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International audience; Before the Omicron era, the neutralizing antibody targeting the SARS-CoV2 Spike protein Sotrovimab has been shown to reduce the risk of COVID-19-related hospitalization in patients who are at high risk for progression (1, 2). We recently showed that early administration of Sotrovimab in Omicron-infected patients with very high-risk for progression was associated with a low rate of COVID-19-related hospitalization within one month after treatment administration (3%), and with no death (1). However, the dominance of the Omicron sublineage BA.2 led health agencies to suspend Sotrovimab emergency use authorizations because of its lower neutralizing ability in vitro compared to BA.1 sublineage (3, 4). Clinical efficiency of Sotrovimab to prevent COVID-19 related complications in high-risk patients with mild-to-moderate COVID-19 Omicron BA.2 remains unknown. Our aim was to compare the clinical and virological outcomes of Omicron BA.1 and BA.2-infected patients with mild-to-moderate COVID-19 who received 500 mg of Sotrovimab IV to prevent COVID-19-related complications.

Our aim was to compare the clinical and virological outcomes of Omicron BA.1 and BA.2-infected patients who received Sotrovimab or Nirmatrelvir to prevent severe COVID-19.In the multicentric prospective ANRS 0003S CoCoPrev cohort study, patients at high-risk for progression with mild-to-moderate BA.1 or BA.2 COVID-19 who received Sotrovimab or Nirmatrelvir were included. Proportion of patients with progression to severe COVID-19, time between the start of treatment to negative PCR, SARS-CoV-2 viral decay, and characterization of resistance variants were determined. A multivariable Cox proportional hazard model was used for time to negative PCR and a mixed effect model for the dynamics of viral decay.Among the 255 included patients, of whom 199/255 (80%) received ≥3 vaccine doses, 195/255 (76%) received Sotrovimab and 60/255 (24%) received Nirmatrelvir. At day 28, new COVID-19-related hospitalization occurred in 4/193 (2%, 95%CI 1-5%) Sotrovimab-treated patients, and 0/55 Nirmatrelvir-treated patient (p=0.24). One out of 55 Nirmatrelvir-treated patients died (2%, 95%CI 0-10%). The median time to negative PCR was 11.5 days (95%CI 10.5-13) in Sotrovimab-treated patients vs. 4 days (95% CI 4-9) in Nirmatrelvir-treated patients (p0.001). Viral decay was faster in patients who received Nirmatrelvir (p0.001). In multivariable analysis Nirmatrelvir and nasopharyngeal PCR cycle threshold value were independently associated with a faster conversion to negative PCR (HR 2.35, 95%CI 1.56-3.56, p0.0001, and HR 1.05, 95%CI 1.01-1.08, p=0.01, respectively).Early administration of Nirmatrelvir in high-risk patients, compared to Sotrovimab, was associated with a faster viral clearance. This may participate to decrease transmission and prevent viral resistance.

Objectives Since 2016, French guidelines have recommended the single-tablet regimen of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/rilpivirine (RPV) as HIV post-exposure prophylaxis (PEP), but few data support this usage. We evaluated the tolerability, treatment completion and occurrence of HIV seroconversion associated with this combination in occupational and non-occupational PEP. Patients and methods We conducted an observational, prospective, multicentre, open-label, non-randomized study in five French HIV centres. Adults requiring PEP according to national French guidelines were prescribed TDF/FTC/RPV one pill once a day for 28 days. Clinical and biological tolerability was assessed at week 4; occurrence of HIV seroconversion was evaluated after week 16. Results From March 2016 to March 2017, 163 courses of PEP were prescribed for 150 sexual exposures (44% heterosexual and 56% MSM) and 13 non-sexual exposures. Five participants stopped PEP after a few days because the source person was HIV uninfected. Of the remaining 158 individuals, 15 (9.5%) were lost to follow-up at week 4, 7 (4.4%) prematurely discontinued PEP [patient's decision/non-adherence (n = 3) or adverse events (gastrointestinal intolerance n = 3, fatigue n = 1)] and 136 (86.1%) completed the 28 day treatment. Overall, 69.6% of participants declared at least one adverse event, mostly of mild to moderate intensity and no serious adverse events or hepatic or renal toxicity occurred. No HIV seroconversion occurred at week 16. Conclusions The low rate of premature treatment interruption, the good tolerability and the absence of documented HIV seroconversion support the current French guidelines of a 28 day course of TDF/FTC/RPV for sexual and non-sexual PEP.

Sepsis causes inflammation-induced immunosuppression with lymphopenia and alterations of CD4+ T-cell functions that renders the host prone to secondary infections. Whether and how regulatory T cells (Treg) are involved in this postseptic immunosuppression is unknown. We observed in vivo that early activation of Treg during Staphylococcus aureus sepsis induces CD4+ T-cell impairment and increases susceptibility to secondary pneumonia. The tumor necrosis factor receptor 2 positive (TNFR2pos) Treg subset endorsed the majority of effector immunosuppressive functions, and TNRF2 was particularly associated with activation of genes involved in cell cycle and replication in Treg, probably explaining their maintenance. Blocking or deleting TNFR2 during sepsis decreased the susceptibility to secondary infection. In humans, our data paralleled those in mice; the expression of CTLA-4 was dramatically increased in TNFR2pos Treg after culture in vitro with S. aureus. Our findings describe in vivo mechanisms underlying sepsis-induced immunosuppression and identify TNFR2pos Treg as targets for therapeutic intervention.

International audience; [No abstract available]

Current guidelines recommend cefazolin as an alternative to antistaphylococcal penicillins (ASPs) in methicillin-susceptible Staphylococcus aureus (MSSA) infective endocarditis despite the lack of comparative study. The objective of this study was to evaluate the comparative outcomes of cefazolin vs. ASPs in MSSA infective endocarditis.This was a retrospective analysis of an observational multicentre cohort study using prospectively collected data from patients with MSSA endocarditis confirmed by endocarditis team and treated either with cefazolin or ASPs between July 2013 and December 2018. Patients were excluded if they received both treatments. The primary outcome was 90-day all-cause mortality.Of 210 patients included, 53 patients (25.2%) received cefazolin and 157 (74.8%) received ASPs. The overall 90-day mortality rate was 27.6% (58/210 patients), 24.5% (13/53) in the cefazolin group vs. 28.7% (45/157) in the ASP group (p 0.561). Premature antimicrobial discontinuation due to adverse events occurred less frequently with cefazolin than with ASPs (0/53 vs. 13/157 patients; p 0.042). In multivariate analysis, there was no difference in 90-day mortality between cefazolin and ASPs (adjusted odds ratio (aOR), 1.2; 95% confidence interval (CI), 0.49-2.91; p 0.681), while age (aOR, 1.06; 95% CI, 1.03-1.09; p 0.001), Charlson comorbidity index (aOR, 1.18; 95% CI, 1.02-1.36 p 0.023), cerebral embolism (aOR, 2.83; 95% CI, 1.33-6.14; p 0.007) and intensive care unit admission (aOR, 4.16; 95% CI, 1.89-9.59; p 0.001) were factors significantly associated with higher mortality.Cefazolin seems to be a possible alternative to ASPs in MSSA endocarditis. More studies are needed to confirm these results and determine which treatment should be recommended as first-line therapy.

Objectives To assess the meningeal penetration of cefazolin and cloxacillin in individuals treated for methicillin-susceptible staphylococcal meningitis. Methods We retrospectively identified individuals treated for Staphylococcus meningitis with measurements of cefazolin or cloxacillin concentrations in cerebrospinal fluid (CSF) using a validated assay of liquid chromatography coupled with mass spectrometry at the Nantes University Hospital between January 2009 and October 2019. Staphylococcus meningitis was defined by a compatible clinical presentation and a microbiological confirmation (positive CSF culture or positive specific PCR). Medical charts were retrospectively reviewed to collect microbiological and clinical data, and to assess therapeutic success. Results Among the 17 included individuals, eight (47%) were treated with cefazolin and nine (53%) with cloxacillin. Median daily dosages of cefazolin and cloxacillin were 8 g (range 6–12 g) and 12 g (range 10–13 g), respectively. Cefazolin and cloxacillin were mainly administered by continuous infusion. Eleven individuals (65%) were men, median (interquartile range (IQR)) age was 54 years (50; 70), 14 (82%) had postoperative meningitis and 3 (18%) had haematogenous meningitis. Median (IQR) antibiotic CSF concentrations were 2.8 mg/L (2.1; 5.2) and 0.66 mg/L (0.5; 0.9) for cefazolin and cloxacillin groups, respectively. Cloxacillin was discontinued in two individuals for therapeutic failure. Conclusions Patients with staphylococcal meningitis treated with high-dose continuous intravenous infusion of cefazolin achieved therapeutic concentrations in CSF. Cefazolin appears to be a therapeutic candidate that should be properly evaluated in this indication.

Introduction L’immunodepression (ID) post-septique est l’une des principales causes de mortalite secondaire au decours du sepsis, notamment en raison des infections nosocomiales qui lui sont associees. Une alteration severe des lymphocytes CD4+ est l’une des caracteristiques de l’ID post-septique. Les lymphocytes T regulateurs (Treg) sont des cellules de l’immunite adaptative connues pour leurs proprietes suppressives et impliquees dans l’ID post-septique. Apres avoir objective les proprietes puissamment immunosuppressives des Treg exprimant le recepteur TNFR2 sur modele murin, notre objectif de travail etait d’etudier chez l’homme les modifications phenotypiques et fonctionnelles des Treg TNFR2+ au cours de l’ID post-septique. Materiels et methodes Nous avons tout d’abord analyse les modifications phenotypiques des lymphocytes T CD4+ parmi les cellules mononuclees du sang peripherique (PBMC) issues d’une biocollection de patients hospitalises pour un choc septique (biocollection IBIS-Sepsis). Nous avons ensuite mis au point un modele de stimulation ex vivo de PBMC de donneurs sains par une culture en presence de S. aureus ou de serums de patients en choc septique. Nous avons choisi l’expression de CTLA4 comme temoin indirect des proprietes suppressives des Treg. Enfin, nous avons evalue les fonctions immunosuppressives des Treg par des tests d’inhibition de la proliferation des lymphocytes T effecteurs (Teff) en presence de Treg. Resultats Nous avons observe une lymphopenie CD4+ associee a une augmentation du ratio Treg sur CD4+, a la fois sur les PBMC issues de patients en choc septique et sur notre modele de stimulation ex vivo de PBMC de donneurs sains. Nous avons egalement observe une expression majoree du CTLA4 chez les Treg TNFR2+ pour les patients en choc septique comme pour notre modele de stimulation ex vivo. Enfin, les resultats de nos tests d’inhibition de proliferation ont montre une inhibition plus forte de la proliferation des Teff par les Treg des patients septiques en comparaison avec les Treg de donneurs sains. Conclusion De maniere concordante avec nos observations sur modele murin, ces resultats suggerent une activation des Treg TNFR2+ au cours de l’ID post-septique, pouvant favoriser la survenue d’infections nosocomiales. Ces constatations sont originales car il n’existe que peu de donnees disponibles sur la thematique des Treg TNFR2+ en contexte de sepsis. L’expression de TNFR2 sur les Treg est une piste interessante pour le developpement de therapies ciblees visant a limiter les consequences de l’immunodepression post-septique.

Objective The Mortalite 2010 survey aimed at describing the causes of death among HIV-infected patients in France in 2010 and their evolution since 2000. Design and methods A national sample of clinical sites, providing HIV care and treatment, notified and documented deaths using a standardized questionnaire. Results The 90 participating wards notified 728 deaths. Median age at death was 50 years (interquartile range 45-58) and 75% were men. The main underlying causes of death were AIDS-related (25% in 2010 vs. 36% in 2005 and 47% in 2000), non-AIDS non-viral hepatitis-related malignancy (22 vs. 17 and 11%), liver-related (11 vs. 15 and 13%), cardiovascular diseases (10 vs. 8 and 7%) and non-AIDS-related infections (9 vs. 4 and 7%). Malignancies (AIDS and non-AIDS-related) accounted for a third of all causes of death. AIDS accounted for 33% of all causes of death among patients mono-infected with HIV vs. only 13% among those co-infected with hepatitis B virus or hepatitis C virus. Conclusion In 2010, 25% of the causes of death among HIV-infected patients remained AIDS-related. Improved screening and earlier HIV treatment should lead to a smaller proportion of deaths due to AIDS. The majority of patients died of various causes, whereas their HIV infection was well controlled under treatment. Improving case management of HIV-infected patients should include a multidisciplinary approach (prevention, screening, treatment), especially in oncology. Smoking cessation should be a priority goal.

Background: The X-linked McLeod syndrome belongs to the group of neuroacanthocytosis syndromes and has a Huntington-disease–like phenotype with a choreatic movement disorder, cognitive alterations, and psychiatric symptoms. Another neuroacanthocytosis syndrome, the autosomal recessive chorea-acanthocytosis, has a similar presentation, but distinct clinical features, believed to be characteristic, such as tongue protrusion dystonia, feeding dystonia, and rubber-man–like appearance. Methods: This work comprised a case series of 3 patients with McLeod syndrome. Results: The 3 patients with McLeod syndrome developed severe feeding dystonia and tongue protrusion as well as rubber-man–like appearance in 1 patient during the course of the disease. Conclusion: These observations indicate that there is an extended phenotypic overlap between McLeod syndrome and chorea-acanthocytosis. © 2011 Movement Disorder Society

This paper presents a model of how different farm support mechanisms affect world price uncertainty. This issue is addressed within the framework of a rational expectations trade model for a storable commodity market. Here, absorption of physical production shocks are tracked separately and are found to be quite different. This model leads to the conclusion that the alleged variance-reducing impact of the free trade regime, while plausible, is a special case of a more general model in which the impact is ambiguous. Copyright 1988 by Oxford University Press.