IntroductionHuman albumin is used in the treatment of complications of cirrhosis. However, the use of long-term human albumin administration is costly and resource demanding for both patients and ...healthcare systems. A precision medicine approach with biomarkers to predict human albumin treatment response, so-called predictive biomarkers, could make this a viable treatment option in patients with cirrhosis and ascites.Methods and analysisALB-TRIAL is a multinational, double-blind, placebo-controlled randomised controlled trial. We aim to validate a predictive biomarker, consisting of a panel of circulating metabolites, to predict the treatment response to human albumin in patients with cirrhosis and ascites. All enrolled patients are stratified into a high-expected or low-expected effect stratum of human albumin based on the biomarker outcome. After stratification, patients in each group are randomised into either active treatment (20% human albumin) or corresponding placebo (0.9% NaCl) every 10th day for 6 months. The primary outcome is the cumulative number of liver-related events (composite of decompensation episodes, transjugular intrahepatic shunt insertion, liver transplantation and death). Key secondary outcomes include time-to-event analysis of primary outcome components, an analysis of the total healthcare burden and a health economic analysis.Ethics and disseminationThe trial obtained ethical and regulatory approval in Denmark, Germany, the Netherlands, Belgium, Hungary and Spain through the Clinical Trials Information System (CTIS) from 13 February 2023, while UK approvals from the Health Regulatory Authority, Medicines and Healthcare products Regulatory Agency and Research Ethics Committee are pending. Findings will be published in peer-reviewed journals, presented at conferences, communicated to relevant stakeholders and in the public registry of CTIS, following trial completion.Trial registration numberNCT05056220 EU CT: 2022-501006-34-01
Antibiotics (ABX) compromise the efficacy of programmed cell death protein 1 (PD-1) blockade in cancer patients, but the mechanisms underlying their immunosuppressive effects remain unknown. By ...inducing the down-regulation of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the ileum, post-ABX gut recolonization by Enterocloster species drove the emigration of enterotropic α4β7 + CD4 + regulatory T 17 cells into the tumor. These deleterious ABX effects were mimicked by oral gavage of Enterocloster species, by genetic deficiency, or by antibody-mediated neutralization of MAdCAM-1 and its receptor, α4β7 integrin. By contrast, fecal microbiota transplantation or interleukin-17A neutralization prevented ABX-induced immunosuppression. In independent lung, kidney, and bladder cancer patient cohorts, low serum levels of soluble MAdCAM-1 had a negative prognostic impact. Thus, the MAdCAM-1–α4β7 axis constitutes an actionable gut immune checkpoint in cancer immunosurveillance.
Recent attention has highlighted the importance of oral microbiota in human health and disease, e.g., in Parkinson’s disease, notably using shotgun metagenomics. One key aspect for efficient shotgun ...metagenomic analysis relies on optimal microbial sampling and DNA extraction, generally implementing commercial solutions developed to improve sample collection and preservation, and provide high DNA quality and quantity for downstream analysis. As metagenomic studies are today performed on a large number of samples, the next evolution to increase study throughput is with DNA extraction automation. In this study, we proposed a semi-automated DNA extraction protocol for human salivary samples collected with a commercial kit, and compared the outcomes with the DNA extraction recommended by the manufacturer. While similar DNA yields were observed between the protocols, our semi-automated DNA protocol generated significantly higher DNA fragment sizes. Moreover, we showed that the oral microbiome composition was equivalent between DNA extraction methods, even at the species level. This study demonstrates that our semi-automated protocol is suitable for shotgun metagenomic analysis, while allowing for improved sample treatment logistics with reduced technical variability and without compromising the structure of the oral microbiome.
Enterococcus cecorum is an emerging pathogen responsible for osteomyelitis, spondylitis, and femoral head necrosis causing animal suffering and mortality and requiring antimicrobial use in poultry. ...Paradoxically, E. cecorum is a common inhabitant of the intestinal microbiota of adult chickens. Despite evidence suggesting the existence of clones with pathogenic potential, the genetic and phenotypic relatedness of disease-associated isolates remains little investigated. Here, we sequenced and analyzed the genomes and characterized the phenotypes of more than 100 isolates, the majority of which were collected over the last 10 years from 16 French broiler farms. Comparative genomics, genome-wide association studies, and the measured susceptibility to serum, biofilm-forming capacity, and adhesion to chicken type II collagen were used to identify features associated with clinical isolates. We found that none of the tested phenotypes could discriminate the origin of the isolates or the phylogenetic group. Instead, we found that most clinical isolates are grouped phylogenetically, and our analyses selected six genes that discriminate 94% of isolates associated with disease from those that are not. Analysis of the resistome and the mobilome revealed that multidrug-resistant clones of
cluster into a few clades and that integrative conjugative elements and genomic islands are the main carriers of antimicrobial resistance. This comprehensive genomic analysis shows that disease-associated clones of
belong mainly to one phylogenetic clade.
Enterococcus cecorum is an important pathogen of poultry worldwide. It causes a number of locomotor disorders and septicemia, particularly in fast-growing broilers. Animal suffering, antimicrobial use, and associated economic losses require a better understanding of disease-associated
isolates. To address this need, we performed whole-genome sequencing and analysis of a large collection of isolates responsible for outbreaks in France. By providing the first data set on the genetic diversity and resistome of
strains circulating in France, we pinpoint an epidemic lineage that is probably also circulating elsewhere that should be targeted preferentially by preventive strategies in order to reduce the burden of
-related diseases.
La frontière entre ce que la modernité distinguera sous les dénominations d’utopie pratique et d’utopie théorique n’étant pas étanche dans La République de Platon, il peut être tentant de comparer ce ...dialogue aux Lois afin de voir quelles propositions relèvent du pratique ou du théorique, mais c’est mal poser la question : en effet, le dialogue étant premièrement théorique d’un point de vue politique, il est plus intéressant de le prendre comme tel et de rechercher ensuite comment une cité existante peut prendre en compte cet idéal régulateur que la philosophie lui propose. Il faut aussi tenir compte du fait que la dimension pratique du dialogue s’exerce surtout à l’égard de l’âme humaine et qu’il est tout aussi intéressant de déterminer dans quelle mesure le propos de La République recoupe l’enseignement éthique dispensé à l’Académie, dont le Phédon offre un aperçu saisissant : si l’on peut parler d’utopie avant l’heure concernant La République, c’est moins au nom de cette interpénétration du théorique et du pratique, qui est également le fait de bon nombres d’utopies modernes, qu’au nom de cette interpénétration du politique et de l’éthique que la modernité a souvent tendance à oublier ; Platon n’invite nullement à faire violence à la cité pour la rendre parfaite malgré elle, comme ont pu le faire les totalitarismes modernes, mais plutôt à se faire violence à soi-même pour devenir sage et juste : ce précurseur de l’utopie qu’était Platon n’avait pas pour but ultime le meilleur des mondes mais d’abord le meilleur des hommes.
La démonstration de l’immortalité de l’âme dans les dialogues de Platon, notamment dans le Phédon, a été abondamment commentée au point d’avoir longtemps servi de référence majeure sur cette ...question. Cette thèse se propose donc de « déconstruire » le propos platonicien relatif à la survie de l’âme afin de découvrir si cette conception n’est pas sous-tendue par des intuitions spontanées que peut avoir tout homme lorsqu’il prend conscience de son être propre et qui, précisément, l’amènent à se penser doté d’une âme survivant à son corps ; que nous dit Platon, explicitement ou non, sur ces intuitions ? De quelles vérités humaines les mythes eschatologiques se font-ils l’écho ? Pour tenter de répondre à cette problématique, la thèse s’ouvre sur une première partie spécifiquement consacrée à un commentaire des développements platoniciens relatifs à l’immortalité de l’âme, ne passant sous silence ni le contexte dans lequel Platon situait ses dialogues ni son projet philosophique, éthique et politique global. Sur la base des conclusions de cette exégèse, s’engage ensuite une analyse des rapports qu’entretient la thèse de la survie post corporis mortem de l’âme avec les principaux aspects de la spécificité humaine mis en jeu dans la démonstration platonicienne ; la dernière partie, enfin, tente d’opérer la synthèse des idées développées antérieurement et propose quelques hypothèses pour identifier les sentiments se situant à la source de la croyance en l’immortalité de l’âme et déterminer si Platon faisait siens ces sentiments ou non : ainsi, la boucle sera bouclée et cette thèse devrait donner de quoi répondre à certaines idées reçues relatives à Platon.
The demonstration of immortality of soul in Plato’s dialogues, notably in Phædo, has been the object of many commentaries : as a result, it has been for a long time the major reference about this question. So, this thesis’ purpose is accomplishing the « deconstruction » of Plato’s writings about soul’s survival : when he begins to know his own being, every human might have spontaneous intuitions which make he thinks his soul survive after body’s death. Maybe such intuitions underlie this concept in Plato’s dialogues : so, what does Plato, explicitly or not, tell about these intuitions ? Which human features underlie his eschatological myths ? In order to try to answer these questions, the actual commentary of Plato’s explanations concering immortality of soul will be the object of thesis’ first part : this commentary will forget neither the context of dialogues nor Plato’s philosophical, ethical and politcal whole plans. This exegesis will lay the foundations for an analysis of links betweem the concept of soul’s survival after body’s death and human specificity’s major aspects which Plato mentions in his explanations ; the last part will try to summarize what has been previously presented and will propose some hypothesis in order to identify human feelings which constitute the source of belief in soul’s immortality and to see if these feelings were Plato’s ones or not. As a result, the thesis will come full circle and might contradict some wrongly widespread ideas concerning Plato.
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