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BACKGROUND: Probiotics, defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host, are widely used despite uncertainty regarding their efficacy and discordant recommendations about their use. The European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Special Interest Group on Gut Microbiota and Modifications provides updated recommendations for the use of probiotics for the management of selected pediatric gastrointestinal disorders. METHODS: All systematic reviews and/or meta-analyses, as well as subsequently published randomized controlled trials (RCTs) (until December 2021), that compared the use of probiotics in all delivery vehicles and formulations, at any dose, with no probiotic (ie, placebo or no treatment), were eligible for inclusion. The recommendations were formulated only if at least 2 RCTs on a similar well-defined probiotic strain were available. The modified Delphi process was used to establish consensus on the recommendations. RESULTS: Recommendations for the use of specific probiotic strains were made for the management of acute gastroenteritis, prevention of antibiotic-associated diarrhea, nosocomial diarrhea and necrotizing enterocolitis, management of Helicobacter pylori infection, and management of functional abdominal pain disorders and infant colic. CONCLUSIONS: Despite evidence to support the use of specific probiotics in some clinical situations, further studies confirming the effect(s) and defining the type, dose, and timing of probiotics are still often required. The use of probiotics with no documented health benefits should be discouraged.

Background: Bronchopulmonary dysplasia (BPD) may induce gastroesophageal reflux (GER). Esophageal impedance baseline values (BI) reflect mucosal inflammation. Our aim was to evaluate BI levels in preterm infants with BPD compared with those without BPD and to identify BI predictors. Methods: This is a retrospective pilot study including infants born <32 weeks' gestational age (GA) who underwent esophageal multichannel intraluminal impedance (MII)-pH. Univariate/multivariate analysis were performed to compare data between BPD and non-BPD infants and to identify BI predictors. A subgroup analysis was performed in infants born <29 weeks' GA, at highest risk for BPD. Results: Ninety-seven patients (median GA 285/7 weeks, mean postnatal age 49 days, 29 with BPD), were studied. BPD infants had significantly lower birth weight compared with non-BPD infants (750 vs. 1275 g), were more immature (274/7 vs. 290/7 weeks GA), were older at MII-pH (79 vs. 38 days) and received less fluids during MII-pH (147 vs. 161 ml/kg/day). The same findings were found in the group of 53 infants born <29 weeks. BPD versus non-BPD infants had significantly lower BI (2050 vs. 2574 ohm, p = 0.007) (<1000 ohm in five BPD infants vs. one non-BPD) whereas the other MII-pH parameters were not significantly different. Multiple regression analysis found that increasing chronological age was positively associated with BI (B = 9.3, p = 0.013) whereas BPD was associated with lower BI (B = −793.4, p < 0.001). Conclusions: BPD versus non-BPD infants had significantly lower BI despite similar MII-pH data. BPD and chronological age predicted BI, whereas only BPD predicted BI in the most immature infants.

Multi-wavelength observations indicate that some starburst galaxies show a dominant non-thermal contribution from their central region. These active galactic nuclei (AGN)-starburst composites are of special interest, as both phenomena on their own are potential sources of highly-energetic cosmic rays and associated gamma-ray and neutrino emission. In this work, a homogeneous, steady-state two-zone multi-messenger model of the non-thermal emission from the AGN corona as well as the circumnuclear starburst region is developed and subsequently applied to the case of NGC 1068, which has recently shown some first indications of high-energy neutrino emission. Here, we show that the entire spectrum of multi-messenger data - from radio to gamma-rays including the neutrino constraint - can be described very well if both, starburst and AGN corona, are taken into account. Using only a single emission region is not sufficient.

Introduction: Measurement of breath hydrogen (H2 ) and methane (CH4 ) excretion after ingestion of test-carbohydrates is used for different diagnostic purposes. There is a lack of standardization among centers performing these tests and this, together with recent technical developments and evidence from clinical studies, highlight the need for a European guideline. Methods: This consensus-based clinical practice guideline defines the clinical indications, performance, and interpretation of H2 -CH4 -breath tests in adult and pediatric patients. A balance between scientific evidence and clinical experience was achieved by a Delphi consensus that involved 44 experts from 18 European countries. Eighty eight statements and recommendations were drafted based on a review of the literature. Consensus (≥80% agreement) was reached for 82. Quality of evidence was evaluated using validated criteria. Results: The guideline incorporates new insights into the role of symptom assessment to diagnose carbohydrate (e.g., lactose) intolerances and recommends that breath tests for carbohydrate malabsorption require additional validated concurrent symptom evaluation to establish carbohydrate intolerance. Regarding the use of breath tests for the evaluation of oro-cecal transit time and suspected small bowel bacterial overgrowth, this guideline highlights confounding factors associated with the interpretation of H2 -CH4 -breath tests in these indications and recommends approaches to mitigate these issues. Conclusion: This clinical practice guideline should facilitate pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, it identifies areas of future research needs to clarify diagnostic and therapeutic approaches. Keywords: fructose; intolerance; lactose; malabsorption; oro-cecal transit time; small intestinal bacterial overgrowth.

Yvan Vandenplas, 1 Helen A Brough, 2– 4 Alessandro Fiocchi, 5 Mohamad Miqdady, 6 Zakiudin Munasir, 7 Silvia Salvatore, 8 Nikhil Thapar, 9 Carina Venter, 10 Mario C Vieira, 11 Rosan Meyer  12, 13 1Vrije Universiteit Brussel (VUB), UZ Brussel, KidZ Health Castle, Brussels, Belgium; 2Department Women and Children’s Health (Pediatric Allergy), School of Life Course Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; 3Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, UK; 4Children’s Allergy Service, Evelina Children’s Hospital, Guy’s and St. Thomas’s NHS Foundation Trust, London, UK; 5Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio, Rome, Italy; 6Department of Pediatrics, Sheikh Khalifa Medical City, College of Medicine & Health Sciences, Khalifa University, Khalifa, United Arab Emirates; 7Department of Child Health, Ciptomangunkusumo Hospital-Medical Faculty Universitas Indonesia, Jakarta, Indonesia; 8Pediatric Department, Hospital “F. Del Ponte”, University of Insubria, Varese, Italy; 9Gastroenterology, Hepatology and Liver Transplant, Queensland Children’s Hospital, Brisbane, Queensland, Australia; 10University of Colorado, Children’s Hospital Colorado, Denver, CO, USA; 11Center for Pediatric Gastroenterology -Hospital Pequeno Príncipe, Curitiba, Brazil; 12Department of Paediatrics, Imperial College, London, UK; 13Department Nutrition and Dietetics, University of Winchester, Winchester, UKCorrespondence: Yvan VandenplasVrije Universiteit Brussel (VUB), UZ Brussel, KidZ Health Castle, Brussels, BelgiumEmail Yvan.vandenplas@uzbrussel.beAbstract: Exclusive breast feeding is recommended in all guidelines as the

Yvan Vandenplas, 1 Helen A Brough, 2– 4 Alessandro Fiocchi, 5 Mohamad Miqdady, 6 Zakiudin Munasir, 7 Silvia Salvatore, 8 Nikhil Thapar, 9 Carina Venter, 10 Mario C Vieira, 11 Rosan Meyer  12, 13 1Vrije Universiteit Brussel (VUB), UZ Brussel, KidZ Health Castle, Brussels, Belgium; 2Department Women and Children’s Health (Pediatric Allergy), School of Life Course Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, UK; 3Peter Gorer Department of Immunobiology, School of Immunology and Microbial Sciences, King’s College London, London, UK; 4Children’s Allergy Service, Evelina Children’s Hospital, Guy’s and St. Thomas’s NHS Foundation Trust, London, UK; 5Translational Research in Pediatric Specialities Area, Division of Allergy, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio, Rome, Italy; 6Department of Pediatrics, Sheikh Khalifa Medical City, College of Medicine & Health Sciences, Khalifa University, Khalifa, United Arab Emirates; 7Department of Child Health, Ciptomangunkusumo Hospital-Medical Faculty Universitas Indonesia, Jakarta, Indonesia; 8Pediatric Department, Hospital “F. Del Ponte”, University of Insubria, Varese, Italy; 9Gastroenterology, Hepatology and Liver Transplant, Queensland Children’s Hospital, Brisbane, Queensland, Australia; 10University of Colorado, Children’s Hospital Colorado, Denver, CO, USA; 11Center for Pediatric Gastroenterology -Hospital Pequeno Príncipe, Curitiba, Brazil; 12Department of Paediatrics, Imperial College, London, UK; 13Department Nutrition and Dietetics, University of Winchester, Winchester, UKCorrespondence: Yvan VandenplasVrije Universiteit Brussel (VUB), UZ Brussel, KidZ Health Castle, Brussels, BelgiumEmail Yvan.vandenplas@uzbrussel.beAbstract: Exclusive breast feeding is recommended in all guidelines as the

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 <10% disagreed. RESULTS The guideline gives an overview over general methodology of $^{13}$ C-breath testing and provides recommendations for the use of $^{13}$ C-breath tests to diagnose Helicobacter pylori infection, measure gastric emptying time, and monitor pancreatic exocrine and liver function in adult and pediatric patients. Other potential applications of $^{13}$ C-breath testing are summarized briefly. The recommendations specifically detail when and how individual $^{13}$ C-breath tests should be performed including examples for well-established test protocols, patient preparation, and reporting of test results. CONCLUSION This clinical practice guideline should improve pan-European harmonization of diagnostic approaches to symptoms and disorders, which are very common in specialist and primary care gastroenterology practice, both in adult and pediatric patients. In addition, this guideline identifies areas of future clinical research involving the use of $^{13}$ C-breath tests.

Purpose: Gastrointestinal symptoms are often related to antibiotic treatment. Their incidence, risk and protective conditions in children are not well defined and represent the aims of this study. Methods: We prospectively enrolled inpatient children submitted to antibiotic treatment. Indication, type, dose and duration of treatment, probiotic supplementation and gastrointestinal symptoms were recorded at recruitment, after two and four weeks. Antibiotic-associated diarrhea (AAD) was defined as the presence of at least 3 loose/liquid stools within 14 days from antibiotic onset. Results: AAD occurred in 59/289 (20.4%) of patients, with increased risk in children younger than 3 years (relative risk [RR]=4.25), in lower respiratory (RR=2.11) and urinary infections (RR=3.67), intravenous administration (RR=1.81) and previous AAD episodes (RR=1.87). Abdominal pain occurred in 27/289 (9.3%), particularly in children >6 years (RR=4.15), with previous abdominal pain (RR=7.2) or constipation (RR=4.06). Constipation was recorded in 23/289 (8.0%), with increased risk in children having surgery (RR=2.56) or previous constipation (RR=7.38). Probiotic supplementation significantly reduced AAD (RR=0.30) and abdominal pain (RR=0.36). Lactobacillus rhamnosus GG (LGG) and L. reuteri significantly reduced AAD (RR=0.37 and 0.35) and abdominal pain (RR=0.37 and 0.24). Conclusion: AAD occurred in 20.4% of children, with increased risk at younger age, lower respiratory and urinary tract infections, intravenous treatment and previous AAD. LGG and L. reuteri reduced both AAD and associated abdominal pain.

The diagnosis of cow’s milk allergy (CMA) is particularly challenging in infants, especially with non-Immunoglobulin E (IgE)-mediated manifestations, and inaccurate diagnosis may lead to unnecessary dietary restrictions. The aim of this study was to assess the accuracy of the cow’s milk-related symptom score (CoMiSSTM) in response to a cow’s milk-free diet (CMFD). We prospectively recruited 47 infants (median age three months) who had been placed on a CMFD due to persisting unexplained gastrointestinal symptoms. We compared data with 94 healthy controls (median age three months). The CoMiSSTM score was completed at recruitment and while on the exclusion diet. In 19/47 (40%) cases a response to the diet occurred. At recruitment CoMiSSTM was significantly higher in cases compared to controls (median score 8 vs. 3; p-value: <0.05), 9 cases had a score ≥12 and 8/9 normalized on CMFD. An oral milk challenge was performed in all 19 responders and six of these had a positive reaction to cow’s milk (CM). In eight infants IgE allergy tests were positive. The receiver operation characteristic (ROC) curve identified a CoMISSTM score of 9 to be the best cut-off value (84% sensitivity, 85% specificity, 80% positive (PPV) and 88% negative predictive value (NPV)) for the response to CMFD. We found CoMiSSTM to be a useful tool to help identify infants with persisting gastrointestinal symptoms and suspected CMA that would benefit from CMFD.

This is a retrospective multicenter nationwide Italian study collecting neonatal anthropometric data of Caucasian subjects with Prader–Willi syndrome (PWS) born from 1988 to 2018. The aim of the study is to provide percentile charts for weight and length of singletons with PWS born between 36 and 42 gestational weeks. We collected the birth weight and birth length of 252 male and 244 female singleton live born infants with both parents of Italian origin and PWS genetically confirmed. Percentile smoothed curves of birth weight and length for gestational age were built through Cole's lambda, mu, sigma method. The data were compared to normal Italian standards. Newborns with PWS showed a lower mean birth weight, by 1/2 kg, and a shorter mean birth length, by 1 cm, than healthy neonates. Females with a 15q11-13 deletion were shorter than those with maternal uniparental maternal disomy of chromosome 15 (p <.0001). The present growth curves may be useful as further traits in supporting a suspicion of PWS in a newborn. Because impaired prenatal growth increases risk of health problems later in life, having neonatal anthropometric standards could be helpful to evaluate possible correlations between the presence or absence of small gestational age and some clinical and metabolic aspects of PWS.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronically progressive or relapsing sensorimotor disorder presumably due to antibody-mediated reactions. It is a rare condition in children, with estimated prevalence as 0.48 per 100,000 among patients younger than 20 years of age. Recommended treatments include immune modulators, intravenous immunoglobulins (IVIgs), steroids, and plasmapheresis. Management of pediatric CIDP is challenging because of the lack of evidence-based efficacy of the current therapies in children. Because of the rarity of this condition, there are no double-blind randomized studies to support the therapeutic choice as well as to identify the optimal first-line therapeutic regimen. IVIgs are widely used but the intravenous administration is usually uncomfortable, especially for children. Subcutaneous immunoglobulins (SCIgs) have proven to be effective in adults with CIDP and in children affected by antibody deficiencies and other different immune and inflammatory disorders. Herein, we described the case of a 7-year-old boy, affected by CIDP who clinically responded to IVIg but was dependent on this therapy. In order to improve his quality of life, we switched to SCIg with excellent result.

Partially hydrolyzed formulas (pHFs) are increasingly used worldwide, both in the prevention of atopic disease in at-risk infants and in the therapeutic management of infants with functional gastrointestinal manifestations. Because prevention is always preferable to treatment, we reviewed the literature aiming to find an answer for the question whether pHF may be recommended for feeding all infants if breast-feeding is not possible. PubMed and Cochrane databases were searched up to December 2014. In addition, to search for data that remained undetected by the searches, we approached authors of relevant articles and major producers of pHFs asking for unpublished data. Because few data were found, nonrandomized, controlled trials and trials in preterm infants were included as well. Overall, only limited data could be found on the efficacy and safety of pHF in healthy term infants. Available data do not indicate that pHFs are potentially harmful for healthy, term infants. With respect to long-term outcomes, particularly referring to immune, metabolic and hormonal effects, data are, however, nonexistent. From a regulatory point of view, pHFs meet the nutrient requirements to be considered as standard formula for term healthy infants. Cost, which is different from country to country, should be considered in the decision-making process. Based on limited available data, the use of pHF in healthy infants is safe with regard to growth. The lack of data, in particular for metabolic consequences and long-term outcomes, is, however, the basis for our recommendation that health authorities should develop and support long-term follow-up studies. Efficacy and long-term safety data are required before a recommendation of this type of formula for all infants can be made.

Up to 50% of infants present with symptoms of regurgitation, infantile colic and/or constipation during the first 12 months of life. Although they are often classed as functional disorders, there is an overlap with cows' milk allergy. We present practical algorithms for the management of such disorders, based on existing evidence and general consensus, with a particular focus on primary health care. Management consists of early recognition of warning signs of organic disease, parental reassurance and nutritional strategies. ConclusionThe proposed algorithms aim to help healthcare providers manage frequent gastrointestinal and cows' milk-related symptoms in infants safely and effectively.

Aim: Implementing international guidelines guarantees high standards of clinical care. A group of experts developed an algorithm to drive the management of common gastrointestinal symptoms in infancy by paediatricians and general practitioners. Methods: The algorithm started from the evidence-based recommendations of the European Society of Gastroenterology, Hepatology and Nutrition and the European Society of Pediatric Infectious Diseases and an updated review of the literature. We used the structured quantitative method of nominal group technique to reach a consensus. Results: A practical algorithm for the management of infants with acute diarrhoea was designed based on the consensus reached for each statement. The management of an infant with acute diarrhoea should include a sequence of actions: (i) a semiquantitative estimate of infant dehydration through validated clinical scores, (ii) rehydration therapy and early refeeding with breast milk or regular formula and (iii) effective agents to reduce the severity and duration of the diarrhoea. Finally, in children with prolonged diarrhoea, the search for aetiology should include persistent infections or reinfections, cows' milk protein allergy and coeliac diseases. Lactose should always be withdrawn. Conclusion: This algorithm provides an evidence-based sequence of interventions to optimise the management of infants with acute diarrhoea.

Up to 50% of infants present with symptoms of regurgitation, infantile colic and/or constipation during the first 12 months of life. Although they are often classed as functional disorders, there is an overlap with cows' milk allergy. We present practical algorithms for the management of such disorders, based on existing evidence and general consensus, with a particular focus on primary health care. Management consists of early recognition of warning signs of organic disease, parental reassurance and nutritional strategies. ConclusionThe proposed algorithms aim to help healthcare providers manage frequent gastrointestinal and cows' milk-related symptoms in infants safely and effectively.

Aim: Implementing international guidelines guarantees high standards of clinical care. A group of experts developed an algorithm to drive the management of common gastrointestinal symptoms in infancy by paediatricians and general practitioners. Methods: The algorithm started from the evidence-based recommendations of the European Society of Gastroenterology, Hepatology and Nutrition and the European Society of Pediatric Infectious Diseases and an updated review of the literature. We used the structured quantitative method of nominal group technique to reach a consensus. Results: A practical algorithm for the management of infants with acute diarrhoea was designed based on the consensus reached for each statement. The management of an infant with acute diarrhoea should include a sequence of actions: (i) a semiquantitative estimate of infant dehydration through validated clinical scores, (ii) rehydration therapy and early refeeding with breast milk or regular formula and (iii) effective agents to reduce the severity and duration of the diarrhoea. Finally, in children with prolonged diarrhoea, the search for aetiology should include persistent infections or reinfections, cows' milk protein allergy and coeliac diseases. Lactose should always be withdrawn. Conclusion: This algorithm provides an evidence-based sequence of interventions to optimise the management of infants with acute diarrhoea.