The incidence and characteristics of venous thromboembolisms in paediatric-onset inflammatory bowel disease; a prospective international cohort study based on the PIBD-SETQuality Safety Registry.

BACKGROUND & AIMS: Guidelines regarding thromboprophylaxis for venous thromboembolisms (VTE) in children with inflammatory bowel disease (IBD) are based on limited paediatric evidence. We aimed to prospectively assess the incidence of VTE in paediatric-onset IBD (PIBD), characterize PIBD patients with VTE, and identify potential IBD-related risk factors. METHODS: From October 2016 till September 2020, paediatric gastroenterologists prospectively replied to the international Safety Registry, monthly indicating whether they had observed a VTE case in a patient <19 years with IBD. IBD details (type, Paris classification, clinical and biochemical disease activity, treatment) and VTE details (type, location, treatment, outcome) were collected. To estimate the VTE incidence, participants annually reported the number of PIBD patients, data source and catchment area of their center. A systematic literature review and meta-analysis was performed to calculate the VTE incidence in the general paediatric population. RESULTS: Participation of 129 PIBD centers resulted in coverage of 24,802 PIBD patients. Twenty cases of VTE were identified (30% Crohn's disease). The VTE incidence was 3.72 [95%CI 2.27 - 5.74] per 10,000 person-years, 14-fold higher than in the general paediatric population (0.27 [95%CI 0.18-0.38], p<0.001). Cerebral sinus venous thrombosis was most frequently reported (50%). All but one patient had active IBD, 45% were using steroids and 45% hospitalized. No patient received thromboprophylaxis, whereas according to current PIBD guidelines, this was recommended in 4/20 patients. CONCLUSION: There is an increased risk of VTE in the PIBD population compared to the general paediatric population. Awareness of VTE occurrence and prevention should be extended to all PIBD patients with active disease, especially those hospitalized

International prospective observational study investigating the disease course and heterogeneity of paediatric-onset inflammatory bowel disease: the protocol of the PIBD-SETQuality inception cohort study

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 &lt;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

TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning

TALPID3/KIAA0586 Regulates Multiple Aspects of Neuromuscular Patterning During Gastrointestinal Development in Animal Models and Human

TALPID3/KIAA0586 is an evolutionary conserved protein, which plays an essential role in protein trafficking. Its role during gastrointestinal (GI) and enteric nervous system (ENS) development has not been studied previously. Here, we analyzed chicken, mouse and human embryonic GI tissues with TALPID3 mutations. The GI tract of TALPID3 chicken embryos was shortened and malformed. Histologically, the gut smooth muscle was mispatterned and enteric neural crest cells were scattered throughout the gut wall. Analysis of the Hedgehog pathway and gut extracellular matrix provided causative reasons for these defects. Interestingly, chicken intra-species grafting experiments and a conditional knockout mouse model showed that ENS formation did not require TALPID3, but was dependent on correct environmental cues. Surprisingly, the lack of TALPID3 in enteric neural crest cells (ENCC) affected smooth muscle and epithelial development in a non-cell-autonomous manner. Analysis of human gut fetal tissues with a KIAA0586 mutation showed strikingly similar findings compared to the animal models demonstrating conservation of TALPID3 and its necessary role in human GI tract development and patterning

Periodontitis is associated with significant hepatic fibrosis in patients with non-alcoholic fatty liver disease

This work was funded by the Diabetes Research and Wellness Fund. WA is in receipt of an MRC New Investigator Award

International prospective observational study investigating the disease course and heterogeneity of paediatric-onset inflammatory bowel disease: the protocol of the PIBD-SETQuality inception cohort study

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

Malignancy and mortality in paediatric-onset inflammatory bowel disease: a 3-year prospective, multinational study from the paediatric IBD Porto group of ESPGHAN

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

Socioeconomic factors associated with liver-related mortality from 1985 to 2015 in 36 developed countries

Background & Aims There is increasing disparity in liver-related mortality worldwide. Although there are many biologic and lifestyle risk factors for liver-related mortality, the effects of inequalities in social and economic determinants of health have received little attention. We investigated changes in liver-related mortality from 1985 through 2015 in 36 countries, using 4 international health and economic databases, and searched for socioeconomic factors that might influence these trends. Methods We collected information on sex- and country-specific liver-related mortality from countries with designated high usability data from the World Health Organization mortality database. We obtained data on alcohol consumption per capita, percentage of adults with body mass index greater than 30kg/m2, health expenditure per capita, gross domestic product per capita, Gini index, national unemployment estimates and diabetes prevalence from the World Health Organization global health observatory data repository, the World Bank database, and the International Diabetes Federation. We examined changes in mortality using Joinpoint regression analysis. Univariate analysis and a mixed-effects linear model were used to identify factors associated with liver-related mortality. Results From 1985 to 2015, mean liver-related deaths per 100,000 persons increased in men, from 23.8 to 26.1, and women, from 9.7 to 11.9. Increased liver-related mortality was associated with male sex, high level of alcohol consumption, obesity, and indicators of national wealth and government health expenditure gross domestic product or government expenditure on health. Conclusions In addition to established risk factors for liver mortality, this study identified addressable economic factors associated with liver-related mortality trends. Healthcare professionals and policy makers may wish to consider these factors to reduce liver-related mortality