Abstract In a phase 3 trial (PANAMO, NCT04333420), vilobelimab, a complement 5a (C5a) inhibitor, reduced 28-day mortality in mechanically ventilated COVID-19 patients. This post hoc analysis of 368 ...patients aimed to explore treatment heterogeneity through unsupervised learning. All available clinical variables at baseline were used as input. Treatment heterogeneity was assessed using latent class analysis (LCA), Ward’s hierarchical clustering (HC) and the adjudication to previously described clinical sepsis phenotypes. The primary outcome was 28-day mortality. For LCA, a 2-class latent model was deemed most suitable. In the LCA model, 82 (22%) patients were assigned to class 1 and 286 (78%) to class 2. Class 1 was defined by more severely ill patients with significantly higher mortality. In an adjusted logistic regression, no heterogeneity of treatment effect (HTE) between classes was observed ( p = 0.998). For HC, no significant classes were found ( p = 0.669). Using the previously described clinical sepsis subtypes, 41 patients (11%) were adjudicated subtype alpha (α), 17 (5%) beta (β), 112 (30%) delta (δ) and 198 (54%) gamma (γ). HTE was observed between clinical subtypes ( p = 0.001) with improved 28-day mortality after treatment with vilobelimab for the δ subtype (OR = 0.17, 95% CI 0.07–0.40, p < 0.001). No signal for harm of treatment with vilobelimab was observed in any class or clinical subtype. Overall, treatment effect with vilobelimab was consistent across different classes and subtypes, except for the δ subtype, suggesting potential additional benefit for the most severely ill patients.
Energetic young pulsars and expanding blast waves supernova remnants (SNRs) are the most visible remains after massive stars, ending their lives, explode in core-collapse supernovae. The Fermi ...Gamma-Ray Space Telescope has unveiled a radio quiet pulsar located near the center of the compact synchrotron nebula inside the supernova remnant CTA 1. The pulsar, discovered through its gamma-ray pulsations, has a period of 316.86 milliseconds and a period derivative of 3.614 x 10⁻¹³ seconds per second. Its characteristic age of 10⁴ years is comparable to that estimated for the SNR. We speculate that most unidentified Galactic gamma-ray sources associated with star-forming regions and SNRs are such young pulsars.
Background
Vilobelimab, a complement 5a (C5a)-specific monoclonal antibody, reduced mortality in critically ill COVID-19 patients in a phase 3 multicentre, randomized, double-blind, ...placebo-controlled study. As part of the study, vilobelimab concentrations and C5a levels as well as antidrug antibodies (ADAs) to vilobelimab were analysed.
Results
From Oct 1, 2020 to Oct 4, 2021, 368 invasively mechanically ventilated COVID-19 patients were randomized: 177 patients were randomly assigned to receive vilobelimab while 191 patients received placebo. Pharmacokinetic sampling was only performed at sites in Western Europe. Blood samples for vilobelimab measurements were available for 93 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. On day 8, after three infusions, mean vilobelimab (trough) concentrations ranged from 21,799.3 to 302,972.1 ng/mL (geometric mean 137,881.3 ng/mL). Blood samples for C5a measurements were available for 94 of 177 (53%) patients in the vilobelimab group and 99 of 191 (52%) patients in the placebo group. At screening, C5a levels were highly elevated and comparable between groups. In the vilobelimab group, median C5a levels were 118.3 ng/mL IQR 71.2–168.2 ng/mL and in the placebo group, median C5a levels were 104.6 ng/mL IQR 77.5–156.6 ng/mL. By day 8, median C5a levels were reduced by 87% in the vilobelimab group (median 14.5 ng/mL IQR 9.5–21.0 ng/mL, p < 0.001) versus an 11% increase in the placebo group (median 119.2 ng/mL IQR 85.9–152.1 ng/mL). Beyond day 8, though plasma sampling was sparse, C5a levels did not reach screening levels in the vilobelimab group while C5a levels remained elevated in the placebo group. Treatment-emergent ADAs were observed in one patient in the vilobelimab group at hospital discharge on day 40 and in one patient in the placebo group at hospital discharge on day 25.
Conclusions
This analysis shows that vilobelimab efficiently inhibits C5a in critically ill COVID-19 patients. There was no evidence of immunogenicity associated with vilobelimab treatment.
Trial
registration
ClinicalTrials.gov, NCT04333420. Registered 3 April 2020,
https://clinicaltrials.gov/ct2/show/NCT04333420
Here we demonstrate a parametric positioning method on a continuous crystal detector. Three different models for the light distribution were tested. Diagnosis of the residues showed that the ...parametric model fits the experimental data better than Gaussian and Cauchy models in our particular experimental setup. Based on the correlation between the spread and the peak value of the light distribution model with the depth of interaction (DOI), we were able to estimate the three-dimensional position of a scintillation event. On our continuous miniature crystal element (cMiCE) detector module with 8 mm thick LYSO crystal, the intrinsic spatial resolution is 1.06 mm at the center and 1.27 mm at the corner using a maximum-likelihood estimation (MLE) method and the parametric model. The DOI resolution (full width at half maximum) is estimated to be approximately 3.24 mm. The positioning method using the parametric model outperformed the Gaussian and Cauchy models, in both MLE and weighted least-squares (WLS) fitting methods. The key feature of this technique is that it requires very little calibration of the detector, but still retains high resolution and high sensitivity.
We use Fermi Gamma-ray Space Telescope detections and upper limits on non-recycled pulsars obtained from the Large Area Telescope (LAT) to constrain how the gamma-ray luminosity L sub(gamma) depends ...on the period P and the period derivative P. We use a Bayesian analysis to calculate a best-fit luminosity law, or dependence of L sub(gamma) on P and P, including different methods for modeling the beaming factor. An outer gap (OG) magnetosphere geometry provides the best-fit model, which is Lgamma alpha P-a Pb where a = 1.36 + or - 0.03 and b = 0.44 + or - 0.02, similar to but not identical to the commonly assumed L sub(gamma) alpha radicalE alpha super(-1.5) P super(0.5). Given upper limits on gamma-ray fluxes of currently known radio pulsars and using the OG model, we find that about 92% of the radio-detected pulsars have gamma-ray beams that intersect our line of sight. By modeling the misalignment of radio and gamma-ray beams of these pulsars, we find an average gamma-ray beaming solid angle of about 3.7pi for the OG model, assuming a uniform beam. Using LAT-measured diffuse fluxes, we place a 2sigma upper limit on the average braking index and a 2sigma lower limit on the average surface magnetic field strength of the pulsar population of 3.8 and 3.2 x 10 super(10) G, respectively. We then predict the number of non-recycled pulsars detectable by the LAT based on our population model. Using the 2 yr sensitivity, we find that the LAT is capable of detecting emission from about 380 non-recycled pulsars, including 150 currently identified radio pulsars. Using the expected 5 yr sensitivity, about 620 non-recycled pulsars are detectable, including about 220 currently identified radio pulsars. We note that these predictions significantly depend on our model assumptions.
Analysis of the Genesis samples is underway. Preliminary elemental abundances based on Genesis sample analyses are in good agreement with in situ-measured elemental abundances made by ACE/SWICS ...during the Genesis collection period. Comparison of these abundances with those of earlier solar cycles indicates that the solar wind composition is relatively stable between cycles for a given type of flow. ACE/SWICS measurements for the Genesis collection period also show a continuum in compositional variation as a function of velocity for the quasi-stationary flow that defies the simple binning of samples into their sources of coronal hole (CH) and interstream (IS).
We present the fourth Fermi Large Area Telescope catalog (4FGL) of γ-ray sources. Based on the first eight years of science data from the Fermi Gamma-ray Space Telescope mission in the energy range ...from 50 MeV to 1 TeV, it is the deepest yet in this energy range. Relative to the 3FGL catalog, the 4FGL catalog has twice as much exposure as well as a number of analysis improvements, including an updated model for the Galactic diffuse γ-ray emission, and two sets of light curves (one-year and two-month intervals). The 4FGL catalog includes 5064 sources above 4 significance, for which we provide localization and spectral properties. Seventy-five sources are modeled explicitly as spatially extended, and overall, 358 sources are considered as identified based on angular extent, periodicity, or correlated variability observed at other wavelengths. For 1336 sources, we have not found plausible counterparts at other wavelengths. More than 3130 of the identified or associated sources are active galaxies of the blazar class, and 239 are pulsars.
Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human ...reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.
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