Variation of Genomic Sites Associated with Severe Covid-19 Across Populations: Global and National Patterns.

BACKGROUND: Information about the distribution of clinically significant genetic markers in different populations may be helpful in elaborating personalized approaches to the clinical management of COVID-19 in the absence of consensus guidelines. AIM: Analyze frequencies and distribution patterns of two markers associated with severe COVID-19 (rs11385942 and rs657152) and look for potential correlations between these markers and deaths from COVID-19 among populations in Russia and across the world. METHODS: We genotyped 1883 samples from 91 ethnic groups pooled into 28 populations representing Russia and its neighbor states. We also compiled a dataset on 32 populations from other regions using genotypes extracted or imputed from the available databases. Geographic maps showing the frequency distribution of the analyzed markers were constructed using the obtained data. RESULTS: The cartographic analysis revealed that rs11385942 distribution follows the West Eurasian pattern: the marker is frequent among the populations of Europe, West Asia and South Asia but rare or absent in all other parts of the globe. Notably, the transition from high to low rs11385942 frequencies across Eurasia is not abrupt but follows the clinal variation pattern instead. The distribution of rs657152 is more homogeneous. The analysis of correlations between the frequencies of the studied markers and the epidemiological characteristics of COVID-19 in a population revealed that higher frequencies of both risk alleles correlated positively with mortality from this disease. For rs657152, the correlation was especially strong (r = 0.59, p = 0.02). These reasonable correlations were observed for the "Russian" dataset only: no such correlations were established for the "world" dataset. This could be attributed to the differences in methodology used to collect COVID-19 statistics in different countries. CONCLUSION: Our findings suggest that genetic differences between populations make a small yet tangible contribution to the heterogeneity of the pandemic worldwide.

Amphiphilic Poly(N-Vinylpyrrolidone) Nanoparticles Loaded with DNA Plasmids Encoding Gn and Gc Glycoproteins of the Rift Valley Fever Virus: Preparation and In Vivo Evaluation.

The aim of the study was to develop amphiphilic poly(N-vinylpyrrolidone) (PVP) nanoparticles (NPs) loaded with DNA plasmids encoding Gn and Gc glycoproteins of the Rift Valley fever virus (RVFV) and to study the humoral response in vivo. DNA plasmids were protected from extracellular nucleases by loading in NPs from PVP derivatives modified with amino acids ß-alanine (Ala7-PVPOD4000) or glycine (Gly7.5-PVP-OD4000) fabricated by the original self-assembly technique. The obtained NPs were administered in mice and the enhancement of humoral response compared to this one in case of immunization with native DNA plasmids was demonstrated. The NPs loaded with DNA plasmids are promising for the fabrication of various DNA particulate vaccines.

Microencapsulated plasmids expressing Gn and Gc glycoproteins of Rift Valley Fever virus enhance humoral immune response in mice.

OBJECTIVES: The aim of the current study was to develop biodegradable alginate (ALG)/poly-L-lysine (PLL) microcapsules (MC) with entrapped plasmids expressing Gn and Gc glycoproteins of Rift Valley Fever virus (RVFV) and to evaluate the humoral immune response in mice. RESULTS: Expressing phRVF/Gn and phRVF/Gc plasmids which encode full-sized Gn and Gc glycoproteins and contain signal fusion protein F sequences of human parainfluenza (HPIV-1) were constructed. To protect the plasmids from cleavage by extracellular nucleases, they were entrapped into multilayer ALG/PLL microcapsules by layer-by-layer technique. To study the efficacy of humoral immune response, both native and microencapsulated plasmids were injected intramuscular into BALB/c mice. The humoral response in the mice immunized with free plasmids was characterized by virus-neutralizing antibody induction (with titres 1:4 to 1:8), while the injection of microencapsulated plasmids allowed to increase the titre level (from 1:16 to 1:32). CONCLUSION: The plasmids microencapsulated in biodegradable MC could be promising for development of DNA vaccines against RVFV.

Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke.

INTRODUCTION: Difficulties in non-vitamin K anticoagulant (NOAC) administration in acute stroke can be associated with changes in pharmacokinetic parameters of NOAC such as biotransformation, distribution, and excretion. Therefore, obtaining data on pharmacokinetics of NOAC and factors that affect it may help develop algorithms for personalized use of this drug class in patients with acute cardioembolic stroke. PATIENTS AND METHODS: Pharmacokinetics of apixaban in patients with acute stroke was studied earlier by Kryukov et al. The present study enrolled 17 patients with cardioembolic stroke, who received 5 mg of apixaban. In order to evaluate the pharmacokinetic parameters of apixaban, venous blood samples were collected before taking 5 mg of apixaban (point 0) and 1, 2, 3, 4, 10, and 12 hours after drug intake. Blood samples were centrifuged at 3000 rpm for 15 minutes. Separate plasma was aliquoted in Eppendorf tubes and frozen at -70°C until analysis. High-performance liquid chromatography mass spectrometry analysis was used to determine apixaban plasma concentration. Genotyping was performed by real-time polymerase chain reaction. CYP3A isoenzyme group activity was evaluated by determining urinary concentration of endogenous substrate of the enzyme and its metabolite (6-ß-hydroxycortisol to cortisol ratio). Statistical analysis was performed using SPSS Statistics version 20.0. The protocol of this study was reviewed and approved by the ethics committee; patients or their representatives signed an informed consent. RESULTS: ABCB1 (rs1045642 and rs4148738) gene polymorphisms do not affect the pharmacokinetics of apixaban as well as CYP3A5 (rs776746) gene polymorphisms. Apixaban pharmacokinetics in groups with different genotypes did not differ statistically significantly. Correlation analysis showed no statistically significant relationship between pharmacokinetic parameters of apixaban and the metabolic activity of CYP3A. CONCLUSION: Questions such as depending on genotyping results for apixaban dosing and implementation of express genotyping in clinical practice remain open for NOACs. Large population studies are required to clarify the clinical significance of genotyping for this drug class.