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Background & Aims: A better understanding of prognostic factors in ulcerative colitis (UC) could improve patient management and reduce complications. We aimed to identify evidence-based predictors for outcomes in pediatric UC, which may be used to optimize treatment algorithms., Methods: Potential outcomes worthy of prediction in UC were determined by surveying 202 experts in pediatric UC. A systematic review of the literature, with selected meta-analysis, was performed to identify studies that investigated predictors for these outcomes. Multiple national and international meetings were held to reach consensus on evidence-based statements., Results: Consensus was reached on 31 statements regarding predictors of colectomy, acute severe colitis (ASC), chronically active pediatric UC, cancer and mortality. At diagnosis, disease extent (6 studies, N = 627; P = .035), Pediatric Ulcerative Colitis Activity Index score (4 studies, n = 318; P < .001), hemoglobin, hematocrit, and albumin may predict colectomy. In addition, family history of UC (2 studies, n = 557; P = .0004), extraintestinal manifestations (4 studies, n = 526; P = .048), and disease extension over time may predict colectomy, whereas primary sclerosing cholangitis (PSC) may be protective. Acute severe colitis may be predicted by disease severity at onset and hypoalbuminemia. Higher Pediatric Ulcerative Colitis Activity Index score and C-reactive protein on days 3 and 5 of hospital admission predict failure of intravenous steroids. Risk factors for malignancy included concomitant diagnosis of primary sclerosing cholangitis, longstanding colitis (>10 years), male sex, and younger age at diagnosis., Conclusions: These evidence-based consensus statements offer predictions to be considered for a personalized medicine approach in treating pediatric UC., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Alterations in the microbiome have been postulated to drive inflammation in IBD. In this pilot randomized controlled trial, we evaluated the effectiveness of quadruple antibiotic cocktail in addition to intravenous-corticosteroids (IVCSs) in acute severe colitis (ASC)., Methods: Hospitalized children with ASC (pediatric ulcerative colitis activity index [PUCAI] ≥65) were randomized into 2 arms: the first received antibiotics in addition to IVCS (amoxicillin, vancomycin, metronidazole, doxycycline/ciprofloxacin [IVCS+AB]), whereas the other received only IVCS for 14 days. The primary outcome was disease activity (PUCAI) at day 5. Microbiome was analyzed using 16S rRNA gene and metagenome., Results: Twenty-eight children were included: 16 in the AB + IVCS arm and 12 in the IVCS arm (mean age 13.9 ± 4.1 years and 23 [82%] with extensive colitis). The mean day-5 PUCAI was 25 ± 16.7 vs 40.4 ± 20.4, respectively (P = 0.037). Only 3 and 2 children, respectively, required colectomy during 1-year follow-up (P = 0.89). Microbiome data at time of admission were analyzed for 25 children, of whom 17 (68%) had a predominant bacterial species (>33% abundance); response was not associated with the specific species, whereas decreased microbiome diversity at admission was associated with day-5 response in the IVCS arm., Conclusion: Patients with ASC have alterations in the microbiome characterized by loss of diversity and presence of predominant bacterial species. Quadruple therapy in addition to IVCS improved disease activity on day 5, but larger studies are needed to determine whether this is associated with improved long-term outcomes (clinicaltrials.gov NCT02033408)., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: We aimed to provide an evidence-supported update of the ECCO-ESPGHAN guideline on the medical management of paediatric Crohn's disease [CD]., Methods: We formed 10 working groups and formulated 17 PICO-structured clinical questions [Patients, Intervention, Comparator, and Outcome]. A systematic literature search from January 1, 1991 to March 19, 2019 was conducted by a medical librarian using MEDLINE, EMBASE, and Cochrane Central databases. A shortlist of 30 provisional statements were further refined during a consensus meeting in Barcelona in October 2019 and subjected to a vote. In total 22 statements reached ≥ 80% agreement and were retained., Results: We established that it was key to identify patients at high risk of a complicated disease course at the earliest opportunity, to reduce bowel damage. Patients with perianal disease, stricturing or penetrating behaviour, or severe growth retardation should be considered for up-front anti-tumour necrosis factor [TNF] agents in combination with an immunomodulator. Therapeutic drug monitoring to guide treatment changes is recommended over empirically escalating anti-TNF dose or switching therapies. Patients with low-risk luminal CD should be induced with exclusive enteral nutrition [EEN], or with corticosteroids when EEN is not an option, and require immunomodulator-based maintenance therapy. Favourable outcomes rely on close monitoring of treatment response, with timely adjustments in therapy when treatment targets are not met. Serial faecal calprotectin measurements or small bowel imaging [ultrasound or magnetic resonance enterography] are more reliable markers of treatment response than clinical scores alone., Conclusions: We present state-of-the-art guidance on the medical treatment and long-term management of children and adolescents with CD., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cognitive impairment is considered a central feature of schizophrenia (SZ) and several rehabilitation treatments have been developed to try to improve cognitive deficits. Aims : The aim of the present study was to analyze the effectiveness of integrated psychological therapy (IPT) compared with a standard treatment (TAU) in two groups of patients with SZ, using a comprehensive testing battery of clinical, cognitive, social cognition and functional outcome domains. Methods: Forty-one patients with SZ were assigned to IPT or TAU groups in a randomized controlled trial (RCT). Psychopathological, neuropsychological, emotional and functional outcome variables were assessed at baseline and after 36 weeks of treatment. Results: The IPT group showed significant improvements than the TAU group regarding clinical and functional outcome variables. Moreover, the IPT group improved significantly in the cognitive domains and emotional functioning. Finally, linear regression has highlighted that the improvement of cognitive variables depends on having done the IPT treatment. Conclusions: IPT seems to be effective in improving clinical, neuropsychological, emotional and functional outcome in chronic SZ inpatients. Further studies would be desirable to deepen the effectiveness of IPT in the field of the psychiatric rehabilitation pointing to the possibility of recovery from mental illness.

Purpose: The present study examined the predictive value of early maladaptive schema (EMS) domains on the diagnosis of binge eating disorder (BED)., Methods: Seventy obese patients seeking treatment for weight loss were recruited and allocated to either group 1 (obese) or group 2 (BED-obese) according to clinical diagnosis. Both groups underwent psychometric assessment for EMS (according to the latest four-factor model), eating and general psychopathologies. Logistic regression analysis was performed on significant variables and BED diagnosis., Results: In addition to showing higher values on all clinical variables, BED-obese patients exhibited significantly higher scores for all four schema domains. Regression analysis revealed a 12-fold increase in risk of BED with 'Impaired Autonomy and Performance'. Depression did not account for a higher risk., Conclusions: Impaired Autonomy and Performance is associated with BED in a sample of obese patients. Schema therapy should be considered a potential psychotherapy strategy in the treatment of BED., Level of Evidence: Level III, case-control study.

The traditional management of inflammatory bowel disease, based on treatment intensification guided by clinical activity alone, has been revised in the last 10 years and a treat-to-target approach has been proposed and is currently under evaluation as a disease-modifying strategy. Treat-to-target focuses on objective and scheduled measures to monitor intestinal damage, with consequent therapeutic adjustments in case of failure to achieve pre-defined targets. Identification of targets has been set out by the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) committee in 2015. Mucosal healing is universally accepted as the main target both in Crohn's disease and ulcerative colitis, given its proven association with better long-term outcomes than clinical remission alone. Equally important is to ensure patients' clinical remission and improve patient-reported outcomes. Transmural healing (for Crohn's disease) and histological remission (for ulcerative colitis), listed as adjunctive targets, are likely to become primary targets in the near future. The ultimate goal of this approach is to modify the natural history of inflammatory bowel diseases by trying to block bowel damage progression, with interventions in the pre-clinical stage. In this review, we will discuss the current recommended therapeutic targets, as well as those that are considered adjunctive targets, with a focus on the limited pediatric literature available. Prospective long-term trials are warranted in order to identify the most appropriate target for the pediatric population and its specific issues. Identification of reliable predictors of disease course, outcome, and response to treatment will help to individually adapt each step of this monitoring algorithm and consequent therapeutic decision.

Introduction: Contemporary pediatric data on pouch outcomes are sparse, especially in the era of laparoscopic surgeries. We aimed to assess outcomes and predictors in children with ulcerative colitis/inflammatory bowel disease (IBD)-unclassified who underwent colectomy and ileal pouch-anal anastomosis., Methods: This was a multicenter retrospective cohort study from 17 IBD centers affiliated with the pediatric IBD Porto group of ESPGHAN. An electronic REDcap system was used to collate baseline characteristics, demographic, clinical, management and surgical data, short- and long-term outcomes, and to identify potential predictors of pouch outcome., Results: Of the 129 patients included, 86 (67%) developed pouchitis during follow-up of median 40 months (interquartile range 26-72), of whom 33 (26%) with chronic pouchitis. Patients operated on by surgeons performing <10 pouch surgeries/year had a higher rate of chronic pouchitis (11/27 [41%] vs 8/54 [15%], P = 0.013) on both univariable and multivariable analyses and also associated with time to pouchitis (P = 0.018) and chronic pouchitis (P = 0.020). At last follow-up, overall pouch performance was rated good/excellent in 86 (74%) patients. Time from colectomy to pouch formation was not associated with pouch outcomes. Despite higher rate of nonsevere surgical complications among children undergoing colectomy at <10 years of age (7/16 [44%] vs 10/92 [11%], P = 0.003), functional outcome and pouchitis rate did not differ., Conclusions: Pouchitis rate in children with ulcerative colitis/IBD unclassified is high. Surgeon experience is the major modifiable risk factor for pouch outcome. Our analyses suggest that pouch surgery can also be performed successfully in young children.

Objective: This study aims to test a model where low self-monitoring (a sub-function of first-person domain of metacognition) and high negative urgency lead to a worsening of binge severity through the mediation of emotional dysregulation in patients with binge eating disorder (BED)., Method: Forty non-BED-obese and 46 BED-obese patients completed a battery of tests assessing metacognition and psychopathology. To test our hypothesized model, a structural equation model (SEM) using maximum likelihood estimation was conducted., Results: BED-obese patients had significantly higher scores in BES, UPPS-P Negative urgency, and DERS total score, and lower MSAS self-monitoring than non-BED-obese, while no differences emerged in the MSAS others-monitoring subscale. The structural model demonstrated very good fit indexes (χ 2 = 1.377, df = 2; p = .502, CMIN/DF = 0.688, CFI = 1.000, RMSEA = 0.000, TLI = 1.047) and all paths were significant in the predicted directions., Conclusions: These preliminary findings show that, low self-monitoring and high negative urgency lead BED-obese patients to express the worsening of binge severity through the mediation of emotional dysregulation. This knowledge may be helpful in the clinical practice to develop a tailor-made treatment. Accordingly, an approach through Metacognitive Interpersonal Therapy could be attempted in BED-obese patients with these characteristics. Highlights Patients with BED exhibited low self-monitoring and high negative urgency. Binge severity was mediated by high level of emotional dysregulation. Metacognitive Interpersonal Therapy may be useful for BED patients., (© 2020 John Wiley & Sons, Ltd and Eating Disorders Association.)

Background: Vaccine-preventable diseases and opportunistic infections in pediatric inflammatory bowel disease (IBD) are increasingly recognized issues. The aims of this study were to evaluate vaccinations, immunization status, and consequent therapeutic management in children with IBD and to analyze the differences among patients diagnosed before (Group 1) and after June 2012 (Group 2)., Methods: This was a multicenter, retrospective cohort investigation. Between July 2016 and July 2017, 430 children with IBD were enrolled in 13 centers. Diagnosis, therapeutic history, vaccinations, and immunization status screening at diagnosis and at immunosuppressant (IM)/biologic initiation and reasons for incomplete immunization were retrieved., Results: Vaccination rates at diagnosis were unsatisfactory for measles, mumps, and rubella (89.3%), Haemophilus influenzae (81.9%), meningococcus C (23.5%), chickenpox (18.4%), pneumococcus (18.6%), papillomavirus (5.9%), and rotavirus (1.9%). Complete immunization was recorded in 38/430 (8.8%) children, but specific vaccines were recommended in 79/430 patients (18.6%), without differences between the 2 groups. At IM start, 22% of children were tested for Epstein-Barr virus (EBV) status, with 96.2% of EBV-naïve patients starting azathioprine, without differences between Groups 1 and 2. Screening for latent tuberculosis (TB) before start of biologics was performed in 175/190 (92.1%), with up to 9 different screening strategies and numerous inconsistencies., Conclusions: We demonstrated a poor immunization status at diagnosis in children with IBD, which was not followed by proper vaccination catch-up. EBV status before IM initiation and latent TB before biologics were not adequately assessed. Thus, the overall impact of the current guidelines seems unsatisfactory., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: The gut-liver axis has been recently investigated in depth in relation to intestinal and hepatic diseases. Key actors are bile acid (BA) receptors, as farnesoid-X-receptor (FXR), pregnane-X-receptor (PXR), and G-protein-coupled-receptor (GPCR; TGR5), that control a broad range of metabolic processes as well as inflammation and fibrosis. The present study aims to investigate the impact of intestinal inflammation on liver health with a focus on FXR, PXR, and TGR5 expression. The strategy to improve liver health by reducing gut inflammation is also considered. Modulation of BA receptors in the inflamed colonic tissues of inflammatory bowel disease (IBD) pediatric patients is analyzed., Methods: A dextran sodium sulphate (DSS) colitis animal model was built. Co-cultures with Caco2 and HepG2 cell lines were set up. Modulation of BA receptors in biopsies of IBD pediatric patients was assessed by real-time PCR and immunohistochemistry., Results: Histology showed inflammatory cell infiltration in the liver of DSS mice, where FXR and PXR were significantly decreased and oxidative stress was increased. Exposure of Caco2 to inflammatory stimuli resulted in the reduction of BA receptor expression in HepG2. Caco2 treatment with dipotassium glycyrrhizate (DPG) reduced these effects on liver cells. Inflamed colon of patients showed altered FXR, PXR, and TGR5 expression., Conclusions: This study strongly suggests that gut inflammation affects hepatic cells by altering BA receptor levels as well as increasing the production of pro-inflammatory cytokines and oxidative stress. Hence, reducing gut inflammation is needed not only to improve the intestinal disease but also to protect the liver.

Aim: To assess the best energy intake in Parenteral Nutrition (PN) for preterm newborns, considering both possible benefits for growth and risk of complications., Methods: Quasi-experimental study comparing two cohorts of newborns, receiving Energy-Enhanced vs. Standard PN (Cohort A, from 1st January 2015 to 31 January 2016 and Cohort B from 1st February 2016 to 31 March 2017; respectively) after implementation of a change in the PN protocol. The primary outcome measure was growth at 24 months of life. The PN associated complications were also measured., Results: We enrolled 132 newborns in two Cohorts, similar for prenatal and postnatal clinical characteristics. Although, body weight and length at 24 months of life were significantly higher (p<0.05) in the Cohort A (11.1, 95% CI 10.6 to 11.6 Kg; 85.0 95% CI 83.8 to 86.2 cm) compared with Cohort B (10.4, 95% CI 9.9 to 10.9 Kg; 81.3 95% CI 79.7 to 82.8 cm), body weight and length Z-Score in the first 24 months of life were similar between the two Cohorts. The rate of PN associated complications was very high in both study Cohorts (up to 98% of enrolments). Multivariate analysis showed that length at 24 months was significantly associated with receiving standard PN (cohort A) in the first week of life and on the energy intake in the first week of life. We also found a marginally insignificant association between Cohort A assignment and body weight at 24 months of life (p = 0.060)., Conclusions: Energy-enhanced PN in early life has not significant effects on long-term growth in preterm newborns. The high prevalence of PN associated complications, poses concerns about the utility of high energy intake recommended by current guidelines for PN., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Patients with paediatric-onset inflammatory bowel disease (PIBD) may develop a complicated disease course, including growth failure, bowel resection at young age and treatment-related adverse events, all of which can have significant and lasting effects on the patient's development and quality of life. Unfortunately, we are still not able to fully explain the heterogeneity between patients and their disease course and predict which patients will respond to certain therapies or are most at risk of developing a more complicated disease course. To investigate this, large prospective studies with long-term follow-up are needed. Currently, no such European or Asian international cohorts exist. In this international cohort, we aim to evaluate disease course and which patients are most at risk of therapy non-response or development of complicated disease based on patient and disease characteristics, immune pathology and environmental and socioeconomic factors., Methods and Analysis: In this international prospective observational study, which is part of the PIBD Network for Safety, Efficacy, Treatment and Quality improvement of care (PIBD-SETQuality), children diagnosed with inflammatory bowel disease <18 years are included at diagnosis. The follow-up schedule is in line with standard PIBD care and is intended to continue up to 20 years. Patient and disease characteristics, as well as results of investigations, are collected at baseline and during follow-up. In addition, environmental factors are being assessed (eg, parent's smoking behaviour, dietary factors and antibiotic use). In specific centres with the ability to perform extensive immunological analyses, blood samples and intestinal biopsies are being collected and analysed (flow cytometry, plasma proteomics, mRNA expression and immunohistochemistry) in therapy-naïve patients and during follow-up., Ethics and Dissemination: Medical ethical approval has been obtained prior to patient recruitment for all sites. The results will be disseminated through peer-reviewed scientific publications., Trial Registration Number: NCT03571373., Competing Interests: Competing interests: MAA received consultation fee and honorarium from Abbvie. SK received consultation fee, research grant or honorarium from Danone, Nestec-Nutrition, Abbvie, Takeda, Celgene, Shire, Pfizer, Biogaia, Janssen, Berlin-Chemie, Mead Johnson, Vifor, Pharmacosmos and ThermoFisher. RKR is supported by an NHS Research Scotland Senior Research Fellowship and has received speakers’s fees, travel support, and/or participated in medical board meetings with Nestle, MSD Immunology, AbbVie, Dr Falk, Takeda, Napp, Mead Johnson and Nutricia&4D Pharma. FR has received speaker fees from Shering-Plough, Nestlé, MeadJohnson, Ferring, MSD, Johnson & Johnson, Centocor and AbbVie; has served as a board member for SAC:DEVELOP (Johnson & Johnson), CAPE (AbbVie), LEA (AbbVie); and has been invited to MSD France, Nestlé Nutrition Institute, Nestlé Health Science, Danone, MeadJohnson, Takeda, Celgene, Biogen, Shire, Pfizer and Therakos. NMC (into employer’s investigator accounts) received speaker fees, advisory board fees and research funding from Eli-Lilly, Takeda, Abbvie Shire Pfizer and 4D Pharma. LdR had collaborations (such as involved in industry-sponsored studies, investigator-initiated study and consultancy) with Shire, Malinckrodt, Nestlé, Celltrion, Abbvie and Pfizer; and received a grant from ZonMw, ECCO and Pfizer. Remaining authors: no competing interests declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Immunomodulators such as thiopurines (azathioprine (AZA)/6-mercaptopurine (6MP)), methotrexate (MTX) and biologics such as adalimumab (ADA) are well established for maintenance of remission within paediatric Crohn's disease (CD). It remains unclear, however, which maintenance medication should be used first line in specific patient groups., Aims: To compare the efficacy of maintenance therapies in newly diagnosed CD based on stratification into high and low-risk groups for severe CD evolution; MTX versus AZA/6MP in low-risk and MTX versus ADA in high-risk patients. Primary end point: sustained remission at 12 months (weighted paediatric CD activity index ≤12.5 and C reactive protein ≤1.5 fold upper limit) without relapse or ongoing requirement for exclusive enteral nutrition (EEN)/steroids 12 weeks after treatment initiation., Methods and Analysis: REDUCE-RISK in CD is an international multicentre open-label prospective randomised controlled trial funded by EU within the Horizon2020 framework (grant number 668023). Eligible patients (aged 6-17 years, new-onset disease receiving steroids or EEN for induction of remission for luminal ± perianal CD are stratified into low and high-risk groups based on phenotype and response to induction therapy. Participants are randomised to one of two treatment arms within their risk group: low-risk patients to weekly subcutaneous MTX or daily oral AZA/6MP, and high-risk patients to weekly subcutaneous MTX or fortnightly ADA. Patients are followed up for 12 months at prespecified intervals. Electronic case report forms are completed prospectively. The study aims to recruit 312 participants (176 low risk; 136 high risk)., Ethics and Dissemination: ClinicalTrials.gov Identifier: (NCT02852694), authorisation and approval from local ethics committees have been obtained prior to recruitment. Individual informed consent will be obtained prior to participation in the study. Results will be published in a peer-reviewed journal with open access., Trial Registration Number: NCT02852694; Pre-results., Competing Interests: Competing interests: RKR is supported by an NHS Research Scotland Senior Research Fellowship, and has received speaker’s fees, travel support and/or participated in medical board meetings with Nestle, MSD Immunology, AbbVie, Dr Falk, Takeda, Napp, Mead Johnson, Nutricia & 4D Pharma. FMR has received speaker fees from Shering-Plough, Nestlé, MeadJohnson, Ferring, MSD, Johnson & Johnson, Centocor, AbbVie; has served as a board member for SAC:DEVELOP(Johnson & Johnson), CAPE (AbbVie), LEA (AbbVie); and has been invited to MSD France, Nestlé Nutrition Institute, Nestlé Health Science, Danone, MeadJohnson, Takeda, Celgene, Biogen, Shire, Pfizer and Therakos. DT received consultation fee, research grant, royalties, or honorarium from Janssen, Pfizer, Hospital for Sick Children, Ferring, Abbvie, Takeda, Biogen, Atlantic Health, Shire, Celgene, Lilly, Neopharm, Roche. LdR received consultation fee, research grant, or honorarium from ZonMw, ECCO, Shire, Malinckrodt, Nestlé, Celltrion, Abbvie and Pfizer. MA received consultation fee and honorarium from Abbvie. SK received consultation fee, research grant, or honorarium from Danone, Nestec-Nutrition, Abbvie, Takeda, Celgene, Shire, Pfizer, Biogaia, Janssen, Berlin-Chemie; Mead Johnson, Vifor, Pharmacosmos, ThermoFisher, (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background & Aims: Although inflammatory bowel diseases (IBD) associated with primary sclerosing cholangitis (PSC) have been well characterized in adults, there have been few pediatric studies, and these were small and produced conflicting results. We investigated features of PSC-IBD in children, compared with children with IBD without PSC., Methods: We performed a retrospective study of 74 children with PSC-IBD, diagnosed from 2000 through 2018, who were each matched with 2 children with ulcerative colitis or IBD-unclassified (controls) based on sex, date of birth, and type of IBD. We compared IBD distribution and clinical activity (remission, medication use, hospitalization, or colectomy) and patient growth between groups. Data were extracted from each hospital contact and analyzed using mixed effects analyses or Cox proportional hazards regression, adjusting for time-dependent medication exposure., Results: Higher proportions of children with PSC-IBD had backwash ileitis, pancolitis, and rectal sparing, and more severe right-sided disease, than controls (P < .05). Patients with PSC-IBD were more likely to be treated with only 5-ASA, compared with controls (odds ratio [OR], 3.04; 95% CI, 1.44-6.41) and to have IBD in clinical remission (OR, 2.94; 95% CI, 1.78-4.87). Risk of colectomy or treatment with a biologic agent was lower in patients with PSC-IBD than controls (hazard ratio, 0.24; 95% CI, 0.12-0.52). However, determination of IBD severity based on symptoms underestimated severity based on endoscopic activity in patients with PSC-IBD. Among patients with IBD in clinical remission, those with PSC were less likely to have endoscopic remission (OR, 0.44; 95% CI, 0.20-0.96). Patients with PSC-IBD were shorter and had lower weight over time, compared with controls., Conclusions: In a retrospective study, we found that features of IBD differed between children with vs without PSC, similar to adults. Despite the mild clinical activity of IBD in patients with PSC, lack of symptoms does not always indicate lack of mucosal inflammation. Children with PSC-IBD have greater growth impairments compared with children with ulcerative colitis or IBD-unclassified., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Introduction: With the current coronavirus disease 2019 (COVID-19) pandemic, concerns have been raised about the risk to children with inflammatory bowel diseases (IBD). We aimed to collate global experience and provide provisional guidance for managing paediatric IBD (PIBD) in the era of COVID-19., Methods: An electronic reporting system of children with IBD infected with SARS-CoV-2 has been circulated among 102 PIBD centres affiliated with the Porto and Interest-group of ESPGHAN. A survey has been completed by major PIBD centres in China and South-Korea to explore management during the pandemic. A third survey collected current practice of PIBD treatment. Finally, guidance points for practice have been formulated and voted upon by 37 PIBD authors and Porto group members., Results: Eight PIBD children had COVID-19 globally, all with mild infection without needing hospitalization despite treatment with immunomodulators and/or biologics. No cases have been reported in China and South Korea but biologic treatment has been delayed in 79 children, of whom 17 (22%) had exacerbation of their IBD. Among the Porto group members, face-to-face appointments were often replaced by remote consultations but almost all did not change current IBD treatment. Ten guidance points for clinicians caring for PIBD patients in epidemic areas have been endorsed with consensus rate of 92% to 100%., Conclusions: Preliminary data for PIBD patients during COVID-19 outbreak are reassuring. Standard IBD treatments including biologics should continue at present through the pandemic, especially in children who generally have more severe IBD course on one hand, and milder SARS-CoV-2 infection on the other.

Background: The main purpose of this study was to assess possible modifications of cognitive performance among schizophrenia patients treated with long-acting injectable antipsychotics (LAIs) of second generation anti-psychotics (SGAs). Our hypothesis is that the shift from the oral formulation to the LAI formulation of SGAs drugs improves the cognitive performance. The secondary objective was to carry out a head to head comparison of two different SGA-LAI treatments [i.e., 1-month Paliperidone Palmitate (PP1M), monthly Aripiprazole (Ari-LAI)] in our study with an independent and real-world setting. Methods: The sample comprised 32 participants who were consecutively recruited over 12 months. Seventeen patients treated with Ari-LAI and 10 treated with PP1M completed psychopathological, neuropsychological and functional assessments. Group differences were explored through chi-squared and t -tests, as appropriate. GLM Repeated Measures were used to study variations of cognitive performance along 12 months and to test differences between drugs. Results: We found an effect of time on the outcomes investigated but this did not depend on the type of LAI used. Conclusions: In comparison with the previous oral treatment with SGAs, patients showed a significant improvement in neurocognitive function after 12 months of treatment with SGA-LAI. Furthermore, there were no differences between the SGA-LAI regimens.Key pointsThe main purpose of this study was to assess possible modification of cognitive performance of patients with Schizophrenia treated with second generation long-acting injectable antipsychotics (SGA-LAIs).The secondary objective was to carry out a head to head comparison of two different SGA-LAIs: Paliperidone Palmitate 1-Month (PP1M) and Aripiprazole Monthly (Ari-LAI).Patients showed a significant improvement in neurocognitive function after 12 months of treatment with SGA-LAI.There were no differences between the SGA-LAI regimens.From a practical point of view, switching to LAI formulation seems to produce further social and cognitive improvements in patients who had already benefitted from oral SGA therapy.

Introduction: Traditional management of patients with Crohn's disease includes symptoms and quality of life improvement. With the advent of biological agents, mucosal healing has become an achievable goal, documented through endoscopy. However, due to the transmural nature of inflammation, the prevention of bowel damage should be included in the aims of a targeted therapeutic strategy., Areas Covered: Updated literature has been searched in PubMed from 2008 to 2020. This review focuses on the state of the art in the innovative therapeutic goals in Crohn's disease, also considering still controversial aspects and future research topics in the management of Crohn's disease., Expert Opinion: Although a widely agreed view supports the notion that mucosal healing and bowel damage control may promote beneficial outcomes (i.e. reduction in hospitalization and surgical rates, avoidance of steroids), long-term robust data are still missing. On the other hand, the development of -omics techniques has expanded our knowledge of the pathogenetic mechanism underlying inflammatory bowel disease and opened up new horizons in precision or personalized medicine.

Background and Aims: Multiple monogenic disorders present as very early onset inflammatory bowel disease (VEO-IBD) or as IBD with severe and atypical features. Establishing a genetic diagnosis may change patients' management and prognosis. In this study, we describe the diagnostic approach to suspected monogenic IBD in a real clinical setting, discussing genetic and phenotypic findings and therapeutic implications of molecular diagnosis., Methods: Information of patients with VEO-IBD and early onset IBD with severe/atypical phenotypes (EO-IBD s/a) managed between 2008-2017 who underwent a genetic workup were collected., Results: Ninety-three patients were included, and 12 (13%) reached a genetic diagnosis. Candidate sequencing (CS) was performed in 47 patients (50%), and next generation sequencing (NGS) was performed in 84 patients (90%). Candidate sequencing had a good diagnostic performance only when guided by clinical features specific for known monogenic diseases, whereas NGS helped finding new causative genetic variants and would have anticipated one monogenic diagnosis (XIAP) and consequent bone marrow transplant (BMT). Patients with monogenic IBD more frequently were male (92% vs 54%; P = 0.02), had extraintestinal findings (100% vs 34%; P < 0.001), and had disease onset ≤1 month of life (25% vs 1%; P = 0.006). Genetic diagnosis impacted patient management in 11 patients (92%), 7 of whom underwent BMT., Conclusion: A genetic diagnosis can be established in a significant proportion of suspected monogenic IBD and has an impact on patients' management. Candidate sequencing may be deployed when clinical findings orientate toward a specific diagnosis. Next generation sequencing should be preferred in patients with nonspecific phenotypes., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Research has demonstrated impaired executive functioning among Binge Eating Disorder (BED) patients that could be influenced by age and weight. We aim to compare decision-making, set-shifting and central coherence between BED-obese patients (BED-Ob), non-BED-obese patients (non-BED-Ob), and normal-weight healthy controls (NW-HC) without the influence of these variables., Methods: Overall, 35 BED-Ob, 32 non-BED-Ob and 26 NW-HC participants completed the Iowa Gambling Task, the Trail Making Test and the Rey-Osterrieth Complex Figure Test., Results: BED-Ob patients showed higher cognitive impairment compared to NW-HC on decision-making, set-shifting, visual attention and memory., Conclusions: BED-Ob patients have an impaired cognitive profile on decision-making, set-shifting, visual attention and memory but not impaired central coherence. As all groups were aged-matched and no significant differences between BED-Ob and non-BED-Ob participants were evident, our results demonstrate that this impairment is independent from weight/age, pointing out that it is BED itself to account for inefficiencies in cognitive functioning., Level of Evidence: Level III, case-control study.

Objective: The present study aimed to (a) assess and compare personological traits and early maladaptive schemas (EMSs) of obese women with and without binge eating disorder (BED) and (b) identify the variables associated with the binge severity., Method: One hundred women (55 BED-obese and 45 non-BED-obese) completed psychopathological and personological self-report questionnaires. A forward stepwise linear regression analysis was performed to assess variables associated with binge eating severity., Results: Not only psychopathological but also personological differences were evident between BED and non-BED-obese women. BED severity was significantly associated with depressivity, emotional deprivation, and defectiveness., Conclusions: Our preliminary findings suggest that BED patients exhibit some EMSs that could be linked to the construct of emotional neglect and specific personological traits closely related to depressive dimensions, emotional lability, and impulsivity. In particular, binge severity is associated with the pervasiveness of depressogenic cognitive schemas, as well as those of emotional deprivation and defectiveness., (© 2019 Wiley Periodicals, Inc.)

Background: Behavioral addiction (BA) is a recent concept in psychiatry. Few studies have investigated the relationship between BA and early maladaptive schemas (EMSs). EMS is the core of Schema Therapy (ST). According to the ST model, psychiatric disorders result from the development of EMSs in response to unmet emotional needs in childhood. Bach et al. (2018) grouped the 18 EMSs into four domains: (1) disconnection and rejection ; (2) impaired autonomy and performance ; (3) excessive responsibility and standards ; and (4) impaired limits . This study aims to assess the possible association of the most frequent BAs with EMSs in a large group of late adolescents and young adults and to evaluate their self-perceived quality of life (QoL)., Methods: A battery of psychological tests assessing food addiction (FA), gambling disorder (GD), internet addiction (IA), and QoL was administered to 1,075 late adolescents and young adults ( N = 637; 59.3% women). A forward-stepwise logistic regression model was run to identify which variables were associated with BAs., Results: Food addiction was more frequent among women and GD among men, while IA was equally distributed. Regarding the EMSs, participants with FA or IA showed significantly higher scores on all four-schema domains, whereas those with GD exhibited higher scores on impaired autonomy and performance and impaired limits . Besides, average scores of all domains increased with the association of two or more comorbid BAs. Self-perceived QoL was lower for participants with FA and IA, but not for those with GD; the presence of comorbid BAs was associated with lower Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Finally, specific EMS domains and demographic variables were associated with each BA., Conclusion: Late adolescents and young adults with FA or IA have a lower perception of their mental and physical health. The most striking result is that FA appears to be associated with the disconnection and rejection schema domain, IA with all the schema domains (except for impaired autonomy and performance ), and GD with impaired autonomy and performance schema domain. In conclusion, our findings suggest that EMS should be systematically assessed during psychotherapy of patients with BAs., (Copyright © 2020 Aloi, Verrastro, Rania, Sacco, Fernandez-Aranda, Jiménez-Murcia, De Fazio and Segura-Garcia.)

Background and Aim: Acute severe colitis [ASC] is associated with significant morbidity in paediatric patients with ulcerative colitis [UC]. Most outcome studies in ASC since tumour necrosis factor alpha [TNFα] antagonists became available have focused on the first year after admission. The aim of this study was to characterise the longer-term outcomes of paediatric patients admitted with ASC., Methods: This retrospective study was conducted in 25 centres across Europe and North America. Data on patients with UC aged <18 years, admitted with ASC (defined as paediatric ulcerative colitis activity index [PUCAI] score ≥65) between 2009 and 2011, were collected at discharge and 1, 3 and 5 years after admission. The primary outcome was colectomy-free rates at each time point., Results: Of the 141 patients admitted with ASC, 137 [97.1%] were treated with intravenous corticosteroids. Thirty-one [22.6%] patients were escalated to second-line therapy, mainly to infliximab. Sixteen patients [11.3%] underwent colectomy before discharge. Long-term follow-up showed colectomy-free rates were 71.3%, 66.4% and 63.6% at 1, 3 and 5 years after initial ASC admission, respectively, and were similar across different age groups. Sub-analysis of colectomy rates in patients with new-onset disease [42.5% of the cohort] yielded similar results. In a multivariate analysis, use of oral steroids in the 3 months before admission, erythrocyte sedimentation rate >70 mm/h, and albumin <2.5 g/dL, were significantly associated with 5-year colectomy risk., Conclusions: High colectomy rates were demonstrated in paediatric UC patients admitted with ASC. Additional studies are required to determine whether intensification of anti-TNFα treatment, close therapeutic drug monitoring, and use of new drugs alter this outcome., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The purpose of this study was to determine whether MRE performed with diffusion-weighted imaging (DWI) sequences is comparable to contrast-enhanced MRE in the detection of active small-bowel inflammation in pediatric patients with Crohn's disease (CD). We included in our study 68 patients with diagnosis of CD between April 2015 and June 2018 that underwent MRE examination. Examination protocol includes coronal and axial FISP, T2-w half-Fourier RARE and DWI sequences, a baseline coronal T1-w fat-saturated ultrafast (GRE) sequence followed by contrast 3D T1-w GRE. All images were assessed by two radiologists who graded each of bowel segments for the presence of inflammation on a four-point confidence scale on the basis of wall thickening and wall signal on DWI and ADC maps and comparing their results with post-contrast images. When considering all bowel segments, we found 41 true positive and 25 true negative on DWI. One false positive case corresponded to the absence of inflammatory histopathology changes at the level of the terminal ileum in a 15-year-old male, and one false negative case was in a 10-year-old female with only jejunal lesion. The corresponding sensitivity, specificity, PPV, NPV and accuracy were 97.6% (95% CI 67.7-99.7), 96.1% (95% CI 66.7-98.5), 97.6% (95% CI 70.8-98.4), 96.1% (95% CI 64.2-90.6) and 97% (95% CI 84.2-97.5), respectively. Analyzing the gadolinium-enhanced set, 35 true positive and 25 true negative results were found. One false positive case was found, and it was the same as with DWI. The corresponding sensitivity, specificity, PPV, NPV and accuracy were 83.3% (95% CI 65.9-86.7), 96.1% (95% CI 68.7-88.9), 97.2% (95% CI 84.3-98.7), 78.1% (95% CI 27.9-72.1) and 88.2% (95% CI 41.2-85.6), respectively. Sensitivity for the detection of active IBD lesion was significantly better with DWI than with CE-T1-w imaging (p = 0.002), whereas the specificity was similar (p = 0.743). Our study has shown that DWI sequences have a high accuracy in detecting the bowel segment affected by CD. These results emphasize the utility to include the DWI/ADC in standard MR enterography protocols and suggest that DWI could replace T1-weighted post-contrast sequences.

Background: Adverse childhood experiences (ACEs) are risk factors for psychiatric disorders, but evidence about their relationship with clinical severity is limited. We aimed to classify patients according to ACEs and to compare these clusters with regards to the clinical severity., Methods: Seventy-four patients with Bipolar Disorder (BD) and 91 patients with a diagnosis within the Schizophrenia Spectrum Disorders (SSDs) were interviewed. The Childhood Experience of Care and Abuse scale (CECA) and the Positive and Negative Symptoms Scale (PANSS) were administered. A two-step cluster analysis was run to identify clusters according to ACEs. PANSS average scores were compared between clusters., Results: Three clusters emerged; significant differences in ACEs distribution were evident. Cluster 1 was characterized by very low frequency of ACEs. ACEs related to lack of support/isolation were more frequent within Cluster 2, instead ACEs related to abuse/neglect were over represented in Cluster 3. The comparison of PANSS through ANOVA demonstrated that Cluster 3 not only had significantly higher scores in all dimensions than Cluster 1 and 2 but also a higher average number of ACEs., Limitations: CECA is a self-report scale and is subject to recall bias., Conclusions: Specific ACEs are related to clinical severity among BD and SSD patients. Early life adversities related to abuse and neglect are associated to greater symptomatic severity than those related to lack of support/isolation. Our findings suggest that a history of ACEs could be used to identify patients at higher risk of unfavorable clinical features., (Copyright © 2019 Elsevier B.V. All rights reserved.)

To evade immunity, many viruses express interferon antagonists that target STAT transcription factors as a major component of pathogenesis. Because of a lack of direct structural data, these interfaces are poorly understood. We report the structural analysis of full-length STAT1 binding to an interferon antagonist of a human pathogenic virus. The interface revealed by transferred cross-saturation NMR is complex, involving multiple regions in both the viral and cellular proteins. Molecular mapping analysis, combined with biophysical characterization and in vitro/in vivo functional assays, indicates that the interface is significant in disease caused by a pathogenic field-strain lyssavirus, with critical roles for contacts between the STAT1 coiled-coil/DNA-binding domains and specific regions within the viral protein. These data elucidate the potentially complex nature of IFN antagonist/STAT interactions, and the spatial relationship of protein interfaces that mediate immune evasion and replication, providing insight into how viruses can regulate these essential functions via single multifunctional proteins., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background & Aims: Pan-enteric capsule endoscopy (PCE) is effective for assessment of small intestinal and colonic Crohn's disease (CD) in pediatric patients. We aimed to determine whether PCE can be used to monitor mucosal healing and deep remission, in a treat to target strategy for pediatric patients with CD., Methods: We performed a prospective study of 48 children with a diagnosis of CD at a tertiary care pediatric gastroenterology unit; 46 patients were included in the final analysis. Biomarker, imaging, and PCE analyses were performed at baseline and after 24 and 52 weeks. Small bowel and colonic mucosal healing were defined by Lewis scores <135 and simple endoscopic score for CD ≤1, respectively. Clinical remission was defined as defined as a pediatric CD activity index score <10 and biomarker-based remission based on normal levels of biomarkers; deep remission was defined as a combination of clinical remission, biomarker-based remission, and mucosal healing. Treatments were adjusted based on findings from PCE (imaging was considered only for patients with negative findings from PCE). Therapies were introduced, optimized, switched, or combined at the discretion of treating clinicians. The primary outcome was the ability of PCE to assess mucosal healing and deep remission at 3 timepoints and to guide a treat to target strategy., Results: PCE detected inflammation in 34 patients (71%) at baseline, 22 patients (46%) at week 24, and 18 patients (39%) at week 52 (P for comparison among timepoints <.05). Findings from PCE led to a change in therapy for 34 patients (71%) at baseline and 11 patients (23%) at 24 weeks, whereas only 2 patients with negative results from PCE (4%) changed therapies based on findings from imaging. When the treat to target strategy was applied, proportions of patients with mucosal healing and deep remission increased from 21% at baseline, to 54% at week 24, to 58% at week 52 (P for comparison among timepoints <.05); 2 patients (4%) did not respond to treatment., Conclusion: In a prospective study of 48 children with CD, we found a treat to target strategy, based on findings from PCE, to significantly increase the proportions of patients with mucosal healing and deep remission., Clinical Trial: gov no: NCT03161886., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Alterations of the immune system are known in eating disorders (EDs), however the importance of cytokine balance in this context has not been clarified. We compared cytokines and growth factors at opposite ends of BMI ranges, in 90 patients classified in relation to BMI, depressive and EDs comorbidities. Serum concentrations of interleukin (IL)-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF) were determined by a biochip analyzer (Randox Labs). Differences were calculated through ANOVA. Possible predictors of higher cytokine levels were evaluated through regression analysis. IL-1α, IL-10, EGF, and IFN-γ were altered individuals with anorexia nervosa (AN) and binge eating disorder (BED). Night-eating was associated with IL-8 and EGF levels, IL-10 concentrations with post-dinner eating and negatively with sweet-eating, long fasting with higher IFN-γ levels. IL-2 increase was not linked to EDs, but to the interaction of depression and BMI. Altogether, for the first time, IL-1α, IL-10, EGF, and IFN-γ were shown to differ between AN and HCs, and between AN and individuals with obesity with or without BED. Only IL-2 was influenced by depression. Dysfunctional eating behaviors predicted abnormal concentrations of IL-10, EGF, IL-8 and IFN-γ.

Background: Very few data regarding the use of infliximab in children with very early-onset inflammatory bowel disease (VEO-IBD) have been reported., Objective: We aimed to assess the efficacy and the safety of infliximab in children with VEO-IBD compared with older children., Methods: Children treated with infliximab were identified within the Italian IBD registry. The primary outcome was the rate of clinical remission at weeks 14 and 54. Secondary outcomes included the proportion of partial clinical response, treatment duration, and incidence of adverse events., Results: Forty-two children with VEO-IBD were compared with 130 children with IBD. Despite significantly higher infliximab withdrawals in VEO-IBD patients during induction (42.9% vs 7.7% p  < 0.01), remission rates at week 14 were similar (28.6% vs 43.8%, p  = 0.10). At week 54 fewer VEO-IBD children were in remission (15.8% vs 54.3%, p  < 0.01). The treatment duration was shorter in VEO-IBD (median 12.0 vs 18.4 months, p  < 0.01). During the induction phase, adverse events were more common in the VEO-IBD group ( p  < 0.01)., Conclusion: Compared with older children, VEO-IBD patients have higher rates of infliximab failures, lower remission rates at one year, and more often experience adverse events during induction.

Objectives: We aimed to identify early noninvasive predictors of clinical and endoscopic remission in children with Crohn disease (CD) under infliximab (IFX)., Methods: Prospective observational study conducted in children with moderate-to-severe CD starting IFX. All patients underwent weighted pediatric CD activity index (wPCDAI) assessment, C-reactive protein and fecal calprotectin (FC) at week 0, 14, and 48. Endoscopy was performed at 0 and 48 weeks. The primary outcome was to determine the ability of 14-week wPCDAI, C-reactive protein, and FC to predict 1-year steroid-free clinical remission and mucosal healing. As a secondary outcome we evaluated their concordance with Simple Endoscopic Score for CD (SES-CD) at week 48., Results: Forty-one children were enrolled. At 1 year, 21 (51%) and 16 (39%) were in clinical and endoscopic remission. Only combined postinduction FC and wPCDAI were able to predict 1-year clinical and endoscopic remission (hazard ratio 4.81 [95% confidence interval 1.76-20.45], P = 0.05 and hazard ratio 5.51 [95% confidence interval 1.83-26.9], P = 0.03). One-year SES-CD moderately correlated with FC (r = 0.52; P = 0.001). The FC cut-off value for mucosal healing was 120.5 μg/g (area under the curve 0.863, 83% sensitivity, 75.5% specificity; P = 0.005). The concordance between wPCDAI and SES-CD was excellent and good for severe disease and remission (k 0.87 and 0.76)., Conclusions: Post induction FC combined with wPCDAI can predict 1-year clinical and endoscopic response to IFX in pediatric CD. FC shows a moderate correlation with SES-CD, whereas wPCDAI has a good concordance with endoscopic remission or severe disease, but not with mild and moderate disease.

Background: Adalimumab (Ada) treatment is an available option for pediatric Crohn's disease (CD) and the published experience as rescue therapy is limited., Objectives: We investigated Ada efficacy in a retrospective, pediatric CD cohort who had failed previous infliximab treatment, with a minimum follow-up of 6 months., Methods: In this multicenter study, data on demographics, clinical activity, growth, laboratory values (CRP) and adverse events were collected from CD patients during follow-up. Clinical remission (CR) and response were defined with Pediatric CD Activity Index (PCDAI) score ≤10 and a decrease in PCDAI score of ≥12.5 from baseline, respectively., Results: A total of 44 patients were consecutively recruited (mean age 14.8 years): 34 of 44 (77%) had active disease (mean PCDAI score 24.5) at the time of Ada administration, with a mean disease duration of 3.4 (range 0.3-11.2) years. At 6, 12, and 18 months, out of the total of the enrolled population, CR rates were 55%, 78%, and 52%, respectively, with a significant decrease in PCDAI scores ( P <0.01) and mean CRP values (mean CRP 5.7 and 2.4 mL/dL, respectively; P <0.01) at the end of follow-up. Steroid-free remission rates, considered as the total number of patients in CR who were not using steroids at the end of this study, were 93%, 95%, and 96% in 44 patients at 6, 12, and 18 months, respectively. No significant differences in growth parameters were detected. In univariate analysis of variables related to Ada efficacy, we found that only a disease duration >2 years was negatively correlated with final PCDAI score ( P <0.01). Two serious adverse events were recorded: 1 meningitis and 1 medulloblastoma., Conclusion: Our data confirm Ada efficacy in pediatric patients as second-line biological therapy after infliximab failure. Longer-term prospective data are warranted to define general effectiveness and safety in pediatric CD patients., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Aim: To investigate by meta-analysis the efficacy of gelatin tannate (GT), a mucosal barrier protector, in children with acute gastroenteritis., Methods: A comprehensive literature search was conducted. Studies were selected according to PICO: Participants: children aged 0-12 years with acute diarrhea; Intervention: GT; Comparison: oral rehydration solution and/or placebo; Outcomes: diarrhea-related outcomes., Results: Three published randomized controlled trials were identified of pediatric diarrhea treated with GT (n = 203) or control (n = 204). GT significantly (p < 0.01) reduced stool frequency at 12 h in two randomized controlled trials. A significant treatment effect (risk ratio = 0.74; p < 0.01) in favor of GT was found for the exploratory composite outcome of 'diarrhea or liquid stools at 24 h' in three studies. Risk ratios in a single study which reported the percentage of patients with liquid stools at 12, 24 and 48 h favored GT at all time points. No significant differences were found between GT and control for patients with diarrhea at 12 or 24 h or for duration of diarrhea., Conclusion: GT improved stool frequency and stool consistency in children with acute diarrhea, although further well-controlled studies would be useful to confirm a beneficial treatment effect.

Background: Research has shown that a history of childhood adversities is common in patients with psychiatric disorders but few studies have investigated links between specific types of adversity and specific psychiatric disorders., Methods: We investigated the frequency of early childhood adversities in a sample consisting of 91 patients with diagnosis of schizophrenic spectrum disorders (SSD), 74 patients with bipolar disorder (BD), 83 patients with major depressive disorder (MDD) and 85 healthy controls and sought to identify adverse early childhood life events that predict the development of major psychiatric disorders. The Childhood Experiences of Care and Abuse questionnaire was used to collect data on traumatic experiences occurring before the age of 17 years and comprehensive demographic data were also collected. The data were analyzed with chi-squared tests, t-tests, post-hoc and logistic regression., Results: Maternal absence/loss and economic difficulties in the early life were more prevalent in the BD group than other groups. Escape from home, cannabis abuse, psychological abuse, physical abuse and loneliness were more frequent in the SSD group than in other groups. Paternal absence, neglect of core needs, serious familial tension and absence of adult and peer confidants were all less common in the HC group than in the other groups. The regression model confirmed that different types of adversities play a crucial role in the development of the three investigated disorders., Conclusions: Our results support that SSD, BD and MDD are associated to different childhood adversities. This suggests that psychosocial interventions that reduce the incidence of these early life adversities might reduce the incidence of severe and disabling psychiatric disorders.

Background and aims: Recent evidences reveal the occurrence of a close relationship among epithelial to mesenchymal transition (EMT), chronic inflammation and fibrosis. ZNF281 is an EMT-inducing transcription factor (EMT-TF) involved in the regulation of pluripotency, stemness, and cancer. The aim of this study was to investigate in vitro, in vivo , and ex vivo a possible role of ZNF281 in the onset and progression of intestinal inflammation. A conceivable contribution of the protein to the development of intestinal fibrosis was also explored. Methods: Human colorectal adenocarcinoma cell line, HT29, and C57BL/6 mice were used for in vitro and in vivo studies. Mucosal biopsy specimens were taken during endoscopy from 29 pediatric patients with Crohn's disease (CD), 24 with ulcerative colitis (UC) and 16 controls. ZNF281 was knocked down by transfecting HT29 cells with 20 nM small interference RNA (siRNA) targeting ZNF281 (siZNF281). Results: We show for the first time that ZNF281 is induced upon treatment with inflammatory agents in HT29 cells, in cultured uninflamed colonic samples from CD patients and in DSS-treated mice. ZNF281 expression correlates with the disease severity degree of CD and UC patients. Silencing of ZNF281 strongly reduces both inflammatory (IL-8, IL-1beta, IL-17, IL-23) and EMT/fibrotic (SNAIL, Slug, TIMP-1, vimentin, fibronectin, and α-SMA) gene expression; besides, it abolishes the increase of extracellular-collagen level as well as the morphological modifications induced by inflammation. Conclusions: The identification of transcription factor ZNF281 as a novel player of intestinal inflammation and fibrosis allows a deeper comprehension of the pathogenetic mechanisms underlying inflammatory bowel disease (IBD) and provide a new target for their cure.

Background: Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease-related inflammation and immune suppression, but data are limited due to their rare occurrence., Aim: To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD., Methods: Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years., Results: In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naïve but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma)., Conclusions: We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas., (© 2018 John Wiley & Sons Ltd.)

Background and Aims: An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment., Methods: A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally., Results: Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES., Conclusions: Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD., (© The Author(s) 2018. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: The contemporary management of ambulatory ulcerative colitis (UC) continues to be challenging with ∼20% of children needing a colectomy within childhood years. We thus aimed to standardize daily treatment of pediatric UC and inflammatory bowel diseases (IBD)-unclassified through detailed recommendations and practice points., Methods: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the Paediatric IBD Porto group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). An extensive literature search with subsequent evidence appraisal using robust methodology was performed before 2 face-to-face meetings. All 40 included recommendations and 86 practice points were endorsed by 43 experts in Paediatric IBD with at least an 88% consensus rate., Results: These guidelines discuss how to optimize the use of mesalamine (including topical), systemic and locally active steroids, thiopurines and, for more severe disease, biologics. The use of other emerging therapies and the role of surgery are also covered. Algorithms are provided to aid therapeutic decision-making based on clinical assessment and the Paediatric UC Activity Index (PUCAI). Advice on contemporary therapeutic targets incorporating the use of calprotectin and the role of therapeutic drug monitoring are presented, as well as other management considerations around pouchitis, extraintestinal manifestations, nutrition, growth, psychology, and transition. A brief section on disease classification using the PIBD-classes criteria and IBD-unclassified is also part of these guidelines., Conclusions: These guidelines provide a guide to clinicians managing children with UC and IBD-unclassified management to provide modern management strategies while maintaining vigilance around appropriate outcomes and safety issues.

Background and Aim: Acute severe colitis (ASC) is one of the few emergencies in pediatric gastroenterology. Tight monitoring and timely medical and surgical interventions may improve outcomes and minimize morbidity and mortality. We aimed to standardize daily treatment of ASC in children through detailed recommendations and practice points which are based on a systematic review of the literature and consensus of experts., Methods: These guidelines are a joint effort of the European Crohn's and Colitis Organization (ECCO) and the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN). Fifteen predefined questions were addressed by working subgroups. An iterative consensus process, including 2 face-to-face meetings, was followed by voting of the national representatives of ECCO and all members of the Paediatric Inflammatory Bowel Disease (IBD) Porto group of ESPGHAN (43 voting experts)., Results: A total of 24 recommendations and 43 practice points were endorsed with a consensus rate of at least 91% regarding diagnosis, monitoring, and management of ASC in children. A summary flowchart is presented based on daily scoring of the Paediatric Ulcerative Colitis Activity Index. Several topics have been altered since the previous 2011 guidelines and from those published in adults., Discussion: These guidelines standardize the management of ASC in children in an attempt to optimize outcomes of this intensive clinical scenario.

Background: The comorbidity of bipolar disorder (BD) and obsessive-compulsive disorder (OCD) has been widely described. Several studies have investigated the cognitive profiles of BD and OCD patients, but studies that compare BD, BD-OCD, and OCD patients in neuropsychological domains do not exist. The purpose of this study was to compare set-shifting, decision making, and central coherence among BD, BD-OCD, and OCD patients., Methods: A battery of neuropsychological tests was administered to 68 patients (22 BD, 26 BD-OCD, 20 OCD). The Young Mania Rating Scale and Hamilton Depression Rating Scale were used to evaluate manic and depressive symptoms, and OCD severity was assessed with the Yale Brown Obsessive Compulsive Scale., Results: No significant differences emerged in decision-making and cognitive flexibility, whereas BD patients had lower scores in the Accuracy Index on Rey-Osterrieth Complex Figure Test and poor response speed on Hayling Sentence Completion Test Part A than OCD patients., Limitations: The small sample size with different BD patients, the cross-sectional design, and the study clinical nature., Conclusions: The most striking result is that, contrary to our hypothesis, comorbidity does not further impair the neurocognitive profile. The clinical relevance of our work could be a shift from the current cognitive rehabilitation model focusing on individualized pathways towards a new overlapping model for all three patient groups. This could make the cognitive rehabilitation faster and less costly. Notwithstanding, these disorders do not only need cognitive training but also various psycho-educative approaches and treatment according to their different clinical profile., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to evaluate the effectiveness and safety of adalimumab (ADA) in children with ulcerative colitis (UC) previously treated with infliximab (IFX)., Methods: Retrospective study including children with UC from a national registry who received ADA therapy. The primary endpoint was the rate of corticosteroid-free remission at week 52. Secondary outcomes were the rate of sustained clinical remission, primary nonresponse, and loss of response at weeks 12, 30, and 52 and rate of mucosal healing and side effects at week 52., Results: Thirty-two children received ADA (median age 10 ± 4 years). Median disease duration before ADA therapy was 27 months. All patients received previous IFX (43% intolerant, 50% nonresponders [37.5% primary, 42.5% secondary nonresponders], 6.7% positive anti-IFX antibodies). Fifty-two weeks after ADA initiation, 13 patients (41%) were in corticosteroid-free remission. Mucosal healing occurred in 9 patients (28%) at 52 weeks. The cumulative probability of a clinical relapse-free course was 69%, 59%, and 53% at 12, 30, and 52 weeks, respectively. Ten patients (31%) had a primary failure and 5 (15%) a loss of response to ADA. No significant differences in efficacy were reported between not-responders and intolerant to IFX (P = 1.0). Overall, 19 patient (59%) maintained ADA during 52-week follow-up. Seven patients (22%) experienced an adverse event, no serious side effects were observed and none resulted in ADA discontinuation., Conclusions: Based on our data, ADA seems to be effective in children with UC, allowing to recover a significant percentage of patients intolerant or not-responding to IFX. The safety profile was good.

Aim: Sclerosing cholangitis (SC) is a chronic cholestatic liver disease that is being increasingly diagnosed in childhood. The long-term course and prognosis of pediatric SC are poorly described., Methods: We reviewed data of pediatric SC patients, followed in two referral centers, during a period of up to 20 years. We aimed to evaluate long-term outcomes according to SC phenotype., Results: Among 45 patients (median age, 10.4 years; male patients, 73.4%) 29 (64.4%) were asymptomatic at presentation. Twenty patients (44%) had a concomitant inflammatory bowel disease (SC/IBD). Autoimmune features were found in 20 patients (44%). Liver biopsy showed severe fibrosis or cirrhosis in 32% of cases. Patients with SC alone had a higher rate of interface hepatitis at liver biopsy than SC/IBD patients. All children received ursodeoxycholic acid at diagnosis, and 17 received steroids and/or azathioprine. After a mean follow-up of 8.7 ± 5.6 years, all patients were alive and seven developed at least one liver-related complication. At the end of follow-up, 10 patients stopped immunosuppressants and two had no therapy. Only two patients underwent liver transplantation. Complication-free survival did not differ between SC/IBD and SC patients, but survival was longer in patients without autoimmune features., Conclusions: In our early diagnosed cohort, the 9-year survival with native liver was better than that reported in other studies. Approximately 15% of patients developed liver-related disease complications, less than previously reported. The long-term course of SC was negatively influenced by the presence of autoimmune features, but not by concomitant IBD., (© 2018 The Japan Society of Hepatology.)

Background and Aims: A growing body of evidence supports the need for detailed attention to nutrition and diet in children with inflammatory bowel disease (IBD). We aimed to define the steps in instituting dietary or nutritional management in light of the current evidence and to offer a useful and practical guide to physicians and dieticians involved in the care of pediatric IBD patients., Methods: A group of 20 experts in pediatric IBD participated in an iterative consensus process including 2 face-to-face meetings, following an open call to Nutrition Committee of the European Society of Pediatric Gastroenterology, Hepatology and Nutrition Porto, IBD Interest, and Nutrition Committee. A list of 41 predefined questions was addressed by working subgroups based on a systematic review of the literature., Results: A total of 53 formal recommendations and 47 practice points were endorsed with a consensus rate of at least 80% on the following topics: nutritional assessment; macronutrients needs; trace elements, minerals, and vitamins; nutrition as a primary therapy of pediatric IBD; probiotics and prebiotics; specific dietary restrictions; and dietary compounds and the risk of IBD., Conclusions: This position paper represents a useful guide to help the clinicians in the management of nutrition issues in children with IBD.

Background: Data on the clinical course and outcomes of pediatric patients with cytomegalovirus (CMV) infection complicating acute severe ulcerative colitis (ASC) are very limited. The aim of our study was to compare outcomes of children with ASC who were CMV positive or CMV negative., Methods: This was a multicenter retrospective case-controlled study, from centers affiliated with the Pediatric Inflammatory Bowel Disease Porto Group of European Society of Pediatric Gastroenterology, Hepatology, and Nutrition. We included CMV-positive children hospitalized for ASC and compared their colectomy rate during hospitalization and up to 1 year thereafter, matched with CMV-negative controls., Results: A total of 56 children were included; 15 CMV positive and 41 CMV negative. More CMV-positive patients were resistant to intravenous corticosteroids as compared with CMV negative (93% and 56% respectively, P = 0.009). Fourteen of the CMV-positive children (93%) were treated with ganciclovir [5/14 (36%) with 5 mg/kg and 9/14 (64%) with 10 mg/kg]. During hospitalization, 3 (20%) CMV-positive and 3 (7.8%) CMV-negative patients required colectomy (P = 0.17). By 12 months, 5 (33%) and 5 (13%) CMV-positive and CMV-negative patients required colectomy, respectively (P = 0.049); the significance was not retained on multivariate analysis., Conclusions: A higher prevalence of CMVpositivity was found in pediatric ulcerative colitis patients who required colectomy within 12 months of hospitalization for ASC. Further studies are needed to clarify the impact of CMV infection on the outcome of acute severe colitis in pediatric patients.

Background: Considering that specific genetic profiles, psychopathological conditions and neurobiological systems underlie human behaviours, the phenotypic differentiation of obese patients according to eating behaviours should be investigated. The aim of this study was to classify obese patients according to their eating behaviours and to compare these clusters in regard to psychopathology, personality traits, neurocognitive patterns and genetic profiles., Methods: A total of 201 obese outpatients seeking weight reduction treatment underwent a dietetic visit, psychological and psychiatric assessment and genotyping for SCL6A2 polymorphisms. Eating behaviours were clustered through two-step cluster analysis, and these clusters were subsequently compared., Results: Two groups emerged: cluster 1 contained patients with predominantly prandial hyperphagia, social eating, an increased frequency of the long allele of the 5-HTTLPR and low scores in all tests; and cluster 2 included patients with more emotionally related eating behaviours (emotional eating, grazing, binge eating, night eating, post-dinner eating, craving for carbohydrates), dysfunctional personality traits, neurocognitive impairment, affective disorders and increased frequencies of the short (S) allele and the S/S genotype., Conclusions: Aside from binge eating, dysfunctional eating behaviours were useful symptoms to identify two different phenotypes of obese patients from a comprehensive set of parameters (genetic, clinical, personality and neuropsychology) in this sample. Grazing and emotional eating were the most important predictors for classifying obese patients, followed by binge eating. This clustering overcomes the idea that 'binging' is the predominant altered eating behaviour, and could help physicians other than psychiatrists to identify whether an obese patient has an eating disorder. Finally, recognising different types of obesity may not only allow a more comprehensive understanding of this illness, but also make it possible to tailor patient-specific treatment pathways., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Dengue virus (DENV) is a major global pathogen that causes significant morbidity and mortality in tropical and subtropical areas worldwide. An improved understanding of the regions within the DENV genome and its encoded proteins that are required for the virus replication cycle will expedite the development of urgently required therapeutics and vaccines. We subjected an infectious DENV genome to unbiased insertional mutagenesis and used next-generation sequencing to identify sites that tolerate 15-nucleotide insertions during the virus replication cycle in hepatic cell culture. This revealed that the regions within capsid, NS1, and the 3' untranslated region were the most tolerant of insertions. In contrast, prM- and NS2A-encoding regions were largely intolerant of insertions. Notably, the multifunctional NS1 protein readily tolerated insertions in regions within the Wing , connector , and β- ladder domains with minimal effects on viral RNA replication and infectious virus production. Using this information, we generated infectious reporter viruses, including a variant encoding the APEX2 electron microscopy tag in NS1 that uniquely enabled high-resolution imaging of its localization to the surface and interior of viral replication vesicles. In addition, we generated a tagged virus bearing an mScarlet fluorescent protein insertion in NS1 that, despite an impact on fitness, enabled live cell imaging of NS1 localization and traffic in infected cells. Overall, this genome-wide profile of DENV genome flexibility may be further dissected and exploited in reporter virus generation and antiviral strategies. IMPORTANCE Regions of genetic flexibility in viral genomes can be exploited in the generation of reporter virus tools and should arguably be avoided in antiviral drug and vaccine design. Here, we subjected the DENV genome to high-throughput insertional mutagenesis to identify regions of genetic flexibility and enable tagged reporter virus generation. In particular, the viral NS1 protein displayed remarkable tolerance of small insertions. This genetic flexibility enabled generation of several novel NS1-tagged reporter viruses, including an APEX2-tagged virus that we used in high-resolution imaging of NS1 localization in infected cells by electron microscopy. For the first time, this analysis revealed the localization of NS1 within viral replication factories known as "vesicle packets" (VPs), in addition to its acknowledged localization to the luminal surface of these VPs. Together, this genetic profile of DENV may be further refined and exploited in the identification of antiviral targets and the generation of reporter virus tools., (Copyright © 2017 American Society for Microbiology.)

Background: Intestinal failure (IF) is the reduction in functioning gut mass below the minimal level necessary for adequate digestion and absorption of nutrients and fluids for weight maintenance in adults or for growth in children. There is a paucity of epidemiologic data on pediatric IF. The purpose of this study was to determine the prevalence, incidence, regional distribution and underlying diagnosis of pediatric chronic IF (CIF) requiring home parenteral nutrition (HPN) in Italy., Methods: Local investigators were selected in 19 Italian centers either of reference for pediatric HPN or having pediatric gastroenterologists or surgeons on staff and already collaborating with the Italian Society for Pediatric Gastroenterology, Hepatology and Nutrition with regard to IF. Data requested in this survey for children at home on Parenteral Nutrition (PN) on 1 December 2016 included patient initials, year of birth, gender, family's place of residence and underlying diagnosis determining IF., Results: We recorded 145 CIF patients on HPN aged ≤19 years. The overall prevalence was 14.12/million inhabitants (95% CI: 9.20-18.93); the overall incidence was 1.41/million inhabitant years (95% CI: 0.53-2.20)., Conclusion: Our survey provides new epidemiological data on pediatric CIF in Italy; these data may be quantitatively useful in developing IF care strategy plans in all developed countries., Competing Interests: The authors declare no conflict of interest.

Background: This European Crohn's and Colitis Organisation [ECCO] topical review focuses on the transition of adolescents with inflammatory bowel disease [IBD] from child-centred to adult-oriented care. The aim was to provide evidence-supported, expert consensus for health professionals taking part in the transition., Methods: An online survey determined the areas of importance for health professionals involved in the transition of adolescents with IBD. Thereafter an expert panel of nine paediatric and five adult gastroenterologists was formed to identify the critical elements of the transition programme, and to prepare core messages defined as 'current practice points'. There is limited literature about transition, therefore this review is mainly based on expert opinion and consensus, rather than on specific evidence., Results: A total of 21 practice points were generated before the first [online] voting round. Practice points that reached >80% agreement were accepted, while those that did not reach 80% agreement were refined during a consensus meeting and subjected to voting. Ultimately, 14 practice points were retained by this review., Conclusion: We present a consensus-based framework for transitional care in IBD that provides a guidance for clinical practice., (Copyright © 2017 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Purpose: Food addiction (FA) refers to a condition characterized by addiction in relation to some high-fat and high-sugar carbohydrate that leads to clinically significant impairment or distress on several areas of functioning. The Yale Food Addiction Scale 2.0 (YFAS 2.0) has been recently updated to measure FA according to the DSM-5 criteria for substance-related and addictive disorders. This study aimed at validating the Italian version of YFAS 2.0., Methods: A sample of 574 Italian university students was involved in this research. Confirmatory Factor Analysis (CFA) and Kuder-Richardson's alpha for dichotomous data were run to evaluate scale structure and reliability. Correlations between YFAS 2.0 and eating psychopathology, binge eating, sleep, and mood symptoms were evaluated., Results: Analogously to the original version, a single factor structure emerged at the CFA. The alpha coefficient was 0.87. Moreover, sound, from moderate to high, correlations were found with other measures., Conclusions: The Italian version of the YFAS 2.0 has demonstrated in a sample of university students to be a useful tool to investigate food addictions. Level of evidence Level V, descriptive study.