Evaluation of the efficacy and safety of intravenous remdesivir in adult patients with severe COVID-19: study protocol for a phase 3 randomized, double-blind, placebo-controlled, multicentre trial.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by a novel corinavirus (later named SARS-CoV-2 virus), was fistly reported in Wuhan, Hubei Province, China towards the end of 2019. Large-scale spread within China and internationally led the World Health Organization to declare a Public Health Emergency of International Concern on 30th January 2020. The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure, and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including MERS-CoV and SARS-CoV, in in vitro and in vivo experiments. It is also inhibitory against the COVID-19 virus in vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe COVID-19. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. This is a phase 3, randomized, double-blind, placebo-controlled, multicentre trial. Adults (≥ 18 years) with laboratory-confirmed COVID-19 virus infection, severe pneumonia signs or symptoms, and radiologically confirmed severe pneumonia are randomly assigned in a 2:1 ratio to intravenously administered remdesivir or placebo for 10 days. The primary endpoint is time to clinical improvement (censored at day 28), defined as the time (in days) from randomization of study treatment (remdesivir or placebo) until a decline of two categories on a six-category ordinal scale of clinical status (1 = discharged; 6 = death) or live discharge from hospital. One interim analysis for efficacy and futility will be conducted once half of the total number of events required has been observed. DISCUSSION: This is the first randomized, placebo-controlled trial in COVID-19. Enrolment began in sites in Wuhan, Hubei Province, China on 6th February 2020. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04257656. Registered on 6 February 2020

Multidifferential study of identified charged hadron distributions in ZZ-tagged jets in proton-proton collisions at s=\sqrt{s}=13 TeV

Jet fragmentation functions are measured for the first time in proton-proton collisions for charged pions, kaons, and protons within jets recoiling against a $Z$ boson. The charged-hadron distributions are studied longitudinally and transversely to the jet direction for jets with transverse momentum 20 $< p_{\textrm{T}} < 100$ GeV and in the pseudorapidity range $2.5 < \eta < 4$. The data sample was collected with the LHCb experiment at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 1.64 fb$^{-1}$. Triple differential distributions as a function of the hadron longitudinal momentum fraction, hadron transverse momentum, and jet transverse momentum are also measured for the first time. This helps constrain transverse-momentum-dependent fragmentation functions. Differences in the shapes and magnitudes of the measured distributions for the different hadron species provide insights into the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb public pages

Study of the B−→Λc+Λˉc−K−B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-} decay

The decay $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ is studied in proton-proton collisions at a center-of-mass energy of $\sqrt{s}=13$ TeV using data corresponding to an integrated luminosity of 5 $\mathrm{fb}^{-1}$ collected by the LHCb experiment. In the $\Lambda_{c}^+ K^{-}$ system, the $\Xi_{c}(2930)^{0}$ state observed at the BaBar and Belle experiments is resolved into two narrower states, $\Xi_{c}(2923)^{0}$ and $\Xi_{c}(2939)^{0}$, whose masses and widths are measured to be $$m(\Xi_{c}(2923)^{0}) = 2924.5 \pm 0.4 \pm 1.1 \,\mathrm{MeV}, \\ m(\Xi_{c}(2939)^{0}) = 2938.5 \pm 0.9 \pm 2.3 \,\mathrm{MeV}, \\ \Gamma(\Xi_{c}(2923)^{0}) = \phantom{000}4.8 \pm 0.9 \pm 1.5 \,\mathrm{MeV},\\ \Gamma(\Xi_{c}(2939)^{0}) = \phantom{00}11.0 \pm 1.9 \pm 7.5 \,\mathrm{MeV},$$ where the first uncertainties are statistical and the second systematic. The results are consistent with a previous LHCb measurement using a prompt $\Lambda_{c}^{+} K^{-}$ sample. Evidence of a new $\Xi_{c}(2880)^{0}$ state is found with a local significance of $3.8\,\sigma$, whose mass and width are measured to be $2881.8 \pm 3.1 \pm 8.5\,\mathrm{MeV}$ and $12.4 \pm 5.3 \pm 5.8 \,\mathrm{MeV}$, respectively. In addition, evidence of a new decay mode $\Xi_{c}(2790)^{0} \to \Lambda_{c}^{+} K^{-}$ is found with a significance of $3.7\,\sigma$. The relative branching fraction of $B^{-} \to \Lambda_{c}^{+} \bar{\Lambda}_{c}^{-} K^{-}$ with respect to the $B^{-} \to D^{+} D^{-} K^{-}$ decay is measured to be $2.36 \pm 0.11 \pm 0.22 \pm 0.25$, where the first uncertainty is statistical, the second systematic and the third originates from the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb public pages

Measurement of the ratios of branching fractions R(D∗)\mathcal{R}(D^{*}) and R(D0)\mathcal{R}(D^{0})

The ratios of branching fractions $\mathcal{R}(D^{*})\equiv\mathcal{B}(\bar{B}\to D^{*}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(\bar{B}\to D^{*}\mu^{-}\bar{\nu}_{\mu})$ and $\mathcal{R}(D^{0})\equiv\mathcal{B}(B^{-}\to D^{0}\tau^{-}\bar{\nu}_{\tau})/\mathcal{B}(B^{-}\to D^{0}\mu^{-}\bar{\nu}_{\mu})$ are measured, assuming isospin symmetry, using a sample of proton-proton collision data corresponding to 3.0 fb${ }^{-1}$ of integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The tau lepton is identified in the decay mode $\tau^{-}\to\mu^{-}\nu_{\tau}\bar{\nu}_{\mu}$. The measured values are $\mathcal{R}(D^{*})=0.281\pm0.018\pm0.024$ and $\mathcal{R}(D^{0})=0.441\pm0.060\pm0.066$, where the first uncertainty is statistical and the second is systematic. The correlation between these measurements is $\rho=-0.43$. Results are consistent with the current average of these quantities and are at a combined 1.9 standard deviations from the predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb public pages

Small-Scale Soil Microbial Community Heterogeneity Linked to Landform Historical Events on King George Island, Maritime Antarctica

Although research on microbial biogeography has made great progress in the past decade, distributions of terrestrial microbial communities in extreme environments such as Antarctica are not well understood. In addition, knowledge of whether and how historical contingencies affect microbial distributions at small spatial scales is lacking. Here, we analyzed soil-borne microbial (bacterial, archaeal, and fungal) communities in 12 quadrat plots around the Fildes Region of King George Island, maritime Antarctica, and the communities were divided into two groups according to the soil elemental compositions and environmental attributes of Holocene raised beach and Tertiary volcanic stratigraphy. Prokaryotic communities of the two groups were well separated; the prokaryotic data were primarily correlated with soil elemental compositions and were secondly correlated with environmental attributes (e.g., soil pH, total organic carbon, NO3-, and vegetation coverage; Pearson test, r = 0.59 vs. 0.52, both P &lt; 0.01). The relatively high abundance of P, S, Cl, and Br in Group 1 (Holocene raised beach site) was likely due to landform uplift. Lithophile-elements (Si, Al, Ca, Sr, Ti, V, and Fe) correlated with prokaryotic communities in Group 2 may have originated from weathering of Tertiary volcanic rock. No significant correlations were found between the fungal community distribution and both the soil elemental composition and environmental attributes in this study; however, Monte Carlo tests revealed that elements Sr and Ti, soil pH, sampling altitude, and moss and lichen species numbers had significant impacts on fungal communities. The elements and nutrients accumulated during the formation of different landforms influenced the development of soils, plant growth, and microbial communities, and this resulted in small-scale spatially heterogeneous biological distributions. These findings provide new evidence that geological evolutionary processes in the Fildes Region were crucial to its microbial community development, and the results highlight that microbial distribution patterns are the legacies of historical events at this small spatial scale. Based on this study, the ice-free regions in maritime Antarctica represent suitable research sites for studying the influence of geomorphological features on microbial distributions, and we envision the possibility of a site-specific landform assignment through the analysis of the soil prokaryotic community structure

Diversity and distribution of heterotrophic flagellates in seawater of the Powell Basin, Antarctic Peninsula

Heterotrophic flagellates are essential components of the marine microbial food web. However, how the changes in flagellate populations reflect environmental changes in marine ecosystems is still unclear, especially in polar regions. In this study, we used pyrosequencing to examine the community structure of heterotrophic flagellates (HFs) in the Powell Basin’s surface waters of the northern Antarctic Peninsula. OTUs (operational taxonomic units) of different taxa and the correlations between community structure and environmental factors were analysed. Eight taxa of HFs were selected for the principal analysis: Telonemia, Picozoa, Rhizaria, Amoebozoa,&nbsp;Apusomonas, Centrohelida, Choanomonada and marine stramenopiles (MASTs). The HFs were defined as heterotrophic picoflagellates (HPFs; &lt;3 μm) and heterotrophic nanoflagellates (HNFs; &gt;3 μm, &lt;20 μm), which had similar dominant phyla (MASTs and Telonemia). However, their taxonomic composition differed. Environmental factors exerted similar effects on the community structure of both HPFs and HNPs. Compared with the correlation between HPF and environmental factors, the correlation between HNF and environmental factors was stronger. Salinity, bacterial biomass and the biological interactions amongst dominant taxa were the main variables to influence the diversity and community structure of HFs

Heterogeneous Parallel Implementation of Large-Scale Numerical Simulation of Saint-Venant Equations

Large-scale floods are one of the major events that impact the national economy and people’s livelihood every year during the flood season. Predicting the factors of flood evolution is a worldwide problem. We use the two-dimensional Saint-Venant equations as an example and for high-performance computing in modelling the flood behavior. Discretization of the two-dimensional Saint-Venant equations with initial and boundary conditions with the finite difference method in the explicit leapfrog scheme is carried out. Afterwards, we employed a large-scale heterogeneous parallel solution on the “SunRising-1” supercomputer system using MPI, OpenMP, Pthread, and OpenCL runtime libraries. On this basis, we applied communication/calculation overlapping and the local memory acceleration to optimize the performance. Finally, various performance tests of the parallel scheme are carried out from different perspectives. We have found this method is efficient and recommend this approach be used in solving systems of partial differential equations similar to the Saint-Venant equations

The Novel Triazolonaphthalimide Derivative LSS-11 Synergizes the Anti-Proliferative Effect of Paclitaxel via STAT3-Dependent MDR1 and MRP1 Downregulation in Chemoresistant Lung Cancer Cells

Multidrug resistance (MDR) is a major cause of the inefficacy and poor response to paclitaxel-based chemotherapy. The combination of conventional cytotoxic drugs has been a plausible strategy for overcoming paclitaxel resistance. Herein, we investigated the cytotoxic effects and underlying mechanism of LSS-11, a novel naphthalimide derivative-based topoisomerase inhibitor, in paclitaxel-resistant A549 (A549/T) lung cancer cells. LSS-11 enhanced cell death in A549/T cells by inducing apoptosis through increasing the DR5 protein level and PARP1 cleavage. Importantly, LSS-11 dose-dependently reduced STAT3 phosphorylation and downregulated its target genes MDR1 and MRP1, without affecting P-gp transport function. Chromatin coimmunoprecipitation (ChIP) assay further revealed that LSS-11 hindered the binding of STAT3 to the MDR1 and MRP1 promoters. Additionally, pharmacological inhibition of p-STAT3 by sulforaphane downregulated MDR1 and MRP1, resulting in A549/T cell death by triggering apoptosis. Collectively, our data show that LSS-11 is a potent naphthalimide-based chemosensitizer that could enhance cell death in paclitaxel-resistant lung cancer cells through the DR5/PARP1 pathway and STAT3/MDR1/MRP1 STAT3 inhibition