Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men

Statistical Analysis of Solar Events Associated with Storm Sudden Commencements over One Year of Solar Maximum During Cycle 23: Propagation from the Sun to the Earth and Effects

International audienceTaking the 32 storm sudden commencements (SSCs) listed by the International Service of Geomagnetic Indices (ISGI) of the Observatory de l’Ebre during 2002 (solar activity maximum in Cycle 23) as a starting point, we performed a multi-criterion analysis based on observations (propagation time, velocity comparisons, sense of the magnetic field rotation, radio waves) to associate them with solar sources, identified their effects in the interplanetary medium, and looked at the response of the terrestrial ionized and neutral environment. We find that 28 SSCs can be related to 44 coronal mass ejections (CMEs), 15 with a unique CME and 13 with a series of multiple CMEs, among which 19 (68%) involved halo CMEs. Twelve of the 19 fastest CMEs with speeds greater than 1000 km s−1 are halo CMEs. For the 44 CMEs, including 21 halo CMEs, the corresponding X-ray flare classes are: 3 X-class, 19 M-class, and 22 C-class flares. The probability for an SSC to occur is 75% if the CME is a halo CME. Among the 500, or even more, front-side, non-halo CMEs recorded in 2002, only 23 could be the source of an SSC, i.e. 5%. The complex interactions between two (or more) CMEs and the modification of their trajectories have been examined using joint white-light and multiple-wavelength radio observations. The detection of long-lasting type IV bursts observed at metric–hectometric wavelengths is a very useful criterion for the CME–SSC events association. The events associated with the most depressed Dst values are also associated with type IV radio bursts. The four SSCs associated with a single shock at L1 correspond to four radio events exhibiting characteristics different from type IV radio bursts. The solar-wind structures at L1 after the 32 SSCs are 12 magnetic clouds (MCs), 6 interplanetary coronal mass ejections (ICMEs) without an MC structure, 4 miscellaneous structures, which cannot unambiguously be classified as ICMEs, 5 corotating or stream interaction regions (CIRs/SIRs), one CIR caused two SSCs, and 4 shock events; note than one CIR caused two SSCs. The 11 MCs listed in 3 or more MC catalogs covering the year 2002 are associated with SSCs. For the three most intense geomagnetic storms (based on Dst minima) related to MCs, we note two sudden increases of the Dst, at the arrival of the sheath and the arrival of the MC itself. In terms of geoeffectiveness, the relation between the CME speed and the magnetic-storm intensity, as characterized using the Dst magnetic index, is very complex, but generally CMEs with velocities at the Sun larger than 1000 km s−1 have larger probabilities to trigger moderate or intense storms. The most geoeffective events are MCs, since 92% of them trigger moderate or intense storms, followed by ICMEs (33%). At best, CIRs/SIRs only cause weak storms. We show that these geoeffective events (ICMEs or MCs) trigger an increased and combined auroral kilometric radiation (AKR) and non-thermal continuum (NTC) wave activity in the magnetosphere, an enhanced convection in the ionosphere, and a stronger response in the thermosphere. However, this trend does not appear clearly in the coupling functions, which exhibit relatively weak correlations between the solar-wind energy input and the amplitude of various geomagnetic indices, whereas the role of the southward component of the solar-wind magnetic field is confirmed. Some saturation appears for Dst values <−100 nT on the integrated values of the polar and auroral indices

Vorapaxar in the secondary prevention of atherothrombotic events

Item does not contain fulltextBACKGROUND: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1. METHODS: We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage. RESULTS: At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001). CONCLUSIONS: Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.)