Front Microbiol

Since 2021, 3 variants of concern (VOC) have spread to France, causing successive epidemic waves. To describe the features of Alpha, Delta and Omicron VOC circulation in the Nouvelle-Aquitaine region, France, between February 2021 and February 2022. Data from the three university hospitals (UH) of Nouvelle-Aquitaine were used to describe regional SARS-CoV-2 circulation (RT-PCR positive rates and identified VOC) as well as its consequences (total number of hospitalizations and admissions in intensive care unit). They were analyzed according to the predominant variant and compared with national data. A total of 611,106 SARS-CoV-2 RT-PCR tests were performed in the 3 Nouvelle-Aquitaine UH during the study period. The 37,750 positive samples were analyzed by variant-specific RT-PCR or whole-genome sequencing. In 2021, Alpha VOC was detected from week 5 until week 35. Delta became the most prevalent variant (77.3%) in week 26, reaching 100% in week 35. It was replaced by Omicron, which was initially detected week 48, represented 77% of positive samples in week 52 and was still predominant in February 2022. The RT-PCR positive rates were 4.3, 4.2, and 21.9% during the Alpha, Delta and Omicron waves, respectively. The ratio between intensive care unit admissions and total hospitalizations was lower during the Omicron wave than during the two previous waves due to the Alpha and Delta variants. This study highlighted the need for strong regional cooperation to achieve effective SARS-CoV-2 epidemiological surveillance, in close association with the public health authorities

Contribution à la compréhension des mécanismes de résistances aux nouvelles bêta-lactamines observés dans des souches cliniques de bacilles à Gram négatif : apports de la biologie moléculaire et de l'analyse pharmacocinétique/pharmacodynamique

Antibiotic resistance has been described since the discovery of the first antibiotics. However, their inappropriate use in both human and veterinary health has led to the emergence and establishment of resistance mechanisms to many classes of antibiotics, including beta-lactams. This class is the standard of car for Gram-negative bacilli treatment, such as Pseudomonas aeruginosa and Klebsiella pneumoniae. New beta-lactams, such as ceftolozane/tazobactam, ceftazidime/avibactam or cefiderocol, have been developed to be effective against multi-drug resistant bacteria. The emergence of specific resistance mechanisms to these last-resort molecules has already been described during their clinical use. Furthermore, numerous diagnostic tools, such as whole genome sequencing, allow the identification of the mechanism(s) potentially responsible for antibiotic resistance.In this context, the aim of this thesis is to use complementary microbiology approaches, like molecular biology, to data modelling methods, in order to characterize mutations responsible for resistance to new beta-lactams.In the first part, a clinical pair of P. aeruginosa, initially susceptible to ceftolozane/tazobactam, then becoming resistant under treatment with this drug, was specifically studied. Mutations probable involved in resistance were identified by whole genome sequencing (AmpC:p.G183D and AmpD:p.H157Y) and then replicated in a reference P. aeruginosa strain (PAO1). Experimental data showed a decorrelation between minimum inhibitory concentrations (MICs) measurements and time-kill curves (TKC) results. Semi-mechanistic pharmacokinetic/pharmacodynamic modelling was used to accurately describe the impact of each mutation, including the contribution to acquired resistance (immediate effect) and adaptive resistance. The tools used in this first part allowed the obtention of results on susceptibility to ceftazidime/avibactam and imipenem. These data are important to understand the effect of individual and associated mutations on antibiotic susceptibility, particularly in the context of the development of in silico susceptibility testing.In a second part, resistance to cefiderocol in clinical isolates of K. pneumoniae was investigated thanks to the implementation of third generation sequencing methods in the laboratory. The description of all resistance mechanisms already present in the isolates was carried out, and a new mutation in the fiu gene, coding a siderophore receptor, was identified for the first time in a clinical isolate.L’antibiorésistance est un phénomène décrit depuis la découverte des premiers antibiotiques. Cependant, leur utilisation déraisonnée, à la fois en santé humain et vétérinaire, a favorisé l’émergence et l’installation de mécanismes de résistance à de nombreuses classes d’antibiotiques, dont les bêta-lactamines. Cette classe constitue le traitement de référence des infections à bacilles Gram-négatifs, comme Pseudomonas aeruginosa et Klebsiella pneumoniae. De nouvelles bêta-lactamines, comme l’association ceftolozane/tazobactam, ceftazidime/avibactam ou encore le cefiderocol, ont été développées pour être efficace sur les bactéries multi-résistantes. L’émergence de mécanismes de résistance spécifiques à ces molécules a malheureusement été décrite lors de leur utilisation clinique. De plus, de nombreux outils de diagnostics, comme le séquençage du génome entier, permettent d’identifier le ou les mécanismes potentiellement responsables de la résistance.Dans ce contexte, le but de cette thèse est d’utiliser des approches complémentaire de microbiologie, incluant de la biologie moléculaire, à des méthodes de modélisation de données, afin de caractériser des mutations responsables de résistance aux nouvelles bêta-lactamines. Dans une première partie, un couple de P. aeruginosa, initialement sensible au ceftolozane/tazobactam, puis devenu résistant sous traitement par cette association, a été spécifiquement étudié. Les mutations probablement responsables de la résistance ont été identifiées par séquençage génome entier (AmpC:p.G183D et AmpD:p.H157Y), puis reproduites dans une souche de référence (PAO1). Les données expérimentales ont montré une décorrélation entre les mesures de concentration minimal inhibitrice (CMI) et les résultats de courbes de bactéricidie (TKC). La modélisation semi-mécanistique pharmacocinétique/pharmacodynamique a permis de décrire de façon précise l’impact de chaque mutation, en incluant la contribution dans la résistance acquise (effet immédiat) et la résistance adaptative. Les outils utilisés lors de cette première partie ont permis l’obtention de résultats sur la sensibilité à l’imipénème et au ceftazidime/avibactam. Ces données sont importantes pour comprendre l’effet de mutations individuelles et associées sur la sensibilité aux antibiotiques, notamment dans le cadre du développement des antibiogrammes in silico.Dans une seconde partie, la résistance au cefiderocol apparue dans des souches cliniques de K. pneumoniae a été investiguée grâce à la mise en place de méthodes de séquençage de troisième génération au sein du laboratoire. La description de tous les mécanismes de résistance déjà présents a pu être réalisée, et une nouvelle mutation dans le gène fiu, jamais identifiée dans une souche clinique, a pu être mise en évidence

Contribution to the understanding of resistance mechanisms to new beta-lactams observed in clinical strains of Gram-negative bacilli : inputs from molecular biology and pharmacokinetic/pharmacodynamic analysis

L’antibiorésistance est un phénomène décrit depuis la découverte des premiers antibiotiques. Cependant, leur utilisation déraisonnée, à la fois en santé humain et vétérinaire, a favorisé l’émergence et l’installation de mécanismes de résistance à de nombreuses classes d’antibiotiques, dont les bêta-lactamines. Cette classe constitue le traitement de référence des infections à bacilles Gram-négatifs, comme Pseudomonas aeruginosa et Klebsiella pneumoniae. De nouvelles bêta-lactamines, comme l’association ceftolozane/tazobactam, ceftazidime/avibactam ou encore le cefiderocol, ont été développées pour être efficace sur les bactéries multi-résistantes. L’émergence de mécanismes de résistance spécifiques à ces molécules a malheureusement été décrite lors de leur utilisation clinique. De plus, de nombreux outils de diagnostics, comme le séquençage du génome entier, permettent d’identifier le ou les mécanismes potentiellement responsables de la résistance.Dans ce contexte, le but de cette thèse est d’utiliser des approches complémentaire de microbiologie, incluant de la biologie moléculaire, à des méthodes de modélisation de données, afin de caractériser des mutations responsables de résistance aux nouvelles bêta-lactamines. Dans une première partie, un couple de P. aeruginosa, initialement sensible au ceftolozane/tazobactam, puis devenu résistant sous traitement par cette association, a été spécifiquement étudié. Les mutations probablement responsables de la résistance ont été identifiées par séquençage génome entier (AmpC:p.G183D et AmpD:p.H157Y), puis reproduites dans une souche de référence (PAO1). Les données expérimentales ont montré une décorrélation entre les mesures de concentration minimal inhibitrice (CMI) et les résultats de courbes de bactéricidie (TKC). La modélisation semi-mécanistique pharmacocinétique/pharmacodynamique a permis de décrire de façon précise l’impact de chaque mutation, en incluant la contribution dans la résistance acquise (effet immédiat) et la résistance adaptative. Les outils utilisés lors de cette première partie ont permis l’obtention de résultats sur la sensibilité à l’imipénème et au ceftazidime/avibactam. Ces données sont importantes pour comprendre l’effet de mutations individuelles et associées sur la sensibilité aux antibiotiques, notamment dans le cadre du développement des antibiogrammes in silico.Dans une seconde partie, la résistance au cefiderocol apparue dans des souches cliniques de K. pneumoniae a été investiguée grâce à la mise en place de méthodes de séquençage de troisième génération au sein du laboratoire. La description de tous les mécanismes de résistance déjà présents a pu être réalisée, et une nouvelle mutation dans le gène fiu, jamais identifiée dans une souche clinique, a pu être mise en évidence.Antibiotic resistance has been described since the discovery of the first antibiotics. However, their inappropriate use in both human and veterinary health has led to the emergence and establishment of resistance mechanisms to many classes of antibiotics, including beta-lactams. This class is the standard of car for Gram-negative bacilli treatment, such as Pseudomonas aeruginosa and Klebsiella pneumoniae. New beta-lactams, such as ceftolozane/tazobactam, ceftazidime/avibactam or cefiderocol, have been developed to be effective against multi-drug resistant bacteria. The emergence of specific resistance mechanisms to these last-resort molecules has already been described during their clinical use. Furthermore, numerous diagnostic tools, such as whole genome sequencing, allow the identification of the mechanism(s) potentially responsible for antibiotic resistance.In this context, the aim of this thesis is to use complementary microbiology approaches, like molecular biology, to data modelling methods, in order to characterize mutations responsible for resistance to new beta-lactams.In the first part, a clinical pair of P. aeruginosa, initially susceptible to ceftolozane/tazobactam, then becoming resistant under treatment with this drug, was specifically studied. Mutations probable involved in resistance were identified by whole genome sequencing (AmpC:p.G183D and AmpD:p.H157Y) and then replicated in a reference P. aeruginosa strain (PAO1). Experimental data showed a decorrelation between minimum inhibitory concentrations (MICs) measurements and time-kill curves (TKC) results. Semi-mechanistic pharmacokinetic/pharmacodynamic modelling was used to accurately describe the impact of each mutation, including the contribution to acquired resistance (immediate effect) and adaptive resistance. The tools used in this first part allowed the obtention of results on susceptibility to ceftazidime/avibactam and imipenem. These data are important to understand the effect of individual and associated mutations on antibiotic susceptibility, particularly in the context of the development of in silico susceptibility testing.In a second part, resistance to cefiderocol in clinical isolates of K. pneumoniae was investigated thanks to the implementation of third generation sequencing methods in the laboratory. The description of all resistance mechanisms already present in the isolates was carried out, and a new mutation in the fiu gene, coding a siderophore receptor, was identified for the first time in a clinical isolate

L'action publique au travail

C'est dans la manière pratique, dans la confrontation quotidienne d'agents de base ou de cadres avec les objets de l'intervention publique que se jouent bien des transformations de l'action publique au travail. Elle se modifie au quotidien dans le travail concret des agents et elle est travaillée par des tensions qui la contraignent au changement. L'expression « action publique » recouvre des objets relevant aussi bien du « service public », des « politiques publiques », de « l'espace public », des « biens publics » et peut donc concerner des administrations, des entreprises publiques ou délégataires de services publics, des hôpitaux mais aussi des associations engagées aux côtés des pouvoirs publics. Des transformations comparables se jouent dans ces différents lieux

A decrease in gamma-synuclein expression within the nucleus accumbens increases cocaine intravenous self-administration in the rat

Except as a marker of cancer progression, gamma-synuclein (GSyn) had received little attention. Recent data showed however that GSyn modulates cocaine-induced locomotor effects, suggesting that it could also play a role in cocaine reinforcing effects. In the rat, siRNAs targeting GSyn expression were injected in the nucleus accumbens and cocaine reinforcing effects were evaluated by means of intravenous self-administration. A dose-response curve was followed by procedures of progressive ratio, extinction, cocaine- and cue-induced reinstatements. Decrease of GSyn expression increased self-administration over a large range of doses. This effect was associated with an increase in cocaine-induced reinstatement. The present data reveal that GSyn exert a specific negative control on cocaine-induced reinforcing and incentive effects

A greedy heuristic for distributing hard real-time applications on an IMA architecture

International audienceCurrent avionics architectures use complex processors, which are shared by many avionics applications according Integrated Modular Avionics (IMA) concepts. Using less complex processors on small aircraft such as helicopters leads to a distributed IMA architecture. Thus the set of partitions has to be distributed on the set of available processors. This distribution has to deal with both schedulability constraints on each processor and end-to-end latency constraints for chains of communicating partitions. Several mapping approaches exist for various applicative contexts. An approach has been proposed in the context of avionics. It implements an exhaustive analysis of all possible mappings. Time needed to perform this exhaustive analysis is drastically limited by incrementally mapping avionics functions and checking both scheduling and end-to-end constraints at each step. This approach is able to map small avionics application. However, it doesn't scale well, mainly because the scheduling space quickly explodes. In this paper, we integrate a greedy heuristic in the approach, in order to limit the scheduling space. We show that the resulting approach scales much better and gives mapping results which are close to those of the exhaustive approach

Communication-aware scheduling on an IMA architecture: invited paper

International audienceIntegrated modular Avionics (IMA or ARINC 651), as it is currently implemented in large aircrafts, uses a limited number of complex processors interconnected through a communication network (AFDX or ARINC 664). The allocation of avionics applications is done according a communicating partitions model (APEX or ARINC 653) needed for guaranteeing robust partitioning when sharing processors (TDMA like schedule) and communication network (APEX channel). On smaller aircrafts (such as helicopters) the objective (due to room and weight constraints) is to use les complex processors and consequently to increase their number. Implementing such a distributed IMA architecture leads to a global (more complex) integration problem, which is twofold. Allocation and scheduling of partitions on each shared processor as well as end-to-end communication delays among distributed partitions must be compatible in order to guarantee timing requirements of distributed avionics applications. This paper points out the complexity of composing the two aspects of this integration problem on different possible target architectures

Mapping real-time communicating tasks on a distributed IMA architecture

International audienceCurrent avionics architectures implemented on large aircraft use complex processors, which are shared by many avionics applications according Integrated Modular Avionics (IMA) concepts. Using less complex processors on smaller aircraft such as helicopters leads to a distributed IMA architecture. Allocation of the avionics applications on a distributed architecture has to deal with two main challenges. A first problem is about the feasibility of a static allocation of partitions on each processing element. The second problem is the worst-case end-to-end communication delay analysis: due to the scheduling of partitions on processing elements which are not synchronized, some allocation schemes are not valid. This paper first presents a mapping algorithm using an integrated approach taking into account these two issues. In a second step, we evaluate, on a realistic helicopter case study, the feasibility of mapping a given application on a variable number of processing elements. Finally, we present a scalability analysis of the proposed mapping algorithm

Draft genome sequence of the Rhinocladiella similis clinical isolate CBS 149759

International audienceRhinocladiella similis is a melanized fungi involved in chromoblastomycosis. R. similis genome has never been sequenced, therefore we propose the first draft genome of R. similis

Phenol-soluble modulins α are major virulence factors of <i>Staphylococcus aureus</i> secretome promoting inflammatory response in human epidermis

International audienc