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- BCX7353 (1)
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Background: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA®, CSL Behring) was established in the 16-week COMPACT trial.
Objective: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC).
Methods: Open-label, randomised, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naïve or who had completed the COMPACT trial, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional up-titration to optimise prophylaxis. ClinicalTrials.gov registration: NCT02316353.
Results: 126 patients with a monthly attack rate of 4.3 in 3 months prior to entry in the COMPACT program were enrolled and treated for a mean of 1·5 years; 44 patients (34·9%) had >2 years exposure. Median steady-state C1-INH functional activity increased to a maximum of 73.0% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11·3 and 8·5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualised attack rates were 1·3 and 1·0, respectively and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for >2 years, 19 (83%) were attack-free during months 25–30 of treatment.
Conclusion: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms.
Background: Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods: Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings: Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance: Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.
Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks.
Objective: Our aim was to determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial).
Methods: APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period.
Results: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred.
Conclusion: Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg per day.
Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species’ threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project – and avert – future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1% of the total number of all species described, and more than 1% of the described species within many taxonomic groups – including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems – www.predicts.org.uk). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.
he first measurement of 3ΛH and 3Λ¯¯¯¯H¯¯¯¯ differential production with respect to transverse momentum and centrality in Pb−Pb collisions at sNN−−−√=5.02~TeV is presented. The 3ΛH has been reconstructed via its two-charged-body decay channel, i.e., 3ΛH→3He+π−. A Blast-Wave model fit of the pT-differential spectra of all nuclear species measured by the ALICE collaboration suggests that the 3ΛH kinetic freeze-out surface is consistent with that of other nuclei. The ratio between the integrated yields of 3ΛH and 3He is compared to predictions from the statistical hadronisation model and the coalescence model, with the latter being favoured by the presented measurements.
This Letter presents the first measurement of event-by-event fluctuations of the net number (difference between the particle and antiparticle multiplicities) of multistrange hadrons Ξ− and Ξ¯¯¯¯+ and its correlation with the net-kaon number using the data collected by the ALICE Collaboration in pp, p−Pb, and Pb−Pb collisions at a center-of-mass energy per nucleon pair sNN−−−√=5.02 TeV. The statistical hadronization model with a correlation over three units of rapidity between hadrons having the same and opposite strangeness content successfully describes the results. On the other hand, string-fragmentation models that mainly correlate strange hadrons with opposite strange quark content over a small rapidity range fail to describe the data.
Measurements of (anti)deuteron and (anti)3He production in the rapidity range |y|< 0.5 as a function of the transverse momentum and event multiplicity in Xe−Xe collisions at a center-of-mass energy per nucleon−nucleon pair of sNN−−−√ = 5.44 TeV are presented. The coalescence parameters B2 and B3 are measured as a function of the transverse momentum per nucleon. The ratios between (anti)deuteron and (anti)3He yields and those of (anti)protons and pions are reported as a function of the mean charged-particle multiplicity density, and compared with two implementations of the statistical hadronization model (SHM) and with coalescence predictions. The elliptic flow of (anti)deuterons is measured for the first time in Xe−Xe collisions and shows features similar to those already observed in Pb−Pb collisions, i.e., the mass ordering at low transverse momentum and the meson−baryon grouping at intermediate transverse momentum. The production of nuclei is particularly sensitive to the chemical freeze-out temperature of the system created in the collision, which is extracted from a grand-canonical-ensemble-based thermal fit, performed for the first time including light nuclei along with light-flavor hadrons in Xe−Xe collisions. The extracted chemical freeze-out temperature Tchem = (154.2 ± 1.1) MeV in Xe−Xe collisions is similar to that observed in Pb−Pb collisions and close to the crossover temperature predicted by lattice QCD calculations.
First measurements of hadron(h)−Λ azimuthal angular correlations in p−Pb collisions at sNN−−−√ = 5.02 TeV using the ALICE detector at the LHC are presented. These correlations are used to separate the production of associated Λ baryons into three different kinematic regions, namely those produced in the direction of the trigger particle (near-side), those produced in the opposite direction (away-side), and those whose production is uncorrelated with the jet-axis (underlying event). The per-trigger associated Λ yields in these regions are extracted, along with the near- and away-side azimuthal peak widths, and the results are studied as a function of associated particle pT and event multiplicity. Comparisons with the DPMJET event generator and previous measurements of the ϕ(1020) meson are also made. The final results indicate that strangeness production in the highest multiplicity p−Pb collisions is enhanced relative to low multiplicity collisions in the jet-like regions, as well as the underlying event. The production of Λ relative to charged hadrons is also enhanced in the underlying event when compared to the jet-like regions. Additionally, the results hint that strange quark production in the away-side of the jet is modified by soft interactions with the underlying event.
The SARS-CoV-2 pandemic has challenged researchers at a global scale. The scientific community’s massive response has resulted in a flood of experiments, analyses, hypotheses, and publications, especially in the field of drug repurposing. However, many of the proposed therapeutic compounds obtained from SARS-CoV-2 specific assays are not in agreement and thus demonstrate the need for a singular source of COVID-19 related information from which a rational selection of drug repurposing candidates can be made. In this paper, we present the COVID-19 PHARMACOME, a comprehensive drug-target-mechanism graph generated from a compilation of 10 separate disease maps and sources of experimental data focused on SARS-CoV-2 / COVID-19 pathophysiology. By applying our systematic approach, we were able to predict the synergistic effect of specific drug pairs, such as Remdesivir and Thioguanosine or Nelfinavir and Raloxifene, on SARS-CoV-2 infection. Experimental validation of our results demonstrate that our graph can be used to not only explore the involved mechanistic pathways, but also to identify novel combinations of drug repurposing candidates.
The transverse momentum (pT) differential production cross section of the promptly-produced charm-strange baryon Ξ0c (and its charge conjugate Ξ0c¯¯¯¯¯¯) is measured at midrapidity via its hadronic decay into π+Ξ− in p−Pb collisions at a centre-of-mass energy per nucleon−nucleon collision sNN−−−√ = 5.02 TeV with the ALICE detector at the LHC. The Ξ0c nuclear modification factor (RpPb), calculated from the cross sections in pp and p−Pb collisions, is presented and compared with the RpPb of Λ+c baryons. The ratios between the pT-differential production cross section of Ξ0c baryons and those of D0 mesons and Λ+c baryons are also reported and compared with results at forward and backward rapidity from the LHCb Collaboration. The measurements of the production cross section of prompt Ξ0c baryons are compared with a model based on perturbative QCD calculations of charm-quark production cross sections, which includes only cold nuclear matter effects in p−Pb collisions, and underestimates the measurement by a factor of about 50. This discrepancy is reduced when the data is compared with a model in which hadronisation is implemented via quark coalescence. The pT-integrated cross section of prompt Ξ0c-baryon production at midrapidity extrapolated down to pT = 0 is also reported. These measurements offer insights and constraints for theoretical calculations of the hadronisation process. Additionally, they provide inputs for the calculation of the charm production cross section in p−Pb collisions at midrapidity.