Pharmacokinetics Informs Remdesivir Dosing for Patients with Severe Renal Impairment

Background: Despite renal impairment (RI) being a risk factor for severe COVID-19, there are no approved antiviral treatment options for patients with severely impaired kidney function (eGFR less than 30 mL/min/1.73 m2 or kidney failure) in the US. At the time remdesivir (RDV) was initially approved for the treatment of COVID-19, the impact of renal impairment (RI) on pharmacokinetics (PK) of RDV, its metabolites, and the excipient, sulfobutylether beta-cyclodextrin sodium (SBECD), was not known. Method(s): Here, we report the PK data supporting dosing of RDV in COVID-19 patients with severely impaired kidney function. PK samples for RDV and metabolites (GS-704277, GS-441524) were collected in the Phase 3 REDPINE study in hospitalized COVID-19 patients with severely impaired kidney function. Participants in this double-blind study were randomized 2:1 to intravenous (IV) remdesivir (200 mg on Day 1, then 100 mg daily up to Day 5) or IV saline as placebo-to-match. SBECD PK was analyzed in a phase 1 study in non-COVID-19 participants with normal kidney function, mild and moderate RI who received 100 mg dose of remdesivir (containing 3000 mg SBECD). The population PK analysis included observations from healthy and COVID-19 patients with full range of renal function across all adult studies. Result(s): Geometric mean exposures (AUCtau) observed in REDPINE Study as compared to PINETREE Study increased up to 553% for the GS-441524 metabolite (dependent on renal elimination) and to a lesser degree GS-704277 (294%, minor renal elimination) and RDV (78.9%;an increase explained by factors other than renal function, namely, hospitalization and body weight) (Table 1). The increased PK exposures were not associated with new safety signals in this study (n=163 remdesivir, n=80 placebo). Population PK analysis identified baseline eGFR as a significant covariate for GS-704277 and GS-441524 clearance, but not for RDV itself. SBECD PK was characterized by short half-life (t1/2) (1.6 hours in normal renal function to 3.8 hours in moderate RI) and fast plasma clearance (7.9 L/h in normal renal function). Analysis of SBECD in severe RI (REDPINE) is ongoing, but accumulation is not expected based on its observed short plasma t1/2. Conclusion(s): Given the observed PK and the absence of any new safety signals associated with increased metabolite levels in patients with severely impaired kidney function, no dose adjustment is recommended for RDV in COVID-19 patients with eGFR < 30 mL/min/1.73 m2, regardless of the need for dialysis.

Principles of management for patients with oral cancer during the COVID-19 pandemic

The outbreak of coronavirus disease 2019 (COVID-19) affects the world. It is highly contagious and spreads quickly. COVID-19 severely increases the medical burden and interferes with our normal work. This article introduces our experience on treat oral cancer patients during the epidemic. The negative impact can be minimized through reasonable and orderly arrangement.Copyright © 2021 The Authors

Direct visualization of single-cell non-repetitive genes by in situ activation of collateral activity of CRISPR/Cas12a inside cells

The spread of drug-resistance bacteria is a serious issue of environment. Tools allowing to image single-cell genes can provide key information about the spatial pattern and heterogeneity of cell population. Herein, we explored the possibility of in situ activation of collateral trans-cleavage activity of CRISPR/Cas12a inside cells, to achieve a direct detection of single-cell non-repetitive genes. CRISPR/Cas12a allows to recognize target genes without the need for denaturation or digestion process. Particularly, the target gene-activated trans-cleavage by CRISPR/ Cas12a inside cells outputs an amplified signal for the gene recognition, allowing to visualize non-repetitive genes. The signal-to-background ratio for imaging drug-resistance gene, oqxB in the Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) was further improved by combining multiple binding of Cas12a, enabled imaging of drug-resistance S. Typhimurium isolated from poultry farm and in the intestinal tract sec-tions. Single-cell investigation of S. Typhimurium under salt stress indicated that drug-sensitive strain owned a survival advantage over drug-resistance strain at high-content salt environment. This gene imaging methods holds potential for detecting the spread of drug resistance in the environment and serves as a means to inves-tigate the relationship between genotype and phenotype at single-cell level.

Design and Feature Analysis of a Thermally Coupled Corona Discharge Air Disinfection Device

The COVID-19 caused by the novel coronavirus is still spreading globally, and blocking its airborne transmission route is of great significance to control the pandemic. The conventional plasma air disinfection devices show advantages in their dynamic and rapid capabilities, but the disinfection performance is limited by a single method, besides, there exists the risk of secondary infection during maintenance. In this work, according to the physiological characteristics of the novel coronavirus, an air disinfection device based on thermally coupled corona discharge was proposed for the improvement of conventional plasma air disinfection technology, which adopted the wire-plate array electrode structure to initiate corona discharge, and utilized heating wires embedded in the collection plate to achieve centralized heating. The discharge para-meters were measured, and a discharge power at stable operation was discovered to be as high as 5.6 W, for which the discharge law was found to obey the Townsend relationship. Measurement and simulation of the thermal parameters showed that, compared with the overall air heating, the efficiency of centralized heating was increased by 17 times, with minimal impact on the ambient temperature. Bacillus amyloliquefaciens and Bacillus subtilis bacteriophages were used as model bacteria and virus to verify the disinfection performance. Results demonstrate that the killing performance is effectively enhanced via thermally coupled corona discharge, with a removal rate of residual virus on the collection plate increasing by 99.97%, thereby reducing the risk of secondary infection. This work lays a device foundation for killing the airborne novel coronavirus, and also provides a technical reference for cutting its airborne transmission. © 2022, High Voltage Engineering Editorial Department of CEPRI. All right reserved.

Towards Privacy-Preserving Spatial Distribution Crowdsensing: A Game Theoretic Approach

Acquiring the spatial distribution of users in mobile crowdsensing (MCS) brings many benefits to users (e.g., avoiding crowded areas during the COVID-19 pandemic). Although the leakage of users’location privacy has received a lot of research attention, existing works still ignore the rationality of users, resulting that users may not obtain satisfactory spatial distribution even if they provide true location information. To solve the problem, we employ game theory with incomplete information to model the interactions among users and seek an equilibrium state through learning approaches of the game. Specifically, we first model the service as a game in the satisfaction form and define the equilibrium for this service. Then, we design a LEFS algorithm for the privacy strategy learning of users when their satisfaction expectations are fixed, and further design LSRE that allows users to have dynamic satisfaction expectations. We theoretically analyze the convergence conditions and characteristics of the proposed algorithms, along with the privacy protection level obtained by our solution. We conduct extensive experiments to show the superiority and various performances of our proposal, which illustrates that our proposal can get more than 85% advantage in terms of the sensing distribution availability compared to the well-known differential privacy based solutions. IEEE