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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.

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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.

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BACKGROUND: There is a limited literature describing the oral microbiome and its diagnostic potential in paediatric inflammatory bowel disease [IBD]. METHODS: We examined the dorsum tongue microbiome by V1-V2 sequencing in a cohort of 156 treatment-naïve children diagnosed with IBD compared to 102 healthy control children. Microbiome changes over time following treatment were examined in a subset of patients and associations between IBD diagnosis and dysbiosis were explored. RESULTS: Analysis of community structure of the microbiome in tongue samples revealed that IBD samples diverged significantly from healthy control samples [PERMANOVA p = 0.0009] and exhibited a reduced abundance of Clostridia in addition to several major oral genera [Veillonella, Prevotella and Fusobacterium species] with an increased abundance of streptococci. This dysbiosis was more marked in patients with severe disease. Higher levels of the potential pathobionts Klebsiella and Pseudomonas spp. were also associated with IBD. In terms of predicted functions, the IBD oral microbiome was potentially more acidogenic and exhibited reduced capacity for B vitamin biosynthesis. We used a machine learning approach to develop a predictive model of IBD which exhibited a mean-prediction AUC [area under the ROC curve] of 0.762. Finally, we examined a subset of 53 patients following 12 months of therapy and could show resolution of oral dysbiosis as demonstrated by a shift towards a healthy community structure and a significant reduction in oral dysbiosis. CONCLUSION: Oral dysbiosis found in children with IBD is related to disease severity and resolves over time following successful IBD treatment.

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GABA type A receptors (GABAARs) belong to the pentameric ligand-gated ion channel (pLGIC) family and play a crucial role in mediating inhibition in the adult mammalian brain. Recently, a major progress in determining the static structure of GABAARs was achieved, although precise molecular scenarios underlying conformational transitions remain unclear. The ligand binding sites (LBSs) are located at the extracellular domain (ECD), very distant from the receptor gate at the channel pore. GABAAR gating is complex, comprising three major categories of transitions: openings/closings, preactivation, and desensitization. Interestingly, mutations at, e.g., the ligand binding site affect not only binding but often also more than one gating category, suggesting that structural determinants for distinct conformational transitions are shared. Gielen and co-workers (2015) proposed that the GABAAR desensitization gate is located at the second and third transmembrane segment. However, studies of our and others' groups indicated that other parts of the GABAAR macromolecule might be involved in this process. In the present study, we asked how selected point mutations (ß2G254V, α1G258V, α1L300V, and ß2L296V) at the M2 and M3 transmembrane segments affect gating transitions of the α1ß2γ2 GABAAR. Using high resolution macroscopic and single-channel recordings and analysis, we report that these substitutions, besides affecting desensitization, also profoundly altered openings/closings, having some minor effect on preactivation and agonist binding. Thus, the M2 and M3 segments primarily control late gating transitions of the receptor (desensitization, opening/closing), providing a further support for the concept of diffuse gating mechanisms for conformational transitions of GABAAR.

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Pentameric ligand gated ion channels (pLGICs) are crucial in electrochemical signaling but exact molecular mechanisms of their activation remain elusive. So far, major effort focused on the top-down molecular pathway between the ligand binding site and the channel gate. However, recent studies revealed that pLGIC activation is associated with coordinated subunit twisting in the membrane plane. This suggests a key role of intersubunit interactions but the underlying mechanisms remain largely unknown. Herein, we investigated a "peripheral" subunit interface region of GABAA receptor where structural modeling indicated interaction between N-terminal α1F14 and ß2F31 residues. Our experiments underscored a crucial role of this interaction in ligand binding and gating, especially preactivation and opening, showing that the intersubunit cross-talk taking place outside (above) the top-down pathway can be strongly involved in receptor activation. Thus, described here intersubunit interaction appears to operate across a particularly long distance, affecting vast portions of the macromolecule.

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The aim of our study was to assess the frequency rate of Candida yeast-like fungi in isolations from nasal and pharyngeal mucosa in patients diagnosed with IM who had undergone an antibiotic therapy. The study was performed in 51 patients aged 17-33. The diagnosis of IM was made on the basis of clinical symptoms, haematological, biochemical and serologic examination results. The material constituted of nasal and pharyngeal swabs. The identification of Candida species was done according to the routine microbiological diagnostics. Our results show that among the Candida genus, C. albicans was the only pathogenic species isolated from patients with IM. It was observed only in pharyngeal swabs in 27.4% of the patients.

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