Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients

Background Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown. Methods Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding. Results A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55). Conclusions Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.

H.E.S.S. programme searching for VHE gamma rays associated with FRBs

Fast Radio Bursts (FRBs) are highly energetic, extremely short-lived bursts of radio flashes. Despite extensive research, the exact cause of these outbursts remains speculative. The high luminosity, short duration, and high dispersion measure of these events suggest they result from extreme, high-energy extragalactic sources, such as highly magnetized and rapidly spinning neutron stars known as magnetars. The number of detected FRBs, including repeating ones, has grown rapidly in recent years. Except for FRB 20200428D, and FRB-like radio burst that is associated to Galactic magnetar SGR 1935+2154, no multi-wavelength counterpart to any FRB has been detected yet. The High Energy Stereoscopic System (H.E.S.S.) telescope has developed a program to follow up FRBs searching for their gamma-ray counterparts, helping to uncover the nature of FRBs and FRB sources. This paper provides an overview of the searches for FRB sources conducted by H.E.S.S., including follow-up observations and simultaneous multi-wavelength campaigns with radio and X-ray observatories. Among the FRB sources observed by H.E.S.S., nine are localized with redshifts ranging between 0.11 and 0.492 from 2015 to 2022. No significant very high energy (VHE) emission was detected during these observations. We report constraints on the VHE luminosity ranging from 1044 erg s-1 and 1048 erg s-1, placing limits on the FRB's region persistent VHE emission and potential FRB afterglow emission across timescales from hours to years

Very-high-energy γ -Ray Emission from Young Massive Star Clusters in the Large Magellanic Cloud

The Tarantula Nebula in the Large Magellanic Cloud is known for its high star formation activity. At its center lies the young massive star cluster R136, providing a significant amount of the energy that makes the nebula shine so brightly at many wavelengths. Recently, young massive star clusters have been suggested to also efficiently produce very high-energy cosmic rays, potentially beyond PeV energies. Here, we report the detection of very-high-energy γ-ray emission from the direction of R136 with the High Energy Stereoscopic System, achieved through a multicomponent, likelihood-based modeling of the data. This supports the hypothesis that R136 is indeed a very powerful cosmic-ray accelerator. Moreover, from the same analysis, we provide an updated measurement of the γ-ray emission from 30 Dor C, the only superbubble detected at TeV energies presently. The γ-ray luminosity above 0.5 TeV of both sources is (2–3) × 1035 erg s−1. This exceeds by more than a factor of 2 the luminosity of HESS J1646−458, which is associated with the most massive young star cluster in the Milky Way, Westerlund 1. Furthermore, the γ-ray emission from each source is extended with a significance of >3σ and a Gaussian width of about 30 pc. For 30 Dor C, a connection between the γ-ray emission and the nonthermal X-ray emission appears likely. Different interpretations of the γ-ray signal from R136 are discussed

Unveiling extended gamma-ray emission around HESS J1813-178

Context. HESS J1813-178 is a very-high-energy γ-ray source spatially coincident with the young and energetic pulsar PSR J1813-1749 and thought to be associated with its pulsar wind nebula (PWN). Recently, evidence for extended high-energy emission in the vicinity of the pulsar has been revealed in the Fermi Large Area Telescope (LAT) data. This motivates revisiting the HESS J1813-178 region, taking advantage of improved analysis methods and an extended dataset. Aims. Using data taken by the High Energy Stereoscopic System (H.E.S.S.) experiment and the Fermi-LAT, we aim to describe the γ-ray emission in the region with a consistent model, to provide insights into its origin. Methods. We performed a likelihood-based analysis on 32 hours of H.E.S.S. data and 12 yr of Fermi-LAT data and we fitted a spectro-morphological model to the combined datasets. These results allowed us to develop a physical model for the origin of the observed γ-ray emission in the region. Results. In addition to the compact very-high-energy γ-ray emission centred on the pulsar, we find a significant yet previously undetected component along the Galactic plane. With Fermi-LAT data, we confirm extended high-energy emission consistent with the position and elongation of the extended emission observed with H.E.S.S. These results establish a consistent description of the emission in the region from GeV energies to several tens of TeV. Conclusions. This study suggests that HESS J1813-178 is associated with a γ-ray PWN powered by PSR J1813-1749. A possible origin of the extended emission component is inverse Compton emission from electrons and positrons that have escaped the confines of the pulsar and form a halo around the PWN.</p

High-Statistics Measurement of the Cosmic-Ray Electron Spectrum with H.E.S.S.

Owing to their rapid cooling rate and hence loss-limited propagation distance, cosmic-ray electrons and positrons (CRe) at very high energies probe local cosmic-ray accelerators and provide constraints on exotic production mechanisms such as annihilation of dark matter particles. We present a high-statistics measurement of the spectrum of CRe candidate events from 0.3 to 40 TeV with the High Energy Stereoscopic System, covering 2 orders of magnitude in energy and reaching a proton rejection power of better than 104. The measured spectrum is well described by a broken power law, with a break around 1 TeV, where the spectral index increases from Γ1=3.25±0.02(stat)±0.2(sys) to Γ2=4.49±0.04(stat)±0.2(sys). Apart from the break, the spectrum is featureless. The absence of distinct signatures at multi-TeV energies imposes constraints on the presence of nearby CRe accelerators and the local CRe propagation mechanisms.</p

The Vanishing of the Primary Emission Region in PKS 1510-089

In 2021 July, PKS 1510-089 exhibited a significant flux drop in the high-energy γ-ray (by a factor 10) and optical (by a factor 5) bands and remained in this low state throughout 2022. Similarly, the optical polarization in the source vanished, resulting in the optical spectrum being fully explained through the steady flux of the accretion disk and the broad-line region. Unlike the aforementioned bands, the very-high-energy γ-ray and X-ray fluxes did not exhibit a significant flux drop from year to year. This suggests that the steady-state very-high-energy γ-ray and X-ray fluxes originate from a different emission region than the vanished parts of the high-energy γ-ray and optical jet fluxes. The latter component has disappeared through either a swing of the jet away from the line of sight or a significant drop in the photon production efficiency of the jet close to the black hole. Either change could become visible in high-resolution radio images

The Inheritance of Histone Modifications Depends upon the Location in the Chromosome in Saccharomyces cerevisiae

Histone modifications are important epigenetic features of chromatin that must be replicated faithfully. However, the molecular mechanisms required to duplicate and maintain histone modification patterns in chromatin remain to be determined. Here, we show that the introduction of histone modifications into newly deposited nucleosomes depends upon their location in the chromosome. In Saccharomyces cerevisiae, newly deposited nucleosomes consisting of newly synthesized histone H3-H4 tetramers are distributed throughout the entire chromosome. Methylation of lysine 4 on histone H3 (H3-K4), a hallmark of euchromatin, is introduced into these newly deposited nucleosomes, regardless of whether the neighboring preexisting nucleosomes harbor the K4 mutation in histone H3. Furthermore, if the heterochromatin-binding protein Sir3 is unavailable during DNA replication, histone H3-K4 methylation is introduced onto newly deposited nucleosomes in telomeric heterochromatin. Thus, a conservative distribution model most accurately explains the inheritance of histone modifications because the location of histones within euchromatin or heterochromatin determines which histone modifications are introduced

Histone Deacetylase Inhibitors Globally Enhance H3/H4 Tail Acetylation Without Affecting H3 Lysine 56 Acetylation

Histone deacetylase inhibitors (HDACi) represent a promising avenue for cancer therapy. We applied mass spectrometry (MS) to determine the impact of clinically relevant HDACi on global levels of histone acetylation. Intact histone profiling revealed that the HDACi SAHA and MS-275 globally increased histone H3 and H4 acetylation in both normal diploid fibroblasts and transformed human cells. Histone H3 lysine 56 acetylation (H3K56ac) recently elicited much interest and controversy due to its potential as a diagnostic and prognostic marker for a broad diversity of cancers. Using quantitative MS, we demonstrate that H3K56ac is much less abundant than previously reported in human cells. Unexpectedly, in contrast to H3/H4 N-terminal tail acetylation, H3K56ac did not increase in response to inhibitors of each class of HDACs. In addition, we demonstrate that antibodies raised against H3K56ac peptides cross-react against H3 N-terminal tail acetylation sites that carry sequence similarity to residues flanking H3K56

TeV flaring activity of the AGN PKS 0625-354 in November 2018

Most $\gamma$-ray detected active galactic nuclei are blazars with one of their relativistic jets pointing towards the Earth. Only a few objects belong to the class of radio galaxies or misaligned blazars. Here, we investigate the nature of the object PKS 0625-354, its $\gamma$-ray flux and spectral variability and its broad-band spectral emission with observations from H.E.S.S., Fermi-LAT, Swift-XRT, and UVOT taken in November 2018. The H.E.S.S. light curve above 200 GeV shows an outburst in the first night of observations followed by a declining flux with a halving time scale of 5.9h. The $\gamma\gamma$-opacity constrains the upper limit of the angle between the jet and the line of sight to $\sim10^\circ$. The broad-band spectral energy distribution shows two humps and can be well fitted with a single-zone synchrotron self Compton emission model. We conclude that PKS 0625-354, as an object showing clear features of both blazars and radio galaxies, can be classified as an intermediate active galactic nuclei. Multi-wavelength studies of such intermediate objects exhibiting features of both blazars and radio galaxies are sparse but crucial for the understanding of the broad-band emission of $\gamma$-ray detected active galactic nuclei in general.Comment: 9 pages, 6 figures, accepted for publication in Astronomy & Astrophysic

Constraints on the intergalactic magnetic field using Fermi-LAT and H.E.S.S. blazar observations

Magnetic fields in galaxies and galaxy clusters are believed to be the result of the amplification of intergalactic seed fields during the formation of large-scale structures in the universe. However, the origin, strength, and morphology of this intergalactic magnetic field (IGMF) remain unknown. Lower limits on (or indirect detection of) the IGMF can be obtained from observations of high-energy gamma rays from distant blazars. Gamma rays interact with the extragalactic background light to produce electron-positron pairs, which can subsequently initiate electromagnetic cascades. The $\gamma$-ray signature of the cascade depends on the IGMF since it deflects the pairs. Here we report on a new search for this cascade emission using a combined data set from the Fermi Large Area Telescope and the High Energy Stereoscopic System. Using state-of-the-art Monte Carlo predictions for the cascade signal, our results place a lower limit on the IGMF of $B > 7.1\times10^{-16}$ G for a coherence length of 1 Mpc even when blazar duty cycles as short as 10 yr are assumed. This improves on previous lower limits by a factor of 2. For longer duty cycles of $10^4$ ($10^7$) yr, IGMF strengths below $1.8\times10^{-14}$ G ($3.9\times10^{-14}$ G) are excluded, which rules out specific models for IGMF generation in the early universe.Comment: 20 pages, 7 figures, 4 tables. Accepted for publication in ApJ Letters. Auxiliary data is provided in electronic format at https://zenodo.org/record/801431