Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

NKp46-mediated Dicer1 inactivation results in defective NK-cell differentiation and effector functions in mice

International audienceMicroRNAs control developmental pathways and effector functions in immune cells. Previous studies have studied the role of microRNAs in natural killer (NK) cells. However, the mouse models of microRNA depletion used were nonNK-specific and only partially depleting, hampering the interpretation of the data obtained. To clarify the role of microRNAs in murine NK cells, we deleted the RNase III enzyme Dicer1 in NKp46-expressing cells. We observed a drastic decrease in several microRNAs specifically in NK cells. Furthermore, the overall size of the "NK-cell" pool was severely decreased, a phenotype associated with compromised survival. Moreover, performing a broad flow cytometry profiling, we show that Dicer1-deficient NK cells failed to complete their differentiation program. In particular, several integrins were inappropriately expressed in mature NK cells. These defects coincided with decreased response to IL-15, a cytokine responsible for "NK-cell" maturation and survival. In addition, Dicer1 deletion impaired key "NK-cell" functions: target cell killing and production of IFN-γ, leading to defective control of metastasis. Dicer1 deletion thus affects "NK-cell" biology in a cell intrinsic manner at several distinct stages

Bacterial Detection Using Unlabeled Phage Amplification and Mass Spectrometry through Structural and Nonstructural Phage Markers

International audienceno abstrac

The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells

International audienceInterleukin 15 (IL-15) controls both the homeostasis and the peripheral activation of natural killer (NK) cells. The molecular basis for this duality of action remains unknown. Here we found that the metabolic checkpoint kinase mTOR was activated and boosted bioenergetic metabolism after exposure of NK cells to high concentrations of IL-15, whereas low doses of IL-15 triggered only phosphorylation of the transcription factor STAT5. mTOR stimulated the growth and nutrient uptake of NK cells and positively fed back on the receptor for IL-15. This process was essential for sustaining NK cell proliferation during development and the acquisition of cytolytic potential during inflammation or viral infection. The mTORC1 inhibitor rapamycin inhibited NK cell cytotoxicity both in mice and humans; this probably contributes to the immunosuppressive activity of this drug in different clinical settings

Bacterial Detection Using Unlabeled Phage Amplification and Mass Spectrometry through Structural and Nonstructural Phage Markers

According to the World Health Organization, food safety is an essential public health priority. In this context, we report a relevant proof of feasibility for the indirect specific detection of bacteria in food samples using unlabeled phage amplification coupled to ESI mass spectrometry analysis and illustrated with the model phage systems T4 and SPP1. High-resolving power mass spectrometry analysis (including bottom-up and top-down protein analysis) was used for the discovery of specific markers of phage infection. Structural components of the viral particle and nonstructural proteins encoded by the phage genome were identified. Then, targeted detection of these markers was performed on a triple quadrupole mass spectrometer operating in the selected reaction monitoring mode. <i>E. coli</i> at 1 × 10⁵, 5 × 10⁵, and 1 × 10⁶ CFU/mL concentrations was successfully detected after only a 2 h infection time by monitoring phage T4 structural markers in Luria–Bertani broth, orange juice, and French bean stew (“cassoulet”) matrices. Reproducible detection of nonstructural markers was also demonstrated, particularly when a high titer of input phages was required to achieve successful amplification. This strategy provides a highly time-effective and sensitive assay for bacterial detection

Welfare barriers and levers for improvement in organic and low-input outdoor pig and poultry production systems

International audienceThe PPILOW project aims to co-construct innovations to improve Poultry and Pig Welfare in Low-input outdoor and Organic farming systems through a multi-actor approach. Its first step was to sum up animal welfare challenges observed in these systems and levers of improvement, from a review of literature data and research projects. Data were completed with information from key informants of the supply chains of poultry meat, eggs and pork in Italy, France, the United Kingdom and Finland. The interviews indicated that the main issues in poultry were: feeding, biosecurity, lack of range use and range management, feather pecking, weather, regulation, flock size or density, predation, bone fractures, lack of robustness, parasitism, pododermatitis, arthrosis, nervousness, water quality, catching and time spent by farmers. The main issues in pig were: feeding, tail biting, mortality, weather, predation, lack of robustness, lack of range use, castration, animal aggressiveness and competition, water quality, range management, human welfare, biosecurity issues, flock size or density, parasitism, insolation burns, joint abnormalities, parturition in freedom and pollution. This information has implemented a participatory approach for proposing welfare-improvement levers. Some issues and potential solutions were included in PPILOW experiments (phytotherapy against parasitism, involvement of animal personality in range use, rearing of entire pig males, genetic selection for reduced piglet mortality, improved farrowing huts for sows and piglets reared on range, avoiding feather pecking in laying hens with intact beaks, avoiding the killing of day-old male chicks etc.), and solution costs evaluated. The results will provide a combination of practical solutions for welfare improvement in Europe. The PPILOW project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement N°816172

Welfare barriers and levers for improvement in organic and low-input outdoor pig and poultry production systems

International audienceThe PPILOW project aims to co-construct innovations to improve Poultry and Pig Welfare in Low-input outdoor and Organic farming systems through a multi-actor approach. Its first step was to sum up animal welfare challenges observed in these systems and levers of improvement, from a review of literature data and research projects. Data were completed with information from key informants of the supply chains of poultry meat, eggs and pork in Italy, France, the United Kingdom and Finland. The interviews indicated that the main issues in poultry were: feeding, biosecurity, lack of range use and range management, feather pecking, weather, regulation, flock size or density, predation, bone fractures, lack of robustness, parasitism, pododermatitis, arthrosis, nervousness, water quality, catching and time spent by farmers. The main issues in pig were: feeding, tail biting, mortality, weather, predation, lack of robustness, lack of range use, castration, animal aggressiveness and competition, water quality, range management, human welfare, biosecurity issues, flock size or density, parasitism, insolation burns, joint abnormalities, parturition in freedom and pollution. This information has implemented a participatory approach for proposing welfare-improvement levers. Some issues and potential solutions were included in PPILOW experiments (phytotherapy against parasitism, involvement of animal personality in range use, rearing of entire pig males, genetic selection for reduced piglet mortality, improved farrowing huts for sows and piglets reared on range, avoiding feather pecking in laying hens with intact beaks, avoiding the killing of day-old male chicks etc.), and solution costs evaluated. The results will provide a combination of practical solutions for welfare improvement in Europe. The PPILOW project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement N°816172

The PPILOW project: Innovations improving welfare in low input and organic pig and poultry farms

International audienceThe PPILOW project aims to co-construct innovations to improve Poultry and Pig Welfare in Low-input outdoor and Organic farming systems through a multi-actor approach. PPILOW implements a participatory approach for proposing and studying welfare-improvement levers. It will provide a combination of practical solutions that can be applied at a pan-European level with specific adjustments depending on citizen’s expectations and the target market. The multi-actor approach consists in involving end-users including farmers, breeding companies, feed producers, consumer associations, retailers, advisers, processors, and scientists in National Practitioner Groups (NPG) in six participating countries. PPILOW partners facilitate the groups by connecting NPG at European level, transferring scientific information, interacting with partners engaged in animal experiments, and co-creating innovations rising from NPG-specific demands. They co-build with PPILOW partners welfare self-assessment tools (development of the PIGLOW app for pigs and refinement of the EBENE® app for poultry), and innovative breeding, feeding, and rearing strategies and techniques to improve the welfare of animals. They co-design protocols, test innovations on farm, and disseminate the results. In turn, they receive insights on methods and scientific results, and inputs from other NPG reinforcing the value of the expected outcomes. Approaches focus on avoiding physical damage and the elimination of layer male chicks, on reducing boar taint of intact male pigs, promoting positive behaviours, animal health, and robustness through field studies with pigs and poultry. Multicriteria analyses of the most effective levers of welfare improvement will be performed to evaluate their economic, social, and environmental impacts based on the ‘One Welfare’ concept; economic and business models will also be developed. To ensure the rapid uptake of the project results by end-users, the close involvement of PPILOW’s NPG throughout the EU will ensure disseminationactivities and the facilitation of change. The PPILOW project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement N°816172. www.ppilow.eu

The PPILOW project: Innovations improving welfare in low input and organic pig and poultry farms

International audienceThe PPILOW project aims to co-construct innovations to improve Poultry and Pig Welfare in Low-input outdoor and Organic farming systems through a multi-actor approach. PPILOW implements a participatory approach for proposing and studying welfare-improvement levers. It will provide a combination of practical solutions that can be applied at a pan-European level with specific adjustments depending on citizen’s expectations and the target market. The multi-actor approach consists in involving end-users including farmers, breeding companies, feed producers, consumer associations, retailers, advisers, processors, and scientists in National Practitioner Groups (NPG) in six participating countries. PPILOW partners facilitate the groups by connecting NPG at European level, transferring scientific information, interacting with partners engaged in animal experiments, and co-creating innovations rising from NPG-specific demands. They co-build with PPILOW partners welfare self-assessment tools (development of the PIGLOW app for pigs and refinement of the EBENE® app for poultry), and innovative breeding, feeding, and rearing strategies and techniques to improve the welfare of animals. They co-design protocols, test innovations on farm, and disseminate the results. In turn, they receive insights on methods and scientific results, and inputs from other NPG reinforcing the value of the expected outcomes. Approaches focus on avoiding physical damage and the elimination of layer male chicks, on reducing boar taint of intact male pigs, promoting positive behaviours, animal health, and robustness through field studies with pigs and poultry. Multicriteria analyses of the most effective levers of welfare improvement will be performed to evaluate their economic, social, and environmental impacts based on the ‘One Welfare’ concept; economic and business models will also be developed. To ensure the rapid uptake of the project results by end-users, the close involvement of PPILOW’s NPG throughout the EU will ensure disseminationactivities and the facilitation of change. The PPILOW project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement N°816172. www.ppilow.eu