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Background Faecal biomarkers have emerged as important tools in managing of inflammatory bowel disease [IBD], which includes Crohn’s disease [CD] and ulcerative colitis [UC]. Aim To identify new biomarkers of gut inflammation in the stools of IBD patients using a proteomic approach. Methods Proteomic analysis of stools was performed in patients with both active CD and CD in remission and in controls by 2-DIGE and MALDI-TOF/TOF MS. An ELISA was used to confirm results in a second cohort of IBD patients and controls. Results 2-DIGE analysis detected 70 spots in the stools of patients with active CD or patients in remission CD and in controls. MALDI-TOF/TOF MS analysis identified 21 proteins with Chymotrypsin C, Gelsolin and Rho GDP-dissociation inhibitor 2 [RhoGDI2] best correlating with the levels of intestinal inflammation. Results were confirmed in a second cohort of IBD patients and controls [57 CD, 60 UC, 31 controls]. The identified faecal markers significantly correlated with the severity of intestinal inflammation in IBD patients [SES-CD in CD, Mayo endoscopic subscore in UC] [CD; Chymotrypsin-C: r = 0.64, p < 0.001; Gelsolin: r = 0.82, p < 0.001; RhoGDI2: r = 0.64, p < 0.001; UC; Chymotrypsin-C: r = 0.76, p < 0.001; Gelsolin: r = 0.75, p < 0.001; RhoGDI2: r = 0.63, p < 0.001]. Moreover, ROC analysis showed that Gelsolin [p < 0.0002] and RhoGDI2 [p < 0.0001] in CD, and RhoGDI2 [p = 0.0004] in UC, have higher sensitivity and specificity than faecal calprotectin in discriminating between patients and controls. Conclusions We show for the first time that 2-DIGE is a reliable method to detect proteins in human stools. Three novel faecal biomarkers of gut inflammation have been identified that display good specificity and sensitivity for identifying IBD and significantly correlate with IBD severity.

Patrizia Alvisi,1 Serena Arrigo,2 Salvatore Cucchiara,3 Paolo Lionetti,4 Erasmo Miele,5 Claudio Romano,6 Alberto Ravelli,7 Daniela Knafelz,8 Stefano Martelossi,9 Graziella Guariso,10 Salvatore Accomando,11 Giovanna Zuin,12 Costantino De Giacomo,13 Lucio Balzani,14 Monia Gennari,15 Marina Aloi3 On behalf of the SIGENP IBD Working Group 1Pediatric Gastroenterology Unit, Pediatric Department, Maggiore Hospital, Bologna, Italy; 2Pediatric Gastroenterology and Endoscopy Unit, G Gaslini Children’s Hospital, Genoa, Italy; 3Pediatric Gastroenterology and Liver Unit, Sapienza University of Rome, Rome, Italy; 4Gastroenterology and Nutrition Unit, Meyer Children’s Hospital, Florence, Italy; 5Pediatric Department, Federico II University of Naples, Naples, Italy; 6Pediatric Gastroenterology, University of Messina, Messina, Italy; 7Gastroenterology and GI Endoscopy Unit, University Department of Pediatrics, Children’s Hospital, Brescia, Italy; 8Hepatology and Gastroenterology Unit, Bambino Gesù Hospital, Rome, Italy; 9Department of Pediatrics, Institute of Child Health, IRCSS Burlo Garofolo, Trieste, Italy; 10University of Padua, Padua, Italy; 11Pediatric Department, University of Palermo, G di Cristina Children’s Hospital, Palermo, Italy; 12Pediatric Unit, Buzzi Hospital, Milan, Italy; 13Pediatric Unit, Niguarda Hospital, Milan, Italy; 14Morgagni Hospital, Forlì, Italy; 15Emergency Pediatric Department, S Orsola Hospital, Bologna, Italy 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 (P2 years was negatively correlated with final PCDAI score (P

Background An altered gut microbiota profile has been widely documented in inflammatory bowel diseases (IBD). The intestinal microbial community has been more frequently investigated in the stools than at the level of the mucosa, while most of the studies have been performed in adults. We aimed to define the gut microbiota profile either by assessing fecal and colonic mucosa samples (inflamed or not) from pediatric IBD patients. Patients and methods Fecal and colonic samples from pediatric IBD (Crohn's disease or ulcerative colitis) and controls were analyzed. The relative abundance of bacteria at phylum and genus/species levels and bacterial diversity were determined through 16S rRNA sequence-based of fecal and mucosal microbiota analysis. Results A total of 59 children with IBD (26 Crohn's disease, 33 ulcerative colitis) and 39 controls were analyzed. A clear separation between IBD and controls in the overall composition of fecal and mucosal microbiota was found, as well as a reduced bacterial richness in the fecal microbiota of IBD. At the phylum level, abundance of Proteobacteria and Actinobacteria occurred in fecal microbiota of IBD, while species with anti-inflammatory properties (i.e., Ruminococcus) were reduced. Fusobacterium prevailed in inflamed IBD areas in comparison to noninflamed and controls samples. Conclusion Significant alterations in gut microbiota profile were shown in our IBD pediatric patients, in whom an abundance of species with a proinflammatory mucosal activity was clearly detected. An analysis of gut microbiota could be incorporated in designing personalized IBD treatment scenarios in future.

OBJECTIVES While the algorithm to diagnose celiac disease (CD) in children with elevated anti-transglutaminase IgA (TGA-IgA) titers (>10 times upper limit of normal, ULN) is well defined, the management of children with low TGA-IgA values represents a clinical challenge. We aimed to identify the diagnostic value of persistently low positive TGA-IgA titers in predicting CD in children. METHODS We retrospectively analyzed children with symptoms or signs of CD, not eligible for a no-biopsy approach. We included children with at least 2 TGA-IgA measurements, endomysial antibody (EMA) assessment and esophagogastroduodenoscopy with biopsies. TGA-IgA values were provided as multiples of ULN. Patients were classified in groups according to median TGA-IgA values: A (TGA-IgA>1 ≤ 5 × ULN; defined as "low-positive"), B (TGA-IgA > 5 < 10 × ULN; "moderate-positive"), and C (controls). RESULTS Data of 281 children were analyzed. Of 162 children in group A, CD was diagnosed in 142 (87.7%), whereas normal duodenal mucosa was found in 20. In group B, all 62 children (100%) received a CD diagnosis. Group C included 57 controls. EMA were undetectable in 31 (15%) of mucosal atrophy cases. On the receiver-operating characteristic curve (area under the curve = 0.910), a mean value of 1.7 ULN showed a sensitivity of 81.4% and specificity of 81.8% to predict mucosal damage. CONCLUSIONS Repeated low or moderate TGA-IgA values (

The occurrence of thrombotic events in adult patients with inflammatory bowel disease (IBD) is linked to multiple interactions between hereditary and acquired risk factors. There are few published data concerning children with iBD. The aim of this study was to investigate the presence of thromboembolic risk factors also in children with iBD.We enrolled three groups of children: one with Crohn disease (cD), one with ulcerative colitis (Uc), and a control group of healthy subjects. For all the participants the potential thromboembolic risk was evaluated clinically and with laboratory tests.We studied: 30 children (25.6%) with CD, 28 (23.9%) with UC, and 59 (50.4%) healthy control subjects. Regarding Pediatric Crohn Disease Activity Index, no significant differences between thromboembolic risk factors and disease activity were detected. Instead, in the patients with UC, stratified with the Pediatric Ulcerative Colitis Activity Index, there was a statistically significant difference in serum fibrinogen levels between patients with mild and moderate/severe disease [3.8 (3.2-4.5) g/L vs 5.7 (4.8-6.2) g/L, P 0.0032]. serum homocysteine levels were lower in healthy controls than in CD (P = 0.176) and UC (P = 0.026). An increased level ofhomocysteine in UC with a homozygous mutation in the methylene tetrahydrofolate reductase C677T gene was also observed.Our study showed that children with IBD have clinical features, acquired and congenital factors that can increase thrombotic risk, similarly to adults.

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.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.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 The aim of this study was to define clusters of activity in a population-based cohort during the first 5 years after diagnosis in children with ulcerative colitis [UC] and to identify early prognostic risk factors. Methods All UC patients from the SIGENP IBD registry with a complete follow-up of at least 5 years were included. Active disease was defined every 6 months in the presence of at least one of the following: clinical activity [Paediatric Ulcerative Colitis Activity Index ≥ 35]; endoscopic activity [Mayo score ≥ 1]; faecal calprotectin > 250 µg/g; hospitalization; surgery; or treatment escalation. Formula-based clusters were generated based on four published questionnaire-based activity patterns in adults, plus one additional cluster. Results In total, 226 patients were identified. Forty-two [19%] had moderate–severe chronically active disease, 31 [14%] chronic–intermittent, 75 [33%] quiescent, 54 [24%] active disease in the first 2 years after the diagnosis, then sustained remission, and 24 [11%] a remission in the first 2 years then an active disease. Mild disease onset along with a lower clinical severity not requiring the use of corticosteroids at 6 months were related to a quiescent disease course at the next follow-up (logistic model area under the curve 0.86 [95% confidence interval 0.78–0.94]; positive predictive value 67%; negative predictive value 70%). Eight per cent of patients needed surgery, none in the quiescent group [p = 0.04]. Conclusions More than one-third of children with UC present with a chronically active or intermittent course during the first 5 years of follow-up. A significant group of patients has active disease in the first 2 years and then sustained remission. Interestingly, after initial treatment, one-third of patients have well-controlled disease throughout.

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.

Introduction Non-alcoholic fatty liver disease (NAFLD), considered the leading cause of chronic liver disease in children, can often progress from non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH). It is clear that obesity is one of the main risk factors involved in NAFLD pathogenesis, even if specific mechanisms have yet to be elucidated. We investigated the distribution of intestinal bifidobacteria and lactobacilli in the stools of four groups of children: obese, obese with NAFL, obese with NASH, and healthy, age-matched controls (CTRLs). Material and methods Sixty-one obese, NAFL and NASH children and 54 CTRLs were enrolled in the study. Anthropometric and metabolic parameters were measured for all subjects. All children with suspected NASH underwent liver biopsy. Bifidobacteria and lactobacilli were analysed in children's faecal samples, during a broader, 16S rRNA-based pyrosequencing analysis of the gut microbiome. Results Three Bifidobacterium spp. (Bifidobacterium longum, Bifidobacterium bifidum, and Bifidobacterium adolescentis) and five Lactobacillus spp. (L. zeae, L. vaginalis, L. brevis, L. ruminis, and L. mucosae) frequently recurred in metagenomic analyses. Lactobacillus spp. increased in NAFL, NASH, or obese children compared to CTRLs. Particularly, L. mucosae was significantly higher in obese (p = 0.02426), NAFLD (p = 0.01313) and NASH (p = 0.01079) than in CTRLs. In contrast, Bifidobacterium spp. were more abundant in CTRLs, suggesting a protective and beneficial role of these microorganisms against the aforementioned diseases. Conclusions Bifidobacteria seem to have a protective role against the development of NAFLD and obesity, highlighting their possible use in developing novel, targeted and effective probiotics.

The incidence of non-alcoholic fatty liver disease (NAFLD) and its more severe and progressive form, non-alcoholic steatohepatitis (NASH) is increasing worldwide. Gut inflammation seems to concur to the pathogenesis of NASH. No drugs are currently approved for NASH treatment.To investigate if inflamed gut directly contributes to the progression of NASH through gut epithelial and vascular barrier impairment and to evaluate the efficacy of dipotassium glycyrrhizate (DPG) to improve the liver disease.A NASH model was set up by feeding mice, for 8 and 13 weeks, with high fat diet with high fructose and glucose (HFD-FG) supplemented periodically with dextran sulfate sodium (DSS) in drinking water. A group was also treated with DPG by gavage. Histological, immunohistochemical and molecular analysis were performed.DSS-induced colitis increased steatosis, inflammatory (IL-6, TNFα, NLRP3, MCP-1) as well as fibrotic (TGF-β, α-SMA) mediator expression in HFD-FG mice. Beneficial effect of DPG was associated with restoration of intestinal epithelial and vascular barriers, evaluated respectively by ZO-1 and PV-1 expression, that are known to limit bacterial translocation.Colonic inflammation strongly contributes to the progression of NASH, likely by favouring bacterial translocation. DPG treatment could represent a novel strategy to reduce liver injury.

Transplant eligibility for hepatocellular carcinoma (HCC) is determined by the imaging identification of tumor burden within the Milan criteria. Transjugular intrahepatic portosystemic shunt(s) (TIPS) reduce portal hypertension but may impact HCC visualization. It was hypothesized that the presence of pretransplant TIPS would correlate with occult HCC and reduced survival. A single-center, retrospective, case control study was performed among liver transplant recipients with HCC (2000-2017). The primary endpoint was occult disease on explant pathology. Backward stepwise logistic regression was performed. The secondary endpoints disease-free survival (DFS) and overall survival (OS) were evaluated with Kaplan-Meier curves and Cox regression analysis. Of 640 patients, 40 had TIPS and more frequently exhibited occult disease (80.0% versus 43.1%; P

Gastrointestinal endoscopy has grown dramatically over the past century, and with subsequent improvements in technology and anaesthesia, it has become a safe and useful tool for evaluation of GI pathology in children. There are substantial differences between paediatric and adult endoscopy beyond size, including: age-related patho-physiology and the different spectrum of diseases in children. Literature on endoscopic procedures in children is sparse but significant. The present review aims at describing the current knowledges on paediatric endoscopy practice and highlights the main areas of differences between paediatric and adult practice.

Background Intestinal transglutaminase (TG2) IgA deposits represent early marker of coeliac disease (CeD) and can predict the evolution towards intestinal atrophy. Aims To validate a double immunohistochemistry method for the determination of intestinal TG2 IgA deposits on formalin-fixed paraffin-embedded biopsies. Methods Immunohistochemistry was tested on: 1) children with overt CeD [persistently positive serum IgA anti-tissue transglutaminase type 2 (TGA-IgA) with moderate or low titer, and histological findings of CeD]; 2) potential CeD (persistently positive serum TGA-IgA and normal intestinal mucosa) and 3) controls (negative serum TGA-IgA and normal intestinal mucosa). Results Samples from 61 children were analyzed (32 overt CeD, 14 potential CeD, and 15 controls). Deposits appeared as focal, multifocal, or confluent extracellular foci of red and brown staining colocalization in the sub-epithelium and around mucosal vessels. Deposits were present in all 32 children with overt CeD and in 9/14 potential CeD. Deposits were never observed in the 15 controls. Patients with higher serum level of TGA-IgA and with mucosal atrophy showed mostly a multifocal/diffuse pattern of deposits distribution. The bulb appeared most severely involved. In potential CeD deposits showed mainly a focal distribution. Conclusion Our results indicate double immunohistochemistry as promising diagnostic tool to improve diagnosis of CeD.

Context Pheochromocytomas and paragangliomas (PCC/PGL) are neuroendocrine tumors with discrete catecholamine profiles that cause incompletely understood metabolic and physiologic changes. Objective The objective was to evaluate relationships between plasma catecholamines, body weight, and hemoglobin A1c (HbA1c). We hypothesized that individual catecholamines would correlate negatively with weight and glucose control. Design A retrospective cohort study was performed (1999-2020). Wilcoxon rank-sum tests compared nonparametric, continuous variables; mixed-effect linear modeling (MEM) evaluated relationships between catecholamines and weight or HbA1c. The median study duration was 54.2 months [interquartile range (IQR) 19.0-95.1]. Setting Tertiary academic hospital. Patients 360 patients were identified prospectively by referral to our center for management or surveillance of PCC/PGL. The median age was 59 years (IQR 45-67) and 56.4% (n = 203) were female. Main outcome measures The primary and secondary outcomes were weight and HbA1c, respectively. Results On multivariable MEM, norepinephrine (P Conclusion Plasma norepinephrine and its metabolite directly correlate with HbA1c and inversely correlate with weight in PCC/PGL. After resection, declining normetanephrine levels correlate with improving HbA1c despite an increase in patient body weight. Persistently elevated catecholamines and decreasing weight are observed in MRD.

Introduction: Tumor necrosis factor-α (TNF-α)-blocking agents are drugs approved for the treatment of inflammatory bowel diseases (IBDs). Infliximab and adalimumab are approved for the treatment of IBD in the pediatric setting with the improvement of therapeutic management. Biological agents, also in the pediatric population, can be administered either alone or in combination with immunomodulators. Their use has raised safety concerns regarding the risk of infections and malignancies.Areas covered: A broad review of the safety concerns for the use of anti-TNF-α drugs in children with IBD was performed, and information regarding the risk of infections and malignancies were updated, also in comparison with the safety of traditional drugs such as steroids and/or immunosuppressants.Expert commentary: Anti-TNF-α drugs have shown favorable safety profiles, and adalimumab treatment is associated with lower immunogenicity compared with infliximab. Heightened awareness and vigilant surveillance leading to prompt diagnosis and treatment are important for optimal management.

Background and Aims Recent evidence implicates gut microbiota (GM) and immune alterations in autism spectrum disorders (ASD). We assess GM profile and peripheral levels of immunological, neuronal and bacterial molecules in ASD children and controls. Alarmin HMGB1 was explored as a non-invasive biomarker to monitor gastrointestinal (GI) symptoms. Methods Thirty ASD children and 14 controls entered into the study. GM metagenomic analysis was performed for 16 ASD patients and 7 controls. GM functional profile was assessed by GO term analysis. Blood levels of IL-1β, TNFα, TGFβ, IL-10, INFγ, IL-8, lipopolysaccharide, Neurotensin, Sortilin1 and GSSG/GSH ratio were analyzed in all subjects by ELISA. Fecal HMGB1 was analyzed by Western blot. Results We observed a significant decrease in bacterial diversity. Furthermore, 82 GO terms underrepresented in ASD. Four of them pointed at 3,3 phenylpropionate catabolism and were imputable to Escherichia coli (E. coli) group. Serum levels of TNFα, TGFβ, NT, and SORT-1 increased in ASD patients. Fecal levels of HMGB1 correlated with GI sign severity in ASD children. Conclusions We suggest that a decrease of E. coli might affect the propionate catabolism in ASD. We report occurrence of peripheral inflammation in ASD children. We propose fecal HMGB1 as a non-invasive biomarker to detect GI symptoms.

The first infliximab biosimilar for the treatment of inflammatory bowel disease (IBD) was introduced in 2013, and today eight anti-TNF alpha biosimilars (three for infliximab and five for adalimumab) have been approved and licensed by the European Medicines Agency. Biosimilars present great potential in terms of cost saving and possible consequential reinvestment in the health care system. The increasing knowledge about the process of biosimilar development and use in IBD and the publication of many prospective clinical studies and real-life clinical experiences have progressively changed the point of view of IBD physicians. In the present position paper, the Italian Group for the Study of Inflammatory Bowel Disease present and discuss their updated statements and positions on this topic, with emphasis on the concepts of biosimilarity and extrapolation across indications, safety and immunogenicity, interchangeability and switching, automatic substitution, and, finally, patient education about biosimilars.

Recent guidelines for celiac disease have allowed a biopsy-free approach in endomysial antibodies (EMAs) positive children with high antitransglutaminase (TGA-IgA) titer [10 time upper limit of normal (ULN)]. Esophagogastroduodenoscopy is still necessary for diagnosis in children with lower title. Because elective pediatric endoscopy has been substantially shouted down during coronavirus disease (COVID-19) pandemic, many children remained undiagnosed - and therefore untreated - for a long time. We aimed to analyze the feasibility and accuracy of a biopsy-free approach in suspected celiac disease children with TGA-IgA values10 ULN to facilitate the diagnostic process by avoiding endoscopy.In this study cohort, we retrospectively analyzed all biopsy-confirmed diagnosis of celiac disease in our center (between 2014 and 2019). The positive predictive value (PPV) of TGA-IgA titers between 5 and 10 ULN and positive EMA in diagnosing celiac disease were determined. Mucosal atrophy and resolution of symptoms after gluten-free diet (GFD) were considered to confirm initial diagnosis.Of 430 celiac disease patients (F: 274; mean age 7.54 years) diagnosed by endoscopy, 84 (F: 46; mean age 8 years) with TGA-IgA between 5 and 10 ULN and positive EMA were identified. The PPV of TGA-IgA between 5 and 10 ULN and positive EMA was 0.93 (95% confidence interval 0.90-0.96). All these children had a symptom resolution and antibodies normalization after GFD.During the COVID-19 outbreak, a temporarily reduction of the TGA-IgA threshold for biopsy-sparing approach seems feasible in EMA positive children with TGA-IgA between 5 and 10 ULN.

Background and Aims. Neurotensin (NT) is a gut hormone secreted by specific endocrine cells scattered throughout the epithelial layer of the small intestine, which has been identified as an important mediator in several gastrointestinal functions and disease conditions. Its potential involvement in celiac disease (CD) has been investigated, but there are conflicting findings. The aim of this study was to evaluate serum NT levels in children with CD at diagnosis, compared to a control group, and to investigate whether NT correlated in CD patients with symptoms, antibody response, and intestinal mucosal damage.Materials and Methods. Children (1-16 years old) undergoing gastrointestinal endoscopy for CD or for other clinical reasons were included in this study. Patients with CD diagnosed according to the 2012 European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines without biopsy were also recruited. Fasting serum samples were analyzed for NT levels using ELISA. Logistic regression, Wilcoxon rank sum, and Spearman’s rank tests were used for statistical analysis.Results. Thirty children (18 females, 2.2-15.9 years old) were enrolled. Of 25 patients who underwent endoscopy, 9 were CD patients, 13 were controls, and 3 were excluded due to nonspecific inflammation at duodenal biopsy. CD was diagnosed in 5 patients without biopsy. NT median was higher in CD patients compared to controls (13.25 (IQR 9.4-17.5) pg/ml vs. 7.8 (IQR 7.6-10) pg/ml;p=0.02). No statistically significant association between NT and clinical, serological, or histological data of CD was observed in this CD cohort.Conclusions. To our knowledge, this is the first study that evaluates NT in CD children from Italy. Results show that NT is higher in the serum of CD children at diagnosis compared to controls. However, larger-scale studies are required to validate these findings. Whether serum NT levels can be an adjunctive marker for pediatric CD remains currently elusive.

Study ObjectivesRecently, a role for gain-of-function (GoF) mutations of the astrocytic potassium channel Kir4.1 (KCNJ10 gene) has been proposed in subjects with Autism–Epilepsy phenotype (AEP). Epilepsy and autism spectrum disorder (ASD) are common and complexly related to sleep disorders. We tested whether well characterized mutations in KCNJ10 could result in specific sleep electrophysiological features, paving the way to the discovery of a potentially relevant biomarker for Kir4.1-related disorders.MethodsFor this case–control study, we recruited seven children with ASD either comorbid or not with epilepsy and/or EEG paroxysmal abnormalities (AEP) carrying GoF mutations of KCNJ10 and seven children with similar phenotypes but wild-type for the same gene, comparing period-amplitude features of slow waves detected by fronto-central bipolar EEG derivations (F3-C3, F4-C4, and Fz-Cz) during daytime naps.ResultsChildren with Kir4.1 mutations displayed longer slow waves periods than controls, in Fz-Cz (mean period = 112,617 ms ± SE = 0.465 in mutated versus mean period = 105,249 ms ± SE = 0.375 in controls, p < 0.001). An analog result was found in F3-C3 (mean period = 125,706 ms ± SE = 0.397 in mutated versus mean period = 120,872 ms ± SE = 0.472 in controls, p < 0.001) and F4-C4 (mean period = 127,914 ms ± SE = 0.557 in mutated versus mean period = 118,174 ms ± SE = 0.442 in controls, p < 0.001).ConclusionThis preliminary finding suggests that period-amplitude slow wave features are modified in subjects carrying Kir4.1 GoF mutations. Potential clinical applications of this finding are discussed.

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.

OBJECTIVE The aim of the study was to systematically review the diagnostic utility of serum biomarkers for the diagnosis of necrotizing enterocolitis (NEC). METHODS We conducted an electronic and manual search of the available evidence. We included studies reporting data on the diagnostic accuracy of "serum" biomarkers for the diagnosis of NEC, available until January 2016. RESULTS We selected 22 studies from the 1296 articles retrieved. Only S100 A8/A9 protein and apolipoprotein-CII showed high sensitivity (100% and 96.4%, respectively) and specificity (90% and 95%, respectively) in the studies using Bell stage II NEC as target condition. High sensitivity and specificity were reported for interleukin-10 (100% and 90%), interleukin1-receptor antagonist (100% and 91.7%), intestinal fatty acid-binding protein (100% and 91%) and ischemia-modified albumin (94.7% and 92%), when tested to predict the evolution from definite to advanced NEC. Given the amount of uncertainty, the limited availability of data and heterogeneity among the populations in the different studies, we were unable to perform a meta-analysis. Major concerns about the applicability stemmed from the spectrum of patients enrolled and the inclusion of diseases different from Bell stage ≥2 NEC as target conditions. CONCLUSIONS We identified only few markers with good diagnostic accuracy and found an overall low quality of the studies on serum NEC biomarkers. In conclusion, data supporting their use are insufficient.

Necroptosis is a caspases-independent form of programmed cell death exhibiting intermediate features between necrosis and apoptosis. Albeit some physiological roles during embryonic development, tissue homeostasis and innate immune response are documented, necroptosis is mainly considered a pro-inflammatory cell death. Key actors of necroptosis are the receptor-interacting-protein-kinases, RIPK1 and RIPK3, and their target, the mixed-lineage-kinase-domain-like protein, MLKL. The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. Altered necroptosis at the intestinal epithelium leads to uncontrolled microbial translocation and deleterious inflammation. Indeed, necroptosis has been associated to chronic inflammatory diseases and cancer. Drugs that inhibit necroptosis could, therefore, be used therapeutically for the treatment of these diseases, and researches to develop such inhibitors are already underway. In this Review, we outline pathways for necroptosis and its role in chronic inflammation and cancer. We also discuss current and developing therapies that target necroptosis machinery.

Endoscopy is a central tool for the evaluation and management of inflammatory bowel disease (IBD). In the last few decades, gastrointestinal (GI) endoscopy has undergone significant technological developments including availability of pediatric-size equipment, enabling comprehensive investigation of the GI tract in children. Simultaneously, professional organization of GI experts have developed guidelines and training programs in pediatric GI endoscopy. This prompted the Porto Group on Pediatric IBD of the European Society for Pediatric Gastroenterology, Hepatology and Nutrition to develop updated guidelines on the role of GI endoscopy in pediatric IBD, specifically taking into considerations of recent advances in the diagnosis, disease stratification, and novel therapeutic targets in these patients.

OBJECTIVES Oral viscous budesonide is a recent therapeutic option for eosinophilic oesophagitis (EoE) compared with dietary restriction and inhaled steroids. This single-centre, open-label, not blinded study aims to evaluate the efficacy and safety of a new, preprepared oral viscous budesonide suspension (PVB) in children and adolescents with EoE. METHODS We treated 36 children with PVB (29 boys; median age 12 years) with EoE diagnosed according to European Society for Paediatric Gastroenterology Hepatology and Nutrition guidelines. Patients 150 cm height received 2 and 4 mg PVB daily, respectively, for 12 weeks. Upper gastrointestinal endoscopy was performed at baseline, after 12 weeks of therapy and 24 weeks after the end of therapy. Baseline and post-treatment scores were calculated for symptoms, endoscopy, and histology. Serum cortisol was performed at baseline, 12, and 36 weeks. RESULTS At the end of PVB trial, endoscopy showed macroscopic remission in 32 patients (88.9%), whereas at histology median pre- and post-treatment peak eosinophil count/high power field (HPF) markedly decreased from 42.2 (range: 15-100) to 2.9 (range: 0-30); moreover, mean symptom and histology scores impressively improved compared with baseline (P

markdownabstractBackground: 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.

Objective Almost 6% of celiac disease (CD) patients at diagnosis are positive for at least one of the main pancreatic islet autoantibodies that characterize type 1 diabetes (T1D). Few information, dated back to almost two decades ago, exist as to whether a gluten-free diet (GFD) could reduce the islet-specific autoimmunity detected in patients at CD diagnosis. Aim of the study was to evaluate the impact of GFD on 31 patients who presented islet-specific autoimmunity at CD diagnosis. Methods CD patient sera collected at diagnosis and throughout the GFD were analyzed for the main humoral autoantibodies so far identified in T1D, directed against one or more among insulin, glutamic-acid decarboxylase, tyrosine-phosphatase 2, and zinc cation-efflux transporter autoantigens. Results GFD (median duration 39 months) was associated to a decrease or disappearance of the islet-specific autoantibodies in 71% of CD patients. Almost 80% of the patients who became autoantibody-negative during the GFD were positive for only one of the islet-specific autoimmune markers at CD diagnosis, with none of them developing diabetes. Conversely, 80% of the CD patients positive at diagnosis for ≥2 islet-specific autoantibodies were still positive after more than two years of GFD, with 25% of them developing T1D. Conclusions Various factors appear to influence, individually or in combination, the effects of the GFD on pancreatic islet-specific autoimmune response detected at CD diagnosis. These factors include the number of diabetes autoantibodies found at CD diagnosis, the adherence to the GFD, its duration and an asymptomatic clinical presentation of CD.

Background A new prepared oral viscous budesonide (PVB) has been effective in inducing clinical and histological remission in pediatric eosinophilic esophagitis (EoE). Aims To evaluate the efficacy of a 12-week maintenance therapy on clinical, endoscopic, and histological remission using half of the dose used in the induction therapy. Methods We prospectively enrolled pediatric patients with active EoE. After 12 weeks of induction therapy with PVB (

Potential celiac disease (PCD) is defined by the presence of positive serum antibodies, HLA-DQ2/DQ8 haplotypes, and a normal small intestinal mucosa (Marsh grade 0-1). This condition occurs in one-fifth of celiac disease (CD) patients and usually represents a clinical challenge. We reviewed genetic, histologic, and clinical features of this specific condition by performing a systematic search on MEDLINE, Embase, and Scholar database. Accordingly, we identified different genetic features in patients with PCD compared to the classical forms. Frequently, signs of inflammation (deposits of immunoglobulin A (IgA) and/or increased number of intraepithelial lymphocytes) can be clearly identify in the mucosa of PCD patients after an accurate histological assessment. Finally, the main challenge is represented by the treatment: the gluten-free diet should be considered only in the presence of gluten-dependent symptoms in both children and adults.What is known: (i) potential celiac disease (PCD) occurs in one-fifth of all celiac diseases (CD), and (ii) despite the absence of classical lesions, clear signs of inflammation are often detectable.What is new: (i) patients with PCD show different genetic features, and (ii) the presence of gluten-dependent symptoms is the main determinant to initiate the gluten-free diet, after a complete diagnostic work-up.

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.

To identify differences between two cohorts of adult and pediatric patients affected by Crohn’s disease (CD), with regard to lesion location in the small intestine and colon-rectum, lesion activity, and prevalence of perianal disease (PD), using MRI as the main diagnostic tool. We retrospectively reviewed 350 consecutive MRI examinations performed between 2013 and 2016 in outpatients or inpatients with histologically proven CD, monitored by the Gastroenterology and Pediatric Units of our Hospital. The magnetic resonance enterography (MRE) protocol for adult and pediatric CD patients routinely includes evaluation of nine different intestinal segments (from jejunum to rectum) and of the anal canal. Intestinal activity was also calculated using a validated score. Perianal disease (PD) was staged. Fisher’s exact test was used and the odds ratio (OR) was calculated. Two hundred and nineteen out of 350 MRI studies (118 adults and 101 children) were included. The prevalence of PD was 34.6% in children and 16.1% in adults (OR = 2.8; p = 0.0017). Pediatric patients showed more frequent rectal involvement (29.7% vs 13.5%, OR = 2.7; p = 0.0045) and higher risk of PD in the presence of rectal disease (p = 0.043; OR = 4.5). In pediatric patients with severe colorectal disease, the prevalence of PD was twofold (86.7% vs 40%; p = 0.072). Using the clinical Montreal classification for lesion location, no significant differences emerged between the two patient populations. MRI showed a significantly higher prevalence of rectal involvement and perianal disease in the pediatric population. These results may have a relevant clinical impact and deserve further investigation. • To our knowledge, this is the largest morphological comparative study available in the literature using MRI as the main diagnostic tool to compare adult patients and children with Crohn’s disease. • Our study showed significant differences between adults and children: a higher prevalence of rectal and perianal fistulous disease (PD) in pediatric patients and an increased prevalence of PD in the presence of severe colon-rectum involvement. • The association of rectal and perianal disease implies a poorer clinical prognosis and a higher risk of disabling complications in pediatric patients.

BACKGROUND: The ideal preparation regimen for pediatric colonoscopy remains elusive, and available preparations continue to represent a challenge for children. The aim of this study was to compare the efficacy, safety, tolerability, and acceptance of 4 methods of bowel cleansing before colonoscopy in children. METHODS: This randomized, investigator-blinded, noninferiority trial enrolled all children aged 2 to 18 years undergoing elective colonoscopy in a referral center for pediatric gastroenterology. Patients were randomly assigned to receive polyethylene glycol (PEG) 4000 with simethicon (PEG-ELS group) or PEG-4000 with citrates and simethicone plus bisacodyl (PEG-CS+Bisacodyl group), or PEG 3350 with ascorbic acid (PEG-Asc group), or sodium picosulfate plus magnesium oxide and citric acid (NaPico+MgCit group). Bowel cleansing was evaluated according to the Boston Bowel Preparation Scale. The primary end point was overall colon cleansing. Tolerability, acceptability, and compliance were also evaluated. RESULTS: Two hundred ninety-nine patients were randomly allocated to the 4 groups. In the per-protocol analysis, PEG-CS+Bisacodyl, PEG-Asc, and NaPico+MgCit were noninferior to PEG-ELS in bowel-cleansing efficacy of both the whole colon (P = .910) and colonic segments. No serious adverse events occurred in any group. Rates of tolerability, acceptability, and compliance were significantly higher in the NaPico+MgCit group. CONCLUSIONS: Low-volume PEG preparations (PEG-CS+Bisacodyl, PEG-Asc) and NaPico+MgCit are noninferior to PEG-ELS in children, representing an attractive alternative to high-volume regimens in clinical practice. Because of the higher tolerability and acceptability profile, NaPico+MgCit would appear as the most suitable regimen for bowel preparation in children.

Background The clinical picture of celiac disease is changing with the emergence of subclinical forms and growing evidence reporting associated neurological disorders. Aims To establish the prevalence of celiac disease in children suffering from recurrent headache. Methods In our retrospective study we collected charts from 1131 children attending our tertiary care Centre for Paediatric Headache over the period 2001–2012. They were screened for celiac disease and positive patients were referred to our Operative Unit for Coeliac disease and confirmed positive children underwent upper endoscopy with multiple duodenal biopsies. Celiac children started a gluten-free diet. Results 883 children (481 females; median age, 9.8 years, range 3–19) performed celiac disease screening, and among them, 11 children (7 females; median age, 8.2 years, range: 4.8–13.9) were diagnosed with celiac disease. Seven children (5 females, median age, 11.9 years, range: 10.3–13.9) had been diagnosed as celiac prior to the neurological evaluation. The prevalence of celiac disease in our sample is 2.04% vs. 1.2% of the general population (p = 0.034). Conclusions Our study demonstrates, on a large series, that celiac disease prevalence is doubled in patients with chronic headache. Screening for celiac disease could be advised as part of the diagnostic work-up in these paediatric patients, particularly among pharmacological non-responders.

Performing well-designed and ethical trials in pediatric inflammatory bowel diseases (IBD) is a priority to support optimal therapy and reduce the unacceptable long lag between adult and pediatric drug approval. Recently, clinical trials in children have been incorporating placebo arms into their protocols under conditions that created controversy. Therefore, 4 organizations (the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition; European Crohn's and Colitis Organization; the Canadian Children IBD Network; and the Global Pediatric IBD Network) jointly provide a statement on the role of placebo in pediatric IBD trials. Consensus was achieved by 94 of 100 (94%) voting committees' members that placebo should only be used if there is genuine equipoise between the active treatment and placebo; for example, this may be considered in trials of drugs with new mechanisms of action without existing adult data, especially when proven effective alternatives do not exist outside the trial. Placebo may also be used in situations where it is an add-on to an effective therapy or to evaluate exit-strategies of maintenance therapy after long-term deep remission. It has been, however, agreed that no child enrolled in a trial should receive a known inferior treatment both within and outside the trial. This also includes withholding therapy in children who show clinical response after a short induction therapy. Given the similarity between pediatric and adult IBD regarding pathophysiology and response to treatments, drugs generally cannot be considered being in genuine equipoise with placebo if it has proven efficacy in adults. Continued collaboration of all stakeholders is needed to facilitate drug development and evaluation in pediatric IBD.

Background and Aims: Recent epidemiological studies showed an increase in ulcerative colitis among children, especially in its aggressive form, requiring surgical treatment. Although medical therapeutic strategies are standardized, there is still no consensus regarding indications, timing and kind of surgery. This study aimed to define the surgical management of paediatric ulcerative colitis and describe attitudes to it among paediatric surgeons. Methods: This was a retrospective cohort study. All national gastroenterology units were invited to participate. From January 2009 to December 2013, data on paediatric patients diagnosed with ulcerative colitis that required surgery were collected. Results: Seven units participated in the study. Seventy-one colectomies were performed (77.3% laparoscopically). Main surgical indications were a severe ulcerative colitis attack (33.8%) and no response to medical therapies (56.3%). A three-stage strategy was chosen in 71% of cases. Straight anastomosis was performed in 14% and J-pouch anastomosis in 86% of cases. A reconstructive laparoscopic approach was used in 58% of patients. Ileo-anal anastomosis was performed by the Knight–Griffen technique in 85.4% and by the pull-through technique in 9.1% of patients. Complications after colectomy, after reconstruction and after stoma closure were reported in 12.7, 19.3 and 35% of cases, respectively. Conclusions: This study shows that there is general consensus regarding indications for surgery. The ideal surgical technique remains under debate. Laparoscopy is a procedure widely adopted for colectomy but its use in reconstructive surgery remains limited. Longer follow-up must be planned to define the quality of life of these patients.

Background: Few case reports describe the clinical features of pancreatic involvement in inflammatory bowel disease. Aim: To investigate prevalence and disease course of inflammatory bowel disease children with pancreatitis and with exclusive hyperamylasemia and hyperlipasemia. Methods: We used a web-registry to retrospectively identify paediatric inflammatory bowel disease patients with hyperamylasemia and hyperlipasemia. Participants were re-evaluated at 6 months and 1 year. Results: From a total of 649 paediatric patients, we found 27 with hyperamylasemia and hyperlipasemia (4.1%). Eleven patients (1.6%) fulfilled diagnostic criteria for acute pancreatitis. Female gender was significantly associated with acute pancreatitis (p = 0.04). Twenty-five children (92.5%) had colonic disease. At 6 months 1/11 children with acute pancreatitis (9%) showed acute recurrent pancreatitis, while 1 patient (9%) had persistent hyperamylasemia and hyperlipasemia. At 12 months, 1 patient showed chronic pancreatitis (9.1%). Of the 16 children with exclusive hyperamylasemia and hyperlipasemia, 4 developed acute pancreatitis (25%), while 1 patient (6.2%) still presented exclusive hyperamylasemia and hyperlipasemia at 6 months. At 12 months, 11/16 patients (68.7%) reached a remission of pancreatic involvement, whereas 5 remaining patients (32.3%) had persistent hyperamylasemia and hyperlipasemia. Conclusions: In inflammatory bowel disease children, acute pancreatitis is more common in colonic disease and in female gender. Pancreatic function should be monitored, considering that pancreatic damage may evolve. (C) 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

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.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 scores135 and simple endoscopic score for CD ≤1, respectively. Clinical remission was defined as defined as a pediatric CD activity index score10 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.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.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.gov no: NCT03161886.

Hematoma expansion (HE) occurs in 1/3 of ICH patients and is associated with poor outcome. Intra-hematomal hypodensity (IHH) on CT has been reported to predict HE, as has the "BRAIN" score. We sought to assess the predictive value of these markers alone and in combination.We performed a retrospective single-center study of ICH patients with CT 6 h from onset. Two blinded neurologists assessed IHH on initial CT. Two HE definitions were examined: 6 ml and 6 ml or 33%. Multivariable logistic regression was used to determine the relationship between IHH and HE. Predictive value of the BRAIN score alone and integrated with IHH was assessed.In 122 included patients, median ICH volume was 13 ml, median time to CT 2.0 h; HE 6 ml occurred in 31% and 6 ml/ 33% in 43% of subjects. IHH were identified in 61% of patients with moderate inter-rater agreement (κ = 0.59). In multivariable analysis, IHH was associated with HE using 6 ml definition (OR 8.3, 95% CI, 2.6-32.8, P 0.001) but not using the 6 ml/ 33% definition (OR 1.9, 95% CI 0.84-4.3, P = 0.12). Rate of HE ( 6 ml) increased across increasing BRAIN score quartiles (Q1:11%, Q2:23%, Q3:43%, Q4:57%, P for trend 0.001). Rate of HE 6 ml in patients with BRAIN score ≥ 10 and IHH was 55%, with either alone was 33%, and with neither was 3%.Combining IHH on non-contrast CT and a simple clinical BRAIN score is a potentially powerful way to predict those patients at very high and very low risk of HE.