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/)

Probing the ionotropic activity of glutamate GluD2 receptor in HEK cells with genetically-engineered photopharmacology

International audienceGlutamate delta (GluD) receptors belong to the ionotropic glutamate receptor family, yet they don't bind glutamate and are considered orphan. Progress in defining the ion channel function of GluDs in neurons has been hindered by a lack of pharmacological tools. Here, we used a chemo-genetic approach to engineer specific and photo-reversible pharmacology in GluD2 receptor. We incorporated a cysteine mutation in the cavity located above the putative ion channel pore, for site-specific conjugation with a photoswitchable pore blocker. In the constitutively open GluD2 Lurcher mutant, current could be rapidly and reversibly decreased with light. We then transposed the cysteine mutation to the native receptor, to demonstrate with high pharmacological specificity that metabotropic glutamate receptor signaling triggers opening of GluD2. Our results assess the functional relevance of GluD2 ion channel and introduce an optogenetic tool that will provide a novel and powerful means for probing GluD2 ionotropic contribution to neuronal physiology

Glutathionylation induces the dissociation of 1-Cys D-peroxiredoxin non-covalent homodimer

1-Cys peroxiredoxins (1-Cys Prxs) are antioxidant enzymes that catalyze the reduction of hydroperoxides into alcohols using a strictly conserved cysteine. 1-Cys B-Prxs, homologous to human PrxVI, were recently shown to be reactivated by glutathione S-transferase (GST) {pi} via the formation of a GST-Prx heterodimer and Prx glutathionylation. In contrast, 1-Cys D-Prxs, homologous to human PrxV, are reactivated by the glutaredoxin-glutathione system through an unknown mechanism. To investigate the mechanistic events that mediate the 1-Cys D-Prx regeneration, interaction of the Prx with glutathione was studied by mass spectrometry and NMR. This work reveals that the Prx can be glutathionylated on its active site cysteine. Evidences are reported that the glutathionylation of 1-Cys D-Prx induces the dissociation of the Prx non-covalent homodimer, which can be recovered by reduction with dithiothreitol. This work demonstrates for the first time the existence of a redox-dependent dimer-monomer switch in the Prx family, similar to the decamer-dimer switch for the 2-Cys Prxs

Birth of a large volcanic edifice offshore Mayotte (Comoros Island, Western Indian Ocean)

International audienc

Birth of a large volcanic edifice offshore Mayotte via lithosphere-scale dyke intrusion

International audienceVolcanic eruptions shape Earth’s surface and provide a window into deep Earth processes. How the primary asthenosphericmelts form, pond and ascend through the lithosphere is, however, still poorly understood. Since 10 May 2018, magmaticactivity has occurred offshore eastern Mayotte (North Mozambique channel), associated with large surface displacements,very-low-frequency earthquakes and exceptionally deep earthquake swarms. Here we present geophysical and marine datafrom the MAYOBS1 cruise, which reveal that by May 2019, this activity formed an 820-m-tall, ~5 km³ volcanic edifice on the seafloor.This is the largest active submarine eruption ever documented. Seismic and deformation data indicate that deep (>55 kmdepth) magma reservoirs were rapidly drained through dykes that intruded the entire lithosphere and that pre-existing subverticalfaults in the mantle were reactivated beneath an ancient caldera structure. We locate the new volcanic edifice at the tip ofa 50-km-long ridge composed of many other recent edifices and lava flows. This volcanic ridge is an extensional feature insidea wide transtensional boundary that transfers strain between the East African and Madagascar rifts. We propose that the massiveeruption originated from hot asthenosphere at the base of a thick, old, damaged lithosphere

Ammando 61, 62 , F. de Palma 45

See paper for full list of authors - 13 pages, 9 figures, accepted for publication in A&AInternational audienceThe addition of a 28 m Cherenkov telescope (CT5) to the H.E.S.S. array extended the experiment's sensitivity to lower energies. The lowest energy threshold is obtained using monoscopic analysis of data taken with CT5, providing access to gamma-ray energies below 100 GeV. Such an extension of the instrument's energy range is particularly beneficial for studies of Active Galactic Nuclei with soft spectra, as expected for those at a redshift > 0.5. The high-frequency peaked BL Lac objects PKS 2155-304 (z = 0.116) and PG 1553+113 (0.43 100 GeV interpreted as being due to interactions with the extragalactic background light (EBL). Multiple observational campaigns of PKS 2155-304 and PG 1553+113 were conducted during 2013 and 2014 using the full H.E.S.S. II instrument. A monoscopic analysis of the data taken with the new CT5 telescope was developed along with an investigation into the systematic uncertainties on the spectral parameters. The energy spectra of PKS 2155-304 and PG 1553+113 were reconstructed down to energies of 80 GeV for PKS 2155-304, which transits near zenith, and 110 GeV for the more northern PG 1553+113. The measured spectra, well fitted in both cases by a log-parabola spectral model (with a 5.0 sigma statistical preference for non-zero curvature for PKS 2155-304 and 4.5 sigma for PG 1553+113), were found consistent with spectra derived from contemporaneous Fermi-LAT data, indicating a sharp break in the observed spectra of both sources at E ~ 100 GeV. When corrected for EBL absorption, the intrinsic H.E.S.S. II mono and Fermi-LAT spectrum of PKS 2155-304 was found to show significant curvature. For PG 1553+113, however, no significant detection of curvature in the intrinsic spectrum could be found within statistical and systematic uncertainties

Characterizing the γ-ray long-term variability of PKS 2155−304 with H.E.S.S. and Fermi-LAT

See paper for full list of authors - 11 pages, 16 figuresInternational audienceStudying the temporal variability of BL Lac objects at the highest energies provides unique insights into the extreme physical processes occurring in relativistic jets and in the vicinity of super-massive black holes. To this end, the long-term variability of the BL Lac object PKS 2155−304 is analyzed in the high (HE, 100 MeV 200 GeV) γ-ray domain. Over the course of ~9 yr of H.E.S.S. observations the VHE light curve in the quiescent state is consistent with a log-normal behavior. The VHE variability in this state is well described by flicker noise (power-spectral-density index βVHE = 1.10+0.10-0.13) on timescales larger than one day. An analysis of ~5.5 yr of HE Fermi-LAT data gives consistent results (βHE = 1.20+0.21-0.23, on timescales larger than 10 days) compatible with the VHE findings. The HE and VHE power spectral densities show a scale invariance across the probed time ranges. A direct linear correlation between the VHE and HE fluxes could neither be excluded nor firmly established. These long-term-variability properties are discussed and compared to the red noise behavior (β ~ 2) seen on shorter timescales during VHE-flaring states. The difference in power spectral noise behavior at VHE energies during quiescent and flaring states provides evidence that these states are influenced by different physical processes, while the compatibility of the HE and VHE long-term results is suggestive of a common physical link as it might be introduced by an underlying jet-disk connection