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Purpose This study aimed to document utility values and the Visual Analog Scale (VAS) with the 5-level version of the EQ-5D questionnaire in a large sample of patients with inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC). Methods QALY-MICI was a cross-sectional survey across three sources in France. Data were collected between 2019 and 2022 for patients 18 and over. The EQ-5D-5 L, the EQ-VAS, the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), the Harvey-Bradshaw Index (HBI) for CD, and the Walmsley Index for UC (SCCAI) were collected. Results A total of 2,841 patients aged over 18 were recruited (1785 with CD, 1056 with UC). The mean age was 40.2 (SD 14.3). The time since diagnosis was 6 years and over for 61.9% of patients. The most impacted dimensions were usual activities, anxiety/ depression, and pain/ discomfort. The mean utility value was 0.863 (SD 0.172) versus 0.905 (SD 0.158) in the French population ( p  = 0.007). The mean VAS value was 68 (SD 19.2) versus 73.4 (SD 22.2) in the general population ( p  = 0.016). Utility values and VAS were similar for CD and UC and higher for men. There was a strong positive correlation between utility values, the VAS, and the SIBDQ score, and a negative correlation between the HBI and the SCCAI. The SIBDQ score and disease activity were the main predictors of utility and VAS. Conclusion The QALY-MICI is, to our knowledge, the first study documenting utility values and VAS using the EQ-5D-5 L questionnaire on a large sample, with a comparison to the general population. Plain English summary Cost-effectiveness analyses have become an important component of assessing new health technologies. They require robust evidence to measure Quality of Life Adjusted Life Year gains. The Euroqol EQ-5D questionnaire is the main standard. Data on its use in inflammatory bowel disease (IBD) with its latest version, EQ-5D-5L, are limited to small samples. This study aimed at estimating utility values for IBD patients on a large sample in France, analysing the relationship between specific IBD quality of life and disease activity indexes, and identifying the main factors impacting patients’ quality of life. A prospective, cross-sectional survey was designed amongst French IBD patients aged 18 and over from three sources (n=2,841) . Utility values for IBD patients were lower than those observed in the French general population across all age groups. Men declared higher values than women. There was no difference between patients with Crohn’s disease and those with ulcerative colitis. Patients with a quiescent disease had similar values to those of the general population.

ObjectiveNatural history of paediatric-onset ulcerative proctitis (UP) is poorly described. Our aim was to describe the phenotype and disease course of incident UP in a population-based study of paediatric-onset UC.Patients and methodsAll patients with UC diagnosed <17 years from 1988 to 2004, and followed during >2 years have been extracted from a population-based registry. UC location was defined according to the Paris classification. Cumulative risks for use of immunosuppressants (IS), anti-tumour necrosis factor alpha (TNF-α) therapy, colonic extension and colectomy were described using Kaplan-Meier method. Risk factors for colonic extension were assessed using Cox proportional hazards models.Results158 patients with paediatric-onset UC (91 females) with a median age at diagnosis of 14.5 years (Q1: 11.4–Q3: 16.1) have been identified and followed during a median of 11.4 years (8.2–15.8). Among them, 25% had UP (E1) at diagnosis and 49% of them presented a colonic extension at maximal follow-up. In these children, the cumulative risk for colonic extension was 10% at 1 year, 45% at 5 years and 52% at 10 years. No parameter at diagnosis was associated with colonic extension in the UP (E1 group). IS use was significantly lower in patients with UP than in those with E2, E3 or E4 location (p=0.049). For the UP cohort, the cumulative risk for colectomy was 3% at 1 year, 10% at 5 years, 13% at 10 years and 13% at 15 years. Risks for colonic extension, treatment with anti-TNF-α and colectomy did not differ between the E1 group and the E2–E3–E4 group.ConclusionsUP is frequent in paediatric-onset UC and should not be considered as a minor disease. Compared with more extensive UC locations, risks for colonic extension, anti-TNF-α therapy and colectomy were similar in UP, whereas the risk for use of IM was lower.

Abstract Introduction A new clinician-administered inflammatory bowel disease (IBD) Disability Index (IBDDI) was recently developed and validated among a population in France. We aimed to validate the IBDDI in a North American setting and adapt for use as a self-report tool. Methods Persons 18-65 years old from the population-based University of Manitoba IBD Research Registry were mailed a self-administered survey. This survey included the IBDDI and several scales that should correlate with a disability measure- the World Health Organization (WHO) Disability Assessment Scale (WHODAS) 2.0, Work and Social Adjustment Scale (WSAS), the Inflammatory Bowel Disease Questionnaire (IBDQ), and the K6-Kessler Emotional Distress Scale. We used Pearson correlation coefficients to assess construct validity, Cronbach's alpha to assess internal consistency, and Factor analysis to assess which of the IBDDI items likely belonged to a single IBD-related disability factor. Results In response to the survey request,1143 (46% of those contacted) participated (61% female, mean age 51, 52% with Crohn's disease). On an index scale from 0-100, 14% had a score ≥50 (extreme disability, 18% of those with Crohn's disease; 10% of those with ulcerative colitis). There were strong correlations between IBDDI and WSAS (0.76), WHODAS (0.76), K6 (0.73), and an inverse correlation with IBDQ (-0.86). The Cronbach's alpha was high (0.88). All but 2 items (number of liquid stools in the past week and arthritis/arthralgia) of the 14 identified for IBDDI loaded highly onto a single factor (factor loading > 0.40). Conclusions The findings support the validity of this new self-report version of the IBDDI as a sound measure of disability in IBD.

In many developing countries, aquaculture is key to ensuring food security for millions of people. It is thus important to measure the full implications of environmental changes on the sustainability of aquaculture. We conduct a double meta-analysis (460 articles) to explore how global warming and antimicrobial resistance (AMR) impact aquaculture. We calculate a Multi-Antibiotic Resistance index (MAR) of aquaculture-related bacteria (11,274 isolates) for 40 countries, of which mostly low- and middle-income countries present high AMR levels. Here we show that aquaculture MAR indices correlate with MAR indices from human clinical bacteria, temperature and countries’ climate vulnerability. We also find that infected aquatic animals present higher mortalities at warmer temperatures. Countries most vulnerable to climate change will probably face the highest AMR risks, impacting human health beyond the aquaculture sector, highlighting the need for urgent action. Sustainable solutions to minimise antibiotic use and increase system resilience are therefore needed. Global environmental changes threaten many food-producing sectors, including aquaculture. Here the authors show that countries most vulnerable to climate change will probably face the highest antimicrobial resistance in aquaculture-related bacteria, and that infected aquatic animals have higher mortality at warmer temperatures.

BackgroundIBDs are chronic destructive disorders that negatively affect the functional status of patients. Recently, the Inflammatory Bowel Disease Disability Index (IBD-DI) was developed according to standard WHO processes. The aims of the current study were to validate the IBD-DI in an independent patient cohort, to develop an index-specific scoring system and to describe the disability status of a well-defined population-based cohort of French patients with IBD.MethodsFrom February 2012 to March 2014, the IBD-DI questionnaire was administered to a random sample of adult patients with an established diagnosis of IBD issued from a French population-based registry. The IBD-DI consists of 28 items that evaluate the four domains of body functions, activity participation, body structures and environmental factors. Validation included item reduction and data structure, construct validity, internal consistency, interobserver and intraobserver reliability evaluations.Results150 patients with Crohn's disease (CD) and 50 patients with UC completed the IBD-DI validation phase. The intraclass correlation coefficient for interobserver reliability was 0.91 and 0.54 for intraobserver reliability. Cronbach's α of internal consistency was 0.86. IBD-DI scores varied from 0 to 100 with a mean of 35.3 (Q1=19.6; Q3=51.8). IBD-DI scores were highly correlated with Inflammatory Bowel Disease Questionnaire (−0.82; p<0.001) and SF-36 (–0.61; p<0.05) scores. Female gender (p<0.001), clinical disease activity (p<0.0001) and disease duration (p=0.02) were associated with higher IBD-DI scores.ConclusionsThe IBD-DI has been validated for use in clinical trials and epidemiological studies. The IBD-DI showed high internal consistency, interobserver reliability and construct validity, and a moderate intraobserver reliability. It comprises 14 questions and ranges from 0 to 100. The mean IBD-DI score was 35.3 and was associated with gender, clinical disease activity and disease duration. Further research is needed to confirm the structural validity and to assess the responsiveness of IBD-DI.Trial registration number2011-A00877-34

Background:Emerging evidence suggests that the intestinal microbiota contributes significantly to autoantibodies production in rheumatoid arthritis (RA). Yet, the detailed mechanisms underlying this process remain obscure. Notably, protein posttranslational modifications (PTMs), specifically acetylation, show remarkable conservation across species, ranging from bacteria to humans. Intriguingly, antibodies against post-translationally modified proteins (AMPA) are detectable before RA onset, with acetylated proteins known to induce a broad antibody response against various PTM proteins.Objectives:This study explores the hypothesis that acetylated proteins in the gut may serve as early antigens, triggering autoantibody production that eventually cross-reacts with joint tissue antigens, potentially accelerating RA onset and exacerbating its severity.Methods:We employed a collagen-induced arthritis (CIA) model in DBA1 mice, analyzing arthritis severity, incidence, AMPA production, and fecal/intestinal PTM status. Submaximally induced CIA (subCIA) mice were orally administered acetylated or native proteins (derived from E.coli or ovalbumin), followed by comprehensive phenotypic analysis in lymphoid organs and joints. Serum reactivity against joints and intestinal contents was assessed, alongside in vitro experiments focusing on T-cell differentiation and B-cell immunization. Additionally, we evaluated the direct effects of acetylated proteins on the intestinal epithelial barrier using Caco-2 cells.Results:Our findings revealed a time-dependent increase in fecal acetylation, acetylated-lysine area in the colon, and anti-acetyl-vimentin antibodies in CIA mice, notably preceding arthritis onset. Oral administration of acetylated proteins to subCIA mice significantly exacerbated arthritis severity compared to native protein administration (Figure 1). These effects were mirrored in immune response alterations, including increased CD138+B220low/-plasma cells and Rorγt+ T-cells in the spleen, IL-17A+CD4+ T-cells in the spleen and paw, alongside heightened serum reactivity to the CIA-mouse joints (Figure 2) and intestinal contents. We performed the co-culture of murine bone marrow-derived dendritic cells and isolated T-cells from the spleens - an increase of GATA3+ RORγt+ and FoxP3+-, RORγt+-subsets after acetylated ovalbumin (ace-OVA) stimulation was observed. To verify the induction of AMPA directly, we immunized B-cells in vitro with ace-OVA as described [1]. The supernatants collected from ace-OVA stimulated B-cells showed increased affinity to CIA mouse paw-lysate. For intestinal barrier integrity assessment, we cultured Caco-2 cells with ace-OVA. The concentration of zonulin in the supernatants of ace-OVA-treated cells was significantly higher, which indicated impairment of epithelial integrity. Overall, in vitro experiments corroborated our findings, underscoring the pivotal role of acetylated proteins in driving AMPA production and joint tissue affinity. Finally, using immunoprecipitation with ace-OVA-fed mice serum, we identified one of the target antigens of induced AMPA, which appeared to be vimentin. This finding was confirmed later by mass spectrometry.Conclusions:This study sheds light on the critical role of acetylated proteins in the intestines as initial antigens for autoantibody production in RA. These early-stage antibodies demonstrate cross-reactivity with joint tissue antigens, suggesting a novel pathway contributing to the disease’s severity. These insights open avenues for innovative therapeutic approaches targeting early autoantibody responses in RA.REFERENCES:[1] Michelchen S et al. J Immunol Methods 2021.Acknowledgements:NIL.Disclosure of Interests:Ippei Miyagawa: None declared, Ilia Gimaev: None declared, Wei Xiang: None declared, Kerstin Dürholz: None declared, Yuichi Maeda: None declared, Eva Schmid: None declared, Heike Danzer: None declared, Britta Eggers: None declared, Sanjukta Gubbi: None declared, Vugar Azizov: None declared, Fabian Schälter: None declared, Michael Frech: None declared, Katrin Marcus-Alic: None declared, Kerstin Sarter: None declared, Yoshiya Tanaka Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho, Mitsubishi-Tanabe, Eisai, Chugai, Taisho, Holger Bang: None declared, Georg Schett: None declared, Mario M. Zaiss: None declared.

Background:Chronic peripheral inflammation is well-documented for its ability to alter the activation of the central nervous system (CNS) in diseases such as rheumatoid arthritis (RA) [1]. Furthermore, the CNS is able to regulate inflammatory processes in the periphery [2]. However, the environmental factors facilitating CNS-mediated suppression of peripheral inflammation in RA remain less explored. The intestinal microbiota produces immunomodulatory metabolites, including short-chain fatty acids (SCFA) [3], and neuroactive substances like histamine, which exhibit local and systemic effects [4]. While histamine is commonly associated with allergic reactions, it also possesses immunoregulatory function [5].Objectives:Our study aimed to elucidate the impact of gut microbiota-derived histamine on peripheral inflammation.Methods:Mice with collagen-induced arthritis (CIA) were orally treated with histamine-producing and control E. coli from the peak of disease (POD). Additionally, mice received oral histamine or histamine receptor agonists (H1RA-H4RA). To delineate the mode of action, mice were treated orally, intraperitoneally, and intrathecally with an H3RA. Untargeted metabolomics analyzed serum and spinal cord extracts from H3RA-treated and untreated CIA mice. Bulk RNA sequencing and Cytek Spectral Flow cytometry examined intestinal sections, spinal cord, and paw-innervating Nervus plantaris. An ex vivo gut explant model assessed the effects of H3R agonist on the activation of the enteric nervous system. Microglia were depleted using a CSF1R blocker, and peripheral nerves in the inflamed paws were blocked by intra-plantar injection of Bupivacaine and QX-314. Differences in vascular leakage in inflamed areas were monitored through a contrast agent-based MRI approach.Results:Our findings reveal that low levels of dietary or gut microbial-derived histamine activate the enteric nervous system, enhance thiamine and inhibitory neurotransmitter concentrations locally in the spinal cord, and restore homeostatic microglia, consequently reducing vascular leakage into inflamed joints. Critical to this pro-resolving effect is selective H3R signaling in the intestine, as systemic and intrathecal applications failed to demonstrate similar outcomes. Microglia depletion or pharmacological silencing of local nerve fibers impaired orally delivered H3R agonist-induced pro-resolving effects. Furthermore, therapeutic nutritional application of the SCFA propionate identified a method to augment local intestinal histamine concentrations in mice and humans. Fecal material supernatant transfers from propionate-treated donor mice mirrored pro-resolving effects observed with direct H3R agonist treatments. Consequently, our study defines a novel gut-CNS-joint axis pathway wherein microbial-derived histamine initiates the resolution of peripheral inflammation in the synovium via the CNS.Conclusion:In conclusion, our study defines a novel gut-CNS-joint axis pathway wherein microbial-derived histamine initiates the resolution of peripheral inflammation in the synovium via the CNS.REFERENCES:[1] Süß P, Rothe T, Hoffmann A, Schlachetzki JCM, Winkler J. The Joint-Brain Axis: Insights From Rheumatoid Arthritis on the Crosstalk Between Chronic Peripheral Inflammation and the Brain. Front Immunol. 2020 Dec 10;11:612104.[2] Waldburger, JM., Firestein, G.S. Regulation of Peripheral Inflammation by the Central Nervous System. Curr Rheumatol Rep 12, 370–378 (2010).[3] Cummings JH, Macfarlane GT. The control and consequences of bacterial fermentation in the human colon. J Appl Bacteriol. 1991 Jun;70(6):443-59.[4] Hegstrand, L.R. and R.J. Hine, Variations of brain histamine levels in germ-free and nephrectomized rats. Neurochemical Research, 1986. 11(2): p. 185-191.[5] Barcik W, Pugin B, Brescó MS, Westermann P, et al. Bacterial secretion of histamine within the gut influences immune responses within the lung. Allergy. 2019 May;74(5):899-909.Acknowledgements:NIL.Disclosure of Interests:None declared.

In this work, we have carried out a comprehensive characterization of the vibrational spectroscopy of the non-planar molecule thianthrene. The combination of infrared, Raman and inelastic neutron scattering spectroscopies is highly complementary and allows all of the modes to be observed. Periodic density-functional theory calculations have provided unambiguous assignments of the spectra. The literature states that C–S stretch modes occur in the 600–800 cm −1 range. We find that while there are modes that involve sulfur motion in this region, this is a consequence of motion in the ortho -phenylene rings. The modes that are driven by the C–S stretches are found in the ~400–500 cm −1 range. The C–S–C bending modes occur in the 200–300 cm −1 range; these have not been previously characterized.