Antiviral Activity of Umifenovir In Vitro against a Broad Spectrum of Coronaviruses,Including the Novel SARS-CoV-2 Virus

An escalating pandemic of the novel SARS-CoV-2 virus is impacting global health, and effective antivirals are needed. Umifenovir (Arbidol) is an indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It has been shown that umifenovir has broad spectrum activity against different viruses. We evaluated the sensitivity of different coronaviruses, including the novel SARS-CoV-2 virus, to umifenovir using in vitro assays. Using a plaque assay, we revealed an antiviral effect of umifenovir against seasonal HCoV-229E and HCoV-OC43 coronaviruses in Vero E6 cells, with estimated 50% effective concentrations (EC50) of 10.0 ± 0.5 µM and 9.0 ± 0.4 µM, respectively. Umifenovir at 90 µM significantly suppressed plaque formation in CMK-AH-1 cells infected with SARS-CoV. Umifenovir also inhibited the replication of SARS-CoV-2 virus, with EC50 values ranging from 15.37 ± 3.6 to 28.0 ± 1.0 µM. In addition, 21–36 µM of umifenovir significantly suppressed SARS-CoV-2 virus titers (≥2 log TCID50/mL) in the first 24 h after infection. Repurposing of antiviral drugs is very helpful in fighting COVID-19. A safe, pan-antiviral drug such as umifenovir could be extremely beneficial in combating the early stages of a viral pandemic.     

From the Cover: Genome-wide association study reveals genetic variants associated with HIV-1C infection in a Botswana study population

Although there have been many studies of gene variant association with different stages of HIV/AIDS progression in United States and European cohorts, few gene-association studies have assessed genic determinants in sub-Saharan African populations, which have the highest density of HIV infections worldwide. We carried out genome-wide association studies on 766 study participants at risk for HIV-1 subtype C (HIV-1C) infection in Botswana. Three gene associations (AP3B1, PTPRA, and NEO1) were shown to have significant association with HIV-1C acquisition. Each gene association was replicated within Botswana or in the United States–African American or United States–European American AIDS cohorts or in both. Each associated gene has a prior reported influence on HIV/AIDS pathogenesis. Thirteen previously discovered AIDS restriction genes were further replicated in the Botswana cohorts, extending our confidence in these prior AIDS restriction gene reports. This work presents an early step toward the identification of genetic variants associated with and affecting HIV acquisition or AIDS progression in the understudied HIV-1C afflicted Botswana population.

HIV infection is a fatal chronic disease that has spread across all continents since its emergence in the early 1980s. Important progress has been made against the epidemic in the last two decades. The global incidence–prevalence ratio has declined from 11.2% in 2000 to 4.6% in 2018. Despite this, the world is not yet on track to end HIV/AIDS as a public health threat (1). There are 38 million (31.6 million to 44.5 million) people in the world living with HIV; 32.7 million (24.8 million to 42.2 million) people who died from AIDS-related conditions since the onset of the pandemic. An estimated 690,000 (500,000 to 970,000) died of HIV/AIDS in 2019 (1). Despite the important breakthroughs in therapeutic approaches, as well as efforts and resources invested in the fight against the HIV epidemic for about four decades, no efficient vaccine or cure exists.Sub-Saharan Africa is the region most affected by the HIV pandemic. Botswana falls within the top three countries with the highest HIV prevalence in the world, with an HIV prevalence rate of 20.3% (17.3 to 21.8) among adults (15 to 49 y of age) (1).Currently HIV-1 subtype C (HIV-1C), which is widespread in the Botswana population, accounts for more than half of all global HIV-1 infections and several times more than any other HIV-1 subtype. Despite this fact, HIV-1C infection remains understudied as prior research largely focused on HIV-1 subtypes (mostly B) more prevalent in Europe and in the United States (2–8).HIV/AIDS exhibits considerable epidemiological heterogeneity (strength of the innate, humoral, and cell-mediated immune responses, variation in response to antiretroviral therapy, ART), much of which may be attributed to host genetic factors (3–8). African populations in general have the highest overall genetic variation, and it has been hypothesized that treatment-naive Botswana people exhibit noticeable heterogeneity in natural disease progression (varying ability to maintain high CD4 counts and low viral load) in part due to the variable host genetic makeup (2, 9). Complex gene and gene–environment interactions affect HIV-1 infection and AIDS progression in major ways (6, 10). Much remains to be discovered about the genetic basis of individual host genetic differences in progression to AIDS in this geographic region.Identification of genetic factors is important for several reasons. For example, the mechanism of HIV/AIDS restriction by genetic variants has previously encouraged the development of salvage pathway antiretroviral medications (e.g., enfuvirtide, maraviroc, which block HIV-1 binding to CCR-5 receptors and membrane fusion), while predicting progression to AIDS for a given genotype can be used to inform clinical trials for new drugs (4, 11–14). In this study, we searched for genetic factors associated with HIV-1C infection/acquisition and disease progression in Botswana.Genome-wide association studies (GWAS) are a standard approach to scan for novel genetic variants that are associated with resistance or susceptibility to a particular disease (15–18). Here, we employed a GWAS approach to discover gene variants that regulate HIV-1C acquisition and are also related to HIV-1 pathogenesis. In this GWAS, we identified several novel genetic variants that demonstrated statistically significant association with HIV-1C infection in a Botswana cohort using single nucleotide polymorphisms (SNPs) determined by Illumina microarray (MA; n = 809) and by whole-genome sequencing (WGS; n = 364). We report gene associations for three HIV-1C associated loci: AP3B1, PTPRA, and NEO1. The discoveries were verified by independent cohort replication and by looking for previously reported implications in HIV-1 host-pathogenesis. We further replicated prior AIDS restriction gene (ARG) association signals from analyses with Botswana HIV-1C cohorts, adding confidence to the existing knowledge about gene influences in HIV/AIDS.     

Results of concomitant cryoablation for atrial fibrillation during mitral valve surgery

Open in a separate window OBJECTIVESConcomitant atrial fibrillation ablation during mitral valve (MV) surgery using radio frequency energy sources has been reported previously with excellent outcomes. However, data regarding the effectiveness of concomitant cryoablation remain limited. This study aimed to assess the efficacy of concomitant cryoablation in patients scheduled for MV surgery.METHODSBetween 2012 and 2020, 242 adult patients who underwent MV surgery and concomitant cryoablation were included. Data on rhythm, medication status and clinical events were assessed at 3, 6 and 12 months, then annually thereafter.RESULTSEarly mortality was 0.4%. The mean follow-up period duration was 43.9 months. The survival rates at 1, 3 and 5 years were 97.3%, 94.3% and 87.7%, respectively. The rates of freedom from atrial arrhythmia paroxysms at 1, 3 and 5 years were 79.0%, 64.0% and 60.5%, respectively. Atrial arrhythmia recurrence was associated with isolated left atrial lesion set (P = 0.038), large right atrial size (P = 0.002), lower surgeon experience (P = 0.003) and atrial fibrillation paroxysms in the early postoperative period (P = 0.002).CONCLUSIONSConcomitant cryoablation during MV surgery is a safe and reproducible technique. The procedure provides acceptable freedom from atrial arrhythmias recurrences during long-term follow-up. The biatrial lesion set has advantages over the left atrium pattern in terms of atrial arrhythmias freedom. Surgeon experience significantly influences atrial fibrillation ablation success. Randomized trials are needed to compare radiofrequency and cryoablation.     

Electrochemical Study of Semiconductor Properties for Bismuth Silicate-Based Photocatalysts Obtained via Hydro-/Solvothermal Approach

Three bismuth silicate-based photocatalysts (composites of Bi₂SiO₅ and Bi₁₂SiO₂₀) prepared via the hydro-/solvothermal approach were studied using electrochemical methods. The characteristic parameters of semiconductors, such as flat band potential, donor density, and mobility of their charge carriers, were obtained and compared with the materials’ photocatalytic activity. An attempt was made to study the effect of solution components on the semiconductor/liquid interface (SLI). In particular, the Mott–Schottky characterization was made in a common model electrolyte (Na₂SO₄) and with the addition of glycerol as a model organic compound for photocatalysis. Thus, a medium close to those in photocatalytic experiments was simulated, at least within the limits allowed by electrochemical measurements. Zeta-potential measurements and electrochemical impedance spectroscopy were used to reveal the processes taking place at the SLI. It was found that the medium in which measurements were carried out dramatically impacted the results. The flat band potential values (E_fb) obtained via the Mott–Schottky technique were shown to differ significantly depending on the solution used in the experiment, which is explained by different processes taking place at the SLI. A strong influence of specific adsorption of commonly used sulfate ions and neutral molecules on the measured values of E_fb was shown.     

Lightsheet-based flow cytometer for whole blood with the ability for the magnetic retrieval of objects from the blood flow

Detection and extraction of circulating tumor cells and other rare objects in the bloodstream are of great interest for modern diagnostics, but devices that can solve this problem for the whole blood volume of laboratory animals are still rare. Here we have developed SPIM-based lightsheet flow cytometer for the detection of fluorescently-labeled objects in whole blood. The bypass channel between two blood vessels connected with the external flow cell was used to visualize, detect, and magnetically separate fluorescently-labeled objects without hydrodynamic focusing. Carriers for targeted drug delivery were used as model objects to test the device performance. They were injected into the bloodstream of the rat, detected fluorescently, and then captured from the bloodstream by a magnetic separator prior to filtration in organs. Carriers extracted from the whole blood were studied by a number of in vitro methods.     

Advantages of imaging photoplethysmography for migraine modeling: new optical markers of trigemino‐vascular activation in rats

BackgroundExistent animal models of migraine are not without drawbacks and limitations. The aim of our study was to evaluate imaging photoplethysmography (PPG) as a method of assessing intracranial blood flow in rats and its changes in response to electrical stimulation of dural trigeminal afferents.MethodsExperiments were carried out with 32 anesthetized adult male Wistar rats. Trigeminovascular system (TVS) was activated by means of electrical stimulation of dural afferents through a closed cranial window (CCW). Parameters of meningeal blood flow were monitored using a PPG imaging system under green illumination with synchronous recording of an electrocardiogram (ECG) and systemic arterial blood pressure (ABP). Two indicators related to blood-flow parameters were assessed: intrinsic optical signals (OIS) and the amplitude of pulsatile component (APC) of the PPG waveform. Moreover, we carried out pharmacological validation of these indicators by determining their sensitivity to anti-migraine drugs: valproic acid and sumatriptan. For statistical analysis the non-parametric tests with post-hoc Bonferroni correction was used.ResultsSignificant increase of both APC and OIS was observed due to CCW electrical stimulation. Compared to saline (n = 11), intravenous administration of both the sumatriptan (n = 11) and valproate (n = 10) by using a cumulative infusion regimen (three steps performed 30 min apart) lead to significant inhibitory effect on the APC response to the stimulation. In contrast, intravenous infusion of any substance or saline did not affect the OIS response to the stimulation. It was found that infusion of either sumatriptan or valproate did not affect the response of ABP or heart rate to the stimulation.ConclusionsImaging PPG can be used in an animal migraine model as a method for contactless assessment of intracranial blood flow. We have identified two new markers of TVS activation, one of which (APC) was pharmacologically confirmed to be associated with migraine. Monitoring of changes in APC caused by CCW electrical stimulation (controlling efficiency of stimulation by OIS) can be considered as a new way to assess the peripheral mechanism of action of anti-migraine interventions.     

Resección robótica del lóbulo hepático caudado: descripción técnica y consideraciones iniciales

Introduction

Firstly described in 2002, the robotic liver surgery has not spread widely due to its high cost and the lack of a standardized training program. Still being considered as a ‘development in progress’ technique, it has however a potential to overcome the traditional limitations of the laparoscopic approach in liver interventions.