Objective:To evaluate current international clinical practice in the assessment and management of rectal stump disease activity following colectomy in paediatric ulcerative colitis (UC). Methods:A web-based survey comprising 18 questions was distributed to paediatric gastroenterologists via European Porto inflammatory bowel disease (IBD) interest group and North America and the United Kingdom pediatric inflammatory bowel disease (PIBD) network groups over 6 months. The questionnaire recorded centre demographics, colectomy practices, rectal stump assessment methods, and management approaches. Responses were analysed using descriptive statistics with subgroup analysis by continent and centre size. Results:Eighty paediatric gastroenterologists from 24 countries completed the survey. Most centres (n = 62, 78%) reported fewer than five colectomies annually, with 59% indicating that all patients retained a rectal stump for at least 3 months post-colectomy. Only 11% of centres had a formal protocol for rectal stump management. Clinical assessment tools varied, with 39% using none, and the remainder favouring Pediatric Ulcerative Colitis Activity Index (PUCAI) or Physician's Global Assessment. Frank rectal bleeding and painful rectal discharge were rated as the most significant symptoms. Endoscopy and histology were the most common investigations. Rectal therapy was the preferred first-line treatment for rectal stump disease recurrence, followed by systemic therapy and observation. There was wide variation in estimates of rectal disease activity at 6 months post-colectomy. Conclusions:There is considerable international variation and lack of standardisation in the management of rectal stump disease in paediatric UC. These findings underscore the need for evidence-based guidelines and collaborative research to optimise care for this understudied population.

Proactive drug monitoring in our national cohort of children with inflammatory bowel disease suggested that 5 mg/kg dosing of infliximab (IFX) was associated with inadequate trough levels (TLs), thus we commenced empiric 10 mg/kg dosing in 2019. This was a retrospective study of patients commenced on 5 or 10 mg/kg IFX between 2018 and 2020. The primary outcome was pre-fourth TL ≥5 µg/mL. Data source verification and analysis were undertaken retrospectively. During the study period, 122 patients were commenced on IFX and eligible for inclusion. Of these, 72% were male, 76% had Crohn's disease (CD), 23% had ulcerative colitis; mean (standard deviation [SD]) age at diagnosis was 11.8 (2.7) years; 60 commenced 5 mg/kg. Baseline parameters were comparable between groups. Fewer patients in the 5 mg/kg than 10 mg/kg group had pre-fourth TLs ≥5 µg/mL (6/48 [12.5%] vs 28/50 [56%], P < .001; mean [SD] TL 3.5 [6.3] vs 10.0 [9.9], P < .001). The 5 mg/kg group was less likely to have target pre-third TLs (6% vs 80%, P < .001); more likely to have treatment escalation (78% vs 45%, P < .001), and less likely to de-escalate (10% vs 29% P = .008). Proactive therapeutic dose monitoring (TDM) was practiced throughout the study period and mean (SD) IFX exposure per kg/week was similar in both groups by 1 year (1.4 [0.43] vs 1.56 [0.56] mg/kg/week, P = .137), as were infliximab durability and clinical outcomes. Our real-world data show that 5 mg/kg infliximab induction does not achieve target TLs in most children with CD. Higher-dose regimens should be considered, especially if proactive therapeutic drug monitoring is not available.

Infiltrating neutrophils are key effector cells in inflammatory bowel disease (IBD) while providing antimicrobial defense and tissue restitution in the intestine. The complexity of neutrophil functions in local environments underscores our limited understanding of how their adaptation in tissues influences disease progression. Here, we demonstrate that neutrophils recruited in murine colitis and infection models, idiopathic IBD, and chronic granulomatous disease-associated IBD undergo extensive transcriptional reprogramming, resulting in the emergence of neutrophil populations that feature unique DUOX2 NADPH oxidase expression. Functional studies utilizing mice with myeloid and neutrophil specific DUOX2 inactivation reveal a vital and dichotomous role for this NADPH oxidase in both colitis and intestinal infection. Niche-directed reprogramming promoted a DUOX2-dependent chemokine and cytokine-rich intestinal environment that amplified and prolonged inflammatory responses, suggesting that selectively suppressing DUOX2 may constitute an anti-inflammatory strategy for IBD treatment. Altering spatiotemporal redox signaling by de novo expression of a ROS-generating enzyme represents an important feature for functional neutrophil diversification in disease, with implications for other neutrophil-driven diseases in specialized niches.

Background: Pediatric acute liver failure (PALF) is a rare and life-threatening condition. In up to 50% of PALF cases, the underlying etiology remains unknown during routine clinical testing. This lack of knowledge complicates clinical management and liver transplantation decisions. Recently, whole-exome sequencing has identified genetic disorders in a large number of cases without specific laboratory biomarkers or metabolic fingerprints. Methods: We describe how further analysis of whole-exome sequencing data combined with proteomic analyses in 5 previously unsolved PALF patients, where no pathogenic variants in genes previously associated with acute liver failure were identified, revealed rare biallelic variants in transient receptor potential cation channel subfamily M member 7 (TRPM7). Results: We establishe TRPM7 as a novel disease gene for PALF. Yet, the cation channel kinase TRPM7 has not been associated with any Mendelian disorder. No homozygous loss-of-function variants were found in in-house exomes or publicly available databases. Rare biallelic TRPM7-variants were significantly enriched in the PALF cohort compared with a pediatric control cohort. Viral infections preceded the majority of PALF episodes. Recurrent PALF episodes characterized the disease course with rapid progression, leading to early death in 3 cases. Proteomic analyses of patient fibroblasts unveiled significantly reduced TRPM7 protein levels, indicative of functional impairment. Severely reduced Mg2+ levels in one individual with a mutation in the channel domain suggests a potential interaction between disturbed Mg2+ homeostasis and PALF. The consistent presence of mutations in the TRPM7 protein-kinase-domain across all patients suggests its specific relevance in PALF. Conclusions: Our data extend the genetic spectrum of recurrent PALF and prompt consideration of TRPM7 in children with unexplained liver failure.

Metaproteomic analysis of microbiome post-translation modifications (PTMm) is challenging, and little is known about the effects of inflammation on the bacterial PTM landscape in IBD. Here, we adapted and optimised fluorescence in situ hybridisation–flow cytometry (FISH-FC) to study microbiome-wide tyrosine phosphorylation (p-Tyr) in children with and without inflammatory bowel disease (IBD). Microbial p-Tyr signal was significantly higher in children with IBD, compared to those without. Faecalibacterium prausnitzii, Bacteroidota, Gammaproteobacteria and Bifidobacteria tended to be more abundant in IBD than in non-IBD control children but there were only minor differences in p-Tyr among these bacterial communities in those with and without IBD. p-Tyr was significantly lower in non-IBD children older than 9 yrs compared with those less than 9 yrs, and the effect was seen in all four bacterial subgroups studied. The opposite trend was seen in patients with IBD. p-Tyr overall is higher in children with IBD but the effects of inflammation on p-Tyr vary according to the bacterial community. The overall microbiome p-Tyr signal changes with age in healthy children. FISH-FC can be used to study the microbiome-wide PTM landscape.

BACKGROUND:Our understanding of the natural history of cystic fibrosis liver disease (CFLD) is limited, leading to uncertainty for patients their families and clinicians when liver abnormalities are identified. AIM:to determine the incidence of CFLD, identify risk factors and document the natural history of liver abnormalities in cystic fibrosis (CF). METHODS:The Irish longitudinal study of CFLD (ILSCFLD) prospectively enrolled 95% of children with CF in 2007. Their liver disease status was classified as (i) advanced liver disease with portal hypertension (CFLD). (ii) nonspecific cystic fibrosis liver disease (NSCFLD) (iii) no liver disease (NoLD) RESULTS: 480/522 (91.9%) children were followed for a median 8.53 years IQR 1.28, of whom 35 (7.29%) had CFLD, 110 (22.9%) NSCFLD and 335 (69.79%) had NoLD. At follow-up 28/445 (6.29%) participants without CFLD at baseline, progressed to CFLD (Incidence 7.51/1000 person years (Pyrs) (95%CI 4.99-10.86). Of these 25/28(89.28%) were <10 years. No participant >10 years of age without clinical or radiological evidence of liver disease at baseline progressed to CFLD. During follow-up 18/35(51.43%) participants with CFLD died or received a transplant, MTx rate 7.75/100 Pyrs (95%CI 4.59-12.25) compared to NSCFLD 2.33/100 Pyrs (95%CI 1.44-3.56) and NoLD 1.13/100 Pyrs (95%CI 0.77-1.59). CFLD was an independent risk factor for mortality in CF. Children with CFLD also had a shorter life expectancy. CONCLUSION:The incidence of CFLD was highest in children under10 years. Children over10 years, with normal hepatic function did not develop CFLD. Research to identify the cause and improve outcome should focus on young children.

BACKGROUND:Outcomes in pediatric ulcerative colitis (UC) are heterogeneous and predictors of disease course eagerly sought. Mucosal atrophy (MA) is characterized by histological abnormalities of colonic intestinal glands.OBJECTIVE:To determine the prevalence of MA in a national inception cohort of pediatric UC and its impact on outcomes.METHODS:Irish children < 16 years old with UC are diagnosed at a single referral center. At diagnosis, patients underwent phenotyping by Paris classification and activity assessment by Pediatric Ulcerative Colitis Activity Index. Biopsies from all colonic segments were evaluated for MA. Patients were followed prospectively. The primary outcome was corticosteroid-free remission at 1 year. Secondary outcomes included relapse, treatment escalation, and colectomy by 2 years.RESULTS:Of 251 pediatric patients with UC (mean age 11.8 years, 55% male), 38 (15%) had MA on diagnostic biopsy. Baseline characteristics were similar between groups with/without MA and there was no difference in steroid-free remission or rates of moderate-severe UC at 1 year. Patients with MA had higher use of steroids (29% vs 15%, P = 0.04) and immunomodulators (40% vs 21%, P = 0.04) at 6 months, higher biologic use at 1 year (34% vs 16%, P = 0.03), earlier first relapse (mean ± SD 29.4 ± 26.1 vs 46.7 ± 43.4 weeks after diagnosis, P = 0.02), and higher colectomy rates by 2 years (21% vs 8%, P = 0.01).CONCLUSIONS:Children with MA at diagnosis had higher colectomy rates despite earlier treatment escalation and similar baseline severity scores. We identify MA as a promising new prognostic marker in children with newly diagnosed UC.

Background:Pediatric ulcerative colitis (UC) is typically more extensive and severe at diagnosis compared with adult disease. Tofacitinib, a Janus kinase inhibitor, has been used since 2018 to induce and maintain remission in UC. There are limited pediatric data regarding its use, either as a monotherapy or in combination with other treatments.Objectives:To determine the real-world experience and outcomes of tofacitinib therapy in the Irish national cohort with pediatric UC.Methods:A retrospective study of tofacitinib outcomes was undertaken at Ireland's single national center for pediatric inflammatory bowel disease. All patients commenced on tofacitinib since its availability in 2019 were included. Baseline and follow-up clinical characteristics, phenotype, Pediatric Ulcerative Colitis Activity Index (PUCAI) scores, and treatments before and after tofacitinib commenced were recorded. The primary outcome was remission by 8 weeks, with other clinical outcomes being recorded to maximal available follow-up.Results:Between November 1, 2019 and June 30, 2022, 15 children (M:F 1:2) were prescribed tofacitinib, 5 as monotherapy. Thirteen had baseline pancolitis at diagnosis and all patients had prior infliximab exposure. The mean time from diagnosis to starting tofacitinib was 381 days (±SD 265). Dual therapy included 5 with infliximab, 4 with vedolizumab, and 1 with adalimumab. The average length of treatment on tofacitinib was 232 days (±SD 170) with 2 patients transitioning to adult services while in remission on tofacitinib therapy. The mean PUCAI score was 48.7 (±SD 14.1) pre-tofacitinib, 16.7 (±SD 15.6) at week 8, and 22.5 (±SD 29.6) by week 16, with a significant reduction in PUCAI by week 16 (P = 0.0004). Eight patients (3 monotherapy) achieved clinical remission, with 4 of the 5 dual therapy patients on infliximab. There were no significant outcome differences between those on mono- or dual therapy. Three patients with combined vedolizumab therapy did not achieve remission, 2 of whom required colectomy by week 24. There were no malignancies, 1 patient developed shingles and another developed herpangina post-tofacitinib. Failure to achieve clinical remission by week 16 was seen in all children who progressed to colectomy (n = 4).Conclusion:Combining tofacitinib with other biologics is effective in select children with refractory UC. Early responders were more likely to achieve a sustained response at week 16. Failure to achieve remission by week 16 of tofacitinib therapy was strongly associated with progression to colectomy.

The mechanisms of action of probiotic bacteria and their effect in combating digestive disorders in humans and animals has been demonstrated and supported in numerous scientific studies. Probiotic bacteria are used in a wide range of nutritional techniques in order to support the host organism during physiological strain, to reduce stress due to technology and to combat diarrheal syndromes (occurring naturally or pharmacologically induced). Based on a rich bibliographic material, this paper presents the role of probiotic bacteria to equilibrate the beneficial microbial population and in bacterial turnover by stimulating the host immune response via specific secretions (eg. bacteriocins) and competitive exclusion of potentially pathogenic germs in the digestive tract (Salmonella, E. coli). In the same context, this review presents the basic studies on the effect of probiotic bacteria in health maintenance for the main species of farm animals: pigs, poultry, cattle and sheep.

Congenital diarrheas and enteropathies (CODEs) constitute a heterogeneous group of individually rare disorders manifesting with infantile-onset chronic diarrhea. Genomic deletions in chromosome 16, encompassing a sequence termed the 'intestine-critical region (ICR)', were recently identified as the cause of an autosomal recessive congenital enteropathy. The regulatory sequence within the ICR is flanked by an unannotated open reading frame termed PERCC1, which plays a role in enteroendocrine cell (EEC) function. We investigated two unrelated children with idiopathic congenital diarrhea requiring home parenteral nutrition attending the Irish Intestinal Failure Program. Currently 12 and 19-years old, these Irish male patients presented with watery diarrhea and hypernatremic dehydration in infancy. Probands were phenotyped by comprehensive clinical investigations, including endoscopic biopsies and serum gastrin level measurements. Following negative exome sequencing, PCR and Sanger sequencing of the entire coding region and intron boundaries of PERCC1 were performed for each proband and their parents. In both patients, serum gastrin levels were low and failed to increase following a meal challenge. While no deletions involving the ICR were detected, targeted sequencing of the PERCC1 gene revealed a shared homozygous c.390C > G stop gain variant. We report clinical and molecular findings in two unrelated patients harboring a shared homozygous variant in PERCC1, comprising the first description of a point mutation in this gene in association with CODE. That both parenteral nutrition dependent children with unexplained diarrhea at our institution harbored a PERCC1 mutation underscores the importance of its inclusion in exome sequencing interpretation.

Background Cystic fibrosis (CF) is a multiorgan disease affecting the lungs pancreas and gastrointestinal tract. Pulmonary complications are the most common manifestation of the disease. Recent advances in the treatment of pulmonary complications have resulted in substantial improvement in life expectancy. Less than 10% of persons with CF (PWCF) develop liver disease (CFLD). There is conflicting evidence about impact of liver disease on mortality in CF, with evidence suggesting that CFLD contributes to increased mortality in CF, while other studies suggest that the impact on mortality is limited. Understanding the contribution of liver disease to mortality in CF is essential if further improvements in life expectancy are to be achieved.Objective: To document the impact of liver disease on life expectancy for PWCF.Methods: This systematic review will be conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P 2015). PubMed, Medline and Embase will be searched for English language publications (1949-2020). Studies reporting the outcome for CFLD will be included where the definition of CFLD is outlined clearly in a CF population. Studies with and without a comparator will be evaluated. Clinical trials of ursodeoxycholic acid will be excluded as well as organ transplantation outcome studies. We will examine all-cause and specific causes of mortality.We will include transplantation in our estimates of all-cause mortality. The Axis Risk of Bias Tool for Observational Studies will be used to evaluate the quality of studies. We will provide a narrative synthesis of our findings using tabular formats to highlight any impact of liver disease on mortality in CF.Conclusion: It is anticipated that this review will bring clarity to the question of whether CFLD shortens life expectancy in PWCF and stimulate new approaches to the management of CFLD.

Background Poorly performing diagnostic tests can impact patient safety. Clinical investigations must have good precision and diagnostic accuracy before widespread use in clinical practice. Transient elastography (TE) measures liver stiffness, a surrogate marker of liver fibrosis in adults and children. Studies to evaluate its repeatability and reproducibility (precision) in children are limited. Our aim was to determine (i) the normal range of TE measurements and (ii) the repeatability and reproducibility of TE in healthy children. Methods TE was performed in 257 healthy children, of whom 235 (91%, mean age 11.7 years, standard deviation (SD) 2.51, 107 were males (45.5%)) had two valid TE measurements performed, at least 24 h apart, by two operators under similar circumstances. High-quality TE images were obtained for each examination. Results The normal range of TE was 2.88–6.52 kPa. The mean difference between paired measurements was 0.044 (SD 0.4). The 95% limits of agreement ranged from −0.8 to +0.76 kPa for repeat measurements. There was a difference of >1 kPa between measurements in 61/235 (25.9%) children. The lack of precision was similar across all age groups. Conclusions This study demonstrates that TE does not have acceptable precision in healthy children, because random measurement variation results in the lack of agreement between paired measurements. Impact The precision and diagnostic accuracy of a new technology must be determined before it is deployed in children in order to ensure that appropriate clinical decisions are made, and healthcare resources are not wasted. TE is widely used to diagnose liver disease in children without adequate evaluation of the precision (repeatability) of TE either in healthy children or children with liver disease. This study demonstrates that TE does not have adequate precision in children. This study was performed in accordance with methods previously published for children. Refinements to the test protocol, such as duration of fasting or probe size, will have to be evaluated for their impact on precision and accuracy before the test is deployed in research studies or clinical practice.

Dysregulated redox signaling and oxidative injury are associated with inflammatory processes and fibrosis. H2O2 generation by NOX4 has been suggested as a key driver in the development of fibrosis and a small molecule drug is under evaluation in clinical trials for idiopathic pulmonary fibrosis and primary biliary cholangitis. Fibrosis is a common complication in Crohn's disease (CD) leading to stricture formation in 35–40% of patients, who require surgical interventions in the absence of therapeutic options. Here we assess NOX4 expression in CD patients with inflammatory or stricturing disease and examine whether loss of NOX4 is beneficial in acute and fibrotic intestinal disease. NOX4 was upregulated in inflamed mucosal tissue of CD and ulcerative colitis (UC) patients, in CD ileal strictures, and in mice with intestinal inflammation. Nox4 deficiency in mice promoted pathogen colonization and exacerbated tissue injury in acute bacterial and chemical colitis. In contrast, in two chronic injury models aberrant tissue remodeling and fibrosis-related gene expression did not differ substantially between Nox4−/− mice and wildtype mice, suggesting that Nox4 is dispensable in TGF-β1-driven intestinal fibrogenesis. While animal models do not recapitulate all the hallmarks of CD fibrosis, the tissue-protective role of Nox4 warrants a cautious approach to pharmacological inhibitors.

Background Cystic fibrosis (CF) is a multiorgan disease affecting the lungs pancreas and gastrointestinal tract. Pulmonary complications are the most common manifestation of the disease. Recent advances in the treatment of pulmonary complications have resulted in substantial improvement in life expectancy. Less than 10% of persons with CF (PWCF) develop liver disease (CFLD). There is conflicting evidence about impact of liver disease on mortality in CF, with evidence suggesting that CFLD contributes to increased mortality in CF, while other studies suggest that the impact on mortality is limited. Understanding the contribution of liver disease to mortality in CF is essential if further improvements in life expectancy are to be achieved. Objective: To document the impact of liver disease on life expectancy for PWCF. Methods: This systematic review will be conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P 2015). PubMed, Medline and Embase will be searched for English language publications (1949-2020). Studies reporting the outcome for CFLD will be included where the definition of CFLD is outlined clearly in a CF population. Studies with and without a comparator will be evaluated. Clinical trials of ursodeoxycholic acid will be excluded as well as organ transplantation outcome studies. We will examine all-cause and specific causes of mortality.We will include transplantation in our estimates of all-cause mortality. The Axis Risk of Bias Tool for Observational Studies will be used to evaluate the quality of studies. We will provide a narrative synthesis of our findings using tabular formats to highlight any impact of liver disease on mortality in CF. Conclusion: It is anticipated that this review will bring clarity to the question of whether CFLD shortens life expectancy in PWCF and stimulate new approaches to the management of CFLD.