Introduction: The increase in the population of immunocompromised patients due to advances in management of end-stage diseases and transplants poses challenges in treating infections caused by multi-drug resistant (MDR) pathogens. Cefiderocol (FDC), a siderophore cephalosporin, has shown efficacy against carbapenem-resistant Gram-negative bacteria. Methods: This retrospective multicentre study investigated the real-world use of FDC in 114 immunocompromised adults treated for MDR infections in 12 French hospitals (June 2020-November 2023). Clinical and microbiological outcomes, including infection cure, relapse, as well as mortality, and resistance acquisition, were assessed at days 28 and 90. Antibiotic prescription compliance with current guidelines was investigated. Results: At day 28, clinical success was achieved in 53.3% of cases, and overall mortality was 37.7%, consistent with other studies (33-37%). Infection-related mortality accounted for 25.4%. Relapse occurred in 17.5% of patients by day 28, rising by an additional 9.8% among survivors by day 90. Resistance acquisition was observed in two cases at day 28 ( Pseudomonas aeruginosa and Stenotrophomonas maltophilia) and in three additional cases by day 90. FDC was used as monotherapy in 49.1% of cases, with a median treatment duration of 10 days. Nearly 25% of strains collected in FDC-treated patients were susceptible to best-practice alternatives. Conclusion: These findings highlight FDC's utility in difficult-to-treat infections, particularly S. maltophilia, but the high relapse rate and resistance acquisition underscore the need for careful monitoring, adherence to guidelines, and reconsideration of empirical use to prevent resistance and improve outcomes in fragile populations. (c) 2024 The Author(s). Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

BACKGROUND:There are no established recommendations for systematic or targeted antifungal prophylaxis in heart transplant recipients (HTRs), resulting in heterogeneous practices. An outbreak of post-surgical invasive aspergillosis (IA) among HTR, which coincided with construction activities near our heart transplant unit, prompted the initiation of primary posaconazole (POS) prophylaxis in patients at highest risk. METHODS:This single-center retrospective descriptive study was conducted from March 2020 to May 2022 and describes the use of POS primary prophylaxis in high-risk HTR. The following risk factors were considered as indications for initiating prophylaxis: re-operation, post-transplantation hemodialysis, post-surgical extracorporeal membrane oxygenation (ECMO), re-transplantation, prolonged post-transplant mechanical ventilation (i.e., >72 h), cytomegalovirus (CMV) infection within the first month post-transplant, and a positive pre-transplant Aspergillus serology. The duration of prophylaxis was individualized, with treatment initiating in response to the risk factor and continuing for a median of 28 days after its resolution. RESULTS:POS prophylaxis was administered in 12 of 33 HTR (36.4%). The most common risk factors encountered were prolonged mechanical ventilation (>72 h, 91.6%) and CMV infection (58.3%). Most patients (91.6%) had at least two risk factors for IA, and more than half (58.3%) had three or more. Notably, no cases of IA were observed during the study period. Some patients experienced liver function abnormalities and drug-drug interactions. CONCLUSION:Targeted POS prophylaxis may be an option for high-risk HTR during an outbreak. Close monitoring of liver function, POS levels, and tacrolimus concentrations is recommended.

OBJECTIVES:To report long-term clinical efficacy, safety, pharmacokinetics, immunogenicity and seroneutralization results of AZD7442 (monoclonal antibodies tixagevimab-cilgavimab) in patients hospitalized with COVID-19. METHODS:In this phase 3, double-blind, randomized, multicentre trial, hospitalized adults with PCR-confirmed SARS-CoV-2 infection were randomly assigned 1:1 to receive AZD7442 or placebo, and followed-up until day 456, with repeated blood sample collections until day 365. Clinical endpoints included clinical status, mortality, rehospitalization, SARS-CoV-2 reinfection, and adverse events. Antidrug antibodies and serum drug concentrations were measured. Analyses were performed on the modified intention-to-treat (mITT) populations, defined as participants who actually received the intervention. RESULTS:Between April 28, 2021, and June 23, 2022, 237 participants were randomly assigned to AZD7442 (n = 127) or placebo (n = 110), and 123 participants actually received AZD7442. Participants were infected with pre-Omicron variants in 58.8% (133/226) of cases, versus 33.2% (75/226) of Omicron BA1, BA2, or BA5, and 8% (18/226) missing data. There was no significant difference in the distribution of the 7-point ordinal scale between the AZD7442 and placebo groups, either on day 15 (primary endpoint) (OR = 0.93 [0.54-1.61], p 0.81), or any other time point. Significantly more rehospitalizations occurred between discharge and day 456 among participants who received AZD7442 in the global mITT population (OR = 2.04 [1.03-4.05], p 0.04), but not in the antigen-positive mITT population (OR = 1.78 [0.80-3.94], p 0.15). No significant differences were observed in mortality, SARS-CoV-2 reinfection, or adverse events. In the AZD7442 group, 12 of 87 participants (13.8%) had treatment-emergent antidrug antibodies versus 5 of 69 (7.2%) in the placebo group (OR = 2.02 [0.66-6.14], p 0.21). Serum drug concentrations were detectable up to day 365 for all sampled participants (35/35). Neutralizing antibody titres were significantly higher in the AZD7442 group up to day 180. CONCLUSIONS:AZD7442 did not demonstrate any clinical benefit and was safe up to 15 months. This study also provides valuable data on the pharmacokinetics, immunogenicity, and neutralizing activity of AZD7442 in patients hospitalized with COVID-19.

Describing morphogenesis generally consists in aggregating the multiple high-resolution spatiotemporal processes involved into reproducible low-dimensional morphological processes consistent across individuals of the same species or group. In order to achieve this goal, biologists often have to submit movies issued from live imaging of developing embryos either to a qualitative analysis or to basic statistical analysis. These approaches, however, present noticeable drawbacks as they can be time consuming, hence unfit for scale, and often lack standardization and a firm foundation. In this work, we leverage the power of a continuum mechanics approach and flexibility of spectral decompositions to propose a standardized framework for automatic detection and timing of morphological processes. First, we quantify whole-embryo scale shape changes in developing ascidian embryos by statistically estimating the strain rate tensor field of its time-evolving surface without the requirement of cellular segmentation and tracking. We then apply to this data spectral decomposition in space using spherical harmonics and in time using wavelets transforms. These transformations result in the identification of the principal dynamical modes of ascidian embryogenesis and the automatic unveiling of its blueprint in the form of scalograms that tell the story of development in ascidian embryos.

INTRODUCTION:Kidney transplant recipients are among the populations at risk for Hepatitis B Virus (HBV) reactivation, and close monitoring is needed for its early detection. METHODS:We describe a case of HBV reactivation in a patient who underwent kidney transplantation more than 30 years ago, with a known serological profile of past HBV infection. RESULTS:Reactivation occurred as a highly replicative infection that went undiagnosed for 7 years due to negative results for HB surface antigen (HBsAg) and high levels of anti-HBs antibodies. Viral genome sequencing showed a high number of mutations in the major hydrophilic region of HBsAg that could explain such a profile. DISCUSSION:This case highlights the usefulness of frequent and systematic HBV viral load testing in patients at risk of reactivation, with anti-hepatitis B core antibodies, regardless of HBsAg detection, aminotransferases, and anti-HBs antibody levels.

IntroductionCytomegalovirus (CMV) remains the predominant opportunistic infection following solid organ transplantation (SOT). While valganciclovir is the drug of choice for CMV prophylaxis, its utility can be compromised due to the risk of cytopenia. Letermovir, a novel agent approved for CMV prophylaxis in allogeneic hematopoietic stem cell transplant recipients and high-risk kidney transplant recipients, exhibits reduced toxicity. This study aims to present the practical application of letermovir as both primary and secondary prophylaxis against CMV in heart transplant recipients (HTR).MethodsIn this observational, retrospective, single-center study, we included all consecutive adult HTRs from June 2020 to January 2022 who were administered letermovir for CMV prophylaxis. We documented instances of CMV breakthrough infections, side effects related to letermovir, changes in neutropenia following the switch from valganciclovir to letermovir, and any drug interactions with the immunosuppressive regimen.ResultsThe study comprised 10 patients: two received primary prophylaxis with letermovir due to a high risk of CMV infection (donor-positive, recipient-negative serostatus), and eight received it as secondary prophylaxis following a CMV infection. The median duration of letermovir administration was 8 months (range 3-12 months). No CMV breakthrough infections were reported while on prophylaxis. However, three patients experienced CMV breakthrough infections after discontinuing letermovir prophylaxis (30%). No significant side effects were observed, although one patient reported digestive intolerance. Among the nine patients on tacrolimus, six needed reduced doses after switching to letermovir.ConclusionThis real-life study appears to support the effectiveness of letermovir prophylaxis in HTR. Nonetheless, the risk of CMV infection post-treatment cessation is notable. Further drug monitoring and research on the efficacy of letermovir for CMV prophylaxis in SOT patients is warranted.

Rationale: Pseudomonas aeruginosa is the major bacterial pathogen colonizing the airways of adult patients with cystic fibrosis (CF) and causes chronic infections that persist despite antibiotic therapy. Intracellular bacteria may represent an unrecognized reservoir of bacteria that evade the immune system and antibiotic therapy. Although the ability of P. aeruginosa to invade and survive within epithelial cells has been described in vitro in different epithelial cell models, evidence of this intracellular lifestyle in human lung tissues is currently lacking. Objectives: To detect and characterize intracellular P. aeruginosa in CF airway epithelium from human lung explant tissues. Methods: We sampled lung explant tissues from patients with CF undergoing lung transplantation and non-CF lung donor control tissue. We analyzed lung tissue sections for the presence of intracellular P. aeruginosa using quantitative culture and microscopy, in parallel to histopathology and airway morphometry. Measurements and Main Results: P. aeruginosa was isolated from the lungs of seven patients with CF undergoing lung transplantation. Microscopic assessment revealed the presence of intracellular P. aeruginosa within airway epithelial cells in three of the seven patients analyzed at a varying but low frequency. We observed those events occurring in lung regions with high bacterial burden. Conclusions: This is the first study describing the presence of intracellular P. aeruginosa in CF lung tissues. Although intracellular P. aeruginosa in airway epithelial cells is likely relatively rare, our findings highlight the plausible occurrence of this intracellular bacterial reservoir in chronic CF infections.

Background Tixagevimab and cilgavimab (AZD7442) are two monoclonal antibodies developed by AstraZeneca for the pre-exposure prophylaxis and treatment of patients infected by SARS-CoV-2. Its effectiveness and safety in patients hospitalized with COVID-19 was not known at the outset of this trial.Methods DisCoVeRy is a phase 3, adaptive, multicentre, randomized, controlled trial conducted in 63 sites in Europe. Participants were randomly assigned (1:1) to receive placebo or tixagevimab-cilgavimab in addition to standard of care. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale. Several clinical, virological, immunological and safety endpoints were also assessed.Findings Due to slow enrolment, recruitment was stopped on July 1st, 2022. The antigen positive modified intention-to-treat population (mITT) was composed of 173 participants randomized to tixagevimab-cilgavimab (N = 91) or placebo (N = 82), 91.9% (159/173) with supplementary oxygen, and 47.4% (82/173) previously vaccinated at inclusion. There was no significant difference in the distribution of the WHO ordinal scale at day 15 between the two groups (odds ratio (OR) 0.93, 95%CI [0.54-1.61]; p = 0.81) nor in any clinical, virological or safety secondary endpoints. In the global mITT (N = 226), neutralization antibody titers were significantly higher in the tixagevimab-cilgavimab group/patients compared to placebo at day 3 (Least-squares mean differences (LSMD) 1.44, 95% Confidence interval (CI) [1.20-1.68]; p < 10−23) and day 8 (LSMD 0.91, 95%CI [0.64-1.18]; p < 10−8) and it was most important for patients infected with a pre-omicron variant, both at day 3 (LSMD 1.94, 95% CI [1.67-2.20], p < 10−25) and day 8 (LSMD 1.17, 95% CI [0.87-1.47], p < 10−9), with a significant interaction (p < 10−7 and p = 0.01 at days 3 and 8, respectively).Interpretation There were no significant differences between tixagevimab-cilgavimab and placebo in clinical endpoints, however the trial lacked power compared to prespecified calculations. Tixagevimab-cilgavimab was well tolerated, with low rates of treatment related events.Funding Trial registration: [ClinicalTrials.gov][1] [NCT04315948][2]. Registered on 13 March 2020 updated on 22 April 2021.### Competing Interest StatementM.H. reports grants from The Belgian Center for Knowledge (KCE), the Fonds Erasme-COVID-Université Libre de Bruxelles and the EU-Horizon program, for the submitted work; and has received support for attending meetings from Pfizer; support for participation on an advisory board for therapeutics on COVID-19; and support for leadership for the Belgian guidelines on therapeutics for COVID-19 and acting as a treasurer for the Belgian Society of Clinical Microbiology and Infectious Diseases. R.G. reports consulting fees from Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, Abbvie, AstraZeneca, Janssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Sankvo; lecture fees from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, Abbvie, Gilead, and Daiichi Sankvo; support for attending meetings from Roche, Amgen, Janssen, AstraZeneca, Novartis, Merck Sharp & Dohme, Celgene, Gilead, Bristol Myers Squibb, Abbvie, and Daiichi Sankvo; participation in a Data Safety and Monitoring Board for Celgene, Novartis, Roche, Bristol Myers Squibb, Takeda, Abbvie, AstraZeneca, Janssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Sankyo; research grants from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Sandoz, Abbvie, Gilead, and Daiichi Sankyo. J.-A.P. reports consulting fees from Pfizer, Merck Sharp & Dohme, and Janssen-Cilag; lecture fees from Pfizer; and support for attending meetings from Pfizer. D.C. reports grants and lecture fees from Janssen and lecture fees from Gilead, outside the submitted work. C.B. reports participation in a Data Safety and Monitoring Board for 4Living Biotech; and consulting fees from Da Volterra and Mylan Pharmaceuticals, outside the submitted work. F.M. reports grants and consulting fees from Da Volterra, grants from Sanofi, and consulting fees from Ipsen, outside the submitted work. All other authors declare no competing interests.### Clinical TrialNCT04315948### Funding StatementThis work received funding from several sources: the European Commission (EU-Response, Grant 101015736), the DIM One Health Ile-de-France (R20117HD) and Astra-Zeneca. We thank all participants who consented to enroll in the trial, as well as all study and site staff whose indispensable assistance made the conduct of the DisCoVeRy trial possible (all listed in the appendix, pp 27-36)### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics committee of the BASG (Bundesamt fur Sicherheit im Gesundheitswesen), Austria, gave ethical approval for this work. Ethics committee of the FAMHP (Federal Agency for Medicines and Health Products), Belgium, gave ethical approval for this work. Ethics committee of the SUKL (Statni Ustav Pro Kontrolu Leciv), Czech Republic, gave ethical approval for this work. Ethics committee of the ANSM (Agence nationale de securite du medicament et des produits de sante), France, gave ethical approval for this work. Ethics committee of the National Organization for Medicines, Greece, gave ethical approval for this work. Ethics committee of the National Institute of Pharmacy and Nutrition (OGYEI), Hungary, gave ethical approval for this work. Ethics committee of the HPRA (Health Products Regulatory Authority), Ireland, gave ethical approval for this work. Ethics committee of the CNER (Comite National d Ethique de Recherche, ministere de la sante), Luxembourg, gave ethical approval for this work. Ethics committee of the NOMA (Norwegian Medical Products Agency), Norway, gave ethical approval for this work. Ethics committee of the Komisja Bioetyczna Przy Uniwersytecie Medycznym W Lodzi, Poland, gave ethical approval for this work. Ethics committee of the Infarmed (National Authority of Medicines and Health Products), Portugal, gave ethical approval for this work. Ethics committee of the SULK (Statni ustav pro kontrolu leciv), Slovakia, gave ethical approval for this work. Ethics committee of the AEMPS (Agencia Espanola de Medicamentos y Productos Sanitarios), Spain, gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesWith publication, deidentified, individual participant data that underlie this Article, along with a data dictionary describing variables in the dataset, will be made available to researchers whose proposed purpose of use is approved by the DisCoVeRy Steering Committee. To request the dataset, please address directly to the corresponding author (florence.ader@chu-lyon.fr) or to the sponsor's representative (helene.esperou{at}inserm.fr) to obtain a data access form. All requests will be evaluated by the Trial Management Team and the DisCoVeRy Steering Committee. For accepted requests, data will be shared after signing a data transfer agreement with the study sponsor. Data will be shared directly or through access on the INSERM repository. Related documents, such as the study protocol, statistical analysis plan, and informed consent form, will be made available (with publication) on request to the corresponding author or to the sponsor's representative. The data will be open access for the informed consent form, protocol, and statistical analysis plan. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04315948&atom=%2Fmedrxiv%2Fearly%2F2024%2F02%2F24%2F2024.02.23.24302586.atom

Expression of concern for ‘Sensing of COVID-19 spike protein in nasopharyngeal samples using a portable surface plasmon resonance diagnostic system’ by Hiba Saada et al., Sens. Diagn., 2022, 1, 1021–1031, https://doi.org/10.1039/D2SD00087C.

Objectives: Bispecific antibodies (BsAbs) are an effective treatment used in relapsed or refractory multiple myeloma. Despite a well-tolerated safety profile, infectious events appear to be frequent in clinical trials. Real-world data on epidemiology, characteristics, risk factors, and outcomes of infections in patients treated with BsAb are still needed. Methods: A retrospective, multicentre study in BsAb-treated patients with multiple myeloma was performed in 14 French centres from December 2020 to February 2023. The primary objective was to describe the incidence of infections that required hospitalization, specific treatment, or adaptation in BsAb administration. Results: Among 229 patients with multiple myeloma treated with BsAb, 153 (67%) received teclistamab, 47 (20%) received elranatamab, and 29 (13%) talquetamab. We reported a total of 234 infections, including 123 (53%) of grade of >= 3. Predominant infections affected the respiratory tract (n = 116, 50%) followed by bacteraemias (n = 36, 15%). The hospitalization rate was 56% ( n = 131), and 20 (9%) infections resulted in death. Global cumulative incidence of the first infection was 70% in all patients, 73% in patients treated with B-cell maturation antigen-targeting, and 51% with GPRC5D-targeting BsAb. In univariate analyses, corticosteroids for cytokine release syndrome (CRS)/immune effector cell-associated neurotoxicity syndrome (ICANS) were associated with a higher risk of first infection (HR = 2.13; 95% CI, 1.38-3.28), whereas GPRC5D-targeting BsAb and anti-bacterial prophylaxis were associated with a lower risk (HR = 0.53; 95% CI, 0.3-0.94 and HR = 0.65; 95% CI, 0.46-0.9). Fine and Gray multivariate model found that only corticosteroids for CRS/ICANS were correlated with a higher risk of first infection (HR = 2.01; 95% CI, 1.27-3.19). Discussions: The implementation of preventive measures that aim to mitigate the risk of infection under BsAb is pivotal, notably in patients who received corticosteroids for CRS/ICANS. (c) 2024 The Authors. Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

OBJECTIVE:To estimate the incidence of hospitalization with a diagnosis of herpes zoster (HZ) and post-herpetic neuralgia (PHN) in France between 2013 and 2020, overall and stratified by age-group and immune status. METHODS:Retrospective observational, database study, using the French hospital discharge database, which includes private and public data for all day-care and inpatient stays. Adults aged ≥18 years, hospitalized between January 1, 2013, and December 31, 2020, with a diagnosis of HZ or PHN, were included. RESULTS:Overall, 62 077 adults had a first hospitalization with a diagnosis of HZ or PHN during the observation period. HZ and/or PHN incidence ranged between 14.6 and 16.3 hospitalizations/100 000 persons and was highest in people aged ≥80 years (97.6 hospitalizations/100 000 persons). The immunocompromised (IC) population accounted for 22% of the overall study population. IC patients had longer lengths of stay for HZ per episode compared with non-IC patients (15.5 ± 19.4 days vs 12.2 ± 13.5 days) and higher in-patient mortality (8% vs 4%). Average annual hospitalization costs per patient were higher in the IC vs non-IC population (€8018 vs €5603). CONCLUSIONS:Older age increases hospitalization rates up to 6-fold and IC status increases in-patient mortality up to two-fold. CLINICAL TRIAL REGISTRATION:The study was conducted by HEVA and data were provided by ATIH according to French regulatory and data protection procedures.

The further development of the frame synchronization method is presented, which uses as a synchronization word the permutation of the elements of the set of integers of the segment [0; M  1], was further developed. It is proposed to use a tuple of M-η pairwise distinct elements of the set of integers of the segment [0; M 1] as a syncword. The elements of this set are encoded with a fixed-length binary code and the minimum binary Hamming distance between the syncword and all its circular shifts is the maximum. The paper established that the maximum value of the minimum Hamming distance for tuples of 15 pairwise distinct elements of the set of integers for M = 16 is equal to 30. A comparative assessment of the frame synchronization effectiveness was performed based on tuples of 15 elements, as well as on permutations of length 16 and 8. A computer simulation model of the frame synchronization system in a binary symmetric communication channel was built. Synchronization indicators were determined with parameters calculated for bit error probability 0,4 and 0,495, as well as requirements for a min-imum probability of correct synchronization of 0,9997 and a maximum probability of false synchronization of 3E-4. The effectiveness of using tuples of pairwise distinct elements in frame synchronization systems has been confirmed. The efficiency indicator depends on com-munication channel bit error probability.

Letermovir is the first approved drug for cytomegalovirus (CMV) infection prophylaxis in adult patients who are CMV positive undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Because CMV infection risk varies from patient to patient, we evaluated whether a risk-based strategy could be effective. In this single-center study, all consecutive adult patients who were CMV positive and underwent allo-HCT between 2015 and 2021 were included. During period 1 (2015-2017), letermovir was not used, whereas during period 2 (2018-2021), letermovir was used in patients at high risk but not in patients at low risk, except in those receiving corticosteroids. In patients at high risk, the incidence of clinically significant CMV infection (csCMVi) in period 2 was lower than that in period 1 (P < .001) by week 14 (10.5% vs 51.6%) and week 24 (16.9% vs 52.7%). In patients at low risk, although only 28.6% of patients received letermovir in period 2, csCMVi incidence was also significantly lower (P = .003) by week 14 (7.9% vs 29.0%) and week 24 (11.2% vs 33.3%). Among patients at low risk who did not receive letermovir (n = 45), 23 patients (51.1%) experienced transient positive CMV DNA without csCMVi, whereas 17 patients (37.8%) experienced negative results. In both risk groups, the 2 periods were comparable for CMV disease, overall survival, progression-free survival, relapse, and nonrelapse mortality. We concluded that a risk-based strategy for letermovir use is an effective strategy which maintains the high efficacy of letermovir in patients at high risk but allows some patients at low risk to not use letermovir.

Les patients transplantés d'organes solides (TOS) suivent un traitement immunosuppresseur (IS) à vie ciblant l'immunité adaptative. Étonnamment, les TOS présentent un risque accru d'infection respiratoire aiguë (IRA) à Pseudomonas aeruginosa (Pa) avec une mortalité de 35 %. Cependant, les facteurs de risque connus de ces IRA relèvent de l'altération de l'immunité innée ou de la barrière épithéliale: cette susceptibilité accrue reste inexpliquée chez les TOS. Ce projet de recherche translationnelle caractérise les modifications induites par IS sur l'épithélium respiratoire au cours de l'IRA à Pa, en criblant toutes les combinaisons existantes. En particulier, les activités de l'acide mycophénolique (MPA, métabolite actif du mycophenolate mofétil -MMF-) et de l'exotoxine de Pa ExoS, qui impliquent le guanosine triphosphate (GTP), sont étudiées. Des cellules bronchiques humaines (BEAS-2B) sont traitées avec toutes les combinaisons d'IS et/ou GTP pendant 24h, puis infectées par Pa (souche PAO1 sauvage ou avec ExoS supprimé -PAO1∆S-). Nous avons évalué la prolifération par compte cellulaire en microscopie confocale, la cytotoxicité par relargage LDH, la mort cellulaire par incorporation d'iodure de propidium en temps réel, l'apoptose par RealTime-Glo®, et la production de cytokines par ELISA et RT-qPCR. Des souris C57BL/6J ont été traitées par MMF intrapéritonéal (à posologie adaptée avec contrôle de taux plasmatiques) pendant 3 jours avant l'infection. Après le sacrifice, un ELISA IL-6/TNFα et un comptage des neutrophiles ont été réalisés sur des lavages broncho-alvéolaires (LBA) murins. Parmi les IS criblés, le MPA seul ou en combinaison augmente la cytotoxicité épithéliale induite par PAO1, et pas par PAO1∆S, d'environ 80 % et accélère la mort cellulaire (de 6 h/24h), sous forme de nécrose (et non d''apoptose). Il diminue la prolifération cellulaire épithéliale de 30% environ sur BEAS-2B. Il diminue également la production des cytokines pro-inflammatoires IL-6 et IL-8 de 40 à 80 %, quel que soit ici le stimulus inflammatoire, en diminuant les activités de transcription de leurs gènes, avant même l'infection. Ces modifications induites par le MPA persistent malgré la correction du nombre de cellules, et sont corrigées par l'ajout de GTP. In vivo, les concentrations d'IL-6, de TNF-α et le recrutement de neutrophiles semblent plus faibles dans le LBA chez les souris traitées par MMF. Après un criblage des combinaisons d'IS utilisées en clinique, nous décrivons plusieurs effets inédits du MPA sur l'épithélium respiratoire. Le MPA altère son intégrité au cours d'une infection à Pa, de façon ExoS-dépendante. Par ailleurs il diminue la capacité de réponse immunitaire épithéliale, effet possiblement retrouvé in vivo. Ces altérations récapitulent deux principaux facteurs de risque d'IRA à Pa. Elles reposent sur la déplétion en GTP, mode d'action classique du MPA. Décrire les effets supplémentaires de l'IS sur l'immunité respiratoire innée et mucosale peut permettre à la fois d'adapter les schémas thérapeutiques lors d'infection respiratoire chez les TOS, et de développer de nouvelles solutions thérapeutiques de type immunomodulateur contre Pa. Aucun lien d'intérêt

Une incidence importante d'infections à pneumocoque (IP) a été observée courant 2022, incluant des patients correctement vaccinés selon le schéma publié par le Haut conseil de la Santé Publique. L'objectif principal était de décrire la population avec IP et d'évaluer le taux de vaccination. Les objectifs secondaires étaient de déterminer les sérotypes des Streptococcus pneumoniae responsables des infections chez les patients vaccinés et d'étudier leur réponse vaccinale. Il s'agit d'une étude descriptive rétrospective monocentrique incluant tous les patients majeurs ayant eu au moins un prélèvement microbiologique positif à S. pneumoniae pendant l'année 2022. Les informations cliniques étaient collectées via le dossier médical informatisé. Cent soixante-huit prélèvements positifs à S. pneumoniae ont été identifiés correspondant à 112 patients (70 hommes avec un âge médian de 62 ans). Une indication vaccinale était retrouvée pour 82,1% des patients (n=92/112), dont la moitié (n=40) présentaient au moins deux indications. Parmi les 92 patients avec indication vaccinale, on notait 46,7% de pathologies respiratoires (n=43), 12,0% de diabète (n=11), 5,4% de cardiopathies (n=5), 0,1% de cirrhose (n=1) et 34,0% d'immunodépression (n=32 avec 1 asplénie, 3 déficits immunitaires primitifs, 10 chimiothérapies, 2 transplantations d'organes, 3 allogreffes, 11 immunosuppresseurs dont corticothérapie et 2 infections par le VIH). La présentation clinique la plus fréquente était la pneumopathie (73,2%, n=82), suivie de la bronchite (15,2%, n=17), puis la bactériémie (1,8%, n=2) et enfin la pleurésie (0,9%, n=1) et la méningite (0,9%, n=1). Parmi les pneumopathies, 13 survenaient en post virales et 23 étaient compliquées d'une bactériémie. Parmi les bronchites, 11 entrainaient une exacerbation respiratoire. Les patients étaient pris en charge en ambulatoire (14,3% n=16), en soins conventionnels (52,7% n=59) ou en réanimation (33,0% n=37) avec un taux de mortalité de 12,5% (n=14/112). Trente-quatre patients étaient vaccinés (n=34/100, 12 données en cours) soit un taux de vaccination de 34,0%. Vingt-six avaient reçu le schéma vaccinal recommandé. La date médiane de vaccination était 2020 avec aucune vaccination remontant à plus de 5 ans. Les sérotypages actuellement disponibles ont mis en évidence 3 sérotypes non vaccinaux (15A, 35B et 35F) et un sérotype vaccinal (19A). Les dosages d'anticorps anti-pneumocoque sont prévus. Ce travail confirme que les infections à S. pneumoniae touchent les patients avec une pathologie respiratoire chronique (46,7%) et les immunodéprimés (34%) malgré un taux de vaccination de 34%. Les deux raisons à ces échecs vaccinaux semblent être l'émergence de sérotypes non vaccinaux (1) et un défaut de réponse vaccinale chez les immunodéprimés (2). Ces données soulignent le besoin de monitorer la réponse vaccinale anti-pneumocoque. (1)Plainvert, ID now, 2023 (2)Cordonnier, Expert Rev Vaccines, 2014 Aucun lien d'intérêt

Ciona larvae display a number of behaviors, including negative phototaxis. In negative phototaxis, the larvae first perform short spontaneous rhythmic casting swims. As larvae are cast in a light field, their photoreceptors are directionally shaded by an associated pigment cell, providing a phototactic cue. This then evokes an extended negative taxis swim. We report here that the larval forebrain of Ciona has a previously uncharacterized single slow-oscillating inhibitory neuron (neuron cor-assBVIN78) that projects to the midbrain, where it targets key interneurons of the phototaxis circuit known as the photoreceptor relay neurons. The anatomical location, gene expression, and oscillation of cor-assBVIN78 suggest homology to oscillating neurons of the vertebrate hypothalamus. Ablation of cor-assBVIN78 results in larvae showing extended phototaxis-like swims, even in the absence of phototactic cues. These results indicate that cor-assBVIN78 has a gating activity on phototaxis by projecting temporally oscillating inhibition to the photoreceptor relay neurons. However, in intact larvae, the frequency of cor-assBVIN78 oscillation does not match that of the rhythmic spontaneous swims, indicating that the troughs in oscillations do not themselves initiate swims but rather that cor-assBVIN78 may modulate the phototaxis circuit by filtering out low-level inputs while restricting them temporally to the troughs in inhibition.