The genomic landscape of ANCA-associated vasculitis: Distinct transcriptional signatures, molecular endotypes and comparison with systemic lupus erythematosus

IntroductionAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) present with a complex phenotype and are associated with high mortality and multi-organ involvement. We sought to define the transcriptional landscape and molecular endotypes of AAVs and compare it to systemic lupus erythematosus (SLE).MethodsWe performed whole blood mRNA sequencing from 30 patients with AAV (granulomatosis with polyangiitis/GPA and microscopic polyangiitis/MPA) combined with functional enrichment and network analysis for aberrant pathways. Key genes and pathways were validated in an independent cohort of 18 AAV patients. Co-expression network and hierarchical clustering analysis, identified molecular endotypes. Multi-level transcriptional overlap analysis to SLE was based on our published data from 142 patients.ResultsWe report here that “Pan-vasculitis” signature contained 1,982 differentially expressed genes, enriched in leukocyte differentiation, cytokine signaling, type I and type II IFN signaling and aberrant B-T cell immunity. Active disease was characterized by signatures linked to cell cycle checkpoints and metabolism pathways, whereas ANCA-positive patients exhibited a humoral immunity transcriptional fingerprint. Differential expression analysis of GPA and MPA yielded an IFN-g pathway (in addition to a type I IFN) in the former and aberrant expression of genes related to autophagy and mRNA splicing in the latter. Unsupervised molecular taxonomy analysis revealed four endotypes with neutrophil degranulation, aberrant metabolism and B-cell responses as potential mechanistic drivers. Transcriptional perturbations and molecular heterogeneity were more pronounced in SLE. Molecular analysis and data-driven clustering of AAV uncovered distinct transcriptional pathways that could be exploited for targeted therapy.DiscussionWe conclude that transcriptomic analysis of AAV reveals distinct endotypes and molecular pathways that could be targeted for therapy. The AAV transcriptome is more homogenous and less fragmented compared to the SLE which may account for its superior rates of response to therapy

Muon Production via the ESSnuSB Project

International audienceESSnuSB plans to produce very intense neutrino beams using the protons from the ESS linac (5 MW, 2 GeV) and a 4-targets horn system. In the ESSnuSB proposed facility a copious number of muons will also be produced. These muons could be used by a future Neutrino Factory to study CP violation in the leptonic sector but also to study neutrino cross-sections. They could also be used to feed a future muon collider. The feasibility and the issues of extracting the intense muon beam produced together with neutrinos are discussed

Energy Deposition and Activation Studies of the ESSnuSB Horn Station

International audienceThe ESS'SB project foresees the production of a very intense neutrino beam to enable the discovery of leptonic CP violation. In addition to the neutrinos, a copious number of muons that could be used by a future Neutrino Factory and a muon collider will also be produced at the same time. This facility will use the world's most intense pulsed spallation neutron source, the European Spallation Source (ESS) in Lund. Its LINAC is expected to be operational by 2023, producing 2 GeV protons with a power of 5 MW. The primary proton beam line completing the linear accelerator will consist of one or several accumulator rings and a proton beam switchyard. The secondary beam line producing neutrinos and muons will consist of a four-horn target station, a decay tunnel and a beam dump. To detect the produced neutrinos a far megaton scale Water Cherenkov detector will be placed at a baseline of about 500 km in one of the existing active mines in Sweden. The estimation of the energy deposited and the activation within this secondary beam line are discussed in this paper

The effect of mastic mouthwash on halitosis and oral hygiene in orthodontic patients: a randomized clinical trial.

BACKGROUND/OBJECTIVES The aim of this trial was to investigate the effect of mastic mouthwash on halitosis using as a proxy the levels of the Volatile Sulfur Compounds (VSCs), and the effect on plaque and gingival indices in adolescents undergoing orthodontic treatment with fixed conventional labial appliances. SUBJECTS/METHODS The study was a double-blinded, placebo-controlled, parallel-group, randomized clinical trial. Thirty patients with fixed orthodontic appliances were randomly allocated at a 1:1 ratio, to either the mastic-mouthwash or the placebo-mouthwash group. Eligibility criteria included ages between 13 and 18, active orthodontic treatment with fixed appliances, good general health, and total initial VSCs levels above 150 ppb. The primary outcome was the objective hydrogen sulfide (H2S) level, measured with the Oral ChromaTM device. The secondary outcomes were (1.) the methyl-mercaptan (CH3SH) and (2.) dimethyl sulfide [(CH3)2S] levels, measured with the same device, (3.) the subjective perception of the own malodour via questionnaires, and (4.) the oral hygiene assessed with the use of the Modified Silness and Löe Plaque Index (PI-M) and the Silness and Löe Gingival Index (GI) at baseline (T0) and after 2 weeks (T1). Stratified randomization by gender was used, and allocation was concealed with opaque numbered sealed envelopes. RESULTS H2S level dropped from 221.00 ppb (T0) to 125.00 ppb (T1), and the difference between treatment groups was statistically significant in favour of the mastic group (coef: 72.34, 95% CI: 8.48, 136.27, P = 0.03). The levels of the other VSCs, the subjective measurements of oral malodour, and the oral hygiene indices did not differ between treatment arms. LIMITATIONS The objective organoleptic assessment by a calibrated examiner was not performed. CONCLUSIONS/IMPLICATIONS Mastic mouthwashes could be an alternative treatment for adolescent patients suffering from halitosis during orthodontic treatment with fixed appliances. REGISTRATION The trial was registered at ClinicalTrials.gov (identifier: NCT05647369)

Rituximab for eosinophilic granulomatosis with polyangiitis with severe vasculitic neuropathy: Case report and review of current clinical evidence

Objective: Rituximab is approved for the treatment of granulomatosis with polyangiitis and microscopic polyangiitis. Our objective was to review published clinical evidence on the efficacy of rituximab in the treatment of eosinophilic granulomatosis and polyangiitis (EGPA). Methods: We describe a case of refractory EGPA with severe vasculitic neuropathy, which responded impressively to B-cell-depleting therapy. A systematic search of the English literature was also performed to capture all available clinical evidence on the use of rituximab in EGPA. Results: We identified a total of 73 EGPA patients who have been treated with rituximab, all data coming from case series or isolated case reports. The majority of patients (85.1%) were treated for refractory or relapsing disease; a mean (SD) of 2.1 (0.9) different immunosuppressive agents were used prior to rituximab administration. Efficacy of RTX therapy was significant in the majority of cases and in a wide variety of disease manifestations; however, a lack of standardized assessment of disease activity before and after treatment was observed in many reports. Overall, 54.0% of patients were treated with a single cycle of rituximab and only 10.8% experienced relapses of the disease. Few significant side effects were observed during a highly variable period of follow-up (3 months to 5 years), mainly severe infections and allergic reactions. Conclusions: RTX seems to be effective in cases of severe EGPA refractory to standard of care immunosuppressive treatment, although support comes from case reports and non-controlled studies. (C) 2015 Elsevier Inc. All rights reserved