic, Ireland, Sweden and Hungary. Incidence rates for paediatric CD have increased up to 9 or 10 per 100 000 population in parts of Europe, including Scandinavia, while rates for paediatric UC are often slightly lower than for CD. Prevalence reported for CD ranged from 8.2 per 100 000 to approximately 60 and, for UC, from 8.3 to approximately 30.ConclusionsThe incidence of paediatric IBD continues to increase throughout Europe. There is stronger evidence of a north–south than an east–west gradient in incidence across Europe. Further prospective studies are needed, preferably multinational and based on IBD registries, using standardized definitions, methodology and timescales.

Objectives The main aim of this study was to determine the impact on clinical practice of the first European Society of Gastroenterology, Hepatology, and Nutrition (ESPGHAN) position paper on the diagnosis and management of nutritional and gastrointestinal problems in children with neurological impairment (NI). Methods In this pilot-study, a web-based questionnaire was distributed between November, 2019 and June, 2020, amongst ESPGHAN members using the ESPGHAN newsletter. Fifteen questions covered the most relevant aspects on nutritional management and gastrointestinal issues of children with NI. A descriptive analysis of responses was performed. Results A total of 150 health professionals from 23 countries responded to the survey. A considerable variation in clinical practice concerning many aspects of nutritional and gastrointestinal management of children with NI was observed. The most frequently used method for diagnosing oropharyngeal dysfunction was the direct observation of meals with or without the use of standardised scores (n = 103). Anthropometric measurements were the most commonly used tools for assessing nutritional status (n = 111). The best treatment for gastroesophageal reflux disease (GERD) was considered to be proton pump inhibitor therapy by most (n = 116) participants. Regarding tube feeding, nearly all respondents (n = 114) agreed that gastrostomy is the best enteral access to be used for long-term enteral feeding. Fundoplication was indicated at the time of gastrostomy placement especially in case of uncontrolled GERD. Conclusions More studies are required to address open questions on adequate management of children with NI. Identifying knowledge gaps paves the way for developing updated recommendations and improving patient care.

The gut-brain axis has recently emerged as a key modulator of human health and the intestinal microbiome has a well-recognised pivotal role in this strong connection. The aim of this narrative review is to update and summarise the effect and clinical applicability of probiotics in paediatric neurogastroenterology. The Cochrane Database and PubMed were searched using keywords relating to different subtypes of functional gastrointestinal disorders (FGIDs) and their symptoms, those relating to the CNS and related neurological or behavioural dysfunction as well as 'probiotic' OR 'probiotics'. Included papers were limited to those including children (aged 0-18 years) and using English language. Although significant effects of specific strains have been reported in infants with FGIDs, heterogeneity amongst the studies (different products and concentrations used and FGID subtypes), has limited the ability to draw an overall conclusion on the clinical value of probiotics. According to different meta-analyses of randomised controlled trials, the use of Lactobacillus reuteri (DSM 17938) was associated with a significant decrease in average crying time in infantile colic. There is moderate evidence for this strain and LGG and limited evidence (based on one study each) for the beneficial effect of VSL#3 and a three-strain bifidobacteria mix in abdominal pain FGIDs, particularly in the irritable bowel disease subgroup of children, but not in functional dyspepsia. There is currently no clear evidence of positive effects of oral probiotics in autistic spectrum disorder. Efficacy and safety of other strains or beneficial effects in other conditions still need to be proven, as probiotic properties are strain-specific, and data cannot be extrapolated to other brain-gut or mood diseases or to other probiotics of the same or different species. To transform the use of probiotics from a tempting suggestion to a promising treatment modality in neurogastroenterological disorders more accurate differentiation of the efficacy-proven strains, clarification of dose, duration, and outcome and a careful selection of the target patients are still necessary. KEYWORDS: autism; behaviour; brain; functional gastrointestinal disorders; mood

The bewildering complexity of the enteric nervous system makes it susceptible to develop a wide array of motility disorders, collectively called enteric neuropathies. These gastrointestinal conditions are among the most challenging to manage, mainly given poor characterization of their etiopathophysiology and outcomes. Not surprisingly, therefore, targeted or curative therapies for enteric neuropathies are lacking and management is largely symptomatic. Nonetheless, recent advances in neurogastroenterology have witnessed improvements in established strategies, such as intestinal transplantation and the emergence of new treatments including novel drugs, electrical pacing, and manipulation of fecal microbiota, as well as stem cell and gene therapy.

Resumen: Los trastornos funcionales de dolor abdominal tienen una alta prevalencia en los niños. Estos trastornos pueden estar presentes por sí solos o en combinación con enfermedades orgánicas, tales como la enfermedad celíaca y las enfermedades inflamatorias intestinales. La inflamación intestinal (infecciosa y no infecciosa) predispone a los niños al desarrollo de hipersensibilidad visceral que puede manifestarse como trastornos funcionales de dolor abdominal, entre ellos el síndrome de intestino irritable. La aparición de síntomas de síndrome de intestino irritable en un paciente con una enfermedad orgánica subyacente, como la enfermedad inflamatoria intestinal, es un reto clínico, dado que la misma sintomatología puede representar un periodo de exacerbación de la enfermedad inflamatoria intestinal o un trastorno de dolor abdominal funcional sobrepuesto. Así mismo, puede ser que los síntomas del síndrome de intestino irritable en un niño con diagnóstico de enfermedad celíaca ocurran por un inadecuado control de la enfermedad celíaca o por la sobreposición con un trastorno de dolor abdominal funcional. Existe poca investigación acerca de la sobreposición de los trastornos funcionales abdominales y las enfermedades orgánicas en niños. Los estudios sugieren que la sobreposición entre los trastornos funcionales de dolor abdominal y la enfermedad inflamatoria intestinal es más común en adultos que en niños. Las causas de estas diferencias de prevalencia son aún desconocidas. Solo se han publicado unos cuantos estudios que tratan el tema de la sobreposición entre la enfermedad celíaca y los trastornos funcionales abdominales en niños. El presente artículo proporciona una revisión de la literatura acerca de la sobreposición entre la enfermedad celíaca, la enfermedad inflamatoria intestinal, y los trastornos funcionales de dolor abdominal en niños, además de establecer comparaciones con estudios realizados en adultos. Abstract: Functional abdominal pain disorders are highly prevalent in children. These disorders can be present in isolation or combined with organic diseases, such as celiac disease and inflammatory bowel diseases. Intestinal inflammation (infectious and non-infectious) predisposes children to the development of visceral hypersensitivity that can manifest as functional abdominal pain disorders, including irritable bowel syndrome. The new onset of irritable bowel syndrome symptoms in a patient with an underlying organic disease, such as inflammatory bowel disease, is clinically challenging, given that the same symptomatology may represent a flare-up of the inflammatory bowel disease or an overlapping functional abdominal pain disorder. Similarly, irritable bowel syndrome symptoms in a child previously diagnosed with celiac disease may occur due to poorly controlled celiac disease or the overlap with a functional abdominal pain disorder. There is little research on the overlap of functional abdominal disorders with organic diseases in children. Studies suggest that the overlap between functional abdominal pain disorders and inflammatory bowel disease is more common in adults than in children. The causes for these differences in prevalence are unknown. Only a handful of studies have been published on the overlap between celiac disease and functional abdominal pain disorders in children. The present article provides a review of the literature on the overlap between celiac disease, inflammatory bowel disease, and functional abdominal pain disorders in children and establish comparisons with studies conducted on adults. Palabras clave: Dolor abdominal, Enfermedad celíaca, Enfermedad inflamatoria intestinal, Niños, Inflamación gastrointestinal, Keywords: Abdominal pain, Celiac disease, Inflammatory bowel disease, Children, Gastrointestinal inflammation

Background Combined pH-impedance monitoring has been suggested as the investigation of choice for diagnosing gastro-oesophageal reflux in children. Although it is superior to oesophageal pH monitoring in detecting all types of reflux episodes (acid, weakly acidic and alkaline) with the ability to evaluate symptom association with reflux events, it is still limited by the lack of true paediatric normal value and the high cost involved (equipment and personnel). Objective To produce a position statement on behalf of the Motility Working Group of the British Society of Paediatric Gastroenterology, Hepatology and Nutrition on the indications and practical application of combined oesophageal pH-impedance monitoring in children. Methods Up-to-date review of available evidence. Results This document provides a practical guide to clinician on indications, methods and results interpretation of paediatric multichannel intraluminal impedance pH (MII-pH). Conclusions MII-pH is increasingly used by paediatricians as the diagnostic tool for assessing gastro-oesophageal reflux disease and symptom association. There is wide variation in paediatric practice and a need for standardised practice.

Intestinal failure (IF), following extensive anatomical or functional loss of small intestine (SI), has debilitating long-term effects on infants and children with this condition. Priority of care is to increase the child’s length of functional intestine, jejunum in particular, to improve nutritional independence. Here we report a robust protocol for reconstruction of autologous intestinal mucosal grafts using primary IF patient materials. Human jejunal intestinal organoids derived from paediatric IF patients can be expanded efficiently in vitro with region-specific markers preserved after long-term culture. Decellularized human intestinal matrix with intact ultrastructure is used as biological scaffolds. Proteomic and Raman spectroscopic analyses reveal highly analogous biochemical composition of decellularized human SI and colon matrix, implying that they can both be utilised as scaffolds for jejunal graft reconstruction. Indeed, seeding of primary human jejunal organoids to either SI or colonic scaffolds in vitro can efficiently reconstruct functional jejunal grafts with persistent disaccharidase activity as early as 4 days after seeding, which can further survive and mature after transplantation in vivo. Our findings pave the way towards regenerative medicine for IF patients.

Background ‘Intractable constipation’ (IC) is constipation unresponsive to 3 months of optimal conventional treatment. Colonic manometry (CM) is recommended as a diagnostic modality for evaluation of these children. This study aimed to review outcomes of children with IC who were managed surgically at a single tertiary care center. Methods Records of children with IC who were treated with ACE (antegrade colonic enema), colostomy, or ileostomy (2006–2018) were reviewed. “Success” was defined as adequate evacuation without need for further unplanned surgery. Data are median (range). Results Sixty-seven children underwent surgery, of whom 56 with preoperative CM were included. Age at surgery was 8.6 (3.3–15.1) years. Eight had normal manometry and underwent ACE with 75% success. Thirty-six had left-sided dysfunction and underwent ACE (18), colostomy (14) or ileostomy (4) as initial intervention with 61, 70, and 100% success. Twelve with pancolonic dysfunction underwent ACE (6) or ileostomy (6) with 60 and 100% success. Twenty underwent repeat manometry 2.2 years (10 months–7.6 years) after surgery. Of 18 with stoma, 8 had resolution or improvement and of these, 7 underwent stoma reversal with a simultaneous ACE. Two patients with ACE had improvement, 1 is still on ACE washouts, and 1 is off all treatment. Ten with persistent dysfunction remain diverted. At 3.2 years (4 months–9.9 years) follow-up, 18 remain on ACE washouts, 9 have colostomy, 19 ileostomy, and 10 are off treatment and doing well. Conclusion We present a large series of patients who were surgically managed for IC. CM may guide therapy in these children. Type of study Retrospective comparative study Level of evidence Level III.

Intestinal failure, following extensive anatomical or functional loss of small intestine, has debilitating long-term consequences for children1. The priority of patient care is to increase the length of functional intestine, particularly the jejunum, to promote nutritional independence2. Here we construct autologous jejunal mucosal grafts using biomaterials from pediatric patients and show that patient-derived organoids can be expanded efficiently in vitro. In parallel, we generate decellularized human intestinal matrix with intact nanotopography, which forms biological scaffolds. Proteomic and Raman spectroscopy analyses reveal highly analogous biochemical profiles of human small intestine and colon scaffolds, indicating that they can be used interchangeably as platforms for intestinal engineering. Indeed, seeding of jejunal organoids onto either type of scaffold reliably reconstructs grafts that exhibit several aspects of physiological jejunal function and that survive to form luminal structures after transplantation into the kidney capsule or subcutaneous pockets of mice for up to 2 weeks. Our findings provide proof-of-concept data for engineering patient-specific jejunal grafts for children with intestinal failure, ultimately aiding in the restoration of nutritional autonomy.

Defecatory disorders in children, including chronic constipation (CC) and fecal incontinence (FI), are common conditions worldwide and have a significant impact on children, their families, and the healthcare system. Anorectal manometry (ARM) and high-resolution anorectal manometry (HRAM) are relatively novel tools for the assessment of anal sphincter function and rectal sensation and have contributed significantly to improving the understanding of the anorectum as a functional unit. ARM has been recognized as the investigation of choice for adults with symptoms of defecation disorders, including fecal incontinence (FI), evacuation difficulties, and constipation. Although it is the gold standard tool in adults, it has yet to be formally accepted as a standardized diagnostic tool in the pediatric age, with limited knowledge regarding indications, protocol, and normal values. ARM/HRAM is slowly becoming recognized among pediatricians, but given that there are currently no agreed guidelines there is a risk that will lead to diversity in practice. The British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN)-Motility Working Group (MWG) therefore has taken the opportunity to provide guidance on the use of ARM/HRAM in children with CC and/or FI.

OBJECTIVE: In therapeutic trials for infant gastroesophageal reflux disease (GERD), ways to define GERD and measure and report study outcomes vary widely. The aim of this study was to develop a core outcome set (COS) for infant GERD. METHODS: The COS was developed using the Delphi technique, adhering to the Outcome Measures in Rheumatology Initiative 2.0 recommendations. Healthcare professionals (HCPs) (predominantly pediatric gastroenterologists and general pediatricians) and parents of infants (age 0-12 months) with GERD, listed up to 5 primary goals of therapy from their perspective and up to 5 persistent signs or symptoms that would signify inadequate treatment. Outcomes mentioned by >10% of participants were included in 2 shortlists. Next, HCPs and parents rated and prioritized outcomes on these shortlists. Outcomes with the highest rank formed the draft COS. The final COS was created after 2 consensus meetings between an expert panel and patient representatives. RESULTS: In total, 125 of 165 HCPs (76%) and 139 of 143 parents (97%) of infants with GERD completed the first phase. The second phase was completed by 83 of 139 HCPs (60%) and 127 of 142 different parents (89%). Outcomes of these phases were discussed during the consensus meetings and a 9-item COS was formed: "Adequate Growth," "Adequate Relief," "Adverse events,", "Crying," "Evidence of Esophagitis," "Feeding Difficulties," "Hematemesis," "No Escalation of Therapy," and "Sleep Problems." CONCLUSIONS: We developed a COS for infant GERD consisting of 9 items that should minimally be measured in future therapeutic trials to decrease study heterogeneity and ease comparability of results.

Enteric neuropathies, such as Hirschsprung disease (HSCR), comprise a number of severe diseases of the enteric nervous system (ENS) of the gastrointestinal (GI) tract with, as yet, no cures. The replacement of absent or diseased enteric neurons via stem cell transplantation directly into diseased gut represents a novel, curative therapy. This idea is supported by over two decades of preclinical research, carried out mainly in mice, demonstrating that neural crest-derived stem cells can be isolated from the gut, expanded in culture, and transplanted into gut in vivo where they migrate, proliferate, differentiate, and become functionally active. Here, we review some of the learnings from these studies, outlining the diseases potentially amenable to stem cell replacement therapy, the animals used to model disease, the different types of stem cells that could be used for therapy, the methodologies developed to prepare and deliver stem cells to the gut, and cell safety considerations. With the significant progress that has already been made by the field, the aim of developing a curative stem cell therapy for devastating diseases of the enteric nervous system is rapidly approaching reality.

Objectives: Jejunal tube feeding (JTF) is increasingly becoming the standard of care for children in whom gastric tube feeding is insufficient to achieve caloric needs. Given a lack of a systematic approach to the care of JTF in paediatric patients, the aim of this position paper is to provide expert guidance regarding the indications for its use and practical considerations to optimize its utility and safety. Methods: A group of members of the Gastroenterology and Nutrition Committees of the European Society of Paediatric Gastroenterology Hepatology and Nutrition and of invited experts in the field was formed in September 2016 to produce this clinical guide. Seventeen clinical questions treating indications and contraindications, investigations before placement, techniques of placement, suitable feeds and feeding regimen, weaning from JTF, complications, long-term care, and ethical considerations were addressed. A systematic literature search was performed from 1982 to November 2018 using PubMed, the MEDLINE, and Cochrane Database of Systematic Reviews. Grading of Recommendations, Assessment, Development, and Evaluation was applied to evaluate the outcomes. During a consensus meeting, all recommendations were discussed and finalized. In the absence of evidence from randomized controlled trials, recommendations reflect the expert opinion of the authors. Results: A total of 33 recommendations were voted on using the nominal voting technique. Conclusions: JTF is a safe and effective means of enteral feeding when gastric feeding is insufficient to meet caloric needs or is not possible. The decision to place a jejunal tube has to be made by close cooperation of a multidisciplinary team providing active follow-up and care.

AIMS AND OBJECTIVES: Children suffering from intestinal failure (IF) endure considerable morbidity and overall have poor survival rates, complicated by the shortage of organs available for transplantation. Therefore, new therapeutic approaches are pivotal if outcomes are to be improved. Over the past years, tissue engineering (TE) has emerged as a possible alternative treatment for many congenital and acquired conditions. TE aims at creating bioengineered organs by means of combining scaffolds with appropriate cell types, which in the intestine are organised within a multilayer structure. In order to generate functional intestine, this cellular diversity and organisation will need to be recreated. While the cells for the epithelial, neural and vascular compartments have been well defined, so far, less attention has been put on the muscular compartment. More recently, mesoangioblasts (MABs) have been identified as a novel source for tissue regeneration since they are able to give rise to vascular and other mesodermal derivatives. To date MABs have not been successfully isolated from intestinal tissue. Therefore, our aim was to demonstrate the possibility of isolating MABs from adult mouse small intestine. MATERIALS AND METHODS: All experiments were carried out using small intestinal tissues from C57BL/6J mice. We applied an established protocol for MAB isolation from the isolated neuromuscular layer of the small intestine. Cultured cells were stained for Ki67 to assess proliferation rates as well as for a panel of pericyte markers to determine their phenotype. RESULTS: Cells were successfully isolated from gut biopsies. Cultured cells showed good proliferative capacity and positivity for at least three pericytes markers found in vessels of the gut neuromuscular wall: neuron-glial antigen 2, alkaline phosphatase and platelet-derived growth factor β. CONCLUSION: This proof-of-principle study lays the foundation for further characterization of MABs as a possible cell source for intestinal smooth muscle regeneration and TE. ispartof: PEDIATRIC SURGERY INTERNATIONAL vol:35 issue:1 pages:29-34 ispartof: location:ITALY, Taormina status: published

The current increasing survival of children with severe central nervous system damage has created a major challenge for medical care. Gastrointestinal and nutritional problems in neurologically impaired children have been recently recognized as an integral part of their disease, often leading to growth failure and worsened quality of life for both children and caregivers. Nutritional support is essential for the optimal care of these children. Undernourished handicapped children might not respond properly to intercurrent diseases and suffer unnecessarily. On the other hand, restoring a normal nutritional status results in a better quality of life in many. The easiest and least invasive method to increase energy intake is to improve oral intake. However, oral intake can be maintained as long as there is no risk of aspiration, the child is growing well and the time required to feed the child remains within acceptable limits. When oral intake is unsafe, insufficient or too time consuming, enteral nutrition should be initiated. Damage to the developing central nervous system may result in significant dysfunction in the gastrointestinal tract and is reflected in impairment in oral-motor function, rumination, gastro-oesophageal reflux (GER), with or without aspiration, delayed gastric emptying and constipation. These problems can all potentially contribute to feeding difficulty in disabled children, carrying further challenging long-term management issues.

Recurrent abdominal pain (RAP) is a common complaint in children. Previously considered a single entity, RAP is now used as a descriptive term and sub-classified in the recently published Rome IV criteria, into four functional abdominal pain disorders (FAPD), including functional dyspepsia and irritable bowel syndrome. All share common pathogenic mechanisms of visceral hypersensitivity and central hypervigilance, resulting from disruption of the microbiota–gut–brain axis and abnormal enteric neuro–immune interactions. Although FAPDs are benign in nature, the persistence of symptoms and effects on everyday life can have significant secondary effects including psychosocial morbidity. The diagnosis of FAPDs is based on careful history and examination looking for ‘alarm signs', although a limited battery of laboratory investigations to screen for organic disease may be of value. The management of FAPDs should be multidisciplinary and based on the bio-psychosocial model of care with careful education and engagement of patients/parents. There is currently little evidence to support the routine use of pharmacotherapy, probiotics or diet and a significant placebo effect should be considered when assessing treatment effect. Hypnotherapy has been shown to be an effective therapy. Approximately 50% of FAPDs cases will achieve resolution, especially those that have engaged with the appropriate model of management.

Background Colonic manometry is the standard diagnostic modality for evaluating colonic motility in children. Intraluminal bisacodyl is routinely used to trigger high-amplitude propagating contractions (HAPCs), a feature of normal colonic motility. Usually, only a single dose (0.2 mg/kg) is suggested. We retrospectively explored whether the use of an additional higher (0.4 mg/kg) dose of bisacodyl increases the yield of colonic manometry. Methods In 103 children (median age: 8.8 years, range 3.2–15.7 years) with a diagnosis of slow transit constipation, colonic motility was recorded for 1 h before and 1 h after each of two incremental doses of bisacodyl (low, L, dose: 0.2 mg/kg, max 10 mg; high, H, dose: 0.4 mg/kg, max 20 mg) and the characteristics of HAPCs analyzed. Key Results High-amplitude propagating contractions were seen in 85 children. H dose significantly increased the proportion of patients with fully propagated HAPCs (H dose: 57/103 [55%], L dose: 27/103 [26%], p

According to international guidelines, polyethylene glycol (PEG) is the laxative of first choice in the treatment of functional constipation in children, both for disimpaction and for maintenance treatment. PEG acts as an osmotic laxative and its efficacy is dose dependent. PEG is highly effective, has a good safety profile, and is well tolerated by children. Only minor adverse events have been reported. Overall the use of PEG in children has been reported to be safe, although in patients predisposed to water and electrolyte imbalances monitoring of serum electrolytes should be considered.

Pediatric gastrointestinal motility disorders represent a range of severe developmental or acquired conditions that disrupt enteric neuromuscular function. Current medical and surgical therapeutic options are very limited but recent advances have highlighted the possibility of improved or curative stem cell-based treatments. Not only has the ability to harvest, propagate and transplant human-derived enteric neural stem cells (ENSCs) been demonstrated but recent in vivo transplantation studies have confirmed that ENSCs are capable of engraftment within recipient intestine of animal models of enteric neuropathy and effecting functional rescue. Pluripotent stem cell-derived cells and pharmacological modulation of both endogenous and transplanted neural stem cells have further enhanced the exciting prospect of clinical application of such stem cell-based therapies in the near future.

Objectives: Chronic intestinal pseudo-obstructive (CIPO) conditions are considered the most severe disorders of gut motility. They continue to present significant challenges in clinical care despite considerable recent progress in our understanding of pathophysiology, resulting in unacceptable levels of morbidity and mortality. Major contributors to the disappointing lack of progress in paediatric CIPO include a dearth of clarity and uniformity across all aspects of clinical care from definition and diagnosis to management. In order to assist medical care providers in identifying, evaluating, and managing children with CIPO, experts in this condition within the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition as well as selected external experts, were charged with the task of developing a uniform document of evidence- and consensus-based recommendations. Methods: Ten clinically relevant questions addressing terminology, diagnostic, therapeutic, and prognostic topics were formulated. A systematic literature search was performed from inception to June 2017 using a number of established electronic databases as well as repositories. The approach of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was applied to evaluate outcome measures for the research questions. Levels of evidence and quality of evidence were assessed using the classification system of the Oxford Centre for Evidence-Based Medicine (diagnosis) and the GRADE system (treatment). Each of the recommendations were discussed, finalized, and voted upon using the nominal voting technique to obtain consensus. Results: This evidence- and consensus-based position paper provides recommendations specifically for chronic intestinal pseudo-obstruction in infants and children. It proposes these be termed paediatric intestinal pseudo-obstructive (PIPO) disorders to distinguish them from adult onset CIPO. The manuscript provides guidance on the diagnosis, evaluation, and treatment of children with PIPO in an effort to standardise the quality of clinical care and improve short- and long-term outcomes. Key recommendations include the development of specific diagnostic criteria for PIPO, red flags to alert clinicians to the diagnosis and guidance on the use of available investigative modalities. The group advocates early collaboration with expert centres where structured diagnosis and management is guided by a multi-disciplinary team, and include targeted nutritional, medical, and surgical interventions as well as transition to adult services. Conclusions: This document is intended to be used in daily practice from the time of first presentation and definitive diagnosis PIPO through to the complex management and treatment interventions such as intestinal transplantation. Significant challenges remain to be addressed through collaborative clinical and research interactions.

BACKGROUND Enteric neuropathies exist as a wide range of human disorders which impact on gastrointestinal motility. Current standard therapies for enteric neuropathies are limited to surgical resection or manipulation (eg, myotomy) of affected gut segments or medical management including both therapy (eg, prokinetic pharmacotherapy) and support such as parenteral nutrition. However, such treatments often result in poor prognosis and significant morbidity. The current limitations in treatment options for enteric neuropathies underline the need for alternative approaches to treat these devastating diseases. Recent advances have highlighted the potential of enteric neural stem cells as a possible treatment option for regenerative medicine, in such cases. PURPOSE The purpose of this review is to provide an up-to-date synopsis of the enteric neural stem cell research field. Here, we review in detail the initial characterization of enteric neural stem cells, early preclinical studies validating their use in murine models through to the most recent findings of therapeutic rescue of diseased gut tissue. We additionally pose a number of questions regarding these recent findings which will need to be addressed prior to clinical translation of this exciting cellular therapeutic.

Gastrointestinal symptoms including constipation, diarrhoea, pain and bloating represent some of the most common clinical problems for patients. These symptoms can often be managed with cheap, widely available medication or will spontaneously resolve. However, for many patients, chronic GI symptoms persist and frequently come to dominate their lives. At one end of the spectrum there is Inflammatory Bowel Disease (IBD) with a clearly defined but expensive treatment pathway. Contrasting with this is Irritable Bowel Syndrome (IBS), likely a collection of pathologies, has a poorly standardised pathway with unsatisfactory clinical outcomes. Managing GI symptoms in adult populations is a challenge. The clinical burden of gastrointestinal disease is also prevalent in paediatric populations and perhaps even harder to treat. In this review we explore some of the recent advances in magnetic resonance imaging (MRI) to study the gastrointestinal tract. Complex in both its anatomical structure and its physiology we are likely missing key physiological markers of disease through relying on symptomatic descriptors of gut function. Using MRI we might be able to characterise previously opaque processes, such as non-propulsive contractility, that could lead to changes in how we understand even common symptoms like constipation. This review explores recent advances in the field in adult populations and examines how this safe, objective and increasingly available modality might be applied to paediatric populations.

Functional abdominal pain disorders are highly prevalent in children. These disorders can be present in isolation or combined with organic diseases, such as celiac disease and inflammatory bowel diseases. Intestinal inflammation (infectious and non-infectious) predisposes children to the development of visceral hypersensitivity that can manifest as functional abdominal pain disorders, including irritable bowel syndrome. The new onset of irritable bowel syndrome symptoms in a patient with an underlying organic disease, such as inflammatory bowel disease, is clinically challenging, given that the same symptomatology may represent a flare-up of the inflammatory bowel disease or an overlapping functional abdominal pain disorder. Similarly, irritable bowel syndrome symptoms in a child previously diagnosed with celiac disease may occur due to poorly controlled celiac disease or the overlap with a functional abdominal pain disorder. There is little research on the overlap of functional abdominal disorders with organic diseases in children. Studies suggest that the overlap between functional abdominal pain disorders and inflammatory bowel disease is more common in adults than in children. The causes for these differences in prevalence are unknown. Only a handful of studies have been published on the overlap between celiac disease and functional abdominal pain disorders in children. The present article provides a review of the literature on the overlap between celiac disease, inflammatory bowel disease, and functional abdominal pain disorders in children and establish comparisons with studies conducted on adults.

Objective: T o de v elop a North American Society for Pediatric Ga str oen te rol og y , He pat olo gy , and Nut ri tio n (N ASP GH AN) and Eu rop ea n Soc ie ty fo r Pe di atr ic Gas tr oen te ro log y , Hep at ol og y , and Nut rit io n (ES PGH AN ) int er nat io nal con se ns us on th e di agn os is an d ma nag em ent of gas tr oes op hag eal refl ux and gas tr oes op hag eal re flu x di sea se in th e ped ia tr ic po pu la tio n. Methods: An international panel of 9 pediatric gastroenterologists and 2 epidemiologists were selected by both societies, which de v eloped these guidelines based on the Delphi principle. Statements were based on systematic literature searches using the best-av ailable e vidence from PubMed, Cumulati ve Index to Nursing and Allied Health Literature, and bibliographies. The committee con v ened in face-to-face meetings 3 times. Consensus was achie v ed for all recommendations through nominal group technique, a structured, quantitati v e method. Articles were e v aluated using the Oxford Centre for Evidence-based Medicine Le vels of Evidence. Using the Oxford Grades of Recommendation, the quality of e vidence of each of the recommendations made by the committee was determined and is summarized in appendices. Results: More than 600 articles were re vie wed for this work. The document provides e vidence-based guidelines for the diagnosis and management of gastroesophageal reflux and gastroesophageal reflux disease in the pediatric population. Conclusions: Th is do cum ent is int end ed to be us ed in dai ly pra cti ce fo r th e de v el op me nt of fut ure cli ni cal pra ct ic e gu ide lin es and as a bas is for cli ni cal tr ia ls . JP GN 49 :49 8 – 54 7, 20 09 . Ke y Wo rd s: Cli nic al pra ct ic e gu id el ine s — Di agn os tic te sts — Ga str oes op hag ea l refl ux (GE R) — Ga str oes op hag ea l refl ux di sea se (GE RD ) — The rap eut ic mod al iti es. # 20 09 by Eu rop ea n Soc ie ty fo r Pe di atr ic Gas tr oen te ro log y , Hep at ol og y , and Nut rit io n and No rt h Am er ica n So ci ety for Pe dia tri c Ga str oen te rol og y , Hep at ol og y , an d Nu tr iti on

OBJECTIVE: The clinical relevance of esophageal baseline impedance (BI) remains to be determined. In the present study, we explored the impact of gastroesophageal reflux disease (GERD) and esophageal dysmotility on BI. METHODS: A total of 18 children with esophageal atresia, 26 children with GERD, and 17 controls prospectively underwent esophagogastroduodenoscopy and pH-impedance monitoring. BI was measured in both proximal and distal esophagus. Gastroesophageal reflux (GER) and bolus transit indicators were defined according to published criteria. RESULTS: Patients with esophageal atresia showed significantly lower proximal and distal BI values (952 [716-1811] Ω; 895 [284-1189] Ω; respectively) compared with those with GERD (3015 [2368-3975] Ω; 2231 [1770-3032] Ω, P < 0.001 and