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Background: Little is known about the role of rehabilitation medicine in obesity. Objective: to examine the benefits of a multidisciplinary rehabilitation program on the quality of life in patients with severe obesity. Methodology: We included 124 patients with obesity (mean age: 57 years; BMI ≥30), in an 8-week in-hospital multidisciplinary supervised program combining physiotherapy, nutrition and psychological support. Clinical, bio-psychological and functional parameters, as well as an obesity-specific quality-of-life score, were acquired at 0 and 8 weeks. Results: The quality-of-life score improved significantly at 8 weeks, from 60.8 to 68.8 (p < 0.0001), and was positively correlated with cardio-respiratory function (r = 0.47; p < 0.0001). Conclusions: Our results highlight the important role of multidisciplinary rehabilitation medicine and its integrated approach to improve the quality of life of people with obesity.

Abstract Objective The radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS). Increasing evidence suggests that the central vein sign (CVS) enhances lesion specificity, allowing for greater MS diagnostic accuracy. This study evaluated the diagnostic performance of the CVS in RIS. Methods Patients were prospectively recruited in a single tertiary center for MS care. Participants with RIS were included and compared to a control group of sex and age‐matched subjects. All participants underwent 3 Tesla magnetic resonance imaging, including postcontrast susceptibility‐based sequences, and the presence of CVS was analyzed. Sensitivity and specificity were assessed for different CVS lesion criteria, defined by proportions of lesions positive for CVS (CVS+) or by the absolute number of CVS+ lesions. Results 180 participants (45 RIS, 45 MS, 90 non‐MS) were included, representing 5285 white matter lesions. Among them, 4608 were eligible for the CVS assessment (970 in RIS, 1378 in MS, and 2260 in non‐MS). According to independent ROC comparisons, the proportion of CVS+ lesions performed similarly in diagnosing RIS from non‐MS than MS from non‐MS (p = 0.837). When a 6‐lesion CVS+ threshold was applied, RIS lesions could be diagnosed with an accuracy of 87%. MS could be diagnosed with a sensitivity of 98% and a specificity of 83%. Adding OCBs or Kappa index to CVS biomarker increased the specificity to 100% for RIS diagnosis. Interpretation This study shows evidence that CVS is an effective imaging biomarker in differentiating RIS from non‐MS, with similar performances to those in MS.

Objective Monofluoroacetate (MFA) is a potent toxin that blocks ATP production via the Krebs cycle and causes acute toxicity in ruminants consuming MFA-containing plants. The rumen bacterium, Cloacibacillus porcorum strain MFA1 belongs to the phylum Synergistota and can produce fluoride and acetate from MFA as the end-products of dehalorespiration. The aim of this study was to identify the genomic basis for the metabolism of MFA by this bacterium. Methods A draft genome sequence for C. porcorum strain MFA1 was assembled and quantitative transcriptomic analysis was performed thus highlighting a candidate operon encoding four proteins that are responsible for the carbon-fluorine bond cleavage. Comparative genome analysis of this operon was undertaken with three other species of closely related Synergistota bacteria. Results Two of the genes in this operon are related to the substrate-binding components of the glycine reductase protein B (GrdB) complex. Glycine shares a similar structure to MFA suggesting a role for these proteins in binding MFA. The remaining two genes in the operon, an antiporter family protein and an oxidoreductase belonging to the radical S-adenosyl methionine superfamily, are hypothesised to transport and activate the GrdB-like protein respectively. Similar operons were identified in a small number of other Synergistota bacteria including type strains of Cloacibacillus porcorum, C. evryensis, and Pyramidobacter piscolens, suggesting lateral transfer of the operon as these genera belong to separate families. We confirmed that all three species can degrade MFA, however, substrate degradation in P. piscolens was notably reduced compared to Cloacibacillus isolates possibly reflecting the loss of the oxidoreductase and antiporter in the P. piscolens operon. Conclusion Identification of this unusual anaerobic fluoroacetate metabolism extends the known substrates for dehalorespiration and indicates the potential for substrate plasticity in amino acid-reducing enzymes to include xenobiotics.

Abstract Next-generation sequencing workflows, using either metabarcoding or metagenomic approaches, have massively contributed to expanding knowledge of the human gut microbiota, but methodological bias compromises reproducibility across studies. Where these biases have been quantified within several comparative analyses on their own, none have measured inter-laboratory reproducibility using similar DNA material. Here, we designed a multicenter study involving seven participating laboratories dedicated to partial- (P1 to P5), full-length (P6) metabarcoding, or metagenomic profiling (MGP) using DNA from a mock microbial community or extracted from 10 fecal samples collected at two time points from five donors. Fecal material was collected, and the DNA was extracted according to the IHMS protocols. The mock and isolated DNA were then provided to the participating laboratories for sequencing. Following sequencing analysis according to the laboratories’ routine pipelines, relative taxonomic-count tables defined at the genus level were provided and analyzed. Large variations in alpha-diversity between laboratories, uncorrelated with sequencing depth, were detected among the profiles. Half of the genera identified by P1 were unique to this partner and two-thirds of the genera identified by MGP were not detected by P3. Analysis of beta-diversity revealed lower inter-individual variance than inter-laboratory variances. The taxonomic profiles of P5 and P6 were more similar to those of MGP than those obtained by P1, P2, P3, and P4. Reanalysis of the raw sequences obtained by partial-length metabarcoding profiling, using a single bioinformatic pipeline, harmonized the description of the bacterial profiles, which were more similar to each other, except for P3, and closer to the profiles obtained by MGP. This study highlights the major impact of the bioinformatics pipeline, and primarily the database used for taxonomic annotation. Laboratories need to benchmark and optimize their bioinformatic pipelines using standards to monitor their effectiveness in accurately detecting taxa present in gut microbiota.

Background: Although visual field (VF) defects are common in compressive pituitary adenoma (CPA), their pathophysiology has not been fully elucidated. The mechanical theory (i.e., direct compression of the optic chiasm by the CPA) and the vascular theory (i.e., compression of the vessels supplying the visual path by the CPA) or their association could explain the visual impairment. The aim of this study was to determine whether the vascular density (VD) improved after surgical decompression of the optic chiasm in CPA patients and whether OCT-A could help to identify predictive factors for postoperative visual recovery. Methods: A prospective controlled study was conducted in patients who underwent transsphenoidal pituitary adenoma surgery. Patients were divided into two groups: with CPA and without CPA (NCPA). All patients underwent a neuro-ophthalmological examination, VF testing, macular and optic disc structural OCT [retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thicknesses] and OCT-A before and then 1 and 6 months after surgery. Results: Twenty-four eyes and fourteen eyes were included, respectively, in the CPA and NCPA groups. None of the VD parameters assessed by OCT-A were significantly improved after surgery in the CPA group. In the CPA group, the mean macular superficial VD was significantly decreased at 6 months. The multivariate analysis failed to identify any preoperative parameters predictive of postoperative VF improvement. Conclusions: Our preliminary findings suggest that the visual impairment observed in CPA patients could not be explained by the vascular theory. None of the preoperative OCT-A parameters allowed a postoperative VF recovery assessment. Trial registration number NCT04074642, ID-RCB 2019-A01186-51 date of registration 30 July 2019.

Abstract Introduction Natalizumab, a therapy for relapsing–remitting multiple sclerosis (RRMS), is associated with a risk of progressive multifocal leukoencephalopathy (PML). Over the last several years, practitioners have used off-label extended interval dosing (EID) of natalizumab to reduce PML risk, despite the absence of a large-scale efficacy evaluation. Methods We conducted a retrospective, multicenter cohort study among adults with RRMS receiving stable standard interval dosing (SID), defined as a ≥ 12-month consecutive period of ≥ 11 natalizumab infusions/year in France. We compared the 12-month risk difference of remaining relapse-free (primary endpoint) between patients who switched to EID (≤ 9 natalizumab infusions) and those who remained on SID, with a noninferiority margin of − 11%. We used propensity score methods such as inverse probability treatment weighting (IPTW) and 1:1 propensity score matching (PSM). Secondary endpoints were annualized relapse rate, disease progression, and safety. Results Baseline characteristics were similar between patients receiving EID (n = 147) and SID (n = 156). The proportion of relapse-free patients 12 months postbaseline was 142/147 in the EID (96.6%) and 144/156 in the SID group (92.3%); risk difference (95% CI) 4.3% (− 1.3 to 9.8%); p

T-cell mediated immunity relies on a vast array of antigen specific T cell receptors (TR). Characterizing the structure of TR loci is essential to study the diversity and composition of T cell responses in vertebrate species. The lack of good-quality genome assemblies, and the difficulty to perform a reliably mapping of multiple highly similar TR sequences, have hindered the study of these loci in non-model organisms. High-quality genome assemblies are now available for the two main genera of Salmonids, Salmo and Oncorhynchus. We present here a full description and annotation of the TRB loci located on chromosomes 19 and 25 of rainbow trout (Oncorhynchus mykiss). To get insight about variations of the structure and composition of TRB locus across salmonids, we compared rainbow trout TRB loci with other salmonid species and confirmed that the basic structure of salmonid TRB locus is a double set of two TRBV-D-J-C loci in opposite orientation on two different chromosomes. Our data shed light on the evolution of TRB loci in Salmonids after their whole genome duplication (WGD). We established a coherent nomenclature of salmonid TRB loci based on comprehensive annotation. Our work provides a fundamental basis for monitoring salmonid T cell responses by TRB repertoire sequencing.

Background: Choroid plexus (ChP) enlargement is an emerging radiological biomarker in multiple sclerosis (MS). Objectives: This study aims to assess ChP volume in a large cohort of patients with radiologically isolated syndrome (RIS) versus healthy controls (HC) and explore its relationship with other brain volumes, disease activity, and biological markers. Methods: RIS individuals were included retrospectively and compared with HC. ChPs were automatically segmented using an in-house automated algorithm and manually corrected. Results: A total of 124 patients fulfilled the 2023 RIS criteria, and 55 HCs were included. We confirmed that ChPs are enlarged in RIS versus HC (mean (±SD) normalized ChP volume: 17.24 (±4.95) and 11.61 (±3.58), respectively, p < 0.001). Larger ChPs were associated with more periventricular lesions (ρ = 0.26; r 2 = 0.27; p = 0.005 for the correlation with lesion volume, and ρ = 0.2; r 2 = 0.21; p = 0.002 for the correlation with lesion number) and lower thalamic volume (ρ = −0.38; r 2 = 0.44; p < 0.001), but not with lesions in other brain regions. Conversely, ChP volume did not correlate with biological markers. No significant difference in ChP volume was observed between subjects who presented or did not have a clinical event or between those with or without imaging disease activity. Conclusions: This study provides evidence that ChP volume is higher in RIS and is associated with measures reflecting periventricular pathology but does not correlate with biological, radiological, or clinical markers of disease activity. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that some lactobacilli strains, particularly Lactiplantibacillus plantarum, have a beneficial effect on obesity-associated syndromes. Several studies have investigated probiotic challenges in models of high-fat diet (HFD)-induced obesity, specifically with respect to its impact on hepatic and/or adipocyte metabolism, gut inflammation and epithelial barrier integrity, and microbiota composition. However, only a few studies have combined these aspects to generate a global understanding of how probiotics exert their protective effects. Here, we used the probiotic strain L. plantarum CNCM I−4459 and explored its impact on a mouse model of HFD-induced obesity. Briefly, mice were administered 1 × 109 CFUs/day and fed HFD for 12 weeks. Treatment with this strain improved insulin sensitivity by lowering serum levels of fasting glucose and fructosamine. Administration of the probiotic also affected the transport and metabolism of glucose, resulting in the downregulation of the hepatic Glut-4 and G6pase genes. Additionally, L. plantarum CNCM I−4459 promoted a decreased concentration of LDL-c and modulated hepatic lipid metabolism (downregulation of Fasn, Plin, and Cpt1α genes). Probiotic treatment also restored HFD-disrupted intestinal microbial composition by increasing microbial diversity and lowering the ratio of Firmicutes to Bacteroidetes. In conclusion, this probiotic strain represents a potential approach for at least partial restoration of the glucose sensitivity and lipid disruption that is associated with obesity.

BackgroundDespite improvements in radiation techniques, pelvic radiotherapy is responsible for acute and delayed bladder adverse events, defined as radiation cystitis. The initial symptoms of bladder injury secondary to pelvic irradiation are likely to occur during treatment or within 3 months of radiotherapy in approximately 50% of irradiated patients, and have a significant impact on their quality of life. The pathophysiology of radiation cystitis is not well understood, particularly because of the risk of complications associated with access to bladder tissue after irradiation, which limits our ability to study this process and develop treatments. ObjectiveIt is an original study combining digital data collection to monitor patients’ symptoms and biological markers during irradiation. The main objective of our study is to evaluate the correlation of biological biomarkers with the intensity of acute radiation cystitis and the quality of life of patients, assessed with the digital telemonitoring platform Cureety. MethodsPatients with intermediate-risk localized prostate cancer who are eligible for localized radiotherapy will be included. Inflammatory biomarkers will be analyzed in urine and blood samples before the start of radiotherapy and at weeks 4, 12, and 48 of irradiation, through quantitative methods such as a multiplex Luminex assay, flow cytometry, and enzyme-linked immunosorbent assay. We will also characterize the patients’ gut and urine microbiota composition using 16S ribosomal RNA sequencing technology. Between sample collection visits, patients will complete various questionnaires related to radiation cystitis symptoms (using the International Prostate Symptom Score), adverse events, and quality of life (using the Functional Assessment of Cancer Therapy–Prostate questionnaire), using the Cureety digital remote monitoring platform. Upon receipt of the questionnaires, an algorithm will process the information and classify patients in accordance with the severity of symptoms and adverse events reported on the basis of Common Terminology Criteria for Adverse Events and International Prostate Symptom Score standards. This will allow us to correlate levels of urinary, blood, and fecal biomarkers with the severity of acute radiation cystitis symptoms and patient-reported quality of life. ResultsThe study started in March 2022. We estimate a recruitment period of approximately 18 months, and the final results are expected in 2024. ConclusionsThis prospective study is the first to explore the overexpression of inflammatory proteins in fluid biopsies from patients with symptoms of acute radiation cystitis. In addition, the 1-year follow-up after treatment will allow us to predict which patients are at risk of late radiation cystitis and to refer them for radioprotective treatment. The results of this study will allow us to develop strategies to limit radiation damage to the bladder and improve the quality of life of patients. Trial RegistrationClinicalTrials.gov NCT05246774; https://clinicaltrials.gov/ct2/show/NCT05246774?term=NCT05246774 International Registered Report Identifier (IRRID)DERR1-10.2196/38362

Abstract Interactions between the prokaryotic microbiome and eukaryotic parasites in the vertebrate gut may affect overall host health and disease. While intertropical areas exhibit a high rate of parasites carriers, such interactions are understudied in these populations. Our objectives were to (1) describe the gut microbiome of individuals living in Madagascar, (2) identify potential associations between bacterial taxa and parasites colonizing the digestive tract and (3) highlight main determinants of the gut microbiota composition in this developing country. Metadata (socioeconomic, diet, clinical) and fecal samples were collected from 219 volunteers from North-West Madagascar (Mahajanga). Fecal microbiome was assessed through 16S rRNA gene sequencing and metabolomics, and related to dietary habits and parasites carriage. We highlight important Malagasy gut microbiome peculiarities. Out of three detected enterotypes, only one is similar to that observed in Westernized countries (Ruminococcus-driven). Functions associated with the two others (Clostridium sensu stricto-driven and Escherichia/Shigella-driven) are mostly directed toward amino acids biosynthesis and degradation, respectively. Diet and protozoan carriage were the main drivers of microbiota composition. High protozoan carriage was associated with higher diversity, richness and microbial functionalities. The gut microbiome of Malagasy strongly differs from that of Westernized countries. Asymptomatic protozoan carriage and dietary habits are the external factors with the deepest impact on gut microbiome. Further studies are needed to understand whether gut microbial richness constitute a predilection niche for protozoans colonization, due to their gazing features, or whether the parasites themselves induce a higher bacterial richness.

Experimental and clinical evidence has demonstrated the potential of probiotic strains in the prevention or treatment of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). However, there is little data on what the methodology leading to the identification of such strains should be. In this work, we propose a new flowchart to identify strains with probiotic potential for the management of IBS and IBD, which we tested on a collection of 39 lactic acid bacteria and Bifidobacteria strains. This flowchart included in vitro tests of immunomodulatory properties on intestinal and peripheral blood mononuclear cells (PBMCs), assessment of the barrier-strengthening effect by measuring transepithelial electric resistance (TEER) and quantification of short-chain fatty acids (SCFAs) and aryl hydrocarbon receptor (AhR) agonists produced by the strains. The in vitro results were then combined in a principal component analysis (PCA) to identify strains associated with an anti-inflammatory profile. To validate our flowchart, we tested the two most promising strains identified in the PCA in mouse models of post-infectious IBS or chemically induced colitis to mimic IBD. Our results show that this screening strategy allows the identification of strains with potential beneficial effects on colonic inflammation and colonic hypersensitivity.

Background: Although visual field (VF) defects are common in compressive pituitary adenoma (CPA), their pathophysiology has not been fully elucidated. The mechanical theory (i.e., direct compression of the optic chiasm by the CPA) and the vascular theory (i.e., compression of the vessels supplying the visual path by the CPA) or their association could explain the visual impairment. The aim of this study was to determine whether the vascular density (VD) improved after surgical decompression of the optic chiasm in CPA patients and whether OCT-A could help to identify predictive factors for postoperative visual recovery. Methods: A prospective controlled study was conducted in patients who underwent transsphenoidal pituitary adenoma surgery. Patients were divided into two groups: with CPA and without CPA (NCPA). All patients underwent a neuro-ophthalmological examination, VF testing, macular and optic disc structural OCT [retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thicknesses] and OCT-A before and then 1 and 6 months after surgery. Results: Twenty-four eyes and fourteen eyes were included, respectively, in the CPA and NCPA groups. None of the VD parameters assessed by OCT-A were significantly improved after surgery in the CPA group. In the CPA group, the mean macular superficial VD was significantly decreased at 6 months. The multivariate analysis failed to identify any preoperative parameters predictive of postoperative VF improvement. Conclusions: Our preliminary findings suggest that the visual impairment observed in CPA patients could not be explained by the vascular theory. None of the preoperative OCT-A parameters allowed a postoperative VF recovery assessment. Trial registration number NCT04074642, ID-RCB 2019-A01186-51 date of registration 30 July 2019. [ABSTRACT FROM AUTHOR]

Background: Little is known about the role of rehabilitation medicine in obesity. Objective: to examine the benefits of a multidisciplinary rehabilitation program on the quality of life in patients with severe obesity. Methodology: We included 124 patients with obesity (mean age: 57 years; BMI ≥30), in an 8-week in-hospital multidisciplinary supervised program combining physiotherapy, nutrition and psychological support. Clinical, bio-psychological and functional parameters, as well as an obesity-specific quality-of-life score, were acquired at 0 and 8 weeks. Results: The quality-of-life score improved significantly at 8 weeks, from 60.8 to 68.8 (p < 0.0001), and was positively correlated with cardio-respiratory function (r = 0.47; p < 0.0001). Conclusions: Our results highlight the important role of multidisciplinary rehabilitation medicine and its integrated approach to improve the quality of life of people with obesity. [ABSTRACT FROM AUTHOR]

Intestinal inflammation shifts microbiota composition and metabolism. How the host monitors and responds to such changes remains unclear. Here, we describe a protective mechanism by which mucosal-associated invariant T (MAIT) cells detect microbiota metabolites produced upon intestinal inflammation and promote tissue repair. At steady state, MAIT ligands derived from the riboflavin biosynthesis pathway were produced by aerotolerant bacteria residing in the colonic mucosa. Experimental colitis triggered luminal expansion of riboflavin-producing bacteria, leading to increased production of MAIT ligands. Modulation of intestinal oxygen levels suggested a role for oxygen in inducing MAIT ligand production. MAIT ligands produced in the colon rapidly crossed the intestinal barrier and activated MAIT cells, which expressed tissue-repair genes and produced barrier-promoting mediators during colitis. Mice lacking MAIT cells were more susceptible to colitis and colitis-driven colorectal cancer. Thus, MAIT cells are sensitive to a bacterial metabolic pathway indicative of intestinal inflammation. Editor's summary: Changes in the gut microbiota have been linked to intestinal inflammation, but how these shifts are sensed by the host is not completely understood. Using an experimental colitis model in mice, El Morr et al. defined a role for mucosal-associated invariant T (MAIT) cells in sensing increases in MAIT ligands associated with the expansion of riboflavin-producing aerotolerant bacteria in the gut lumen. MAIT cells are then activated upon sensing these ligands and produce anti-inflammatory molecules and mediators of tissue repair. In the absence of MAIT cells, mice are more susceptible to colitis pathology and progression to colorectal cancer. —Christiana Fogg [ABSTRACT FROM AUTHOR]

IntroductionMany patients are referred to multiple sclerosis (MS) tertiary centers to manage brain white matter hyperintensities (WMH). Multiple diagnoses can match in such situations, and we lack proper tools to diagnose complex cases.ObjectiveThis study aimed to prospectively analyze and correlate with the final diagnosis, cerebrospinal fluid (CSF) interleukin (IL)-1β, soluble IL-2 receptor (CD25), IL-6, IL-10, and kappa free light chains (KFLC) concentrations in patients presenting with brain WMH.MethodsAll patients over 18 years addressed to our MS tertiary center for the diagnostic workup of brain WMH were included from June 1, 2020, to June 1, 2021. Patients were separated into three groups—MS and related disorder (MSARD), other inflammatory neurological disorder (OIND), and non-inflammatory neurological disorder (NIND) groups—according to clinical presentation, MRI characteristics, and biological workup.ResultsA total of 176 patients (129 women, mean age 45.8 ± 14.7 years) were included. The diagnosis was MSARD (n = 88), OIND (n = 35), and NIND (n = 53). Median CSF KFLC index and KFLC intrathecal fraction (IF) were higher in MSARD than in the OIND and NIND groups; p < 0.001 for all comparisons. CSF CD25 and IL-6 concentrations were higher in the OIND group than in both the MSARD and NIND groups; p < 0.001 for all comparisons. KFLC index could rule in MSARD when compared to NIND (sensitivity, 0.76; specificity, 0.91) or OIND (sensitivity, 0.73; specificity, 0.76). These results were similar to those with oligoclonal bands (sensitivity, 0.59; specificity, 0.98 compared to NIND; sensitivity, 0.59; specificity, 0.88 compared to OIND). In contrast, elevated CSF CD25 and IL-6 could rule out MSARD when compared to OIND (sensitivity, 0.58 and 0.88; specificity, 0.95 and 0.74, respectively).DiscussionOur results show that, as OCBs, KFLC biomarkers are helpful tools to rule in MSARD, whereas elevated CSF CD25 and IL-6 rule out MSARD. Interestingly, CSF IL-6 concentration could help identify neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody-associated disease, and central nervous system (CNS) vasculitis. These results need to be confirmed within more extensive and multicentric studies. Still, they sustain that KFLC, CSF CD25, and CSF IL-6 could be reliable biomarkers in brain WMH diagnostic workup for differentiating MSARD from other brain inflammatory MS mimickers.

Abstract Background Chronic immune-mediated diseases are rapidly expanding and notoriously difficult to cure. Altered relatively stable intestinal microbiota configurations are associated with several of these diseases, and with a possible pre-disease condition (more susceptible to disease development) of the host-microbiota ecosystem. These observations are reminiscent of the behavior of an ecosystem with alternative stable states (different stable configurations that can exist under identical external conditions), and we recently postulated that health, pre-disease and disease represent such alternative states. Here, our aim was to examine if alternative stable states indeed exist in the intestinal ecosystem. Results Rats were exposed to varying concentrations of DSS in order to create a wide range of mildly inflammatory conditions, in a context of diet-induced low microbiota diversity. The consequences for the intestinal microbiota were traced by 16S rRNA gene profiling over time, and inflammation of the distal colon was evaluated at sacrifice, 45 days after the last DSS treatment. The results provide the first formal experimental proof for the existence of alternative stable states in the rat intestinal ecosystem, taking both microbiota and host inflammatory status into consideration. The alternative states are host-microbiota ecosystem states rather than independent and dissociated microbiota and host states, and inflammation can prompt stable state-transition. Based on these results, we propose a conceptual model providing new insights in the interplay between host inflammatory status and microbiota status. These new insights call for innovative therapeutic strategies to cure (pre-)disease. Conclusions We provide proof of concept showing the existence of alternative stable states in the rat intestinal ecosystem. We further propose a model which, if validated in humans, will support innovative diagnosis, therapeutic strategy, and monitoring in the treatment of chronic inflammatory conditions. This model provides a strong rationale for the application of combinatorial therapeutic strategies, targeting host and microbiota rather than only one of the two in chronic immune-mediated diseases. Video Abstract

In jawed vertebrates, two major T cell populations have been characterized. They are defined as α/β or γ/δ T cells, based on the expressed T cell receptor. Salmonids (family Salmonidae) include two key teleost species for aquaculture, rainbow trout (Oncorhynchus mykiss) and Atlantic salmon (Salmo salar) which constitute important models for fish immunology and important targets for vaccine development. The growing interest to decipher the dynamics of adaptive immune responses against pathogens or vaccines has resulted in recent efforts to sequence the immunoglobulin (IG) or antibodies and T cell receptor (TR) repertoire in these species. In this context, establishing a comprehensive and coherent locus annotation is the fundamental basis for the analysis of high-throughput repertoire sequencing data. We therefore decided to revisit the description and annotation of TRA/TRD locus in Atlantic salmon and two strains of rainbow trout (Swanson and Arlee) using the now available high-quality genome assemblies. Phylogenetic analysis of functional TRA/TRD V genes from these three genomes led to the definition of 25 subgroups shared by both species, some with particular feature. A total of 128 TRAJ genes were identified in Salmo, the majority with a close counterpart in Oncorhynchus. Analysis of expressed TRA repertoire indicates that most TRAV gene subgroups are expressed at mucosal and systemic level. The present work on TRA/TRD locus annotation along with the analysis of TRA repertoire sequencing data show the feasibility and advantages of a common salmonid TRA/TRD nomenclature that allows an accurate annotation and analysis of high-throughput sequencing results, across salmonid T cell subsets.

Objective: The radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS). Increasing evidence suggests that the central vein sign (CVS) enhances lesion specificity, allowing for greater MS diagnostic accuracy. This study evaluated the diagnostic performance of the CVS in RIS. Methods: Patients were prospectively recruited in a single tertiary center for MS care. Participants with RIS were included and compared to a control group of sex and age‐matched subjects. All participants underwent 3 Tesla magnetic resonance imaging, including postcontrast susceptibility‐based sequences, and the presence of CVS was analyzed. Sensitivity and specificity were assessed for different CVS lesion criteria, defined by proportions of lesions positive for CVS (CVS+) or by the absolute number of CVS+ lesions. Results: 180 participants (45 RIS, 45 MS, 90 non‐MS) were included, representing 5285 white matter lesions. Among them, 4608 were eligible for the CVS assessment (970 in RIS, 1378 in MS, and 2260 in non‐MS). According to independent ROC comparisons, the proportion of CVS+ lesions performed similarly in diagnosing RIS from non‐MS than MS from non‐MS (p = 0.837). When a 6‐lesion CVS+ threshold was applied, RIS lesions could be diagnosed with an accuracy of 87%. MS could be diagnosed with a sensitivity of 98% and a specificity of 83%. Adding OCBs or Kappa index to CVS biomarker increased the specificity to 100% for RIS diagnosis. Interpretation: This study shows evidence that CVS is an effective imaging biomarker in differentiating RIS from non‐MS, with similar performances to those in MS. [ABSTRACT FROM AUTHOR]