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1. Improving motion‐mask segmentation in thoracic CT with multiplanar U‐nets

Author: Nicolas Pinon, Maciej Orkisz, Jean-Christophe Richard, Ludmilla Penarrubia, Eduardo Enrique Dávila Serrano, David Sarrut, Emmanuel Roux, Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation Médicale, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), and Imagerie Tomographique et Radiothérapie
Subjects: Lung Neoplasms, Computer science, Image registration, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Robustness (computer science), Carcinoma, Non-Small-Cell Lung, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Image Processing, Computer-Assisted, Humans, Segmentation, Generalizability theory, Computer vision, Four-Dimensional Computed Tomography, Artificial neural network, SARS-CoV-2, business.industry, Deep learning, Process (computing), COVID-19, General Medicine, 3. Good health, 030220 oncology & carcinogenesis, Memory footprint, Artificial intelligence, business
Abstract: International audience; Purpose. Motion-mask segmentation from thoracic computed tomography (CT) images is the process of extracting the region that encompasses lungs and viscera, where large displacements occur during breathing. It has been shown to help image registration between different respiratory phases. This registration step is, for example, useful for radiotherapy planning or calculating local lung ventilation. Knowing the location of motion discontinuity, that is, sliding motion near the pleura, allows a better control of the registration preventing unrealistic estimates. Nevertheless, existing methods for motion-mask segmentation are not robust enough to be used in clinical routine. This article shows that it is feasible to overcome this lack of robustness by using a lightweight deep-learning approach usable on a standard computer, and this even without data augmentation or advanced model design.Methods. A convolutional neural-network architecture with three 2D U-nets for the three main orientations (sagittal, coronal, axial) was proposed. Predictions generated by the three U-nets were combined by majority voting to provide a single 3D segmentation of the motion mask. The networks were trained on a database of nonsmall cell lung cancer 4D CT images of 43 patients. Training and evaluation were done with a K-fold cross-validation strategy. Evaluation was based on a visual grading by two experts according to the appropriateness of the segmented motion mask for the registration task, and on a comparison with motion masks obtained by a baseline method using level sets. A second database (76 CT images of patients with early-stage COVID-19), unseen during training, was used to assess the generalizability of the trained neural network.Results. The proposed approach outperformed the baseline method in terms of quality and robustness: the success rate increased from urn:x-wiley:00942405:media:mp15347:mp15347-math-0001 to urn:x-wiley:00942405:media:mp15347:mp15347-math-0002 without producing any failure. It also achieved a speed-up factor of 60 with GPU, or 17 with CPU. The memory footprint was low: less than 5 GB GPU RAM for training and less than 1 GB GPU RAM for inference. When evaluated on a dataset with images differing by several characteristics (CT device, pathology, and field of view), the proposed method improved the success rate from urn:x-wiley:00942405:media:mp15347:mp15347-math-0003 to urn:x-wiley:00942405:media:mp15347:mp15347-math-0004.Conclusion. With 5-s processing time on a mid-range GPU and success rates around urn:x-wiley:00942405:media:mp15347:mp15347-math-0005, the proposed approach seems fast and robust enough to be routinely used in clinical practice. The success rate can be further improved by incorporating more diversity in training data via data augmentation and additional annotated images from different scanners and diseases. The code and trained model are publicly available.
Published: 2021
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2. Longitudinal changes in compliance, oxygenation and ventilatory ratio in COVID-19 versus non-COVID-19 pulmonary acute respiratory distress syndrome

Author: Ferhat Meziani, Julien Demiselle, Nicolas Fage, Antoine Studer, Sibylle Cunat, Jean-Christophe Richard, Alain Mercat, François Beloncle, Satar Mortaza, Hamid Merdji, Laurent Brochard, Bertrand Pavlovsky, Christophe Desprez, Julie Helms, Valérie Seegers, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Strasbourg, Université de Strasbourg (UNISTRA), Integrated Center for Oncology [Angers] (ICO), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), LUNAM Université [Nantes Angers Le Mans], Regenerative NanoMedicine [Strasbourg] (RNM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), St. Michael's Hospital, University of Toronto, RICHARD, Jean-Christophe, and Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC)
Subjects: Male, ARDS, Letter, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], medicine.medical_treatment, Respiratory mechanics, Respiratory failure, Critical Care and Intensive Care Medicine, Severity of Illness Index, Body Mass Index, Positive-Pressure Respiration, 03 medical and health sciences, Dead space, 0302 clinical medicine, Mechanical ventilation, Medicine, Humans, 030212 general & internal medicine, Respiratory system, Propensity Score, Acute Respiratory Distress Syndrome, Aged, Respiratory Distress Syndrome, Pulmonary Gas Exchange, business.industry, SARS-CoV-2, RC86-88.9, Research, Medical emergencies. Critical care. Intensive care. First aid, Oxygenation, Middle Aged, medicine.disease, Respiration, Artificial, Respiratory Function Tests, [SDV] Life Sciences [q-bio], Compliance (physiology), Clinical trial, Intensive Care Units, 030228 respiratory system, Anesthesia, Female, Blood Gas Analysis, business, Covid-19, Body mass index
Abstract: Background Differences in physiology of ARDS have been described between COVID-19 and non-COVID-19 patients. This study aimed to compare initial values and longitudinal changes in respiratory system compliance (CRS), oxygenation parameters and ventilatory ratio (VR) in patients with COVID-19 and non-COVID-19 pulmonary ARDS matched on oxygenation. Methods 135 patients with COVID-19 ARDS from two centers were included in a physiological study; 767 non-COVID-19 ARDS from a clinical trial were used for the purpose of at least 1:2 matching. A propensity-matching was based on age, severity score, oxygenation, positive end-expiratory pressure (PEEP) and pulmonary cause of ARDS and allowed to include 112 COVID-19 and 198 non-COVID pulmonary ARDS. Results The two groups were similar on initial oxygenation. COVID-19 patients had a higher body mass index, higher CRS at day 1 (median [IQR], 35 [28–44] vs 32 [26–38] ml cmH2O−1, p = 0.037). At day 1, CRS was correlated with oxygenation only in non-COVID-19 patients; 61.6% and 68.2% of COVID-19 and non-COVID-19 pulmonary ARDS were still ventilated at day 7 (p = 0.241). Oxygenation became lower in COVID-19 than in non-COVID-19 patients at days 3 and 7, while CRS became similar. VR was lower at day 1 in COVID-19 than in non-COVID-19 patients but increased from day 1 to 7 only in COVID-19 patients. VR was higher at days 1, 3 and 7 in the COVID-19 patients ventilated using heat and moisture exchangers compared to heated humidifiers. After adjustment on PaO2/FiO2, PEEP and humidification device, CRS and VR were found not different between COVID-19 and non-COVID-19 patients at day 7. Day-28 mortality did not differ between COVID-19 and non-COVID-19 patients (25.9% and 23.7%, respectively, p = 0.666). Conclusions For a similar initial oxygenation, COVID-19 ARDS initially differs from classical ARDS by a higher CRS, dissociated from oxygenation. CRS become similar for patients remaining on mechanical ventilation during the first week of evolution, but oxygenation becomes lower in COVID-19 patients. Trial registration: clinicaltrials.gov NCT04385004
Published: 2021
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3. Protracted viral shedding and viral load are associated with ICU mortality in Covid-19 patients with acute respiratory failure

Author: Louis Chauvelot, François Dhelft, Sophie Trouillet-Assant, Laure Folliet, Laurent Bitker, Jean-Christophe Richard, Bruno Lina, Emilie Frobert, A Belot, Florent Wallet, and Mehdi Mezidi
Subjects: medicine.medical_specialty, SARS-COV-2, Critical Care and Intensive Care Medicine, Acute respiratory failure, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Intensive care, Pulmonary fibrosis, medicine, Viral load, 030212 general & internal medicine, Viral shedding, Bronchiectasis, Lung, Acute respiratory distress syndrome, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, COVID-19, Retrospective cohort study, lcsh:RC86-88.9, medicine.disease, Polymerase chain reaction, Pneumonia, medicine.anatomical_structure, business
Abstract: BackgroundProtracted viral shedding is common in hospitalized patients with COVID-19 pneumonia, and up to 40% display signs of pulmonary fibrosis on computed tomography (CT) after hospital discharge. We hypothesized that COVID-19 patients with acute respiratory failure (ARF) who die in intensive care units (ICU) have a lower viral clearance in the respiratory tract than ICU patients discharged alive, and that protracted viral shedding in respiratory samples is associated with patterns of fibroproliferation on lung CT. We, therefore, conducted a retrospective observational study, in 2 ICU of Lyon university hospital.Results129 patients were included in the study, of whom 44 (34%) died in ICU. 432 RT-PCR for SARS-CoV-2 were performed and 137 CT scans were analyzed. Viral load was significantly higher in patients deceased as compared to patients alive at ICU discharge (p 95 %:15–21] in patients alive at ICU discharge and 26 days [CI95 %:17-infinity] in non-survivors at ICU discharge. Competitive risk regression identified patients who died in ICU and age as independent risk factors for longer time to SARS-CoV-2 negativation on RT-PCR, while antiviral treatment was independently associated with shorter time. None of the CT scores exploring fibroproliferation (i.e., bronchiectasis and reticulation scores) were significantly associated with time to SARS-CoV-2 negativation.ConclusionsViral load in respiratory samples is significantly lower and viral shedding significantly shorter in ICU survivors of COVID-19 associated acute respiratory failure. Protracted viral shedding is unrelated to occurrence of fibrosis on lung CT.
Published: 2020

4. Pulmonary aspergillosis in critically ill patients with Coronavirus Disease 2019 (COVID-19)

Author: F. Wallet, Laurent Argaud, Florence Persat, Jean Turc, Jean Menotti, Jean-Christophe Richard, Charline Miossec, Martine Wallon, Damien Dupont, S. Paulus, Florence Ader, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Université de Lyon-Université de Lyon, Hôpital Edouard Herriot [CHU - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Hôpital Louis Pradel [CHU - HCL], Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CarMeN, laboratoire, Centre de recherche en neurosciences de Lyon (CRNL), and Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Critical Illness, [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Aspergillosis, intensive care unit, law.invention, 03 medical and health sciences, 0302 clinical medicine, law, Internal medicine, pulmonary aspergillosis, Pandemic, Humans, Medicine, 030212 general & internal medicine, Aged, Aged, 80 and over, Invasive Pulmonary Aspergillosis, 0303 health sciences, Aspergillus, biology, SARS-CoV-2, 030306 microbiology, Critically ill, business.industry, Brief Report, COVID-19, General Medicine, Middle Aged, acute respiratory distress syndrome, medicine.disease, biology.organism_classification, Intensive care unit, 3. Good health, [SDV] Life Sciences [q-bio], Intensive Care Units, Pulmonary aspergillosis, Infectious Diseases, AcademicSubjects/SCI00960, Female, AcademicSubjects/MED00010, business, COVID-19 associated pulmonary aspergillosis (CAPA)
Abstract: Occurrence of putative invasive pulmonary aspergillosis was screened in 153 consecutive adult intensive care unit (ICU) patients with respiratory samples addressed for mycological diagnosis during a 6-week period at the emergence of coronavirus disease 2019 (COVID-19) pandemic. Positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) was observed for 106 patients (69.3%). Nineteen of them (17.9%) with positive Aspergillus results were considered as having putative invasive pulmonary aspergillosis. These observations underline the risk of pulmonary aspergillosis in COVID-19 patients, even in patients not previously known to be immunosuppressed, advocating active search for Aspergillus infection and prompt antifungal treatment. Standardized surveillance protocols and updated definitions for ICU putative invasive pulmonary aspergillosis are needed. Lay Abstract Adult ICU patients with respiratory samples addressed for mycological diagnosis were screened during the emergence of COVID-19 pandemic. Positive SARS-CoV-2 PCR was observed for 106 patients, nineteen of them (17.9%) having aspergillosis. This underlines the risk of aspergillosis in COVID-19 patients.
Published: 2020
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5. Continuous positive airway pressure for respiratory support during COVID-19 pandemic: a frugal approach from bench to bedside

Author: Bilal Badat, Nicolas Mongardon, Keyvan Razazi, C. Deguillard, Frédéric Schlemmer, Mehdi Khellaf, Raphaëlle Huguet, Pascal Lim, Nicolas de Prost, François Templier, Karim Jaffal, Dominique Savary, Francois Morin, Elena Fois, Yvon Deplante, François Beloncle, François Perier, Constance Guillaud, Laurent Brochard, Philippe Grimbert, Armand Mekontso Dessap, Anne-Fleur Haudebourg, Jean-Christophe Richard, Samuel Tuffet, Manuella Pons, Vincent Audard, Arnaud Lesimple, Alain Mercat, Guillaume Carteaux, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Henri Mondor [Créteil], Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre Hospitalier Universitaire [Grenoble] (CHU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département de neurosciences (CHU Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, University of Toronto, Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Henri Mondor, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Chard-Hutchinson, Xavier, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: medicine.medical_specialty, medicine.medical_treatment, Continuous positive airway pressure, Context (language use), Respiratory physiology, Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, Work of breathing, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Anesthesiology, medicine, Intubation, Tidal volume, Acute hypoxemic respiratory failure, Frugal innovation, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, COVID-19, 030208 emergency & critical care medicine, lcsh:RC86-88.9, Oxygenation, 3. Good health, respiratory tract diseases, 030228 respiratory system, Emergency medicine, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business
Abstract: Background We describe a frugal approach (focusing on needs, performance, and costs) to manage a massive influx of COVID-19 patients with acute hypoxemic respiratory failure (AHRF) using the Boussignac valve protected by a filter (“Filter Frugal CPAP”, FF-CPAP) in and out the ICU. Methods (1) A bench study measured the impact of two filters with different mechanical properties on CPAP performances, and pressures were also measured in patients. (2) Non-ICU healthcare staff working in COVID-19 intermediate care units were trained with a video tutorial posted on a massive open online course. (3) A clinical study assessed the feasibility and safety of using FF-CPAP to maintain oxygenation and manage patients out of the ICU during a massive outbreak. Results Bench assessments showed that adding a filter did not affect the effective pressure delivered to the patient. The resistive load induced by the filter variably increased the simulated patient’s work of breathing (6–34%) needed to sustain the tidal volume, depending on the filter’s resistance, respiratory mechanics and basal inspiratory effort. In patients, FF-CPAP achieved pressures similar to those obtained on the bench. The massive training tool provided precious information on the use of Boussignac FF-CPAP on COVID-19 patients. Then 85 COVID-19 patients with ICU admission criteria over a 1-month period were studied upon FF-CPAP initiation for AHRF. FF-CPAP significantly decreased respiratory rate and increased SpO2. Thirty-six (43%) patients presented with respiratory indications for intubation prior to FF-CPAP initiation, and 13 (36%) of them improved without intubation. Overall, 31 patients (36%) improved with FF-CPAP alone and 17 patients (20%) did not require ICU admission. Patients with a respiratory rate > 32 breaths/min upon FF-CPAP initiation had a higher cumulative probability of intubation (p Conclusion Adding a filter to the Boussignac valve does not affect the delivered pressure but may variably increase the resistive load depending on the filter used. Clinical assessment suggests that FF-CPAP is a frugal solution to provide a ventilatory support and improve oxygenation to numerous patients suffering from AHRF in the context of a massive outbreak.
Published: 2021
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6. Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs

Author: Andrés Pizzorno, Thomas Julien, Alexandre Belot, Jean-Baptiste Fassier, Stéphane Paul, Jean-Laurent Casanova, Manuel Rosa-Calatrava, Blandine Padey, Thierry Walzer, Antonin Bal, Karen Brengel-Pesce, Marine Villard, Sophie Trouillet-Assant, Florence Morfin, Bruno Lina, Valérie Cheynet, Victoria Duliere, Mehdi Mezidi, Marine Mommert, Jean-Christophe Richard, Paul Bastard, William Mouton, Jonathan Lopez, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Bio-Mérieux [Marcy l'Etoile], BIOMERIEUX, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anesthésie et de Soins Intensifs [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Institut des Agents Infectieux [Lyon] (IAI), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Unité Mixte de Recherche Epidémiologique et de Surveillance Transport Travail Environnement (UMRESTTE UMR_T9405), Université de Lyon-Université de Lyon-Université Gustave Eiffel, Université de Lyon, Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Howard Hughes Medical Institute (HHMI), ANR-20-COVI-0003,GENCOVID,Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé(2020), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Paris Cité, Equipe HAL, Identification des défauts monogéniques de l'immunité responsables des formes sévères de COVID-19 chez les patients précédemment en bonne santé - - GENCOVID2020 - ANR-20-COVI-0003 - COVID-19 - VALID, and Instituts Hospitalo-Universitaires - Institut Hospitalo-Universitaire Imagine - - Imagine2010 - ANR-10-IAHU-0001 - IAHU - VALID
Subjects: Nasal cavity, antivirus agent, Immunology, Mucous membrane of nose, 03 medical and health sciences, 0302 clinical medicine, Immunity, medicine, Immunology and Allergy, Nose, 030304 developmental biology, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, business.industry, Autoantibody, interferon, respiratory system, 3. Good health, medicine.anatomical_structure, Viral replication, 030220 oncology & carcinogenesis, business, Viral load, Interferon type I, autoantibody, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract: International audience; IFN-I and IFN-III immunity in the nasal mucosa is poorly characterized during SARS-CoV-2 infection. We analyze the nasal IFN-I/III signature, namely the expression of ISGF-3–dependent IFN-stimulated genes, in mildly symptomatic COVID-19 patients and show its correlation with serum IFN-α2 levels, which peak at symptom onset and return to baseline from day 10 onward. Moreover, the nasal IFN-I/III signature correlates with the nasopharyngeal viral load and is associated with the presence of infectious viruses. By contrast, we observe low nasal IFN-I/III scores despite high nasal viral loads in a subset of critically ill COVID-19 patients, which correlates with the presence of autoantibodies (auto-Abs) against IFN-I in both blood and nasopharyngeal mucosa. In addition, functional assays in a reconstituted human airway epithelium model of SARS-CoV-2 infection confirm the role of such auto-Abs in abrogating the antiviral effects of IFN-I, but not those of IFN-III. Thus, IFN-I auto-Abs may compromise not only systemic but also local antiviral IFN-I immunity at the early stages of SARS-CoV-2 infection.
Published: 2021
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7. Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial

Author: Florence Ader, Maude Bouscambert-Duchamp, Maya Hites, Nathan Peiffer-Smadja, Julien Poissy, Drifa Belhadi, Alpha Diallo, Minh-Patrick Lê, Gilles Peytavin, Thérèse Staub, Richard Greil, Jérémie Guedj, Jose-Artur Paiva, Dominique Costagliola, Yazdan Yazdanpanah, Charles Burdet, France Mentré, Alexander Egle, Michael Joannidis, Bernd Lamprecht, Antoine Altdorfer, Leila Belkhir, Vincent Fraipont, Gil Verschelden, Jérôme Aboab, Hafid Ait-Oufella, Claire Andrejak, Pascal Andreu, Laurent Argaud, Firouzé Bani-Sadr, François Benezit, Mathieu Blot, Elisabeth Botelho-Nevers, Lila Bouadma, Olivier Bouchaud, David Bougon, Kevin Bouiller, Fanny Bounes-Vardon, David Boutoille, Alexandre Boyer, Cédric Bruel, André Cabié, Emmanuel Canet, Charles Cazanave, Cyrille Chabartier, Catherine Chirouze, Raphaël Clere-Jehl, Johan Courjon, Flora Crockett, François Danion, Agathe Delbove, Jean Dellamonica, Félix Djossou, Clément Dubost, Alexandre Duvignaud, Olivier Epaulard, Loïc Epelboin, Murielle Fartoukh, Karine Faure, Emmanuel Faure, Tristan Ferry, Cécile Ficko, Samy Figueiredo, Benjamin Gaborit, Rostane Gaci, Amandine Gagneux-Brunon, Sébastien Gallien, Denis Garot, Guillaume Geri, Sébastien Gibot, François Goehringer, Marie Gousseff, Didier Gruson, Yves Hansmann, Olivier Hinschberger, Stéphane Jaureguiberry, Vanessa Jeanmichel, Solen Kerneis, Antoine Kimmoun, Kada Klouche, Marie Lachâtre, Karine Lacombe, Fabrice Laine, Jean-Philippe Lanoix, Odile Launay, Bruno Laviolle, Vincent Le Moing, Jérôme Le Pavec, Yves Le Tulzo, Paul Le Turnier, David Lebeaux, Benjamin Lefevre, Sylvie Leroy, François-Xavier Lescure, Henry Lessire, Benjamin Leveau, Paul Loubet, Alain Makinson, Denis Malvy, Charles-Hugo Marquette, Guillaume Martin-Blondel, Martin Martinot, Julien Mayaux, Armand Mekontso-Dessap, Ferhat Meziani, Jean-Paul Mira, Jean-Michel Molina, Xavier Monnet, Joy Mootien, Bruno Mourvillier, Marlène Murris-Espin, Jean-Christophe Navellou, Saad Nseir, Walid Oulehri, Thomas Perpoint, Gilles Pialoux, Benoît Pilmis, Vincent Piriou, Lionel Piroth, Valérie Pourcher, Jean-Pierre Quenot, François Raffi, Jean Reignier, Matthieu Revest, Jean-Christophe Richard, Béatrice Riu-Poulenc, Céline Robert, Pierre-Alexandre Roger, Claire Roger, Elisabeth Rouveix-Nordon, Yvon Ruch, Nadia Saidani, Naomi Sayre, Eric Senneville, Albert Sotto, Francois Stefan, Charles Tacquard, Nicolas Terzi, Julien Textoris, Guillaume Thiery, Jean-François Timsit, Violaine Tolsma, Jean-Marie Turmel, Florent Valour, Florent Wallet, Guilhem Wattecamps, Yoann Zerbib, Marc Berna, Jean Reuter, Sandra Braz, Joao-Miguel Ferreira Ribeiro, José-Artur Paiva, Roberto Roncon-Albuquerque, Alexandre Gaymard, Bruno Lina, Sarah Tubiana, Sandrine Couffin-Cadièrgues, Hélène Esperou, Aline Dechanet, Christelle Delmas, Claire Fougerou, Noémie Mercier, Marion Noret, Juliette Saillard, Priyanka Velou, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Internal Medicine, Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université libre de Bruxelles (ULB), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Imperial College London, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), ANRS - Maladies infectieuses émergentes (ANRS - MIE), Institut National de la Santé et de la Recherche Médicale (INSERM), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Universidade do Porto = University of Porto, Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), CHU Pontchaillou [Rennes], Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), ARN régulateurs bactériens et médecine (BRM), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), European Union Commission, French Ministry of Health, Domaine d'intérêt majeur One Health Île-de-France, REACTing, Fonds Erasme-COVID-Université Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation., Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology, and UCL - (SLuc) Service de médecine interne générale
Subjects: Male, medicine.medical_specialty, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Population, 030204 cardiovascular system & hematology, Antiviral Agents, law.invention, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, 0302 clinical medicine, Randomized controlled trial, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, law, Internal medicine, Humans, Medicine, media_common.cataloged_instance, 030212 general & internal medicine, European union, education, Contraindication, ComputingMilieux_MISCELLANEOUS, Aged, media_common, Mechanical ventilation, education.field_of_study, Alanine, business.industry, COVID-19, Standard of Care, Odds ratio, Articles, Middle Aged, Respiration, Artificial, Adenosine Monophosphate, COVID-19 Drug Treatment, 3. Good health, Europe, Hospitalization, Oxygen, Clinical trial, Infectious Diseases, Clinical research, Female, business
Abstract: Summary Background The antiviral efficacy of remdesivir against SARS-CoV-2 is still controversial. We aimed to evaluate the clinical efficacy of remdesivir plus standard of care compared with standard of care alone in patients admitted to hospital with COVID-19, with indication of oxygen or ventilator support. Methods DisCoVeRy was a phase 3, open-label, adaptive, multicentre, randomised, controlled trial conducted in 48 sites in Europe (France, Belgium, Austria, Portugal, Luxembourg). Adult patients (aged ≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and illness of any duration were eligible if they had clinical evidence of hypoxaemic pneumonia, or required oxygen supplementation. Exclusion criteria included elevated liver enzymes, severe chronic kidney disease, any contraindication to one of the studied treatments or their use in the 29 days before random assignment, or use of ribavirin, as well as pregnancy or breastfeeding. Participants were randomly assigned (1:1:1:1:1) to receive standard of care alone or in combination with remdesivir, lopinavir–ritonavir, lopinavir–ritonavir and interferon beta-1a, or hydroxychloroquine. Randomisation used computer-generated blocks of various sizes; it was stratified on severity of disease at inclusion and on European administrative region. Remdesivir was administered as 200 mg intravenous infusion on day 1, followed by once daily, 1-h infusions of 100 mg up to 9 days, for a total duration of 10 days. It could be stopped after 5 days if the participant was discharged. The primary outcome was the clinical status at day 15 measured by the WHO seven-point ordinal scale, assessed in the intention-to-treat population. Safety was assessed in the modified intention-to-treat population and was one of the secondary outcomes. This trial is registered with the European Clinical Trials Database, EudraCT2020-000936-23, and ClinicalTrials.gov, NCT04315948. Findings Between March 22, 2020, and Jan 21, 2021, 857 participants were enrolled and randomly assigned to remdesivir plus standard of care (n=429) or standard of care only (n=428). 15 participants were excluded from analysis in the remdesivir group, and ten in the control group. At day 15, the distribution of the WHO ordinal scale was: (1) not hospitalised, no limitations on activities (61 [15%] of 414 in the remdesivir group vs 73 [17%] of 418 in the control group); (2) not hospitalised, limitation on activities (129 [31%] vs 132 [32%]); (3) hospitalised, not requiring supplemental oxygen (50 [12%] vs 29 [7%]); (4) hospitalised, requiring supplemental oxygen (76 [18%] vs 67 [16%]); (5) hospitalised, on non-invasive ventilation or high flow oxygen devices (15 [4%] vs 14 [3%]); (6) hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation (62 [15%] vs 79 [19%]); (7) death (21 [5%] vs 24 [6%]). The difference between treatment groups was not significant (odds ratio 0·98 [95% CI 0·77–1·25]; p=0·85). There was no significant difference in the occurrence of serious adverse events between treatment groups (remdesivir, 135 [33%] of 406 vs control, 130 [31%] of 418; p=0·48). Three deaths (acute respiratory distress syndrome, bacterial infection, and hepatorenal syndrome) were considered related to remdesivir by the investigators, but only one by the sponsor's safety team (hepatorenal syndrome). Interpretation No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support. Funding European Union Commission, French Ministry of Health, Domaine d'interet majeur One Health Ile-de-France, REACTing, Fonds Erasme-COVID-Universite Libre de Bruxelles, Belgian Health Care Knowledge Centre, Austrian Group Medical Tumor, European Regional Development Fund, Portugal Ministry of Health, Portugal Agency for Clinical Research and Biomedical Innovation. Translation For the French translation of the abstract see Supplementary Materials section.
Published: 2021
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8. Feasibility and safety of ultra-low tidal volume ventilation without extracorporeal circulation in moderately severe and severe ARDS patients

Author: Sophie Marqué, Michel Muller, Laurent Bitker, Jack Richecoeur, J. Dellamonica, Gaetan Beduneau, Gwenaël Prat, Jean-Pierre Quenot, Jean-Christophe Richard, E. Soum, Romain Tapponnier, Antoine Gros, Laboratoire d'Astrophysique de l'Observatoire Midi-Pyrénées (LATT), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut national des sciences de l'Univers (INSU - CNRS)-Observatoire Midi-Pyrénées (OMP), Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Météo France-Centre National d'Études Spatiales [Toulouse] (CNES)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Centre National de la Recherche Scientifique (CNRS), Chimie, biologie et radicaux libres - UMR 6517 (CBRL), Université de la Méditerranée - Aix-Marseille 2-Université Paul Cézanne - Aix-Marseille 3-Université de Provence - Aix-Marseille 1-Centre National de la Recherche Scientifique (CNRS), CHRU Brest - Service de Réanimation Médicale (CHU - BREST - Réa Med), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Groupe de Recherche sur le Handicap Ventilatoire (GRHV), Institute for Research and Innovation in Biomedicine (IRIB), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université Nice Sophia Antipolis (1965 - 2019) (UNS)
Subjects: Male, Extracorporeal Circulation, ARDS, Ventilator-Induced Lung Injury, medicine.medical_treatment, Lung injury, Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Positive-Pressure Respiration, 03 medical and health sciences, 0302 clinical medicine, Tidal Volume, medicine, Humans, ComputingMilieux_MISCELLANEOUS, Tidal volume, Aged, Acidosis, Mechanical ventilation, Respiratory Distress Syndrome, business.industry, Extracorporeal circulation, 030208 emergency & critical care medicine, Middle Aged, respiratory system, medicine.disease, Respiration, Artificial, 3. Good health, Respiratory acidosis, 030228 respiratory system, Anesthesia, Breathing, Feasibility Studies, Female, medicine.symptom, business, Follow-Up Studies
Abstract: Mechanical ventilation with ultra-low tidal volume (VT) during ARDS may reduce alveolar strain, driving pressure and hence ventilator-induced lung injury, with the main drawback of worsening respiratory acidosis. We hypothesized that VT could be reduced down to 4 ml/kg, with clinically significant decrease in driving pressure, without the need for extracorporeal CO2 removal, while maintaining pH > 7.20. We conducted a non-experimental before-and-after multicenter study on 35 ARDS patients with PaO2/FiO2 ≤ 150 mmHg, within 24 h of ARDS diagnosis. After inclusion, VT was reduced to 4 ml/kg and further adjusted to maintain pH ≥ 7.20, respiratory rate was increased up to 40 min−1 and PEEP was set using a PEEP–FiO2 table. The primary judgment criterion was driving pressure on day 2 of the study, as compared to inclusion. From inclusion to day 2, driving pressure decreased significantly from 12 [9–15] to 8 [6–11] cmH2O, while VT decreased from 6.0 [5.9–6.1] to 4.1 [4.0–4.7] ml/kg. On day 2, VT was below 4.2 ml/kg in 65% [CI95% 48%–79%], and below 5.25 ml/kg in 88% [CI95% 74%–95%] of the patients. 2 patients (6%) developed acute cor pulmonale after inclusion. Eleven patients (32%) developed transient severe acidosis with pH
Published: 2019
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9. Voxel-wise assessment of lung aeration changes on CT images using image registration: application to acute respiratory distress syndrome (ARDS)

Author: Maciej Orkisz, Claude Guérin, Bruno Neyran, Margarita M. Gómez Ballén, Alfredo Morales Pinzón, Daniela Florentina Sicaru, Eduardo Enrique Dávila Serrano, Camila García Hernández, Jean-Christophe Richard, Leslie Evelyn Solórzano Vargas, Marcela Hernández Hoyos, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Imagerie et modélisation Vasculaires, Thoraciques et Cérébrales (MOTIVATE), Facultad de Ingeniería [Univ de los Andes Colombia] (UNIANDES), Universidad de los Andes [Bogota] (UNIANDES), Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, Hypoxie : Physiopathologie Respiratoire et Cardiovasculaire (HP2 ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service de Réanimation Médicale [Grenoble], CHU Grenoble-Hôpital Michallon, University Politehnica of Bucarest, Service Informatique et développements, Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Orkisz, Maciej
Subjects: ARDS, Swine, Computer science, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, Computed tomography, 02 engineering and technology, computer.software_genre, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, Voxel, Computer vision, Expiration, Lung, Acute Respiratory Distress Syndrome, Image registration, ComputingMilieux_MISCELLANEOUS, Respiratory Distress Syndrome, medicine.diagnostic_test, General Medicine, Computer Graphics and Computer-Aided Design, Computer Science Applications, medicine.anatomical_structure, [INFO.INFO-TI]Computer Science [cs]/Image Processing [eess.IV], Computer Vision and Pattern Recognition, Alveolar recruitment, 0206 medical engineering, Biomedical Engineering, Health Informatics, Image processing, Acute respiratory distress, 03 medical and health sciences, Computed Tomography, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, medicine, Animals, Radiology, Nuclear Medicine and imaging, business.industry, medicine.disease, 020601 biomedical engineering, Disease Models, Animal, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Surgery, Artificial intelligence, Tomography, X-Ray Computed, business, computer
Abstract: International audience; Purpose: To improve the accuracy of global and regional alveolar-recruitment quantification in CT scan pairs by accounting for lung-tissue displacements and deformation, (2) To propose a method for local-recruitment calculation.Methods: Recruitment was calculated by subtracting the quantity of non-aerated lung tissues between expiration and inspiration. To assess global recruitment, lung boundaries were first interactively delineated at inspiration, and then they were warped based on automatic image registration to define the boundaries at expiration. To calculate regional recruitment, the lung mask defined at inspiration was cut into pieces, and these were also warped to encompass the same tissues at expiration. Local-recruitment map was calculated as follows: For each voxel at expiration, the matching location at inspiration was determined by image registration, non-aerated voxels were counted in the neighborhood of the respective locations, and the voxel count difference was normalized by the neighborhood size. The methods were evaluated on 120 image pairs of 12 pigs with experimental acute respiratory distress syndrome.Results: The dispersion of global- and regional-recruitment values decreased when using image registration, compared to the conventional approach neglecting tissue motion. Local-recruitment maps overlaid onto the original images were visually consistent, and the sum of these values over the whole lungs was very close to the global-recruitment estimate, except four outliers.Conclusions: Image registration can compensate lung-tissue displacements and deformation, thus improving the quantification of alveolar recruitment. Local-recruitment calculation can also benefit from image registration, and its values can be overlaid onto the original image to display a local-recruitment map. They also can be integrated over arbitrarily shaped regions to assess regional or global recruitment.
Published: 2019
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10. Accuracy of P0.1 measurements performed by ICU ventilators: a bench study

Author: Pierre-Yves Olivier, Jean-Christophe Richard, Lise Piquilloud, Alice Vuillermoz, Elise Yvin, Alain Mercat, and François Beloncle
Subjects: medicine.medical_treatment, Respiratory failure, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, Mechanical ventilation, Occlusion pressure, Medicine, Respiratory effort, Inspiratory effort, Pressure drop, Respiratory drive, business.industry, Research, Limits of agreement, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, 030228 respiratory system, Reference values, Breathing, business, Biomedical engineering
Abstract: Background Occlusion pressure at 100 ms (P0.1), defined as the negative pressure measured 100 ms after the initiation of an inspiratory effort performed against a closed respiratory circuit, has been shown to be well correlated with central respiratory drive and respiratory effort. Automated P0.1 measurement is available on modern ventilators. However, the reliability of this measurement has never been studied. This bench study aimed at assessing the accuracy of P0.1 measurements automatically performed by different ICU ventilators. Methods Five ventilators set in pressure support mode were tested using a two-chamber test lung model simulating spontaneous breathing. P0.1 automatically displayed on the ventilator screen (P0.1vent) was recorded at three levels of simulated inspiratory effort corresponding to P0.1 of 2.5, 5 and 10 cm H2O measured directly at the test lung and considered as the reference values of P0.1 (P0.1ref). The pressure drop after 100 ms was measured offline on the airway pressure–time curves recorded during the automated P0.1 measurements (P0.1aw). P0.1vent was compared to P0.1ref and to P0.1aw. To assess the potential impact of the circuit length, P0.1 were also measured with circuits of different lengths (P0.1circuit). Results Variations of P0.1vent correlated well with variations of P0.1ref. Overall, P0.1vent underestimated P0.1ref except for the Löwenstein® ventilator at P0.1ref 2.5 cm H2O and for the Getinge group® ventilator at P0.1ref 10 cm H2O. The agreement between P0.1vent and P0.1ref assessed with the Bland–Altman method gave a mean bias of − 1.3 cm H2O (limits of agreement: 1 and − 3.7 cm H2O). Analysis of airway pressure–time and flow–time curves showed that all the tested ventilators except the Getinge group® ventilator performed an occlusion of at least 100 ms to measure P0.1. The agreement between P0.1vent and P0.1aw assessed with the Bland–Altman method gave a mean bias of 0.5 cm H2O (limits of agreement: 2.4 and − 1.4 cm H2O). The circuit’s length impacted P0.1 measurements’ values. A longer circuit was associated with lower P0.1circuit values. Conclusion P0.1vent relative changes are well correlated to P0.1ref changes in all the tested ventilators. Accuracy of absolute values of P0.1vent varies according to the ventilator model. Overall, P0.1vent underestimates P0.1ref. The length of the circuit may partially explain P0.1vent underestimation.
Published: 2019
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11. Analysis of the transcriptome of bovine endometrial cells isolated by laser micro-dissection (2): impacts of post-partum negative energy balance on stromal, glandular and luminal epithelial cells

Author: Patrice Humblot, Gilles Charpigny, Olivier Sandra, Mariam Raliou, Wiruntita Chankeaw, Göran Andersson, Claudia Bevilacqua, Yongzhi Guo, Christophe Richard, Theodoros Ntallaris, Sandra Lignier, Damien Plassard, Swedish University of Agricultural Sciences (SLU), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Animal Bredding and Genetics, FP7-KBBE-2012-6 Prolific and Grant agreement number 311776/Seventh Framework Programme, Charpigny, gilles, Collaborative Research: Sediment Nanomagnetism and Environmental Change: The Microbial Mineral Link - 2003-09-01 - 2007-08-31 - 0311776 - VALID, Rajamangala University of Technology Thanyaburi (RMUTT), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), European Project: 0311776(2003), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)
Subjects: Cell type, Stromal cell, Negative energy balance, RNA-Seq, Biology, QH426-470, Transcriptome, Andrology, 03 medical and health sciences, Endometrium, Pregnancy, Animal and Dairy Science, Cell type-specific, Gene expression, Genetics, Animals, Humans, Lactation, Gene, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030304 developmental biology, Inflammation, 0303 health sciences, [SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Dissection, Lasers, Postpartum Period, 0402 animal and dairy science, [SDV.BA.MVSA] Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health, Embryo, Epithelial Cells, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, LCM, 04 agricultural and veterinary sciences, Acquired immune system, 040201 dairy & animal science, Cattle, Female, RNA-seq, Energy Metabolism, TP248.13-248.65, Research Article, Biotechnology
Abstract: Background In post-partum dairy cows, the energy needs to satisfy high milk production induces a status of more or less pronounced Negative Energy Balance (NEB). NEB associated with fat mobilization impairs reproductive function. In a companion paper, we described constitutive gene expression in the three main endometrial cell types (stromal, glandular and luminal epithelial cells) isolated by laser capture micro-dissection (LCM) showing the specificities of their transcriptomic profiles. This study investigates the specific impact of NEB on gene expression in these cells around 80 days after parturition at day 15 of the oestrus cycle and describes their specific response to NEB. Results Following the description of their constitutive expression, the transcriptome profiles obtained by RNA sequencing of the three cells types revealed that differences related to the severity of NEB altered mainly specific patterns of expression related to individual cell types. Number of differentially expressed genes between severe NEB (SNEB) and mild NEB (MNEB) cows was higher in ST than in LE and GE, respectively. SNEB was associated with differential expression of genes coding for proteins involved in metabolic processes and embryo-maternal interactions in ST. Under-expression of genes encoding proteins with functions related to cell structure was found in GE whereas genes encoding proteins participating in pro-inflammatory pathways were over-expressed. Genes associated to adaptive immunity were under-expressed in LE. Conclusion The severity of NEB after calving is associated with changes in gene expression around 80 days after parturition corresponding to the time of breeding. Specific alterations in GEs are associated with activation of pro-inflammatory mechanisms. Concomitantly, changes in the expression of genes encoding proteins involved in cell interactions and maternal recognition of pregnancy takes place in ST. The combination of these effects possibly altering the uterine environment and embryo maternal interactions may negatively influence the establishment of pregnancy.
Published: 2021
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12. Analysis of the transcriptome of bovine endometrial cells isolated by laser micro-dissection (1): specific signatures of stromal, glandular and luminal epithelial cells

Author: Christophe Richard, Olivier Sandra, Theodoros Ntallaris, Gilles Charpigny, Wiruntita Chankeaw, Yongzhi Guo, Sandra Lignier, Patrice Humblot, Göran Andersson, Mariam Raliou, Claudia Bevilacqua, Damien Plassard, Swedish University of Agricultural Sciences (SLU), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Animal Bredding and Genetics, 311776/FP7-KBBE-2016-6, PROLIFIC, Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Charpigny, gilles, Collaborative Research: Sediment Nanomagnetism and Environmental Change: The Microbial Mineral Link - 2003-09-01 - 2007-08-31 - 0311776 - VALID, École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and European Project: 0311776(2003)
Subjects: Cell signaling, Stromal cell, Biology, QH426-470, Endometrium, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Cell type-specific, medicine, Genetics, Animals, Embryo Implantation, Cell adhesion, [SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology, 030304 developmental biology, Enzyme linked receptor protein signaling pathway, 0303 health sciences, 030219 obstetrics & reproductive medicine, Dissection, Lasers, Cow, Cilium movement, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, LCM, Epithelial Cells, Clinical Science, Cell biology, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, medicine.anatomical_structure, Cattle, Female, RNA-seq, Stromal Cells, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, TP248.13-248.65, Extracellular matrix organization, Biotechnology, Research Article
Abstract: Background A number of studies have examined mRNA expression profiles of bovine endometrium at estrus and around the peri-implantation period of pregnancy. However, to date, these studies have been performed on the whole endometrium which is a complex tissue. Consequently, the knowledge of cell-specific gene expression, when analysis performed with whole endometrium, is still weak and obviously limits the relevance of the results of gene expression studies. Thus, the aim of this study was to characterize specific transcriptome of the three main cell-types of the bovine endometrium at day-15 of the estrus cycle. Results In the RNA-Seq analysis, the number of expressed genes detected over 10 transcripts per million was 6622, 7814 and 8242 for LE, GE and ST respectively. ST expressed exclusively 1236 genes while only 551 transcripts were specific to the GE and 330 specific to LE. For ST, over-represented biological processes included many regulation processes and response to stimulus, cell communication and cell adhesion, extracellular matrix organization as well as developmental process. For GE, cilium organization, cilium movement, protein localization to cilium and microtubule-based process were the only four main biological processes enriched. For LE, over-represented biological processes were enzyme linked receptor protein signaling pathway, cell-substrate adhesion and circulatory system process. Conclusion The data show that each endometrial cell-type has a distinct molecular signature and provide a significantly improved overview on the biological process supported by specific cell-types. The most interesting result is that stromal cells express more genes than the two epithelial types and are associated with a greater number of pathways and ontology terms.
Published: 2021
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13. PGE2 Supplementation of Oocyte Culture Media Improves the Developmental and Cryotolerance Performance of Bovine Blastocysts Derived From a Serum-Free in vitro Production System, Mirroring the Inner Cell Mass Transcriptome

Author: Gilles Charpigny, Brigitte Marquant-Le Guienne, Christophe Richard, Pierre Adenot, Olivier Dubois, Valérie Gélin, Nathalie Peynot, Nathalie Daniel, Vincent Brochard, Fabienne Nuttinck, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Allice, and ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010)
Subjects: 0301 basic medicine, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, QH301-705.5, prostaglandin signaling, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, epigenetic regulation, Cryopreservation, Andrology, Transcriptome, Cell and Developmental Biology, 03 medical and health sciences, 0302 clinical medicine, medicine, Inner cell mass, Blastocyst, Biology (General), [SDV.BDD]Life Sciences [q-bio]/Development Biology, reproductive and urinary physiology, Original Research, 030219 obstetrics & reproductive medicine, Embryogenesis, apoptosis, embryo development, Cell Biology, Blastomere, pluripotency, Oocyte, Embryonic stem cell, 030104 developmental biology, medicine.anatomical_structure, embryonic structures, periconceptional environment, cell cycle, embryonic cell, Developmental Biology
Abstract: The culture media used throughout the in vitro production (IVP) of bovine embryos remain complex. The serum added to culture media in order to improve embryo development negatively impacts the cryotolerance of blastocysts. Periconceptional prostaglandin E2 (PGE2) signaling is known to exert prosurvival effects on in vitro-generated blastocysts. The purpose of the present study was to evaluate the effects on developmental and cryotolerance performance of a serum-free (SF) IVP system that included defined oocyte culture media supplemented or not with PGE2, versus serum-containing (SC) IVP. RNA-sequencing analysis was used to examine the gene expression of ICM derived under the different IVP conditions. We assessed the degree of cryotolerance of grade-I blastocysts during a three-day post-thaw culture by measuring survival and hatching rates, counting trophectoderm and inner cell mass (ICM) blastomere numbers. We also determined the proportion of ICM cells expressing octamer-binding transcription factor 4 protein (OCT4/POU5F1). We showed that grade-I blastocyst development rates under SF + PGE2 conditions were similar to those obtained under SC conditions, although the cleavage rate remained significantly lower. SC IVP conditions induced changes to ICM gene expression relative to several metabolic processes, catabolic activities, cell death and apoptosis. These alterations were associated with significantly higher levels of ICM cell death at day 7 post-fertilization, and lower survival and hatching rates after thawing. SF IVP conditions supplemented or not with PGE2 induced changes to ICM gene expression related to DNA replication, metabolism and double-strand break repair processes, and were associated with significantly larger ICM cell populations after thawing. SF + PGE2 IVP induced changes to ICM gene expression related to epigenetic regulation and were associated with a significantly higher proportion of ICM cells expressing OCT4. For the first time, our study thus offers a comprehensive analysis of the ICM transcriptome regulated by IVP culture conditions in terms of the cellular changes revealed during culture for three days after thawing.
Published: 2021
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14. Polyclonal expansion of TCR Vb 21.3 + CD4 + and CD8 + T cells is a hallmark of multisystem inflammatory syndrome in children

Author: Olivier Dauwalder, David Klatzmann, Marie Duperril, Marion Moreews, Christine Lombard, Behrouz Kassai, Fanny Bajolle, Jean-Laurent Casanova, Anne-Laure Mathieu, Guillaume Monneret, Magali Perret, Rémi Pescarmona, Aurélie Portefaix, Jacqueline Marvel, Laurent Abel, Christophe Malcus, Tiphaine Louazon, Anne Moulin-Zinsch, Mehdi Mezidi, Lisa Giovannini-Chami, Omran Allatif, Hugues Patural, Thierry Walzer, Emilie Chopin, Francois Vandenesh, Encarnita Mariotti-Ferrandiz, Fabienne Venet, Céline Dupieux, Valérie Launay, Paul Bastard, Sophie Trouillet-Assant, Jean-Christophe Richard, Olivier Thaunat, Shen-Ying Zhang, Marine Villard, Samira Khaldi-Plassart, Kahina Saker, Alexandre Belot, Sophia Djebali, Marlène Dreux, Alicia Bellomo, Isabelle Rouvet, Robin Pouyau, Etienne Javouhey, Margaux Guerder, Sonia Teyssedre, Valérie Dubois, Kenz Le Gouge, Hugues Flodrops, Jean-Marie De Guillebon, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Hospices Civils de Lyon (HCL), Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l’enfant / National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children [Lyon] (RAISE), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hôpital Edouard Herriot [CHU - HCL], Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques - EA 7426 (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre National de Reference des Staphylocoques, Université de Lyon, Centre hospitalier de Valence, Hôpital Louis Pradel [CHU - HCL], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), INSERM U1059, SAINBIOSE - Santé, Ingénierie, Biologie, Saint-Etienne (SAINBIOSE-ENSMSE), Centre Ingénierie et Santé (CIS-ENSMSE), École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-École des Mines de Saint-Étienne (Mines Saint-Étienne MSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Pédiatriques de Nice Lenval (CHU-Lenval), Centre Hospitalier Universitaire de Nice (CHU Nice), Université Côte d'Azur (UCA), CIC CHU Lyon (inserm), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Rockefeller University [New York], Etablissement français du sang - Auvergne-Rhône-Alpes (EFS), Hôpital de la Croix-Rousse [CHU - HCL], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Departement Hospitalo- Universitaire - Inflammation, Immunopathologie, Biothérapie [Paris] (DHU - I2B), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière] (I3), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Santé Ingénierie Biologie Saint-Etienne (SAINBIOSE), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-16-RHUS-0001,iMAP,iMAP(2016), Référent HAL, CIRI, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, T cell, [SDV]Life Sciences [q-bio], Immunology, T-cell receptor, Toxic shock syndrome, General Medicine, Human leukocyte antigen, Biology, medicine.disease, 3. Good health, [SDV] Life Sciences [q-bio], 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, medicine.anatomical_structure, Antigen, medicine, Cytotoxic T cell, 030212 general & internal medicine, Cytokine storm, CD8
Abstract: International audience; Multisystem inflammatory syndrome in children (MIS-C) is a delayed and severe complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease (KD) and toxic shock syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared with 16 KD, 58 TSS, and 42 coronavirus disease 2019 (COVID-19) cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFN-γ, sCD25, MCP1, and IL-1RA) in MIS-C, TSS, and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of patients with MIS-C and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3 + T cells from patients with MIS-C expressed high levels of HLA-DR, CD38, and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS, and acute COVID-19.
Published: 2021
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15. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19

Author: Lionel Piroth, Bruno Mourvillier, Joy Mootien, François-Xavier Lescure, Emmanuel Faure, S. Gallien, Dominique Costagliola, Jean-Christophe Richard, Noemie Mercier, Florent Wallet, Yazdan Yazdanpanah, Marion Noret, Claire Andrejak, Jean-Philippe Lanoix, Julien Poissy, Johan Courjon, Saad Nseir, François Danion, Violaine Tolsma, Alain Makinson, Odile Launay, Raphaël Clere-Jehl, Bruno Lina, Drifa Belhadi, Valérie Pourcher, Antoine Kimmoun, Karine Lacombe, Juliette Saillard, Maude Bouscambert-Duchamp, Stéphane Jauréguiberry, Charles Burdet, Toni Alfaiate, Olivier Epaulard, Minh Patrick Lê, Gilles Peytavin, Elisabeth Botelho-Nevers, Thérèse Staub, Guillaume Martin-Blondel, Alpha Diallo, Lila Bouadma, Aline Dechanet, François Goehringer, Florence Ader, Nathan Peiffer-Smadja, Jean-Christophe Navellou, Christelle Delmas, Rostane Gaci, Kevin Bouiller, Maya Hites, André Cabié, Jean Reuter, Sylvie Leroy, Axelle Dupont, François Raffi, Amandine Gagneux-Brunon, Jean Reignier, Clément Dubost, Hospices Civils de Lyon (HCL), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Services de Maladies Infectieuses et Tropicales [CHU Bichat], AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, National Institute for Health Research [Cambridge, UK], Imperial College London, Unité de Glycobiologie Structurale et Fonctionnelle (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHU Lille, Centre National de Reference des virus des Infections Respiratoires France Sud [HCL, Lyon], Virology and human respiratory Pathologies - Virology and human respiratory Pathologies (VirPath), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre d'investigation Clinique [CHU Bichat] - Épidémiologie clinique (CIC 1425), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANRS France Recherche Nord & sud Sida-hiv hépatites, Institut de Santé Publique, Université de Médecine Carol Davila, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service des Maladies Infectieuses et Tropicales [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), French-Clinical Research Infrastructure Network - F-CRIN [Paris] (Cardiovascular & Renal Clinical Trialists - CRCT ), Cardiovascular and Renal Clinical Trialists [Vandoeuvre-les-Nancy] (INI-CRCT), Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu [Nancy], Service de Réanimation Médicale [CHRU Nancy], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre National de Référence du Paludisme [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre hospitalier universitaire de Nantes (CHU Nantes), Université de Nantes (UN), Les Hôpitaux Universitaires de Strasbourg (HUS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), Nouvel Hôpital Civil de Strasbourg, Fédération Hospitalo-Universitaire (OMICARE), Centre de Recherche d’Immunologie et d’Hématologie [Strasbourg], Fédération de Médecine Translationnelle de Strasbourg (FMTS), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Annecy-Genevois [Saint-Julien-en-Genevois], Centre d'Investigation Clinique Antilles-Guyane (CIC - Antilles Guyane), Université des Antilles et de la Guyane (UAG)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française], Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], Etablissement français du don du sang [Montpellier], CHU de la Martinique [Fort de France], Hôpital d'Instruction des Armées Begin, Service de Santé des Armées, Université Paris-Saclay, Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay), CB - Centre Borelli - UMR 9010 (CB), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université de Paris (UP), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut de pharmacologie moléculaire et cellulaire (IPMC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), FHU OncoAge - Pathologies liées à l’âge [CHU Nice] (OncoAge), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Emile Muller [Mulhouse] (CH E.Muller Mulhouse), Groupe Hospitalier de Territoire Haute Alsace (GHTHA), Centre hospitalier régional Metz-Thionville (CHR Metz-Thionville), Centre Hospitalier Universitaire de Reims (CHU Reims), Université de Reims Champagne-Ardenne (URCA), Université Lille Nord de France (COMUE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Pierre Louis d'Epidémiologie et de Santé Publique (iPLESP), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CIC Cochin Pasteur (CIC 1417), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP)-Groupe hospitalier Broca-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Saint-Antoine [AP-HP], Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR ), Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie, Infectious and Tropical Diseases Department [Montpellier], Institut de Recherche pour le Développement (IRD)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), CIC Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Toulouse [Toulouse], Physiopathologie et biothérapies des infections muqueuses (GIMAP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM), Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Fédération d’Infectiologie Multidisciplinaire de l’Arc Alpin [CHU Grenoble-Alpes], Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Croix-Rousse [CHU - HCL], Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA), Centre Hospitalier de Luxembourg [Luxembourg] (CHL), Institut des Agents Infectieux [Lyon] (IAI), Réseau national de recherche clinique en infectiologie (RENARCI), CHU Amiens-Picardie, Université libre de Bruxelles (ULB), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Agence Nationale de Recherches sur le Sida et les Hépatites Virales (ANRS), Université de Lorraine (UL), Hôpital Bicêtre, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Université des Antilles (UA)-Etablissement français du don du sang [Montpellier]-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU de Fort de France-Centre Hospitalier Andrée Rosemon [Cayenne, Guyane Française]-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Institut National de la Santé et de la Recherche Médicale (INSERM)-Université des Antilles et de la Guyane (UAG), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Université Côte d'Azur (UCA), Université de Lille, Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Département Maladies Infectieuses et Tropicales, Hôpital Universitaire, Montpellier, France, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CIC Saint Etienne, Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Nord (Saint Etienne), Optimisation thérapeutique en Neuropsychopharmacologie (OPTeN (UMR_S_1144 / U1144)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Unité de Glycobiologie Structurale et Fonctionnelle - UMR 8576 (UGSF), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Département d'Epidemiologie, Biostatistique et Recherche Clinique (DEBRC), Centre National de Référence du Paludisme [CHU Pitié-Salpétrière] (CNRpalu), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPCité), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Pharmacologie Moléculaire et Cellulaire [UNIV Côte d'Azur] (UPMC)-Université Côte d'Azur (UCA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Service de Maladies Infectieuses et Tropicales [CHU Pitié-Salpêtrière], AP-HP, Hôpital Henri-Mondor Albert-Chenevier, Service d'Immunologie Clinique et Maladies Infectieuses 94000 Créteil, France, Université Paris-Est Créteil Val-de-Marne - Faculté de médecine (UPEC Médecine), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Services des Maladies Infectieuses et Tropicales [CHU Saint-Antoine], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service des maladies infectieuses et tropicales [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Jean Monnet [Saint-Étienne] (UJM), CHU Grenoble, Université Grenoble Alpes (UGA), Institut de biologie structurale (IBS - UMR 5075), Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes (UGA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Laboratoire Chrono-environnement (UMR 6249) (LCE), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre d'Investigation Clinique - Epidémiologie Clinique Saint-Etienne (CIC-EC), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, Service de Santé des Armées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Ecole Normale Supérieure Paris-Saclay (ENS Paris Saclay)-Université Paris Cité (UPC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôtel-Dieu-Groupe hospitalier Broca-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), Université Montpellier 1 (UM1)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], Lopinavir/ritonavir, law.invention, 0302 clinical medicine, Randomized controlled trial, law, immune system diseases, MESH: Antiviral Agents* / therapeutic use, 030212 general & internal medicine, MESH: Treatment Outcome, education.field_of_study, MESH: Middle Aged, virus diseases, Lopinavir, General Medicine, MESH: Lopinavir / therapeutic use, 3. Good health, Infectious Diseases, MESH: Interferon beta-1a / therapeutic use, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Pharmaceutical Preparations, MESH: Hydroxychloroquine / therapeutic use, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Article, medicine.drug, Hydroxychloroquine, Microbiology (medical), medicine.medical_specialty, 030106 microbiology, Population, Antiviral Agents, 03 medical and health sciences, Interferon β-1a, Internal medicine, medicine, Humans, education, Adverse effect, MESH: COVID-19* / drug therapy, MESH: Drug Combinations, MESH: Humans, business.industry, SARS-CoV-2, Drug Repositioning, Interferon beta-1a, COVID-19, MESH: Adult, MESH: Male, MESH: Ritonavir / therapeutic use, Ritonavir, business, MESH: Female, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; Objectives: We evaluated the clinical, virological and safety outcomes of lopinavir/ritonavir, lopinavir/ritonavir-interferon (IFN)-β-1a, hydroxychloroquine or remdesivir in comparison to standard of care (control) in coronavirus 2019 disease (COVID-19) inpatients requiring oxygen and/or ventilatory support.Methods: We conducted a phase III multicentre, open-label, randomized 1:1:1:1:1, adaptive, controlled trial (DisCoVeRy), an add-on to the Solidarity trial (NCT04315948, EudraCT2020-000936-23). The primary outcome was the clinical status at day 15, measured by the WHO seven-point ordinal scale. Secondary outcomes included quantification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in respiratory specimens and pharmacokinetic and safety analyses. We report the results for the lopinavir/ritonavir-containing arms and for the hydroxychloroquine arm, trials of which were stopped prematurely.Results: The intention-to-treat population included 583 participants-lopinavir/ritonavir (n = 145), lopinavir/ritonavir-IFN-β-1a (n = 145), hydroxychloroquine (n = 145), control (n = 148)-among whom 418 (71.7%) were male, the median age was 63 years (IQR 54-71), and 211 (36.2%) had a severe disease. The day-15 clinical status was not improved with the investigational treatments: lopinavir/ritonavir versus control, adjusted odds ratio (aOR) 0.83, (95% confidence interval (CI) 0.55-1.26, p 0.39), lopinavir/ritonavir-IFN-β-1a versus control, aOR 0.69 (95%CI 0.45-1.04, p 0.08), and hydroxychloroquine versus control, aOR 0.93 (95%CI 0.62-1.41, p 0.75). No significant effect of investigational treatment was observed on SARS-CoV-2 clearance. Trough plasma concentrations of lopinavir and ritonavir were higher than those expected, while those of hydroxychloroquine were those expected with the dosing regimen. The occurrence of serious adverse events was significantly higher in participants allocated to the lopinavir/ritonavir-containing arms.Conclusion: In adults hospitalized for COVID-19, lopinavir/ritonavir, lopinavir/ritonavir-IFN-β-1a and hydroxychloroquine improved neither the clinical status at day 15 nor SARS-CoV-2 clearance in respiratory tract specimens.
Published: 2021
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16. Type‐I Interferon assessment in 45 minutes using the FilmArray ® PCR platform in SARS‐CoV‐2 and other viral infections

Author: Andrew Hemmert, Alexandre Belot, Jean-Baptiste Fassier, Etienne Javouhey, Matthew Hockin, Magali Perret, Karen Brengel-Pesce, Sophie Trouillet-Assant, Mehdi Mezidi, François Mallet, Marine Mommert, Sébastien Viel, Jean-Christophe Richard, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), BIOMERIEUX, Physiopathologie de l'immunodépression associée aux réponses inflammatoires systémiques / Pathophysiology of Injury-induced Immunosuppression (PI3), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de référence des rhumatismes inflammatoires et maladies auto-immunes systémiques rares de l’enfant / National Referee Centre for Rheumatic and AutoImmune and Systemic Diseases in Children [Lyon] (RAISE), Lyon Immunopathology Federation (LIFe), Hôpital de la Croix-Rousse [CHU - HCL], and Hôpital Femme Mère Enfant [CHU - HCL] (HFME)
Subjects: 0301 basic medicine, Pediatric emergency, Adult, Male, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Short Communication, Health Personnel, Pcr assay, Immunology, Biology, FilmArray®, Polymerase Chain Reaction, 03 medical and health sciences, 0302 clinical medicine, Interferon, COVID‐19, medicine, Humans, Immunology and Allergy, Basic, Child, Volume concentration, Aged, SARS-CoV-2, COVID-19, Interferon-alpha, Virology, Clinical application, New Technology, Clinical trial, Short Communication|Basic, 030104 developmental biology, In vitro diagnostic, Interferon Type I, Female, Early stage disease, 030215 immunology, medicine.drug
Abstract: Low concentrations of type‐I interferon (IFN) in blood seem to be associated with more severe forms of Coronavirus disease 2019 (COVID‐19). However, following the type‐I interferon response (IR) in early stage disease is a major challenge. We evaluated detection of a molecular interferon signature on a FilmArray® system, which includes PCR assays for four interferon stimulated genes. We analyzed three types of patient populations: (i) children admitted to a pediatric emergency unit for fever and suspected infection, (ii) ICU‐admitted patients with severe COVID‐19, and (iii) healthcare workers with mild COVID‐19. The results were compared to the reference tools, that is, molecular signature assessed with Nanostring® and IFN‐α2 quantification by SIMOA® (Single MOlecule Array). A strong correlation was observed between the IR measured by the FilmArray®, Nanostring®, and SIMOA® platforms (r‐Spearman 0.996 and 0.838, respectively). The FilmArray® panel could be used in the COVID‐19 pandemic to evaluate the IR in 45‐min with 2 min hand‐on‐time at hospitalization and to monitor the IR in future clinical trials., The type‐I Interferon response impairment increases the risk of severe forms of viral infections (like in COVID‐19 disease). We proposed a new integrated tool allowing the fast assessment of type‐I Interferon response (based on interferon stimulated gene expression measurement) to improve patient management.
Published: 2021
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17. Metabolomic differences in blastocoel and uterine fluids collected in vivo by ultrasound biomicroscopy on rabbit embryos

Author: Michele Dahirel, Gilles Renault, Nathalie Daniel, Eve Mourier, Carmen Marchiol, Julie Gatien, Lydie Nadal-Desbarats, Véronique Duranthon, Christophe Richard, Franck Lager, Pascale Chavatte-Palmer, Sophie Calderari, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Plateforme MIMA2, Institut National de la Recherche Agronomique (INRA), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Allice, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme Scientifique et Technique 'Analyses des Systèmes Biologiques' (PST-ASB), Université Francois Rabelais [Tours], École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: 0301 basic medicine, metabolite, Microscopy, Acoustic, Uterus, Ultrasound biomicroscopy, rabbit, Biology, Andrology, 03 medical and health sciences, 0302 clinical medicine, Metabolomics, Pregnancy, In vivo, medicine, Animals, [SDV.BDD]Life Sciences [q-bio]/Development Biology, blastocoel, 030219 obstetrics & reproductive medicine, [SDV.BA]Life Sciences [q-bio]/Animal biology, Embryogenesis, Blastocoel, Rabbit (nuclear engineering), Embryo, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, General Medicine, pre-implantation embryo, Embryo, Mammalian, Body Fluids, Blastocyst, 030104 developmental biology, medicine.anatomical_structure, Reproductive Medicine, uterine fluid, Metabolome, Female, Rabbits, ultrasound biomicroscopy
Abstract: The success of embryo development and implantation depends in part on the environment in which the embryo evolves. However, the composition of the uterine fluid surrounding the embryo in the peri-implantation period remains poorly studied. In this work, we aimed to develop a new strategy to visualize, collect, and analyze both blastocoelic liquid and juxta-embryonic uterine fluid from in vivo peri-implantation rabbit embryos. Using high-resolution ultrasound biomicroscopy, embryos were observed as fluid-filled anechoic vesicles, some of which were surrounded by a thin layer of uterine fluid. Ultrasound-guided puncture and aspiration of both the blastocoelic fluid contained in the embryo and the uterine fluid in the vicinity of the embryo were performed. Using nuclear magnetic resonance spectroscopy, altogether 24 metabolites were identified and quantified, of which 21 were detected in both fluids with a higher concentration in the uterus compared to the blastocoel. In contrast, pyruvate was detected at a higher concentration in blastocoelic compared to uterine fluid. Two acidic amino acids, glutamate and aspartate, were not detected in uterine fluid in contrast to blastocoelic fluid, suggesting a local regulation of uterine fluid composition. To our knowledge, this is the first report of simultaneous analysis of blastocoelic and uterine fluids collected in vivo at the time of implantation in mammals, shedding new insight for understanding the relationship between the embryo and its local environment at this critical period of development.
Published: 2021
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18. Pressurized intra-peritoneal aerosol chemotherapy (PIPAC): increased intraperitoneal pressure does not affect distribution patterns but leads to deeper penetration depth of doxorubicin in a sheep model

Author: Myriam Mimouni, Pierre Adenot, Julien Cohen, François Vialard, Arnaud Fauconnier, Thomas Lilin, Christophe Richard, Valérie Gelin, Pascale Chavatte-Palmer, Martine Letheule, Benoit Lecuelle, Cyrille Huchon, Michèle Dahirel, Olivier Sandra, Anne Tarrade, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de gynécologie et obstétrique [CHI Poissy-Saint Germain], CHI Poissy-Saint-Germain, Centre de recherche biomédicale (CRBM), École nationale vétérinaire d'Alfort (ENVA)-Université Paris-Est (UPE), Risques cliniques et sécurité en santé des femmes et en santé périnatale (RISCQ), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Lariboisière-Fernand-Widal [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Cancer Research, medicine.medical_treatment, PIPAC, Ovary, [SDV.CAN]Life Sciences [q-bio]/Cancer, Andrology, Caecum, 03 medical and health sciences, chemistry.chemical_compound, Peritoneal cavity, 0302 clinical medicine, Drug Delivery Systems, Peritoneum, Genetics, medicine, Pressure, Animals, Doxorubicin, Tissue Distribution, DAPI, Intraperitoneum pressure, Cecum, RC254-282, Peritoneal Neoplasms, Aerosols, Cell Nucleus, Chemotherapy, Antibiotics, Antineoplastic, Sheep, biology, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Penetration (firestop), [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, biology.organism_classification, medicine.anatomical_structure, Oncology, chemistry, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Female, Omentum, Peritoneal carcinomatosis, medicine.drug, Research Article
Abstract: Background Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is an innovative treatment against peritoneal carcinomatosis. Doxorubicin is a common intra-venous chemotherapy used for peritoneal carcinomatosis and for PIPAC. This study evaluated the impact of increased PIPAC intraperitoneal pressure on the distribution and cell penetration of doxorubicin in a sheep model. Methods Doxorubicin was aerosolized using PIPAC into the peritoneal cavity of 6 ewes (pre-alpes breed): N = 3 with 12 mmHg intraperitoneal pressure (“group 12”) and N = 3 with 20 mmHg (“group 20”). Samples from peritoneum (N = 6), ovarian (N = 1), omentum (N = 1) and caecum (N = 1) were collected for each ewe. The number of doxorubicin positive cells was determined using the ratio between doxorubicine fluorescence-positive cell nuclei (DOXO+) over total number of DAPI positive cell nuclei (DAPI+). Penetration depth (μm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei over the total number of cell nuclei that were stained with DAPI. Penetration depth (μm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei. Results DOXO+ nuclei were identified in 87% of samples. All omental samples, directly localized in front of the nebulizer head, had 100% DOXO+ nuclei whereas very few nuclei were DOXO+ for caecum. Distribution patterns were not different between the two groups but penetration depth in ovary and caecum samples was significantly deeper in group 20. Conclusions This study showed that applying a higher intra-peritoneal pressure during PIPAC treatment leads to a deeper penetration of doxorubicin in ovarian and caecum but does not affect distribution patterns.
Published: 2021
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19. Analysis of blood parameters and molecular endometrial markers during early reperfusion in two ovine models of uterus transplantation

Author: Barbara Hersant, Valérie Gelin, Laurent Galio, Mariam Raliou, François Vialard, Olivier Dubois, Anne Couturier-Tarrade, Corinne Giraud-Delville, Angéline Favre-Inhofer, Gilles Charpigny, Olivier Sandra, Nathalie Cornet, Jean-Marc Ayoubi, Romain Bosc, Aurélie Revaux, Marie Carbonnel, Pascale Chavatte-Palmer, Raphaël Coscas, Christophe Richard, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hôpital Foch [Suresnes], Service de chirurgie plastique et reconstructive [Mondor], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Ambroise Paré [AP-HP], Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, The authors received funding (financial and material support) from the Foch Foundation. Angéline Favre-Inhofer and Nathalie Cornet were paid a stipend by the Foch Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), and Chavatte-Palmer, Pascale
Subjects: [SDV.MHEP.CHI] Life Sciences [q-bio]/Human health and pathology/Surgery, Physiology, Uterus, 030230 surgery, Endometrium, Vascular Medicine, 0302 clinical medicine, Ischemia, Medicine and Health Sciences, Immune Response, 030219 obstetrics & reproductive medicine, Multidisciplinary, Anastomosis, Surgical, Arteries, Dissection, medicine.anatomical_structure, Reperfusion Injury, Gestation, Medicine, Female, Anatomy, Research Article, medicine.medical_specialty, Histology, Science, Immunology, Urology, [SDV.MHEP.CHI]Life Sciences [q-bio]/Human health and pathology/Surgery, Anastomosis, [SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, [SDV.BDLR.RS]Life Sciences [q-bio]/Reproductive Biology/Sexual reproduction, Veins, 03 medical and health sciences, Signs and Symptoms, Uterus transplantation, medicine, Animals, Vein, Inflammation, Sheep, business.industry, Reproductive System, Biology and Life Sciences, medicine.disease, [SDV.MHEP.GEO] Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics, Reperfusion, Cardiovascular Anatomy, Blood Vessels, Clinical Medicine, business, Physiological Processes, Transcriptome
Abstract: The dissection of the veins is the trickiest step of Uterine transplantation (UTx). Performing the anastomosis of a single uterine vein could bring a therapeutic benefit and simplification of surgery and serve for managing unilateral venous thromboses. The objectives of this project were to evaluate the expression of early markers of ischemia-reperfusion and to compare findings following one or two vein anastomoses. Orthotopic uterine auto-transplantations were performed on an ovine model with anastomosis of either two (group 1) or one utero-ovarian veins (group 2). Blood gases, histology and ischemia- reperfusion markers transcripts (PTGS2, IL6, IL8, SOD2, C3, BAX/BCL2 and TLR4) were analyzed as well as PTGS2 protein expression using Western Blot and fluorescence immunolocalization on endometrial biopsies after 3h of reperfusion. Ten ewes were included in the experimentation, 4 were in group1, 3 in group 2, the others being sham operated controls. No significant differences were observed between the two phenotypes. Based on these results, the anastomosis of one single uterine vein appears to be an approach consistent with short-term graft survival. Further experiments will be needed to confirm the reliability of this approach, especially the long-term follow-up of the uterine graft including its ability to support gestation to term.
Published: 2021
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20. Challenging the Ex Vivo Lung Perfusion Procedure With Continuous Dialysis in a Pig Model

Author: Antoine Roux, Isabelle Schwartz-Cornil, Matthieu Glorion, Edouard Sage, Fany Blanc, Morgan Le Guen, Jean-Jacques Leplat, Didier Journois, Céline Urien, Luc Jouneau, Julien De Wolf, Jérôme Estephan, Christophe Richard, Hôpital Foch [Suresnes], Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génétique Animale et Biologie Intégrative (GABI), Université Paris-Saclay-AgroParisTech-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Service de pneumologie [Hôpital Foch], Université de Paris - UFR Médecine Paris Centre [Santé] (UP Médecine Paris Centre), and Université de Paris (UP)
Subjects: Swine, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Cell, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Renal Dialysis, Animals, Humans, Medicine, Lung, Dialysis, 030304 developmental biology, 0303 health sciences, Transplantation, business.industry, Cell growth, Pig model, Organ Preservation, Metabolism, 3. Good health, Perfusion, medicine.anatomical_structure, 030220 oncology & carcinogenesis, business, Ex vivo, Lung Transplantation
Abstract: International audience; Background: Normothermic ex vivo lung perfusion (EVLP) increases the pool of donor lungs by requalifying marginal lungs refused for transplantation through the recovery of macroscopic and functional properties. However the cell response and metabolism occurring during EVLP generate a nonphysiological accumulation of electrolytes, metabolites, cytokines and other cellular byproducts which may have deleterious effects both at the organ and cell levels, with impact on transplantation outcomes.Methods: We analyzed the physiological, metabolic and genome-wide response of lungs undergoing a 6-hour EVLP procedure in a pig model in 4 experimental conditions: without perfusate modification, with partial replacement of fluid, and with adult or pediatric dialysis filters.Results: Adult and pediatric dialysis stabilized the electrolytic and metabolic profiles while maintaining acid-base and gas exchanges. Pediatric dialysis increased the level of IL-10 and IL-6 in the perfusate. Despite leading to modification of the perfusate composition, the 4 EVLP conditions did not affect the gene expression profiles which were associated in all cases with increased cell survival, cell proliferation, inflammatory response and cell movement, and with inhibition of bleeding.Conclusions: Management of EVLP perfusate by periodic replacement and continuous dialysis has no significant effect on the lung function nor on the gene expression profiles ex vivo. These results suggest that the accumulation of dialysable cell products does not significantly alter the lung cell response during EVLP, a finding that may have impact on EVLP management in the clinic.
Published: 2021
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21. Prevalence and risk factors of hemodynamic instability associated with preload-dependence during continuous renal replacement therapy in a prospective observational cohort of critically ill patients

Author: Paul Chabert, Louis Chauvelot, Jean-Christophe Richard, Guillaume Chazot, Laure Folliet, Laurent Bitker, Guillaume David, Mehdi Mezidi, Nader Chebib, Judith Provoost, Hodane Yonis, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, and RICHARD, Jean-Christophe
Subjects: medicine.medical_specialty, Supine position, Net ultrafiltration rate, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Thermodilution, 030232 urology & nephrology, Cardiac index, Critical Care and Intensive Care Medicine, Preload-dependence, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Renal replacement therapy, Risk factor, RC86-88.9, business.industry, Research, Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, Acute circulatory failure, Odds ratio, Acute kidney injury, [SDV] Life Sciences [q-bio], Prone position, Cohort, Cardiology, Hemodynamic instability, business, Pulse contour, Cohort study
Abstract: Background Hemodynamic instability is a frequent complication of continuous renal replacement therapy (CRRT). Postural tests (i.e., passive leg raising in the supine position or Trendelenburg maneuver in the prone position) combined with measurement of cardiac output are highly reliable to identify preload-dependence and may provide new insights into the mechanisms involved in hemodynamic instability related to CRRT (HIRRT). We aimed to assess the prevalence and risk factors of HIRRT associated with preload-dependence in ICU patients. We conducted a single-center prospective observational cohort study in ICU patients with acute kidney injury KDIGO 3, started on CRRT in the last 24 h, and monitored with a PiCCO® device. The primary endpoint was the rate of HIRRT episodes associated with preload-dependence during the first 7 days after inclusion. HIRRT was defined as the occurrence of a mean arterial pressure below 65 mmHg requiring therapeutic intervention. Preload-dependence was assessed by postural tests every 4 h, and during each HIRRT episode. Data are expressed in median [1st quartile–3rd quartile], unless stated otherwise. Results 42 patients (62% male, age 69 [59–77] year, SAPS-2 65 [49–76]) were included 6 [1–16] h after CRRT initiation and studied continuously for 121 [60–147] h. A median of 5 [3–8] HIRRT episodes occurred per patient, for a pooled total of 243 episodes. 131 episodes (54% [CI95% 48–60%]) were associated with preload-dependence, 108 (44%, [CI95% 38–51%]) without preload-dependence, and 4 were unclassified. Multivariate analysis (using variables collected prior to HIRRT) identified the following variables as risk factors for the occurrence of HIRRT associated with preload-dependence: preload-dependence before HIRRT [odds ratio (OR) = 3.82, p 8 h (OR = 0.56, p −1 increase, p −1 m−2 increase, p p Conclusions In this single-center study, HIRRT associated with preload-dependence was slightly more frequent than HIRRT without preload-dependence in ICU patients undergoing CRRT. Testing for preload-dependence could help avoiding unnecessary decrease of fluid removal in preload-independent HIRRT during CRRT.
Published: 2020
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22. Impact of advance directives on the variability between intensivists in the decisions to forgo life-sustaining treatment

Author: Jean-Michel Constantin, Axelle Van Lander, Laurent Argaud, Jean-Christophe Richard, Bertrand Souweine, Céline Lambert, Renaud Guérin, Alexandre Fratani, Jean Dellamonica, Russell Chabanne, Jeremy Bourenne, Kada Klouche, Margot Smirdec, Nicolas Terzi, Pierre Asfar, Jean-Pierre Quenot, A Lautrette, Cécile Aubron, Philippe Verdier, Virginie Guastella, Pierre-Marie Bertrand, Anne Medard, Jean-Marc Doise, Nathanael Eisenmann, Samir Jaber, Bruno Pereira, Jean Reignier, Jean-Philippe Rigaud, Mercé Jourdain, Julie Delmas, CHU Clermont-Ferrand, Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Unité de Biostatistiques [CHU Clermont-Ferrand], Direction de la recherche clinique et de l’innovation [CHU Clermont-Ferrand] (DRCI), CHU Clermont-Ferrand-CHU Clermont-Ferrand, Service d'Anesthésie et de Soins Intensifs [Hôpital de la Croix-Rousse - HCL], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôtel-Dieu de Nantes, Centre hospitalier de Dieppe, Centre Hospitalier Chalon-sur-Saône William Morey, Hôpital de la Timone [CHU - APHM] (TIMONE), Centre Hospitalier Rodez, Centre Hospitalier de Cannes, Hôpital de Montluçon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Centre Jean Perrin [Clermont-Ferrand] (UNICANCER/CJP), UNICANCER, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nice (CHU Nice), CHU Grenoble, Service d'Anesthésie réanimation [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AutomédiCation aCcompagnement Pluriprofessionnel PatienT (ACCePPT), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Laboratoire de Neurosciences Intégratives et Cliniques - UFC (EA 481) (NEURO), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Laboratoire Microorganismes : Génome et Environnement (LMGE), Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neurosciences Intégratives et Cliniques - UFC (UR 481) (NEURO), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and MORNET, Dominique
Subjects: Adult, Male, medicine.medical_specialty, Critical Care, [SDV]Life Sciences [q-bio], Relative standard deviation, Decision Making, Intensivist, Critical Care and Intensive Care Medicine, Advance directives, 03 medical and health sciences, 0302 clinical medicine, Qualitative analysis, Life sustaining treatment, Physicians, Surveys and Questionnaires, medicine, Humans, 030212 general & internal medicine, Prospective Studies, Trial registration, Fear of pain, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, lcsh:RC86-88.9, Middle Aged, Decisions to forgo life-sustaining treatment, [SDV] Life Sciences [q-bio], 030228 respiratory system, Withholding Treatment, Emergency medicine, ICU, Female, France, business
Abstract: Background There is wide variability between intensivists in the decisions to forgo life-sustaining treatment (DFLST). Advance directives (ADs) allow patients to communicate their end-of-life wishes to physicians. We assessed whether ADs reduced variability in DFLSTs between intensivists. Methods We conducted a multicenter, prospective, simulation study. Eight patients expressed their wishes in ADs after being informed about DFLSTs by an intensivist-investigator. The participating intensivists answered ten questions about the DFLSTs of each patient in two scenarios, referring to patients’ characteristics without ADs (round 1) and then with (round 2). DFLST score ranged from 0 (no-DFLST) to 10 (DFLST for all questions). The main outcome was variability in DFLSTs between intensivists, expressed as relative standard deviation (RSD). Results A total of 19,680 decisions made by 123 intensivists from 27 ICUs were analyzed. The DFLST score was higher with ADs than without (6.02 95% CI [5.85; 6.19] vs 4.92 95% CI [4.75; 5.10], p p = 0.84). Inter-intensivist agreement on DFLSTs was weak with ADs (intra-class correlation coefficient: 0.28). No factor associated with DFLSTs was identified. A qualitative analysis of ADs showed focus on end-of-life wills, unwanted things and fear of pain. Conclusions ADs increased the DFLST rate but did not reduce variability between the intensivists. In the decision-making process using ADs, the intensivist’s decision took priority. Further research is needed to improve the matching of the physicians’ decision with the patient’s wishes. Trial registration ClinicalTrials.gov Identifier: NCT03013530. Registered 6 January 2017; https://clinicaltrials.gov/ct2/show/NCT03013530.
Published: 2020
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23. Transpulmonary pressures in obese and non-obese COVID-19 ARDS

Author: François Dhelft, Laurent Papazian, Jean-Marie Forel, Florence Daviet, Laurent Bitker, Ines Gragueb, Hodane Yonis, Paul Chabert, Mehdi Mezidi, Jean-Christophe Richard, Christophe Guervilly, Sami Hraiech, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hôpital Nord [CHU - APHM], Centre d'études et de recherche sur les services de santé et la qualité de vie (CEReSS), Aix Marseille Université (AMU), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), RICHARD, Jean-Christophe, and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: medicine.medical_specialty, ARDS, Coronavirus disease 2019 (COVID-19), [SDV]Life Sciences [q-bio], Respiratory physiology, Positive expiratory pressure, Critical Care and Intensive Care Medicine, 03 medical and health sciences, 0302 clinical medicine, Non obese, Anesthesiology, Internal medicine, medicine, Letter to the Editor, Lung, business.industry, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, respiratory system, medicine.disease, respiratory tract diseases, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, 030228 respiratory system, Cohort, Cardiology, business, therapeutics, circulatory and respiratory physiology
Abstract: Background Data on respiratory mechanics of COVID-19 ARDS patients are scarce. Respiratory mechanics and response to positive expiratory pressure (PEEP) may be different in obese and non-obese patients. Methods We investigated esophageal pressure allowing determination of transpulmonary pressures (PL ) and elastances (EL) during a decremental PEEP trial from 20 to 6 cm H2O in a cohort of COVID-19 ARDS patients. Results Fifteen patients were investigated, 8 obese and 7 non-obese patients. PEEP ≥ 16 cm H2O for obese patients and PEEP ≥10 cm H2O for non-obese patients were necessary to obtain positive expiratory PL. Change of PEEP did not alter significantly ΔPL or elastances in obese patients. However, in non-obese patients lung EL and ΔPL increased significantly with PEEP increase. Chest wall EL was not affected by PEEP variations in both groups.
Published: 2020
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24. Quantitative-analysis of computed tomography in COVID-19 and non COVID-19 ARDS patients: A case-control study

Author: Laure Folliet, Laurent Bitker, Eduardo Enrique Dávila Serrano, Ludmilla Penarrubia, Paul Chabert, Loic Boussel, Mehdi Mezidi, Louis Chauvelot, Judith Provoost, Pierre Lecam, Hodane Yonis, Guillaume David, Jean-Christophe Richard, François Dhelft, Maciej Orkisz, Hospices Civils de Lyon (HCL), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Informatique et développements, CCSD, Accord Elsevier, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Adult, Male, ARDS, Coronavirus disease 2019 (COVID-19), [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Computed tomography, Body weight, Critical Care and Intensive Care Medicine, Article, Positive-Pressure Respiration, 03 medical and health sciences, 0302 clinical medicine, medicine, Image Processing, Computer-Assisted, Humans, Prospective Studies, Lung, Lung Compliance, Aged, Respiratory Distress Syndrome, medicine.diagnostic_test, Acute respiratory distress syndrome, business.industry, Case-control study, COVID-19, 030208 emergency & critical care medicine, Middle Aged, respiratory system, medicine.disease, Lung weight, 3. Good health, respiratory tract diseases, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Tidal hyperinflation, 030228 respiratory system, Case-Control Studies, Driving pressure, Female, Nuclear medicine, business, Lung tissue, Tomography, X-Ray Computed, Transpulmonary pressure
Abstract: Purpose The aim of this study was to assess whether the computed tomography (CT) features of COVID-19 (COVID+) ARDS differ from those of non-COVID-19 (COVID−) ARDS patients. Materials and methods The study is a single-center prospective observational study performed on adults with ARDS onset ≤72 h and a PaO2/FiO2 ≤ 200 mmHg. CT scans were acquired at PEEP set using a PEEP-FiO2 table with VT adjusted to 6 ml/kg predicted body weight. Results 22 patients were included, of whom 13 presented with COVID-19 ARDS. Lung weight was significantly higher in COVID− patients, but all COVID+ patients presented supranormal lung weight values. Noninflated lung tissue was significantly higher in COVID− patients (36 ± 14% vs. 26 ± 15% of total lung weight at end-expiration, p, Graphical abstract Unlabelled Image, Highlights • Lung weight is significantly increased in all COVID+ ARDS patients. • Lung potential for recruitment of COVID+ ARDS patients is lower than COVID− ARDS. • A substantial proportion of COVID+ patients exhibit large amount of tidal hyperinflation.
Published: 2020
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25. Response to Ventilator Adjustments for Predicting Acute Respiratory Distress Syndrome Mortality. Driving Pressure versus Oxygenation

Author: Nadir Yehya, Carol L. Hodgson, Laurent Brochard, Jean-Christophe Richard, Marcelo B. P. Amato, Ewan C. Goligher, and Alain Mercat
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Acute respiratory distress, Positive-Pressure Respiration, 03 medical and health sciences, 0302 clinical medicine, Arterial oxygen tension, Fraction of inspired oxygen, Internal medicine, medicine, Tidal Volume, Humans, 030212 general & internal medicine, Lung, Positive end-expiratory pressure, Original Research, Respiratory Distress Syndrome, Ventilators, Mechanical, business.industry, Oxygenation, respiratory system, respiratory tract diseases, 030228 respiratory system, Cardiology, business, circulatory and respiratory physiology
Abstract: Rationale: Clinicians commonly use short-term physiologic markers to assess the benefit of ventilator adjustments. Improved arterial oxygen tension/pressure (Pa(O(2)))/fraction of inspired oxygen (Fi(O(2))) after ventilator adjustment in acute respiratory distress syndrome is associated with lower mortality. However, as driving pressure (ΔP) reflects lung stress and strain, changes in ΔP may more accurately reflect benefits or harms of ventilator adjustments compared with changes in oxygenation. Objectives: We aimed to compare the association between mortality and the changes in Pa(O(2))/Fi(O(2)) and ΔP following protocolized ventilator changes. Methods: We assessed associations between mortality and changes in Pa(O(2))/Fi(O(2)) (ΔPa(O(2))/Fi(O(2))) and ΔP (ΔΔP) after postrandomization positive end-expiratory pressure (PEEP) and tidal volume adjustment in reanalyses of the ALVEOLI (Assessment of Low Tidal Volume and Elevated End-Expiratory Volume to Obviate Lung Injury) and ExPress (Expiratory Pressure) trials. We included subjects with available pre- and postintervention Pa(O(2))/Fi(O(2)) and ΔP (372 in ALVEOLI and 596 in ExPress). In each separate trial cohort, we performed multivariable Cox regression testing the association between ΔPa(O(2))/Fi(O(2)) and ΔΔP with mortality. Results: In ALVEOLI, when analyzed as separate variables, ΔPa(O(2))/Fi(O(2)) was associated with mortality only in subjects in whom PEEP increased, whereas ΔΔP was associated with mortality irrespective of direction of PEEP change. When modeled together, improved ΔPa(O(2))/Fi(O(2)) was not associated with mortality, whereas ΔΔP remained associated with mortality (adjusted hazard ratio [aHR], 1.50 per 5 cm H(2)O increase; 95% confidence interval [95% CI], 1.21–1.85). When modeled together in ExPress, ΔΔP (aHR, 1.42; 95% CI, 1.14–1.78) was more strongly associated with mortality than ΔPa(O(2))/Fi(O(2)) (aHR, 0.95 per 25 mm Hg increase; 95% CI, 0.90–1.00). Conclusions: Reduced ΔP following protocolized ventilator changes was more strongly and consistently associated with lower mortality than was increased Pa(O(2))/Fi(O(2)), making ΔΔP more informative about benefit from ventilator adjustments. Our results reinforce the primacy of ΔP, rather than oxygenation, as the key variable associated with outcome.
Published: 2020

26. Software for CT-image Analysis to Assist the Choice of Mechanical-Ventilation Settings in Acute Respiratory Distress Syndrome

Author: Maciej Orkisz, Laurent Bitker, François Dhelft, Jean-Christophe Richard, Eduardo Enrique Dávila Serrano, Service Informatique et développements, Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Réanimation Médicale, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université de Lyon, Lyon, France, Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Leszek J Chmielewski, Ryszard Kozera, Arkadiusz Orłowski, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL), and Rayet, Béatrice
Subjects: medicine.medical_specialty, ARDS, Coronavirus disease 2019 (COVID-19), Computer science, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, medicine.medical_treatment, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, Hyperinflation, Acute respiratory distress, Disease, Lung injury, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 030218 nuclear medicine & medical imaging, Lung segmentation, 03 medical and health sciences, 0302 clinical medicine, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, Thoracic images, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Intensive care medicine, Computed tomography, Mechanical ventilation, Lung, Acute respiratory distress syndrome, medicine.disease, medicine.anatomical_structure, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 030217 neurology & neurosurgery
Abstract: International audience; Acute respiratory distress syndrome (ARDS) is a critical impairment of the lung function, which occurs - among others - in severe cases of patients with Covid-19. Its therapeutic management is based on mechanical ventilation, but this may aggravate the patient's condition if the settings are not adapted to the actual lung state. Computed tomography images allow for assessing the lung ventilation with fine spatial resolution, but their quantitative analysis is hampered by the contrast loss due to the disease. This article describes software developed to assist the clinicians in this analysis by implementing semi-automatic algorithms as well as interactive tools. The focus is the assessment of the cyclic hyperinflation, which may lead to ventilator-induced lung injury. For this purpose aerated parts of the lungs were segmented in twenty ARDS patients, half with Covid-19. The results were in very good agreement with manual segmentation performed by experts: 5:3% (5.1 ml) mean difference in measured cyclic hyperinflation.
Published: 2020
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27. Type I IFN immunoprofiling in COVID-19 patients

Author: Rémi Pescarmona, Anne Conrad, Bruno Lina, Martine Valette, Sylvie Pons, Vanessa Escuret, Tristan Ferry, Christelle Compagnon, Geneviève Billaud, Maude Bouscambert, Florent Valour, Christine Lombard, William Mouton, Pierre Lecam, Sandrine Roux, Fabienne Venet, Patrick Miailhes, Valérie Cheynet, Claire Triffault-Fillit, Sophie Trouillet-Assant, Pierre Chauvelot, Marine Villard, Clément Munier, Louis Chauvelot, Sébastien Viel, Guillaume David, Emilie Frobert, Agathe Becker, Laure Folliet, Lorna Garnier, Laurent Bitker, Paul Chabert, Florence Ader, Alexandre Gaymard, Jean-Christophe Richard, Grégory Destras, Laurence Josset, Magali Perret, Antonin Bal, Karen Brengel-Pesce, Guy Oriol, Thomas Perpoint, Laurence Generenaz, Cécile Pouderoux, Florence Morfin, Marielle Perry, Mehdi Mezidi, Christian Chidiac, Yonis Hodane, Judith Provoost, Nicholas Benech, Alexandre Belot, Thierry Walzer, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), BIOMERIEUX, Centre de référence des rhumatismes inflammatoires et maladies autoimmunes systémiques rares de l'enfant [Hôpital Femme Mère Enfant, HCL] (RAISE), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), COVID HCL Study group: William Mouton, Guy Oriol, Christelle Compagnon, Laurence Generenaz, Valérie Cheynet, Florence Ader, Agathe Becker, Nicholas Benech, Pierre Chauvelot, Christian Chidiac, Anne Conrad, Tristan Ferry, Patrick Miailhes, Thomas Perpoint, Marielle Perry, Cécile Pouderoux, Sandrine Roux, Claire Triffault-Fillit, Florent Valour, Yonis Hodane, Louis Chauvelot, Paul Chabert, Judith Provoost, Guillaume David, Laure Folliet, Pierre Lecam, Geneviève Billaud, Maude Bouscambert, Vanessa Escuret, Emilie Frobert, Antonin Bal, Grégory Destras, Laurence Josset, Florence Morfin, Clément Munier, Martine Valette, Fabienne Venet, Lorna Garnier, Rémi Pescarmona, Christine Lombard, Thierry Walzer, ANR-20-COVI-0025,iCovid,Immunopathologie du COVID-19 à l'Assistance Publique Hôpitaux de Paris(2020), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and CCSD, Accord Elsevier
Subjects: Adult, Male, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Pneumonia, Viral, Immunology, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, Pandemic, Medicine, Humans, Immunology and Allergy, Viral immunology, Pandemics, 030304 developmental biology, Aged, Aged, 80 and over, 0303 health sciences, biology, business.industry, SARS-CoV-2, COVID-19, Middle Aged, medicine.disease, biology.organism_classification, Virology, [SDV] Life Sciences [q-bio], Pneumonia, 030220 oncology & carcinogenesis, Interferon Type I, Female, business, Coronavirus Infections
Abstract: International audience; No abstract available
Published: 2020
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28. Recruitability and effect of PEEP in SARS-Cov-2-associated acute respiratory distress syndrome

Author: Bertrand Pavlovsky, Nicolas Fage, François Beloncle, Alain Mercat, Pierre Asfar, Christophe Desprez, Pierre-Yves Olivier, Jean-Christophe Richard, Département de Médecine Intensive et Réanimation [Angers], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-IFR10, BP received a 1-year research fellowship grant from the University Hospital of Réunion, France. CD and NF received a 1-year research fellowship grant from the University Hospital of Angers, France., and Bodescot, Myriam
Subjects: ARDS, medicine.medical_specialty, medicine.medical_treatment, SARS-Cov-2, Respiratory mechanics, Context (language use), Respiratory physiology, Pulmonary compliance, Respiratory failure, Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, 0302 clinical medicine, Mechanical ventilation, Interquartile range, Internal medicine, medicine, Positive end-expiratory pressure, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Recruitability, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Acute respiratory distress syndrome, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, respiratory system, medicine.disease, respiratory tract diseases, 030228 respiratory system, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Cardiology, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business, Covid-19, circulatory and respiratory physiology
Abstract: Background A large proportion of patients with a SARS-Cov-2-associated respiratory failure develop an acute respiratory distress syndrome (ARDS). It has been recently suggested that SARS-Cov-2-associated ARDS may differ from usual non-SARS-Cov-2-associated ARDS by higher respiratory system compliance (CRS), lower potential for recruitment with positive end-expiratory pressure (PEEP) contrasting with severe shunt fraction. The purpose of the study was to systematically assess respiratory mechanics and recruitability in SARS-Cov-2-associated ARDS. Methods Gas exchanges, CRS and hemodynamics were assessed at 2 levels of PEEP (15 cmH2O and 5 cmH2O) within 36 h (day1) and from 4 to 6 days (day 5) after intubation. The recruited volume was computed as the difference between the volume expired from PEEP 15 to 5 cmH2O and the volume predicted by compliance at PEEP 5 cmH2O (or above airway opening pressure). The recruitment-to-inflation (R/I) ratio (i.e. the ratio between the recruited lung compliance and CRS at PEEP 5 cmH2O) was used to assess lung recruitability. A R/I ratio value higher than or equal to 0.5 was used to define highly recruitable patients. Results The R/I ratio was calculated in 25 of the 26 enrolled patients at day 1 and in 15 patients at day 5. At day 1, 16 (64%) were considered as highly recruitable (R/I ratio median [interquartile range] 0.7 [0.55–0.94]) and 9 (36%) were considered as poorly recruitable (R/I ratio 0.41 [0.31–0.48]). The PaO2/FiO2 ratio at PEEP 15 cmH2O was higher compared to PEEP 5 cmH2O only in highly recruitable patients (173 [139–236] vs 135 [89–167] mmHg; p 2/FiO2 or CRS measured at PEEP 15 cmH2O or at PEEP 5 cmH2O nor changes in PaO2/FiO2 or CRS in response to PEEP changes allowed to identify highly or poorly recruitable patients. Conclusion In this series of 25 patients with SARS-Cov-2 associated ARDS, 64% were considered as highly recruitable and only 36% as poorly recruitable based on the R/I ratio performed on the day of intubation. This observation suggests that a systematic R/I ratio assessment may help to guide initial PEEP titration to limit harmful effect of unnecessary high PEEP in the context of Covid-19 crisis.
Published: 2020
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29. Critical steps for initiating an animal uterine transplantation model in sheep: Experience from a case series

Author: Valérie Mougenot, Aurélie Revaux, François Vialard, Valerie Gelin, Jean Marc Ayoubi, Pascale Chavatte-Palmer, Marie Carbonnel, Arash Rafii, Olivier Sandra, Christophe Richard, Romain Bosc, Barbara Hersant, Angeline Favre-Inhofer, Hôpital Foch [Suresnes], Gamètes, implantation, gestation (GIG), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Université Paris Saclay (COmUE), CHU Henri Mondor, Institut National de la Recherche Agronomique (INRA), Department of Genetic Medicine and Obstetrics and Gynecology, Weill Cornell Medicine [Qatar], Laboratoire de Cytogénétique, and CHI Poissy-Saint-Germain
Subjects: sheep, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Uterus, 030230 surgery, Anastomosis, Transplantation, Autologous, 03 medical and health sciences, Uterine transplantation, 0302 clinical medicine, Uterus transplantation, Animals, Medicine, [INFO]Computer Science [cs], Iliac vessels, 030219 obstetrics & reproductive medicine, uterus, business.industry, Anastomosis, Surgical, General Medicine, Surgery, Transplantation, Dissection, learning curve, medicine.anatomical_structure, Models, Animal, Female, infertility, business, transplantation
Abstract: Background Recent reports have demonstrated uterus transplantation as a relevant solution to treat absolute uterine infertility. Training on animal models is a prerequisite to set up a uterine transplantation program in humans. Sheep have been used as an optimal model for training and research as they display similar vessels size to human. While the ovine model might seem easy there are many difficulties in performing this complex surgery. In this study we describe through our experience the critical initial steps toward building a learning curve toward an optimal ovine uterine transplantation model. Materials We performed nine orthotopic uterine autotransplantations using end-to-side anastomoses to the external iliac vessels in sheep. We recorded the duration of all surgical steps and pointed out specific difficulties and solution found. Results We were able to perform optimal uterine dissection after the first 5 cases and optimal bilateral arterial and venous anastomoses, after 7 and 9 cases respectively. The main factors associated to success rate were optimal exposure, appropriate equipment, careful vessel preparation and modification of the anastomosis technique. Conclusion As uterine transplantation research programs are expanding, setting up an ovine model to train and perform research is critical. Such model is complex and requires optimized multidisciplinary approach to build an efficient learning curve.
Published: 2018
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30. Effects of positive end-expiratory pressure strategy in supine and prone position on lung and chest wall mechanics in acute respiratory distress syndrome

Author: Andreas D. Waldmann, Stephan H. Bohm, Jean-Christophe Richard, Hodane Yonis, Mehdi Mezidi, Romain Tapponnier, Claude Guérin, Zakaria Riad, Francisco José Parrilla, Jordi Mancebo, Floriane Lissonde, and Loredana Baboi
Subjects: medicine.medical_specialty, ARDS, Supine position, Respiratory physiology, Critical Care and Intensive Care Medicine, Esophageal pressure, 03 medical and health sciences, Prone position, 0302 clinical medicine, Internal medicine, Medicine, Lung volumes, 030212 general & internal medicine, Positive end-expiratory pressure, Acute respiratory distress syndrome, business.industry, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, Oxygenation, lcsh:RC86-88.9, respiratory system, medicine.disease, respiratory tract diseases, Electrical impedance tomography, Cardiology, business, Transpulmonary pressure, therapeutics, circulatory and respiratory physiology
Abstract: Background: In acute respiratory distress syndrome (ARDS) patients, it has recently been proposed to set positive end-expiratory pressure (PEEP) by targeting end-expiratory transpulmonary pressure. This approach, which relies on the measurement of absolute esophageal pressure (Pes), has been used in supine position (SP) and has not been investigated in prone position (PP). Our purposes were to assess Pes-guided strategy to set PEEP in SP and in PP as compared with a PEEP/FIO2 table and to explore the early (1 h) and late (16 h) effects of PP on lung and chest wall mechanics. Results: We performed a prospective, physiologic study in two ICUs in university hospitals on ARDS patients with -PaO2/FIO2 < 150 mmHg. End-expiratory Pes (Pes, ee) was measured in static (zero flow) condition. Patients received PEEP set according to a PEEP/FIO2 table then according to the Pes-guided strategy targeting a positive (3 +/- 2 cmH(2)O) static end-expiratory transpulmonary pressure in SP. Then, patients were turned to PP and received same amount of PEEP from PEEP/FIO2 table then Pes-guided strategy. Respiratory mechanics, oxygenation and end-expiratory lung volume (EELV) were measured after 1 h of each PEEP in each position. For the rest of the 16-h PP session, patients were randomly allocated to either PEEP strategy with measurements done at the end. Thirty-eight ARDS patients (27 male), mean +/- SD age 63 +/- 13 years, were included. There were 33 primary ARDS and 26 moderate ARDS. -PaO2/FIO2 ratio was 120 +/- 23 mmHg. At same PEEP/FIO2 table-related PEEP, Pes, ee averaged 9 +/- 4 cmH(2)O in both SP and PP (P = 0.88). With PEEP/FIO2 table and Pes-guided strategy, PEEP was 10 +/- 2 versus 12 +/- 4 cmH(2)O in SP and 10 +/- 2 versus 12 +/- 5 cmH(2)O in PP (PEEP strategy effect P = 0.05, position effect P = 0.96, interaction P = 0.96). With the Pes-guided strategy, chest wall elastance increased regardless of position. Lung elastance and transpulmonary driving pressure decreased in PP, with no effect of PEEP strategy. Both PP and Pes-guided strategy improved oxygenation without interaction. EELV did not change with PEEP strategy. At the end of PP session, respiratory mechanics did not vary but EELV and -PaO2/FIO2 increased while -PaCO2 decreased. Conclusions: There was no impact of PP on Pes measurements. PP had an immediate improvement effect on lung mechanics and a late lung recruitment effect independent of PEEP strategy.
Published: 2018
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31. Lung Segmentation by Cascade Registration

Author: M. Hernández Hoyos, Maciej Orkisz, Jean-Christophe Richard, A. Morales Pinzón, Grupo IMAGINE, Universidad de los Andes [Bogota] (UNIANDES), Imagerie et modélisation Vasculaires, Thoraciques et Cérébrales (MOTIVATE), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Réanimation Médicale, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Université de Lyon, Lyon, France, Hôpital de la Croix-Rousse [CHU - HCL], and Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL)
Subjects: medicine.medical_specialty, Image Registration, Similarity (geometry), Matching (graph theory), [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Computer science, Biomedical Engineering, Biophysics, Image registration, 030218 nuclear medicine & medical imaging, Image (mathematics), 03 medical and health sciences, Computed Tomography, Segmentation, 0302 clinical medicine, medicine, Sequence, business.industry, Contrast (statistics), Pattern recognition, Cascade, ARDS, Radiology, Artificial intelligence, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, 030217 neurology & neurosurgery
Abstract: Objectives The aim of this work is to delineate the lungs in three-dimensional image sequences of the same subject, with decreasing inhomogeneous contrasts, and to assess the applicability of the method to quantify the aeration in subjects diagnosed with acute respiratory distress syndrome (ARDS). Methods Assuming that the first, and most-contrasted, image of the sequence can be successfully segmented by an existing method, we propose to align the remaining images with the first one, using a cascade of successive registrations, and then to deform the initial segmentation, using a cascade of transformations. Because the lungs slide against the rib cage, the registration requires the use of motion masks that separate the moving organs from less moving ones. Nevertheless, while such masks can be relatively easily obtained in well-contrasted images, obtaining them in images locally lacking contrast is challenging. Our main contribution is the method proposed to generate appropriate motion masks for the entire image sequence despite the decreasing contrasts. This method also uses the principle of cascade registrations and transformations starting from an initial mask obtained in the most-contrasted image of the sequence. Material The entire segmentation method was applied to CT images of 16 piglets with induced ARDS, 20 through 35 images per piglet, acquired at varying mechanical-ventilation conditions. Results The processing time was less than 15 minutes/image, on average. Dice similarity index with an independent standard was of 0.963 globally, but clearly worse overlap was locally measured in the bottom-most region of the lungs (average Dice of 0.810), where the largest displacements and contrast variations were observed. Conclusions The proposed method allows lung segmentation despite the loss of contrast, and can be used to quantify the lung aeration in subjects with ARDS. An improvement in the bottom-most region may be foreseen by combining gray-level based registration and anatomical-landmark matching.
Published: 2017
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32. Predicting Extubation Outcome by Cough Peak Flow Measured Using a Built-in Ventilator Flow Meter

Author: Jean-Christophe Richard, Bernard Vincent, Claude Guérin, Hodane Yonis, Jean-François Burle, Romain Tapponnier, Jack Barbier, Raul Fernandez, Maria Cleyet, Florent Gobert, and Marie-Aude Labaune
Subjects: Male, Pulmonary and Respiratory Medicine, Biometry, medicine.medical_treatment, Peak Expiratory Flow Rate, Critical Care and Intensive Care Medicine, Flow measurement, Spontaneous breathing trial, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, medicine, Humans, Prospective Studies, Tidal volume, Aged, Mechanical ventilation, Extubation failure, Receiver operating characteristic, business.industry, Area under the curve, 030208 emergency & critical care medicine, Equipment Design, General Medicine, Middle Aged, Respiration, Artificial, Cough, ROC Curve, 030228 respiratory system, Respiratory failure, Anesthesia, Airway Extubation, Female, business, Ventilator Weaning
Abstract: BACKGROUND: Successful weaning from mechanical ventilation depends on the patient9s ability to cough efficiently. Cough peak flow (CPF) could predict extubation success using a dedicated flow meter but required patient disconnection. We aimed to predict extubation outcome using an overall model, including cough performance assessed by a ventilator flow meter. METHODS: This was a prospective observational study conducted from November 2014 to October 2015. Before and after a spontaneous breathing trial, subjects were encouraged to cough as strongly as possible before freezing the ventilator screen to assess CPF and tidal volume (VT) in the preceding inspiration. Early extubation success rate was defined as the proportion of subjects not re-intubated 48 h after extubation. Diagnostic performance of CPF and VT was assessed by using the area under the curve of the receiver operating characteristic curve. Cut-off values for CPF and VT were defined according to median values and used to describe the performance of a predictive test combining them with risk factors of early extubation failure. RESULTS: Among 673 subjects admitted, 92 had a cough assessment before extubation. For the 81 subjects with early extubation success, the median CPF was −67.7 L/min, and median VT was 0.646 L. For the 11 subjects with early extubation failure, the median CPF was −57.3 L/min, and median VT was 0.448 L. Area under the curve was 0.61 (95% CI 0.37–0.83) for CPF and 0.64 (95% CI 0.42–0.84) for CPF/VT combined. After dichotomization (CPF 0.55 L), there was a synergistic effect to predict early extubation success (P CONCLUSIONS: CPF measured using the flow meter of an ICU ventilator was able to predict extubation success and to build a composite score to predict extubation failure. The results were close to that found in previous studies that used a dedicated flow meter. This could help to identify high-risk subjects to prevent extubation failure. (ClinicalTrials.gov registration NCT02847221.)
Published: 2017
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33. Utilisation hors AMM d’immunoglobulines intraveineuses dans le traitement de la myocardite lupique : à propos de deux cas et revue de la littérature

Author: Christiane Broussolle, G. Leboucher, Pascal Sève, C. Bernard, Jean-Christophe Richard, N. Cordel, and N. Charhon
Subjects: 030203 arthritis & rheumatology, Gynecology, medicine.medical_specialty, Myocarditis, Systemic lupus erythematosus, business.industry, Gastroenterology, 030204 cardiovascular system & hematology, medicine.disease, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Intravenous Immunoglobulin Therapy, Intravenous Immunoglobulins, Internal Medicine, Medicine, business
Abstract: Resume Introduction Plusieurs cas cliniques ont rapporte le benefice des immunoglobulines intraveineuses (IgIV) au cours du lupus. Observations Nous decrivons ici deux cas de myocardite lupique traites par IgIV a dose immunomodulatrice. Le premier concerne une patiente de 42 ans qui presentait une myocardite lupique resistante au traitement par corticoides et cyclophosphamide. Les IgIV a la dose de 2 g/kg ont permis une amelioration clinique en quelques jours. Le second cas concerne une patiente de 43 ans qui etait traitee par IgIV a la dose de 2 g/kg suite au diagnostic de myocardite et chez qui les immunosuppresseurs etaient contre-indiques du fait du recent contexte d’endocardite infectieuse. Une amelioration clinique etait observee avec une augmentation de la fraction d’ejection du ventricule gauche de 20 % a 60 % en quelques jours. Nous rapportons egalement neuf observations similaires issues de la litterature. Conclusion L’utilisation des IgIV dans la myocardite lupique n’est pas reconnue officiellement mais pourrait etre une alternative lorsque les therapies conventionnelles ont echoue ou sont contre-indiquees.
Published: 2017
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34. A tree-matching algorithm: Application to airways in CT images of subjects with the acute respiratory distress syndrome

Author: Maciej Orkisz, Leonardo Flórez-Valencia, Alfredo Morales Pinzón, Marcela Hernández Hoyos, Jean-Christophe Richard, Imagerie et modélisation Vasculaires, Thoraciques et Cérébrales (MOTIVATE), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Systems and Computing Engineering Department, School of Engineering, (Universidad de los Andes), Service de Réanimation Médicale, Hospices Civils de Lyon (HCL)-Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Grupo Takina, and Pontificia universidad Javeriana, Cali
Subjects: Mathematical optimization, Airway tree, Swine, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, medicine.medical_treatment, Respiratory System, Health Informatics, Computed tomography, Acute respiratory distress, Sensitivity and Specificity, 030218 nuclear medicine & medical imaging, Single measure, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, Radiology, Nuclear Medicine and imaging, Blossom algorithm, Mathematics, Mechanical ventilation, Respiratory Distress Syndrome, Acute respiratory distress syndrome, Radiological and Ultrasound Technology, medicine.diagnostic_test, business.industry, Reproducibility of Results, Pattern recognition, Computer Graphics and Computer-Aided Design, 030228 respiratory system, Models, Animal, Graph (abstract data type), Tree matching, Computer Vision and Pattern Recognition, Artificial intelligence, Tomography, X-Ray Computed, business, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Algorithms
Abstract: International audience; To match anatomical trees such as airways, we propose a graph-based strategy combined with an appropriate distance function. The strategy was devised to cope with topological and geometrical differences that may arise between trees corresponding to the same subject, but extracted from images acquired in different conditions. The proposed distance function, called father/family distance, combines topological and geometrical information in a single measure, by calculating a sum of path-to-path distances between sub-trees of limited extent. To use it successfully, the branches of these sub-trees need to be brought closer, which is obtained by successively translating the roots of these sub-trees prior to their actual matching. The work herein presented contributes to a study of the acute respiratory distress syndrome, where a series of pulmonary CT images from the same subject is acquired at varying settings (pressure and volume) of the mechanical ventilation. The method was evaluated on 45 combinations of synthetic trees, as well as on 15 pairs of real airway trees: nine corresponding to end-expiration and end-inspiration with the same pressure, and six corresponding to end-inspiration with significantly different pressures. It achieved a high rate of successful matches with respect to a hand-made reference containing a total of 2391 matches in real data: sensitivity of 94.3% and precision of 92.8%, when using the basic parameter settings of the algorithm.
Published: 2017
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35. How exhaustive are out of hospital cardiac arrest registers? The example of the Northern French Alps Cardiac Arrest Registry

Author: Jean-Christophe Richard, Cécile Ricard, Alexis Descatha, Adrien Drouet, Arnaud Gaillard, Guillaume Debaty, Dominique Savary, Guillaume Geri, Marc Fadel, Samu 74, Hôpital Annecy, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), S.A.R.L. ACTER, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vieillissement et Maladies chroniques : approches épidémiologique et de santé publique (VIMA), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), SAMU, CHU Grenoble, Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: Emergency Medical Services, cardiac arrest registers, medicine.medical_specialty, business.industry, MEDLINE, 030208 emergency & critical care medicine, 030204 cardiovascular system & hematology, Emergency Nursing, completness, Cardiopulmonary Resuscitation, Out of hospital cardiac arrest, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Emergency medicine, Emergency Medicine, medicine, Humans, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Registries, Cardiology and Cardiovascular Medicine, business, Out-of-Hospital Cardiac Arrest
Abstract: International audience; Improving management and survival of out-of-hospital cardiac arrest (OHCA) is a major public health issue.1 It has become essential to use standardized variables and implement registries to collect high quality data in the real-world setting.2 Besides internal validity, one of the most important requirements for registries is their completeness. We aimed to compare the completeness of the Northern French Alps Cardiac Arrest Registry (RENAU AC) with data from two other emergency systems.
Published: 2020
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36. Pre-Hospital Extracorporeal Cardiopulmonary Resuscitation

Author: Matteo Pozzi, Jean-François Obadia, Jean Christophe Richard, David Pinero, Eric Cesareo, Pierre Yves Dubien, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Jean Monnet [Saint-Étienne] (UJM)-Hospices Civils de Lyon (HCL)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: medicine.medical_specialty, business.industry, [SDV]Life Sciences [q-bio], medicine.medical_treatment, MEDLINE, 030208 emergency & critical care medicine, 030204 cardiovascular system & hematology, Cardiopulmonary Resuscitation, Hospitals, Heart Arrest, 03 medical and health sciences, 0302 clinical medicine, Anesthesiology and Pain Medicine, Emergency medicine, medicine, Humans, Extracorporeal cardiopulmonary resuscitation, Cardiopulmonary resuscitation, Cardiology and Cardiovascular Medicine, business
Published: 2020
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37. Potential for Lung Recruitment Estimated by the Recruitment-to-Inflation Ratio in Acute Respiratory Distress Syndrome. A Clinical Trial

Author: Niall D. Ferguson, Nuttapol Rittayamai, Michael C. Sklar, Lorenzo Del Sorbo, Ibrahim Soliman, Detajin Junhasavasdikul, Jean-Christophe Richard, Laurent Brochard, Domenico Luca Grieco, Michela Rauseo, Lu Chen, and Eddy Fan
Subjects: Pulmonary and Respiratory Medicine, Inflation, Adult, Male, medicine.medical_specialty, media_common.quotation_subject, Blood Pressure, Acute respiratory distress, Critical Care and Intensive Care Medicine, Positive-Pressure Respiration, 03 medical and health sciences, 0302 clinical medicine, medicine, Pressure, Humans, 030212 general & internal medicine, Prospective Studies, media_common, Aged, Respiratory Distress Syndrome, business.industry, Pulmonary Gas Exchange, Reproducibility of Results, Middle Aged, respiratory tract diseases, Lung recruitment, Clinical trial, Treatment Outcome, 030228 respiratory system, Point-of-Care Testing, Emergency medicine, Female, business, Lung Volume Measurements
Abstract: Rationale: Response to positive end-expiratory pressure (PEEP) in acute respiratory distress syndrome depends on recruitability. We propose a bedside approach to estimate recruitability accounting ...
Published: 2019

38. Gastric insufflation during cardiopulmonary resuscitation: A study in human cadavers

Author: Ian R. Drennan, Gilles Bronchti, Paul Ouellet, Domenico Luca Grieco, Emmanuel Charbonney, Thomas Piraino, Caroline Fritz, Bilal Badat, Stéphane Delisle, Laurent Brochard, Jean-Christophe Richard, Dominique Savary, Arnaud Lesimple, Alain Mercat, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Medical Science [Toronto], University of Toronto, Air Liquide, Catholic University of the Sacred Heart [Rome, Italy], Fondazione 'Policlinico Universitario A. Gemelli' [Rome], McMaster University [Hamilton, Ontario], Ecole Polytechnique Fédérale de Lausanne (EPFL), Université du Québec à Trois-Rivières (UQTR), Université de Montréal (UdeM), Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Vitalité Health Network, Keenan Research Centre of the Li Ka Shing Knowledge Institute [Toronto], and Hôpital d'Annecy
Subjects: Male, esophageal sphincter pressure, [SDV]Life Sciences [q-bio], medicine.medical_treatment, cardio pulmonary resuscitation, Gastric Dilatation, Heart Massage, 030204 cardiovascular system & hematology, Emergency Nursing, interrupted chest compressions, survival, intubation, 03 medical and health sciences, 0302 clinical medicine, medicine, Cadaver, Humans, Cardiopulmonary resuscitation, inflation, chest compression, basic life-support, Aged, small tidal volumes, model, Lung, Noninvasive Ventilation, business.industry, ventilation, Stomach, 030208 emergency & critical care medicine, cardiac-arrest, medicine.disease, Gastrostomy, Cardiopulmonary Resuscitation, Heart Arrest, Pneumonia, medicine.anatomical_structure, Research Design, Anesthesia, Emergency Medicine, Breathing, esophageal pressure, Female, Gastric insufflation, gastric insufflation, Cardiology and Cardiovascular Medicine, Airway, business, Pulmonary Ventilation
Abstract: International audience; Introduction: Bag-valve-mask ventilation is the first-line ventilation method during cardiopulmonary resuscitation (CPR). Risks include excessive volume delivery and gastric insufflation, the latter increasing the risk of pneumonia. The efficacy of ventilation can also be reduced by airway closure. We hypothesized that continuous chest compression (CC) could limit the risk of gastric insufflation compared to the recommended 30:2 interrupted CC strategy. This experimental study was performed in human "Thiel" cadavers to assess the respective impact of discontinuous vs. continuous chest compressions on gastric insufflation and ventilation during CPR.Methods: The 30:2 interrupted CC technique was compared to continuous CC in 5 non-intubated cadavers over a 6 min-period. Flow and Airway Pressure were measured at the mask. A percutaneous gastrostomy allowed measuring the cumulative gastric insufflated volume. Two additional cadavers were equipped with esophageal and gastric catheters instead of the gastrostomy.Results: For the 7 cadavers studied (4 women) median age of death was 79 [74-84] years. After 6 min of CPR, the cumulative gastric insufflation measured in 5 cadavers was markedly reduced during continuous CC compared to the interrupted CC strategy: (1.0 [0.8-4.1] vs. 5.9 [4.0-5.6] L; p < 0.05) while expired minute ventilation was slightly higher during continuous than interrupted CC (1.9 [1.4-2.8] vs. 1.6 [1.1-2.7] L/min; P < 0.05). In 2 additional cadavers, the progressive rise in baseline gastric pressure was lower during continuous CC than interrupted CC (1 and 2 cmH2O vs. 12 and 5.8 cmH2O).Conclusion: Continuous CC significantly reduces the volume of gas insufflated in the stomach compared to the recommended 30:2 interrupted CC strategy. Ventilation actually delivered to the lung is also slightly increased by the strategy.
Published: 2019
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39. Oocyte maturation under lipotoxic conditions induces carryover transcriptomic and functional alterations during post-hatching development of good-quality blastocysts: novel insights from a bovine embryo-transfer model

Author: Ken Declerck, Pieter Meysman, Wim Vanden Berghe, Christophe Richard, Katrien Sprangers, Waleed F.A. Marei, K. L. J. Desmet, Peter E.J. Bols, Isabelle Hue, Gerrit T.S. Beemster, Jo L.M.R. Leroy, Kris Laukens, Department of Veterinary Sciences, University of Antwerp (UA), Department of Theriogenology, Cairo University, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Biology, Department of Mathematics & Computer Science (Antwerp), Department of Biomedical Sciences, and This study was supported by the Flemish Research Fund (FWO grant 11L8716N and FWO project 42/FAO10300/6541)
Subjects: animal structures, Veterinary medicine, interferon-τ, embryo, Biology, fatty acids, maternal metabolism, Transcriptome, Andrology, 03 medical and health sciences, 0302 clinical medicine, Pregnancy, Gene expression, medicine, metabolic disorders, Animals, Humans, implantation, Epigenetics, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, 030219 obstetrics & reproductive medicine, embryo metabolism, Rehabilitation, Embryogenesis, Obstetrics and Gynecology, Embryo, Embryo culture, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Oocyte, Embryo Transfer, Embryo transfer, In Vitro Oocyte Maturation Techniques, medicine.anatomical_structure, Blastocyst, Reproductive Medicine, embryonic structures, gene expression, Oocytes, Cattle, Female, Human medicine
Abstract: STUDY QUESTION Does oocyte maturation under lipolytic conditions have detrimental carry-over effects on post-hatching embryo development of good-quality blastocysts after transfer? SUMMARY ANSWER Surviving, morphologically normal blastocysts derived from bovine oocytes that matured under lipotoxic conditions exhibit long-lasting cellular dysfunction at the transcriptomic and metabolic levels, which coincides with retarded post-hatching embryo development. WHAT IS KNOWN ALREADY There is increasing evidence showing that following maturation in pathophysiologically relevant lipotoxic conditions (as in obesity or metabolic syndrome), surviving blastocysts of good (transferable) morphological quality have persistent transcriptomic and epigenetic alteration even when in vitro embryo culture takes place under standard conditions. However, very little is known about subsequent development in the uterus after transfer. STUDY DESIGN, SIZE, DURATION Bovine oocytes were matured in vitro in the presence of pathophysiologically relevant, high non-esterified fatty acid (NEFA) concentrations (HIGH PA), or in basal NEFA concentrations (BASAL) as a physiological control. Eight healthy multiparous non-lactating Holstein cows were used for embryo transfers. Good-quality blastocysts (pools of eight) were transferred per cow, and cows were crossed over for treatments in the next replicate. Embryos were recovered 7 days later and assessed for post-hatching development, phenotypic features and gene expression profile. Blastocysts from solvent-free and NEFA-free maturation (CONTROL) were also tested for comparison. PARTICIPANTS/MATERIALS, SETTING, METHODS Recovered Day 14 embryos were morphologically assessed and dissected into embryonic disk (ED) and extraembryonic tissue (EXT). Samples of EXT were cultured for 24 h to assess cellular metabolic activity (glucose and pyruvate consumption and lactate production) and embryos’ ability to signal for maternal recognition of pregnancy (interferon-τ secretion; IFN-τ). ED and EXT samples were subjected to RNA sequencing to evaluate the genome-wide transcriptome patterns. MAIN RESULTS AND THE ROLE OF CHANCE The embryo recovery rate at Day 14 p.i. was not significantly different among treatment groups (P > 0.1). However, higher proportions of HIGH PA embryos were retarded in growth (in spherical stage) compared to the more elongated tubular stage embryos in the BASAL group (P LARGE-SCALE DATA The datasets of RNA sequencing analysis are available in the NCBI’s Gene Expression Omnibus (GEO) repository, series accession number GSE127889 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE127889). Datasets of differentially expressed genes and their gene ontology functions are available in the Mendeley datasets at http://dx.doi.org/10.17632/my2z7dvk9j.2. LIMITATIONS, REASONS FOR CAUTION The bovine model was used here to allow non-invasive embryo transfer and post-hatching recovery on Day 14. There are physiological differences in some characteristics of post-hatching embryo development between human and cows, such as embryo elongation and trophoblastic invasion. However, the main carry-over effects of oocyte maturation under lipolytic conditions described here are evident at the cellular level and therefore may also occur during post-hatching development in other species including humans. In addition, post-hatching development was studied here under a healthy uterine environment to focus on carry-over effects originating from the oocyte, whereas additional detrimental effects may be induced by maternal metabolic disorders due to adverse changes in the uterine microenvironment. RNA sequencing results were not verified by qPCR, and no solvent control was included. WIDER IMPLICATIONS OF THE FINDINGS Our observations may increase the awareness of the importance of maternal metabolic stress at the level of the preovulatory oocyte in relation to carry-over effects that may persist in the transferrable embryos. It should further stimulate new research about preventive and protective strategies to optimize maternal metabolic health around conception to maximize embryo viability and thus fertility outcome. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Flemish Research Fund (FWO grant 11L8716N and FWO project 42/FAO10300/6541). The authors declare there are no conflicts of interest.
Published: 2019
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40. Formal guidelines: management of acute respiratory distress syndrome

Author: Jean Daniel Chiche, Henri Faure, Cecile Aubron, Alain Combes, Alain Mercat, Armand Mekontso-Dessap, Didier Dreyfuss, Jean-Christophe Richard, Samir Jaber, Jean Marie Forel, Laurent Papazian, Claude Guérin, Antoine Vieillard-Baron, Damien Roux, Laurent Brochard, Hôpital Nord [CHU - APHM], Médecine Intensive Réanimation [CHRU Brest], Université de Brest (UBO)-Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), Service de réanimation médicale, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), University of Toronto at Scarborough, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Service de réanimation-Détresses Respiratoires et Infections Sévères [Hôpital Nord - APHM] (DRIS), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital Nord [CHU - APHM], Hôpital de la Croix-Rousse [CHU - HCL], Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Henri Mondor, Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre de Recherche en Acquisition et Traitement de l'Image pour la Santé (CREATIS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Modeling & analysis for medical imaging and Diagnosis (MYRIAD), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Hôpital Ambroise Paré [AP-HP], Hôpital Robert Ballanger [Aulnay-sous-Bois], Centre Hospitalier Régional Universitaire de Brest (CHRU Brest)-Université de Brest (UBO), University of Toronto [Scarborough, Canada], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), MORNET, Dominique, Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL)
Subjects: medicine.medical_specialty, ARDS, medicine.medical_treatment, Acute respiratory distress, Review, Critical Care and Intensive Care Medicine, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, Plateau pressure, 0302 clinical medicine, Anesthesiology, medicine, Extracorporeal membrane oxygenation, Tidal volume, business.industry, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, medicine.disease, 3. Good health, Prone position, 030228 respiratory system, Anesthesia, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, business, Early phase
Abstract: International audience; Fifteen recommendations and a therapeutic algorithm regarding the management of acute respiratory distress syndrome (ARDS) at the early phase in adults are proposed. The Grade of Recommendation Assessment, Development and Evaluation (GRADE) methodology has been followed. Four recommendations (low tidal volume, plateau pressure limitation, no oscillatory ventilation, and prone position) had a high level of proof (GRADE 1 + or 1 -); four (high positive end-expiratory pressure [PEEP] in moderate and severe ARDS, muscle relaxants, recruitment maneuvers, and venovenous extracorporeal membrane oxygenation [ECMO]) a low level of proof (GRADE 2 + or 2 -); seven (surveillance, tidal volume for non ARDS mechanically ventilated patients, tidal volume limitation in the presence of low plateau pressure, PEEP > 5 cmH2O, high PEEP in the absence of deleterious effect, pressure mode allowing spontaneous ventilation after the acute phase, and nitric oxide) corresponded to a level of proof that did not allow use of the GRADE classification and were expert opinions. Lastly, for three aspects of ARDS management (driving pressure, early spontaneous ventilation, and extracorporeal carbon dioxide removal), the experts concluded that no sound recommendation was possible given current knowledge. The recommendations and the therapeutic algorithm were approved by the experts with strong agreement.
Published: 2019
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41. New physiological insights in ventilation during cardiopulmonary resuscitation

Author: Jean-Christophe Richard, Dominique Savary, Ricardo Luiz Cordioli, Domenico Luca Grieco, and Emmanuel Charbonney
Subjects: business.industry, medicine.medical_treatment, Respiration, 030208 emergency & critical care medicine, Critical Care and Intensive Care Medicine, Respiration, Artificial, Cardiopulmonary Resuscitation, Heart Arrest, Positive-Pressure Respiration, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, Anesthesia, Hyperventilation, Breathing, Medicine, Humans, Cardiopulmonary resuscitation, medicine.symptom, business, Hemodynamic effects
Abstract: In the setting of cardiopulmonary resuscitation (CPR), classical physiological concept about ventilation become challenging. Ventilation may exert detrimental hemodynamic effects that must be balanced with its expected benefits. The risks of hyperventilation have been thoroughly addressed, even questioning the need for ventilation, emphasizing the need to prioritize chest compression quality. However, ventilation is mandatory for adequate gas exchange as soon as CPR is prolonged. Factors affecting the capability of chest compressions to produce alveolar ventilation are poorly understood. In this review, we discuss the conventional interpretation of interactions between ventilation and circulation, from the perspective of novel physiological observations.Many patients with cardiac arrest exhibit 'intrathoracic airway closure.' This phenomenon is associated with lung volume reduction, impedes chest compressions to generate ventilation and overall limits the delivered ventilation. This phenomenon can be reversed by the application of small levels of positive end-expiratory pressure. Also, a novel interpretation of the capnogram can rate the magnitude of this phenomenon, contributing to clarify the physiological meaning of exhaled CO2 and may help assess the real amount of delivered ventilation.Recent advances in the understanding of ventilatory physiology during CPR shows that capnogram analysis not only provides information on the quality of resuscitation but also on the amount of ventilation produced by chest compressions and on the total amount of ventilation.
Published: 2018

42. Hemodynamic effects of extended prone position sessions in ARDS

Author: Zakaria Riad, Floriane Lissonde, Hodane Yonis, Jean-Christophe Richard, Sophie Perinel-Ragey, Martin Ruste, Laurent Bitker, Claude Guérin, and Aurore Louf-Durier
Subjects: Cardiac output, medicine.medical_specialty, Supine position, Cardiac index, Hemodynamics, Critical Care and Intensive Care Medicine, Prone position, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, 030212 general & internal medicine, Transpulmonary thermodilution, Positive end-expiratory pressure, Ejection fraction, Acute respiratory distress syndrome, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, 030208 emergency & critical care medicine, lcsh:RC86-88.9, Cardiology, Dobutamine, business, Cardiac preload, medicine.drug
Abstract: Background Hemodynamic response to prone position (PP) has never been studied in a large series of patients with acute respiratory distress syndrome (ARDS). The primary aim of this study was to estimate the rate of PP sessions associated with cardiac index improvement. Secondary objective was to describe hemodynamic response to PP and during the shift from PP to supine position. Methods The study was a single-center retrospective observational study, performed on ARDS patients, undergoing at least one PP session under monitoring by transpulmonary thermodilution. PP sessions performed more than 10 days after ARDS onset, or with any missing cardiac index measurements before (T1), at the end (T3), and after the PP session (T4) were excluded. Changes in hemodynamic parameters during PP were tested after statistical adjustment for volume of fluid challenges, vasopressor and dobutamine dose at each time point to take into account therapeutic changes during PP sessions. Results In total, 107 patients fulfilled the inclusion criteria, totalizing 197 PP sessions. Changes in cardiac index between T1 and T2 (early response to PP) and between T1 and T3 (late response to PP) were significantly correlated (R2 = 0.42, p
Published: 2018
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43. PSXVI-12 Long term effects of cloning by nuclear transfer on monocytes methylome in Dairy Cattle

Author: M Gasselin, L Notebaert, J Perrier, J.A.A. Pires, Hélène Jammes, Christine Leroux, Luc Jouneau, Christophe Richard, V. Gelin, Michael Weber, Hélène Kiefer, A. Prézelin, and Gilles Foucras
Subjects: 2. Zero hunger, Cloning, 0303 health sciences, 0402 animal and dairy science, 04 agricultural and veterinary sciences, General Medicine, Computational biology, Biology, 040201 dairy & animal science, Term (time), 03 medical and health sciences, Abstracts, DNA methylation, Genetics, Animal Science and Zoology, Dairy cattle, 030304 developmental biology, Food Science
Abstract: To produce embryos by nuclear transfer, it needs a great epigenetic reprogramming of somatic nucleus into embryonic nucleus: this reprogramming is highly dependent of oocyte capacity. Thus, each nucleus is placed in a different environment as soon as the oocyte-somatic cell fusion. This way, the cloned animals obtained using the same fibroblast line, have the same nuclear genotype, but are indubitably epigenetically different ([1]). DNA methylation, is one of the more important epigenetic modification analyzed contributes play a role in regulating gene expression and consequently in different biological processes, such as those involved in health and disease. In this study, we analyzed the genome-wide DNA methylation of a purified subpopulation of immune cells, such as monocytes from cloned and controls Holstein (n=5 per group). Born in an experimental INRA’s farm the cows were breed exactly under the same conditions limiting environmental changes. All growth, health and reproductive information has been collected. Cows were hormonally synchronized, the ovulation detected by ultrasonography and blood samples collected at D15 of cycle. Monocyte purification was performed from peripheral blood mononuclear cells obtained by Ficoll gradient, using CD14+ antibody beads. Genome-wide DNA methylation was analyzed by Reduced Representation Bisulfite Sequencing (RRBS; [2]). After sequencing, the reads were analyzed using our dedicated pipeline (https://github.com/FAANG/faang-methylation/tree/master/RRBS-toolkit). After mapping to the reference genome (UMD3.1 assembly), around of 40% of uniquely mapped reads were obtained. Only CpGs covered between 10X and 500X were analyzed and used to calculate a DNA methylation score which was not different between cloned and control groups. However, PCA described a clear separation between cloned and control groups. Differential analysis of the 10 libraries provided differentially methylated cytosine (DMCs) between the two groups, corresponding to DMRs. This study therefore highlights CpGs and regions displaying a specific methylation pattern in cloned cows.
Published: 2018

44. Effects of dietary arginine supplementation in pregnant mares on maternal metabolism, placental structure and function and foal growth

Author: Josiane Aioun, Morgane Robles, Pascale Chavatte-Palmer, Michèle Dahirel, E. Derisoud, Christophe Richard, Cédric Dubois, Juliane Calvez, Anne Couturier-Tarrade, Audrey Prézelin, Audrey Geeverding, Laurence Wimel, Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Université Paris Saclay (COmUE), Institut Français du Cheval et de l'Equitation, Physiologie de la Nutrition et du Comportement Alimentaire (PNCA), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Station expérimentale, ARVALIS - Institut du végétal [Paris], IFCE Argifoal, Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Dubois, Cedric, and Wimel, Laurence
Subjects: 0301 basic medicine, equidae, Arginine, animal diseases, [SDV]Life Sciences [q-bio], Placenta, lcsh:Medicine, 0302 clinical medicine, Pregnancy, parity, reproduction, pregnancy, gestation, arginine, placenta, horse, lcsh:Science, reproductive and urinary physiology, poulain, media_common, 2. Zero hunger, Multidisciplinary, biology, méthylation de l'ADN, Gene Expression Regulation, Developmental, medicine.anatomical_structure, Foal, chorion, Gestation, Female, Reproduction, expression génique, media_common.quotation_subject, yearling (horse), grossesse, Andrology, 03 medical and health sciences, Insulin resistance, biology.animal, medicine, Animals, Horses, résistance à l'insuline, business.industry, lcsh:R, Horse, DNA Methylation, medicine.disease, 030104 developmental biology, gene expression, lcsh:Q, Insulin Resistance, business, 030217 neurology & neurosurgery
Abstract: Foals born to primiparous mares are lighter and less mature than those born to multiparous dams. Factors driving this difference are not totally understood. Using 7 multiparous and 6 primiparous standardbred mares, we demonstrated that, in late gestation, primiparous mares were less insulin resistant compared to multiparous mares, and that their foals had reduced plasma amino-acid concentrations at birth compared to foals born to multiparous mares. Vascular development, as observed through structure and gene expression, and global DNA methylation were also reduced in primiparous placentas. Another group of 8 primiparous mares was orally supplemented with L-arginine (100 g/day, 210d to term). L-arginine improved pregnancy-induced insulin resistance and increased maternal L-arginine and L-ornithine plasma concentrations but foal plasma amino acid concentrations were not affected at birth. At birth, foal weight and placental biometry, structure, ultra-structure and DNA methylation were not modified. Placental expression of genes involved in glucose and fatty acid transfers was increased. In conclusion, maternal insulin resistance in response to pregnancy and placental function are reduced in primiparous pregnancies. Late-gestation L-arginine supplementation may help primiparous mares to metabolically adapt to pregnancy and improve placental function. More work is needed to confirm these effects and ascertain optimal treatment conditions.
Published: 2018
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45. Bovine scavenger receptor class A (SR-A) exhibit specific patterns of regulation in the endometrium during the oestrous cycle and early pregnancy

Author: Patrick Lonergan, Iain Martin Sheldon, Gareth D. Healey, Nadéra Mansouri-Attia, A. Vitorino Carvalho, Christophe Richard, Corinne Giraud-Delville, Niamh Forde, Caroline Eozenou, Olivier Sandra, Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Université Paris Saclay (COmUE), School of Agriculture and Food Science, University College Dublin [Dublin] (UCD), Swansea University, French Ministry for Teaching and Research - Doctoral School Universite Paris Sud [ED419], INRA - Phase Department, Agence Nationale de la Recherche [ANR-08-GENM-037], European Network of Excellence 'Embryo Implantation Control' [LSHN-CT-2004-512040], AIP Bioressources CHIPSTRAFFIC, Science Foundation Ireland, Higher Education Authority Irish Centre for High-End Computing, UK Biotechnology and Biological Sciences Research Council [BB/I017240/1], European Project: 312097,EC:FP7:KBBE,FP7-KBBE-2012-6-singlestage,FECUND(2013), and École nationale vétérinaire - Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)
Subjects: medicine.medical_treatment, [SDV]Life Sciences [q-bio], Estrous Cycle, Reproductive technology, Biology, Endometrium, Andrology, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Pregnancy, Gene expression, Genetics, medicine, Animals, implantation, [INFO]Computer Science [cs], Embryo Implantation, Scavenger receptor, Molecular Biology, reproductive and urinary physiology, Progesterone, 030304 developmental biology, Estrous cycle, 0303 health sciences, 030219 obstetrics & reproductive medicine, In vitro fertilisation, Scavenger Receptors, Class A, Embryo, medicine.disease, medicine.anatomical_structure, Reproductive Medicine, Gene Expression Regulation, Pregnancy, Animal, Animal Science and Zoology, Cattle, Female, Developmental Biology, Biotechnology
Abstract: International audience; In mammals, tight regulation of maternal endometrial function is critical for pregnancy success. In bovine species, endometrial expression of members of the scavenger receptor class A (SR-A) has been listed in high-throughput analyses, but very little is known about the involvement of these immune factors during implantation in mammals. To provide first insights into the contribution of SR-A to endometrial physiology, we analysed the expression and regulation of all members of SR-A (SR-A1, SR-A3-SR-A6) during the oestrous cycle and early pregnancy in cattle. Levels of SR-A1 were increased on Day 20 of pregnancy, whereas SR-A3 levels were increased on Day 13 of the oestrous cycle and of the pregnancy. Although SR-A4 levels were reduced on Day 20 of the oestrous cycle, they remained high in pregnant animals. SR-A5 levels increased by Day 13 of the oestrous cycle and decreased on Day 20, but remained high in pregnant animals. Interferon- does not affect SR-A gene expression, whereas progesterone regulates the expression of the SR-A3 and SR-A5 transcripts. Endometrial SR-A3 appeared significantly higher in cows carrying invitro-produced embryos than in AI cows. Our data suggest that members of the SR-A family are involved in endometrial remodelling and regulation of endometrial gland physiology, both processes being critical for implantation in mammals.
Published: 2018
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46. Hypoxemia in the ICU: prevalence, treatment, and outcome

Author: Jean-Christophe Richard, Marc Danguy des Déserts, and Tài PHAM
Subjects: Epidemiology, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, ARDS-acute respiratory failure, lcsh:RC86-88.9, Critical Care and Intensive Care Medicine, respiratory tract diseases, Invasive ventilation, Hypoxemia, Critical care, 03 medical and health sciences, 0302 clinical medicine, 030228 respiratory system, 030212 general & internal medicine, circulatory and respiratory physiology
Abstract: Background Information is limited regarding the prevalence, management, and outcome of hypoxemia among intensive care unit (ICU) patients. We assessed the prevalence and severity of hypoxemia in ICU patients and analyzed the management and outcomes of hypoxemic patients. Methods This is a multinational, multicenter, 1-day point prevalence study in 117 ICUs during the spring of 2016. All patients hospitalized in an ICU on the day of the study could be enrolled. Hypoxemia was defined as a PaO2/FiO2 ratio ≤ 300 mmHg and classified as mild (PaO2/FiO2 between 300 and 201), moderate (PaO2/FiO2 between 200 and 101), and severe (PaO2/FiO2 ≤ 100 mmHg). Results Of 1604 patients included, 859 (54%, 95% CI 51–56%) were hypoxemic, 51% with mild (n = 440), 40% with moderate (n = 345), and 9% (n = 74) with severe hypoxemia. Among hypoxemic patients, 61% (n = 525) were treated with invasive ventilation, 10% (n = 84) with non-invasive ventilation, 5% (n = 45) with high-flow oxygen therapy, 22% (n = 191) with standard oxygen, and 1.6% (n = 14) did not receive oxygen. Protective ventilation was widely used in invasively ventilated patients. Twenty-one percent of hypoxemic patients (n = 178) met criteria for acute respiratory distress syndrome (ARDS) including 65 patients (37%) with mild, 82 (46%) with moderate, and 31 (17%) with severe ARDS. ICU mortality was 27% in hypoxemic patients and significantly differed according to severity: 21% in mild, 26% in moderate, and 50% in patients with severe hypoxemia, p
Published: 2018
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47. How Ventilation Is Delivered During Cardiopulmonary Resuscitation: An International Survey

Author: Abdo Khoury, Laurent Suppan, Dominique Savary, Aissam Lyazidi, Ricardo Luiz Cordioli, François Templier, Stéphane Delisle, Laurent Brochard, and Jean-Christophe Richard
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Internationality, Respiratory rate, medicine.medical_treatment, education, Heart Massage, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, law.invention, 03 medical and health sciences, 0302 clinical medicine, Opinion survey, law, Surveys and Questionnaires, Ventilator settings, medicine, Humans, Cardiopulmonary resuscitation, Practice Patterns, Physicians', Ventilators, Mechanical, business.industry, International survey, 030208 emergency & critical care medicine, General Medicine, Evidence-based medicine, Respiration, Artificial, Cardiopulmonary Resuscitation, Emergency medicine, Ventilation (architecture), Practice Guidelines as Topic, Guideline Adherence, business
Abstract: BACKGROUND: Recommendations regarding ventilation during cardiopulmonary resuscitation (CPR) are based on a low level of scientific evidence. We hypothesized that practices about ventilation during CPR might be heterogeneous and may differ worldwide. To address this question, we surveyed physicians from several countries on their practices during CPR. METHODS: We used a Web-based opinion survey. Links to the survey were sent by e-mail newsletters and displayed on the Web sites of medical societies involved in CPR practice from December 2013 to March 2014. RESULTS: 1,328 surveys were opened, and 548 were completed (41%). Responses came from 54 countries, but 64% came from 6 countries. Responders were mostly physicians (89%). From this group, 97% declared following specific CPR guidelines. Regarding practices, 28% declared always or frequently adopting only continuous chest compressions without additional ventilation. With regard to mechanical chest compression devices, 38% responded that such devices were available to them; when used, 28% declared always or frequently experiencing problems with ventilation such as frequent alarms. During bag-mask ventilation in intubated patients, 18% declared stopping chest compression during insufflation, and 39% applied > 10 breaths/min, which conflicts with international CPR guidelines. When a ventilator was used, the volume controlled mode was the most common strategy cited, but there was heterogeneity regarding ventilator settings for PEEP, trigger, FIO2, and breathing frequency. SpO2 and end-tidal CO2 were the 2 most monitored variables cited. CONCLUSIONS: Physicians indicated heterogeneous practices that often differ significantly from international CPR guidelines. This may reflect the low level of evidence and a lack of detailed recommendations concerning ventilation during CPR.
Published: 2018

48. Transcervical collection of bovine embryos up to Day 21: An 8-year overview

Author: Yvan Heyman, Séverine A. Degrelle, A. Neveux, Pascale Chavatte-Palmer, Isabelle Hue, Christophe Richard, Evelyne Campion, V. Gelin, Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), UE 1298 Unité Commune d'Expérimentation Animale, Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), NRA, APISGENE, agroBI AIP, AIP Bioresources CHIPSTRAFFIC, MODE-LONG, ANR ANR-06-GANI-03 ANR-08-Genm-03, FP6-SABRE, European Network of Excellence EMBIC LSHN-CT -2,004 LSHN-CT 512,040, and FP7-PLURISYS HEALTH-F4-2009-223485
Subjects: medicine.medical_treatment, elongation, 0302 clinical medicine, Food Animals, Pregnancy, Luteolysis, Conceptus, Small Animals, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Insemination, Artificial, media_common, 0303 health sciences, 030219 obstetrics & reproductive medicine, Embryo, 3. Good health, medicine.anatomical_structure, conceptus, embryonic structures, Tissue and Organ Harvesting, Female, medicine.medical_specialty, animal structures, media_common.quotation_subject, embryo, Embryonic Development, Gestational Age, Superovulation, Semen, Environment, Biology, Insemination, 03 medical and health sciences, Reproductive Techniques, Ovulation Induction, medicine, Animals, Blastocyst, Ovulation, 030304 developmental biology, Gynecology, blastocyst, Equine, Research, Artificial insemination, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Embryo, Mammalian, developmental stage, Cattle, Animal Science and Zoology, Follicle Stimulating Hormone
Abstract: International audience; Transcervical embryo collection is used routinely in the bovine species throughout the world to collect Day 6 to Day 9 embryos (early embryos) for genetic selection. For research purposes, however, the collection of embryos at later stages of pregnancy, i.e., Days 12 to 21 (late embryos), is needed. So far, for the recovery of late embryos, females are euthanized and embryo collection is performed after recovery of the genital tract. To reduce the number of animals used and still provide valuable material for embryo research, we have therefore developed a transcervical technique to collect late embryos. The objective of this study was to compare embryo recovery results at early and late stages within our laboratory. Altogether, 232 cows were used for this study. One hundred forty-five flushes were performed to collect embryos from Days 6 to 9, and 251 flushes were performed to collect embryos from Days 12 to 21. For the early embryos, a classical three-way collection equipment was used. To collect the late embryos, the same equipment was used, but the extensible flexible catheter that goes inside the external rigid catheter was removed, so that larger embryos could be collected through the remaining larger hole (two-way collection). All females were submitted to ovum pick up to remove the dominant follicle and were subsequently superovulated with FSH. Luteolysis was induced 48 hours before artificial insemination. Two artificial inseminations were performed with frozen semen, 48 and 56 hours after PGF2α injection. Before embryo collection, cows were treated with an epidural injection of a local anesthetic drug. The presence of CL was checked, and they were counted by rectal palpation. For all collections, the cervix was prepared with the initial introduction of a dilator. Then, the catheter was introduced in one horn, and the cuff was inflated as low as possible. For the collection of late embryos, the flushing solution (30 mL) was injected slowly twice to suspend the embryos before flushing the horn with 500 mL, and the same operation was performed on the second horn. There was no significant difference in the number of embryos collected per flush in the early- and late-stage (758 embryos collected, 5.22 ± 6.02 per flush vs. 1238 embryos collected, 4.93 ± 5.07 per flush, respectively). The number of embryos collected per CL, however, was significantly lower in the early versus late group (0.39 ± 0.32% vs. 0.44 ± 0.34%, respectively). The late collection allowed the retrieval of full conceptuses (embryonic and extraembryonic tissues), even at very late stages such as Days 18 to 21. Careful collection is needed, however, so that conceptuses are not damaged or torn: the horn must be massaged gently and the flush should be ideally recovered in one single flow. This technique is a powerful tool to collect the late-stage embryos for research purposes. Because it is not traumatic, animals can be used again for the same procedure.
Published: 2015
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49. Change in cardiac output during Trendelenburg maneuver is a reliable predictor of fluid responsiveness in patients with acute respiratory distress syndrome in the prone position under protective ventilation

Author: Sophie Debord, Laurent Bitker, Romain Tapponnier, Zakaria Riad, Floriane Lissonde, Claude Guérin, Sophie Perinel Ragey, Aurore Louf-Durier, Mylène Aublanc, Hodane Yonis, Jean-Christophe Richard, and Florent Gobert
Subjects: Cardiac output, Male, medicine.medical_specialty, ARDS, medicine.medical_treatment, Trendelenburg position, Trendelenburg, Cardiac index, Fluid responsiveness, Critical Care and Intensive Care Medicine, Statistics, Nonparametric, Head-Down Tilt, 03 medical and health sciences, Prone position, 0302 clinical medicine, Internal medicine, medicine, Humans, Prospective Studies, Tidal volume, Aged, Monitoring, Physiologic, Analysis of Variance, Respiratory Distress Syndrome, Acute respiratory distress syndrome, business.industry, Research, lcsh:Medical emergencies. Critical care. Intensive care. First aid, Hemodynamics, 030208 emergency & critical care medicine, Acute circulatory failure, lcsh:RC86-88.9, Middle Aged, medicine.disease, Respiration, Artificial, Pulse pressure, Intensive Care Units, 030228 respiratory system, ROC Curve, Cardiology, Fluid Therapy, Female, business, Protective ventilation
Abstract: Background Predicting fluid responsiveness may help to avoid unnecessary fluid administration during acute respiratory distress syndrome (ARDS). The aim of this study was to evaluate the diagnostic performance of the following methods to predict fluid responsiveness in ARDS patients under protective ventilation in the prone position: cardiac index variation during a Trendelenburg maneuver, cardiac index variation during an end-expiratory occlusion test, and both pulse pressure variation and change in pulse pressure variation from baseline during a tidal volume challenge by increasing tidal volume (VT) to 8 ml.kg-1. Methods This study is a prospective single-center study, performed in a medical intensive care unit, on ARDS patients with acute circulatory failure in the prone position. Patients were studied at baseline, during a 1-min shift to the Trendelenburg position, during a 15-s end-expiratory occlusion, during a 1-min increase in VT to 8 ml.kg-1, and after fluid administration. Fluid responsiveness was deemed present if cardiac index assessed by transpulmonary thermodilution increased by at least 15% after fluid administration. Results There were 33 patients included, among whom 14 (42%) exhibited cardiac arrhythmia at baseline and 15 (45%) were deemed fluid-responsive. The area under the receiver operating characteristic (ROC) curve of the pulse contour-derived cardiac index change during the Trendelenburg maneuver and the end-expiratory occlusion test were 0.90 (95% CI, 0.80–1.00) and 0.65 (95% CI, 0.46–0.84), respectively. An increase in cardiac index ≥ 8% during the Trendelenburg maneuver enabled diagnosis of fluid responsiveness with sensitivity of 87% (95% CI, 67–100), and specificity of 89% (95% CI, 72–100). The area under the ROC curve of pulse pressure variation and change in pulse pressure variation during the tidal volume challenge were 0.52 (95% CI, 0.24–0.80) and 0.59 (95% CI, 0.31–0.88), respectively. Conclusions Change in cardiac index during a Trendelenburg maneuver is a reliable test to predict fluid responsiveness in ARDS patients in the prone position, while neither change in cardiac index during end-expiratory occlusion, nor pulse pressure variation during a VT challenge reached acceptable predictive performance to predict fluid responsiveness in this setting. Trial registration ClinicalTrials.gov, NCT01965574. Registered on 16 October 2013. The trial was registered 6 days after inclusion of the first patient. Electronic supplementary material The online version of this article (doi:10.1186/s13054-017-1881-0) contains supplementary material, which is available to authorized users.
Published: 2017

50. Prosurvival effect of cumulus prostaglandin G/H synthase 2/prostaglandin2 signaling on bovine blastocyst: impact on in vivo posthatching development

Author: Pierre Adenot, Alice Jouneau, Ludivine Laffont, Brigitte Marquant-Le Guienne, Gilles Charpigny, Fabienne Nuttinck, Véronique Duranthon, Isabelle Hue, Martine Chebrout, Christophe Richard, Sylvie Ruffini, Biologie du Développement et Reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA), Université Paris-Saclay, Recherche et Développement, LACTALIS (LACTALIS NUTRITION), Biologie du développement et reproduction (BDR), and École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, cell-proliferation, chemistry.chemical_compound, 0302 clinical medicine, blastocyste, Pregnancy, cumulus–oocyte interaction, prostaglandin synthase, Biologie de la reproduction, Prostaglandin E2, [SDV.BDD]Life Sciences [q-bio]/Development Biology, blastocyst stage, Reproductive Biology, 030219 obstetrics & reproductive medicine, Apoptosis Regulator, Biologie du développement, apoptosis, Embryo, General Medicine, Development Biology, cyclooxygenase, medicine.anatomical_structure, Embryology and Organogenesis, Female, embryo, gastrulation, lipid mediator, Embryologie et organogenèse, medicine.drug, production d'embryon, Prostaglandin, Embryonic Development, Fertilization in Vitro, Biology, Dinoprostone, Andrology, 03 medical and health sciences, medicine, Animals, Blastocyst, Trophoblast, [SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology, Cell Biology, Oocyte, Embryonic stem cell, In Vitro Oocyte Maturation Techniques, 030104 developmental biology, [SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis, Reproductive Medicine, chemistry, Prostaglandin-Endoperoxide Synthases, Cattle
Abstract: Remerciements à l'Unité UCEA de Bressonvilliers, à V. Gelin et A. Neveu pour leur aide.; Apoptotic activity is a common physiological process which culminates at the blastocyst stage in the preimplantation embryo of many mammals. The degree of embryonic cell death can be influenced by the oocyte microenvironment. However, the prognostic significance of the incidence of apoptosis remains undefined. Prostaglandin E2 (PGE2) derived from prostaglandin G/H synthase-2 (PTGS2) activity is a well-known prosurvival factor that is mainly studied in oncology. PGE2 is the predominant PTGS2-derived prostaglandin present in the oocyte microenvironment during the periconceptional period. Using an in vitro model of bovine embryo production followed by transfer and collection procedures, we investigated the impact of periconceptional PGE2 on the occurrence of spontaneous apoptosis in embryos and on subsequent in vivo posthatching development. Different periconceptional PGE2 environments were obtained using NS-398, a specific inhibitor of PTGS2 activity, and exogenous PGE2. We assessed the level of embryonic cell death in blastocysts at day 8 postfertilization by counting total cell numbers, by the immunohistochemical staining of active caspase-3, and by quantifying terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling signals and apoptosis regulator (BCL-2/BAX) mRNA expression. Morphometric parameters were used to estimate the developmental stage of the embryonic disk and the extent of trophoblast elongation on day 15 conceptuses. Our findings indicate that periconceptional PGE2 signaling durably impacts oocytes, conferring increased resistance to spontaneous apoptosis in blastocysts and promoting embryonic disk development and the elongation process during preimplantation development.
Published: 2017
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