Extracorporeal Membrane Oxygenation for Severe Acute Respiratory Distress Syndrome associated with COVID-19: An Emulated Target Trial Analysis.

RATIONALE: Whether COVID patients may benefit from extracorporeal membrane oxygenation (ECMO) compared with conventional invasive mechanical ventilation (IMV) remains unknown. OBJECTIVES: To estimate the effect of ECMO on 90-Day mortality vs IMV only Methods: Among 4,244 critically ill adult patients with COVID-19 included in a multicenter cohort study, we emulated a target trial comparing the treatment strategies of initiating ECMO vs. no ECMO within 7 days of IMV in patients with severe acute respiratory distress syndrome (PaO2/FiO2 <80 or PaCO2 ≥60 mmHg). We controlled for confounding using a multivariable Cox model based on predefined variables. MAIN RESULTS: 1,235 patients met the full eligibility criteria for the emulated trial, among whom 164 patients initiated ECMO. The ECMO strategy had a higher survival probability at Day-7 from the onset of eligibility criteria (87% vs 83%, risk difference: 4%, 95% CI 0;9%) which decreased during follow-up (survival at Day-90: 63% vs 65%, risk difference: -2%, 95% CI -10;5%). However, ECMO was associated with higher survival when performed in high-volume ECMO centers or in regions where a specific ECMO network organization was set up to handle high demand, and when initiated within the first 4 days of MV and in profoundly hypoxemic patients. CONCLUSIONS: In an emulated trial based on a nationwide COVID-19 cohort, we found differential survival over time of an ECMO compared with a no-ECMO strategy. However, ECMO was consistently associated with better outcomes when performed in high-volume centers and in regions with ECMO capacities specifically organized to handle high demand. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Silica and Zirconia supported olefin metathesis pre-catalysts: Synthesis, catalytic activity and multiple-use in dimethyl carbonate

International audienceThis study is aimed at designing and synthesising new olefin metathesis catalysts grafted onto porous solid supports and using them in dimethyl carbonate (DMC) an eco-friendly solvent. Two hybrid organic-inorganic Hoveyda-type catalysts were prepared in a few steps by initial grafting of a tailor-made ligand by sol-gel process onto porous silica and zirconia. The new hybrid organic-inorganic catalysts were then engaged in a series of model ring closing metathesis reactions (RCM) in the eco-friendly solvent DMC and their multiple-use was studied

Modélisation spatialisée des besoins, de la production, et des flux de fourrages en vue de la création d’une filière « Fourrages » sur l’île de La Réunion

International audienceIn the early 2010s, cattle breeding cooperatives in Reunion Island resorted to importing hay from France, as an emergency response to a shortage in forages caused by episodes of severe drought. These events highlighted the vulnerability of the livestock farms in terms of self sufficiency. With a view to improve the self-sufficiency of livestock farms, CIRAD was asked to quantify the supply of and demand for fodder and to propose scenarios for structuring a conserved fodder sector (hay, wrapped fodder, straw) at the island level. CIRAD has therefore developed a dynamic and spatially explicit forage flow simulation model integrating a fine geolocation of herbivore farms and all the island's grasslands and sugarcane plots. The annual fodder production of the department was evaluated at 114,050 tons of dry matter. The annual fodder requirement of livestock was evaluated at 110,550 tons of dry matter. The fodder balance highlights the under-use of unharvested grass in the summer season, leading to tensions over the availability of conserved fodder in the winter season in particular. The seasonal balances are also contrasted according to the island's sub-regions due to a strong spatial and temporal variability of fodder supply and demand. The simulations made it possible to quantify the necessary flows between sub-regions, to represent the networks of actors and to evaluate the improvement of the coverage of needs according to the implementation of new practices at the level of production and the positioning of storage places. This study led to technical and logistical recommendations; these results were taken up and developed by a consultancy agency in the context of an expert appraisal aimed at evaluating the technical and economic feasibility of such a fodder sector in Reunion Island.Au début des années 2010, les coopératives d'élevage de bovins à La Réunion ont eu recours à l'importation de foin depuis la France métropolitaine, pour répondre en urgence à un déficit de fourrage associé à des épisodes de sécheresse marquée. Ces événements ont mis en lumière la fragilité des élevages en termes d'autonomie fourragère. Dans l'optique d'accroître l'autonomie des élevages, il a été demandé au CIRAD de quantifier l'offre et la demande en fourrages et de proposer des scénarios de structuration d'une filière de fourrages conservés (foin, enrubanné, paille) à l'échelle de l'île. Le CIRAD a donc développé un modèle dynamique et spatialisé de simulation des flux de fourrages intégrant une géolocalisation fine des élevages d'herbivores et de l'ensemble des parcelles de prairies et de canne à sucre de l'île. La production fourragère annuelle du département a été évaluée à 114 050 tonnes de matière sèche. Le besoin annuel en fourrages des cheptels a lui été évalué à 110 550 tonnes de matière sèche. Le bilan fourrager, met en avant une sous-valorisation de l'herbe sur pied en saison des pluies qui conduit à des tensions autour de la disponibilité des fourrages conservés en saison sèche plus particulièrement. Les bilans saisonniers sont également contrastés selon les sous-régions de l'île du fait d'une forte variabilité spatiale et temporelle de l'offre et de la demande en fourrages. Les simulations ont permis de quantifier les flux nécessaires entre sous-régions, de représenter les réseaux d'acteurs et d'évaluer l'amélioration de la couverture des besoins en fonction de la mise en place de nouvelles pratiques au niveau de la production et du positionnement des lieux de stockages. Cette étude a abouti à des préconisations techniques et logistiques ; ces résultats ont été repris et valorisés par un bureau d'étude dans le cadre d'une expertise visant à évaluer la faisabilité technico-économique d'une telle filière de fourrages à La Réunion

Proteoliposomes as new tool to select active VHH binders by phage display technology

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A New in Silico antibody similarity measure both identifies large sets of epitope binders with distinct CDRs and accurately predicts off-target reactivity

International audienceDeveloping a therapeutic antibody is a long, tedious, and expensive process. Many obstacles need to be overcome, such as biophysical properties (issues of solubility, stability, weak production yields, etc.), as well as cross-reactivity and subsequent toxicity, which are major issues. No in silico method exists today to solve such issues. We hypothesized that if we were able to properly measure the similarity between the CDRs of antibodies (Ab) by considering not only their evolutionary proximity (sequence identity) but also their structural features, we would be able to identify families of Ab recognizing similar epitopes. As a consequence, Ab within the family would share the property to recognize their targets, which would allow (i) to identify off-targets and forecast the cross-reactions, and (ii) to identify new Ab specific for a given target. Testing our method on 238D2, an antagonistic anti-CXCR4 nanobody, we were able to find new nanobodies against CXCR4 and to identify influenza hemagglutinin as an off-target of 238D2

Combined Multiplexed Phage Display, High-Throughput Sequencing, and Functional Assays as a Platform for Identifying Modulatory VHHs Targeting the FSHR

Developing modulatory antibodies against G protein-coupled receptors is challenging. In this study, we targeted the follicle-stimulating hormone receptor (FSHR), a significant regulator of reproduction, with variable domains of heavy chain-only antibodies (VHHs). We built two immune VHH libraries and submitted them to multiplexed phage display approaches. We used next-generation sequencing to identify 34 clusters of specifically enriched sequences that were functionally assessed in a primary screen based on a cAMP response element (CRE)-dependent reporter gene assay. In this assay, 23 VHHs displayed negative or positive modulation of FSH-induced responses, suggesting a high success rate of the multiplexed strategy. We then focused on the largest cluster identified (i.e., PRC1) that displayed positive modulation of FSH action. We demonstrated that PRC1 specifically binds to the human FSHR and human FSHR/FSH complex while potentiating FSH-induced cAMP production and Gs recruitment. We conclude that the improved selection strategy reported here is effective for rapidly identifying functionally active VHHs and could be adapted to target other challenging membrane receptors. This study also led to the identification of PRC1, the first potential positive modulator VHH reported for the human FSHR