[Predictors of thromboembolic complications in patients with severe SARS-CoV-2 coronavirus infection].

AIM: To identify predictors of the development of thromboembolic complications (TECs) in patients with severe SARS-CoV-2 coronavirus infection. MATERIALS AND METHODS: A single-center observational retrospective study included 1634 patients with a confirmed diagnosis of SARS-CoV-2 coronavirus infection. The patients were divided into 2 groups depending on the availability of the feasibility study. The criterion for inclusion of patients in the main group was the presence of venous feasibility studies in 127 patients (group I), the comparison group consisted of 1507 patients in whom the course of COVID-19 was not complicated by the development of feasibility studies (group II). RESULTS: When performing computed tomography of the chest organs, it was revealed that patients with a feasibility study had a higher percentage of lung tissue damage than patients in the comparison group: 55% [37.5; 67.5] and 37.5% [25.0; 47.5], respectively (p<0.001). The average values of C-reactive protein in I patients group were 129 [60.1; 211] ng/l, which was significantly higher than in II patients group - 41.0 [12.2; 97.6] ng/l (p<0.001), interleukin-6 - 176 [52.9; 471] pg/ml and 39.4 [11.0; 107] pg/ml (p<0.001), respectively. A one-factor regression analysis proved a significant contribution of comorbid pathology to the development of feasibility studies in patients with COVID-19. The presence of three nosologies at the same time: arterial hypertension, coronary heart disease (CHD) and chronic kidney disease increased the probability of a feasibility study by 4.81 times (odds ratio 4.8117, 95% confidence interval 3.2064-7.2207), in patients with arterial hypertension, CHD, chronic kidney disease and type 2 diabetes - by 5.63 times (odds ratio 5.6321, 95% confidence interval 3.1870-9.9531). CONCLUSION: The presence of severe comorbid pathology significantly increased the risk of developing a feasibility study in patients with COVID-19. The most significant predictors of the development of feasibility studies in patients with severe SARS-CoV-2 coronavirus infection. They are: CHD, arterial hypertension and type 2 diabetes.

[Description of the case of adverse pasteurellosis in a cirrhosis patient. Case report].

The article describes a clinical case of an unfavorable course of pasteurellosis in a patient with liver cirrhosis. Possible variants of the clinical course, clinical and epidemiological data, on the basis of which pasteurellosis can be suspected, modern recommendations for antibiotic therapy are considered.

[Features of the coefficient of variation of hematological indicators in persons of middle, elderly and senile age with pneumonia.]

Pneumonia is the leading mortality rate among all infectious diseases. It has been established that the reliable risk group for morbidity and mortality from this nosology includes persons over 60 years of age, and with age the severity of the disease only increases. According to literary data, one of the reasons for the decline in adaptation capabilities of older persons is the phenomenon of «age desinhronosis¼, which manifests itself in significant fluctuations in the parameters of the internal environment of the body. The purpose of this work was to compare the coefficients of intra- and interindividual biological variation. For this purpose, a retrospective study of clinical blood analysis in patients suffering from pneumonia of unspecified etiology was carried out in terms of three age groups: medium, elderly and senile. Features of biological variation depending on age have been found, the differences identified have been justified according to available theories.

[Pharmacoepidemiological research of COVID-19 in the Russian Federation EGIDA-2020].

AIM: An analysis of coronavirus infection in Russia and evaluation of different AVT regimens effectiveness. MATERIALS AND METHODS: The study involved a retrospective analysis of 1082 patient records with laboratory-confirmed COVID-19 in 17 regions of Russia. The number of men and women was equal, mean age 48.718.1 (median 50). Patients with moderate COVID-19 (85%) versus mild COVID-19 (15%) were characterized by higher age (median 54 vs 21 years; p0.001), higher body mass index (27.8 vs 23.4; p0.001), prevalence of chronic diseases (75.3% vs 8.5%; p0.001), including circulatory system diseases (37.8%). Moderate COVID-19 characterized higher intoxication (10.86.1 vs 4.22.7 days; p0.001) and catarrhal symptoms duration (10.25.4 vs 6.14.1 days; p0.001). RESULTS: During hospitalization 92% of the patients received AVT, 77% antibiotics, and 16% corticosteroids. Umifenovir therapy resulted in a significant reduction of intoxication (8.75.5 vs 11.75.5 days; p0.001) and catarrhal symptoms duration (8.85.1 vs 12.04.9 days; p0.001) compared to the group without AVT. The usage of INF reduced intoxication symptoms compared with the group without AVT (8.97.5 vs 11.75.5; p0.05). Therapy with hydroxychloroquine, imidazolylethanamide pentandioic acid, and lopinavir + ritonavir combination did not affect the course of COVID-19. Most of adverse reactions were related to antibiotics. CONCLUSION: Umifenovir therapy and inclusion of interferon in AVT regimens was associated improvement in the clinical manifestation of the disease among patients.

[The problem of diagnosis and differential diagnosis of botulism in pregnant women. Case report].

The article describes a clinical observation of a severe course of a sporadic case of foodborne botulism in a woman at 32 weeks gestation with a successful resolution of pregnancy by independent childbirth. No adverse effects of botulism on pregnancy, delivery, and fetal development were noted. Anti-botulinum serum was administered to the patient no earlier than 96 hours from the onset of the disease. The paper analyzes the clinical picture of botulism, on the basis of which it is necessary to carry out a differential diagnosis.

[Visceral leishmaniasis: a challenging diagnosis in internal medicine].

Leishmaniasis is a vector-born parasitic disease characterized by predominant cutaneous or visceral involvement with fever, hepatosplenomegaly and anemia. Leishmaniasis has relatively high prevalence in tropical and subtropical areas. Several sporadic and mostly imported cases are detected in Russian Federation. Nevertheless, some local incidents are noted in southern areas (Crimea, Dagestan). Lack of epidemiological alertness hampers confirmation of diagnosis and may lead to incorrect treatment. The article summarizes current state of knowledge in epidemiology, diagnostic approach and treatment of leishmaniasis. Particular clinical case is discussed.

[Small Molecular Inhibitors of DNA Double Strand Break Repair Pathways Increase the ANTI-HBV Activity of CRISPR/Cas9].

The CRISPR/Cas9 nuclease system can effectively suppress the replication of the hepatitis B virus (HBV), while covalently closed circular DNA (cccDNA), a highly resistant form of the virus, persists in the nuclei of infected cells. The most common outcome of DNA double-strand breaks (DSBs) in cccDNA caused by CRISPR/Cas9 is double-strand break repair by nonhomologous end-joining, which results in insertion/deletion mutations. Modulation of the DNA double-strand break repair pathways by small molecules was shown to stimulate CRISPR/Cas9 activity and may potentially be utilized to enhance the elimination of HBV cccDNA. In this work, we used inhibitors of homologous (RI-1) and nonhomologous (NU7026) end-joining and their combination to stimulate antiviral activity of CRISPR/Cas9 on two cell models of HBV in vitro, i.e., the HepG2-1.1merHBV cells containing the HBV genome under the tet-on regulated cytomegalovirus promoter and the HepG2-1.5merHBV cells containing constitutive expression of HBV RNA under the wild-type promoter. The treatment of the cells with RI-1 or NU7026 after lentiviral transduction of CRISPR/Cas9 drops the levels of cccDNA compared to the DMSO-treated control. RI-1 and NU7026 resulted in 5.0-6.5 times more significant reduction in the HBV cccDNA level compared to the mock-control. In conclusion, the inhibition of both homologous and nonhomologous DNA double-strand break repair pathways increases the elimination of HBV cccDNA by CRISPR/Cas9 system in vitro, which may potentially be utilized as a therapeutic approach to treat chronic hepatitis B.

[Features of central hemodynamics in patients with community - acquired pneumonia depending on the course of the disease and cardiovascular comorbidity].

AIM: The study of intracardiac hemodynamics and blood flow in the pulmonary circuit in patients with community - acquired pneumonia, depending on the presence of concomitant pathology of the cardiovascular system and the severity of the pathological process. MATERIALS AND METHODS: In 43 patients with community - acquired pneumonia (22 men, 21 women, mean age 67±17 years), the functional state of pulmonary - cardiac hemodynamics was assessed by echodoplerography. All subjects were divided into 2 groups: 1st group - 25 patients with community - acquired pneumonia (mean age 49±18 years) without concomitant pathology of the cardiovascular system and 2nd group - 18 patients with community - acquired pneumonia (mean age 70.1±11 years) with concomitant cardiovascular disease. RESULTS: The main ultrasound parameters did not differ from the normal values in patients from the 1st group. In patients from the 2nd group there was a significant deterioration of several pulmonary - cardiac hemodynamics parameters, decrease of left ventricular ejection fraction, significant myocardial hypertrophy of the left ventricle and left atrium size increase. Regarding the right heart chambers it was revealed dilatation of the right ventricle, increasing of the estimated systolic pressure in the right ventricle, deterioration of right ventricle myocardial diastolic function, increase of the: RV/LV size ratio, LV eccentricity index, RV myocardium thickness, diameter of the pulmonary artery, velocity of pulmonary regurgitation and the area right atrium size. In addition, the amplitude of systolic displacement of the tricuspid valve ring and the intensity of inspiratory collapse of the inferior vena cava decreased. Correlation analysis of clinical and laboratory parameters, which are markers of endogenous intoxication, oxygen saturation of arterial blood (SpO2), separately for two groups of patients with community - acquired pneumonia, showed a reliable correlation with a number of informative and used in the practice echocardiography parameters of pulmonary cardiac hemodynamics, characterizing systolic (systolic movement amplitude of the tricuspid valve ring - TAPSE), as well as diastolic function (E/A of the right ventricle) of the heart. CONCLUSION: The relationship between the severity of pulmonary - cardiac hemodynamics disturbances in patients with community - acquired pneumonia, having comorbid pathology, contributing to the deterioration of pulmonary - cardiac hemodynamics and more severe course of the disease with markers of the inflammatory process and oxygen saturation of arterial blood decrease is revealed.

[Review of current and future directions of antiviral therapy of influenza and acute respiratory viral infections in Russia].

AIM: to determine the perspectives for the use of drugs with combined antiviral, anti - inflammatory and immunomodulatory activity on the basis of medical studies of existing antiviral drugs for the treatment of influenza and acute respiratory viral infections in Russia. MATERIALS AND METHODS: A brief review of the antiviral drugs used in Russia for the treatment of influenza and acute respiratory viral infections was conducted on the basis of 37 articles published in Scopus, Web of Science (WoS), and RSCI databases in the period from 1997 to 2018. RESULTS: Resistance to neuraminidase inhibitors (oseltamivir, zanamivir), is slowly developing due to the mutations of the neuraminidase gene H275Y and Q136K. Most influenza A viruses remain resistant to adamantane antivirals. Repeated use of immunomodulators with indirect antiviral action leads to a hyporeactivity of the immune system and, subsequently, to a decrease in their effectiveness. Positive clinical and laboratory data in clinical trials were obtained using Enisamium iodide, a drug with combined action - direct antiviral, and immunomodulatory. CONCLUSION: According to the WHO strategy, the results of the review demonstrate the need for continued research of medications with combined antiviral and pathogenetic effects on the infectious process caused by influenza and acute respiratory viral infections.

[Antimycotic therapy impact on oral mucosa Candida species composition in HIV-infected patients]. / Vliianie antimikoticheskoi terapii na vidovoi i shtammovyi sostav gribov roda Candida polosti rta bol'nykh VICh-infektsiei.

RESEARCH OBJECTIVES: the analysis of a specific and strains drift of Candida in HIV/AIDS patients with oropharyngeal candidiasis and the analysis of Candida sensitivity dynamics to reference antimycotic drugs. The study comprised 49 HIV-infected patients aged 20-69 years. The study revealed candidiasis treatment provides specific and strains drift of Candida. Eradication of fluconazole sensitive C. albicans leads to growth of more resistant strains (C. glabratae, krusei, tropicalis) thus lowering antimycotic therapy efficacy. The efficacy improvement requires selective approach to candidiasis treatment with azol agents.

INCREASED FORMATION OF PHOSPHORYLATED H2AX FOCI IN NUCLEI OF CELLS INFECTED BY HEPATITIS B AND B+D VIRUSES.

Liver cirrhosis and hepatocellular carcinoma are the most common outcomes of chronic hepatitis B. Hepatitis B virus (HBV) induces transformation and cell death in chronic hepatitis B (CHB). DNA double strand breaks (DSBs) represent the most dangerous type of genome damage. It was shown previously that generation of phosphorylated histone H2AX foci is a reliable marker of DSBs. The aim of this study was to analyse generation of yH2AX foci in HBV and hepatitis D virus (HDV) infection in vitro and in liver biopsies of patients with CHB and CHB with delta-agent (CHD). Human hepatoma cell line HepG2-1.1merHBV with activated HBV life cycle was used to perform real-time PCR for analysis of pregenomic RNA, HBV DNA, HBV cccDNA and for immunocytochemical analysis of yH2AX. Liver biopsies from CHB and CHD patients were analyzed to confirm the results. HBV induces multiple discrete yH2AX foci in HepG2-1.1merHBV cells in vitro and in biopsies of CHB and CHB+D patients. The ratio of hepatocytes w/o yH2AX foci is significantly lower (49,9+/-12,3% vs. 85,5+/-0,9%, p.

THE ROLE OF DNA-METHYLTRANSFERASES IN THE LIFE CYCLE OF HEPATITIS B VIRUS AND PATHOGENESIS OF CHRONIC HEPATITIS B.

Chronic hepatitis B is caused by a persistent form of hepatitis B virus, covalently closed circular DNA (cccDNA). Stability of cccDNA is associated with intracellular localization of cccDNA and formation of minichromosome, regulated by epigenetic mechanisms. One of the key mechanisms in epigenetics is methylation of DNA on CpG islands. Expression levels of DNA-methyltransferases (DNMTs) in chronic hepatitis B patients were shown to be upregulated. Nevertheless, the role of DNMTs in the life cycle of HBV and their effects on the cell remain elusive. In this review, we discuss latest achievements on the role of DNMTs in chronic hepatitis B and HBV in vitro models.

[Hepatitis C can be cured: will hepatitis B become next?] / Gepatit S stal izlechim. Gepatit V - sleduiushchii?

Chronic hepatitis B (CHB) and C (CHC) are one of the leading causes of cirrhosis and liver cancer with over a million of people dying annually from their consequences. In Russia CHB and CHC morbidity and related mortality show an upward trend. As a result of recent breakthroughs in antiviral therapeutics CHC became a curable disease. Modern therapeutics effectively suppress viral replication in CHB patients, but withdrawal of antivirals usually results in disease relapse. Loss of HBsAg required for the so called 'functional cure' is a very rare event. Moreover, 'complete cure' when the virus is entirely eliminated from the body is not possible due to a persistent form of covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) in hepatocytes refractory to modern antivirals. Today, there is a plethora of new promising medications being at different stages of development that target different steps of viral life cycle, including inhibitors of interaction between HBV and its entry receptor NTCP, inhibitors of HBV cccDNA, inhibitors of nucleocapsid assembly, technologies of genome editing (TALENs, CRISPR/Cas etc) and RNA-interference. In addition to direct acting antivirals, there is a number of approaches aimed at enhancement of the innate and adaptive immune responses. In experimental conditions, some of these approaches or their combinations help to achieve functional cure. However, complete elimination of the virus is possible only using technologies of genome editing, capable of specific cccDNA degradation. Nuclease systems are currently at their early stages of development, and there is a long way to prove their efficacy and safety. Nevertheless, highly promising results of the recent years leave no doubt that CRISPR/Cas systems and similar technologies can become the basis of CHB therapy.

[Overexpression of DNA-methyltransferases in persistency of cccDNA pool in chronic hepatitis B]. / Rol' giperékspressii DNK-metiltransferaz v persistentsii kol'tsevoi kovalentno zamknutoi DNK pri khronicheskom gepatite V.

AIM: To define the role of DNA-methyltransferases of type 1 and type 3A in hepatitis B viral cycle. MATERIAL AND METHODS: Human hepatoma cells HepG2 with stable expression of 1.1-mer HBV genome were transfected with vectors encoding DNA-methyltransferase 1 (DNMT1), DNA-methyltransferase 3A (DNMT3A) or were co-transfected with these vectors. Total HBV DNA copy number, relative expression of pregenomic RNA (pgRNA), S-protein-encoding RNA (S-RNA) and cccDNA were analyzed by quantitative and semi-quantitative real-time PCR-analysis with TaqMan probes for assessment of DNMTs-mediated effects on HBV. RESULTS: DNMT1 and DNMT3A suppress HBV transcription and replication, though to different magnitude. cccDNA pool is enlarged statistically significantly ≈2-fold (P<0.005) after transfection of DNMT3A, but is unaltered under DNMT1 treatment. CONCLUSION: DNMT3A regulates the size of cccDNA pool and is important for persistency of HBV infection.

[Identification of Shiga toxin in patients with acute intestinal infections in the presence of mono- and mixed-O-antigens of pathogens]. / Vyiavlenie Shiga-toksina u bol'nykh ostrymi kishechnymi infektsiiami v prisutstvii mono- i mikst-O-antigenov vozbuditelei.

AIM: To investigate the time course of changes in the detection rates and levels of Shiga toxin antigen (STA) in their stool and middle-molecule circulating immune complexes (CICs) containing IgG (IgG CIC) in patients with acute intestinal infections (AIIs) in the presence of the body's circulation of mono- and mixed-LPS/O-antigens of intestinal pathogens. SUBJECTS AND METHODS: A total of 147 patients aged 15 to 55 years who had been hospitalized with AIIs were examined. The diagnosis was bacteriologically verified in 19% of the patients; in the others, it was confirmed by the detection of LPS/O-antigens of Shigella, Salmonella, Yersinia, and Campylobacter in their stool by means of the reaction of coagglutination (RCA) on glass slides. Plates for RCA displayed STA in the fecal and IgG CIC samples. RESULTS: Mono- and mixed infections were detected in 32 and 68%, respectively. The RCA plates exhibited STA in 25.2% of the fecal samples and in 90.5% of the IgG CIC ones from patients with AIIs and did not in those from donors. In monoinfection, the detection rates and levels of STA in the feces became lower in the course of the disease and remained unchanged in IgG CIC and the levels of STA also decreased in the feces, but increased in IgG CIC in mixed infection. CONCLUSION: In 25.2% of the patients with early AIIs, their stools show free STA; its detection rate and levels are significantly higher in mixed infections than those in monoinfection. The level of STA in serum IgG CIC was significantly higher in mixed infection, suggesting an active immune response to the pathogen. Given that the Shiga toxin-producing strains are present in patients with AIIs, caution should be exercised in the choice of an antibacterial drug to prevent horizontal gene transfer and to enhance toxin production and the body's intoxication. One of the advantages of RCA is the possibility of rapidly changing the spectrum of test systems, depending on the region of their application and the epidemiological situation.

[Prevalence of DNA viruses in maxillofacial area of HIV-infected]. / Porazhennost' DNK-virusami cheliustno-litsevoi oblasti bol'nykh s VICh-infektsiei.

DNA viruses have high oncogenic risk viruses; they cause emergence of Kaposi sarcoma, Lymphoma, Squamous cell carcinoma. HIV immunodeficiency promotes increase in frequency of such tumors. Etiotropic therapy of HIV patients considerably reduces prevalence of DNA viruses and a viral malignization.

[Specific features of lymphoid infiltration in liver biopsy in patients with chronic viral hepatitis B and C].

AIM: To study characteristics of leukocytic infiltration of the liver in patients with chronic viral hepatitis B and C (CVHB and CVHC) with consideration of hepatitis activity and fibrosis severity. MATERIAL AND METHODS: The examination of 37 patients with CVHB (n = 13) and CVHC (n = 24) included liver puncture biopsy by Mengini, subsequent histological and morphological investigation of liver biopsy with immunohisto- and immunocytochemistry. RESULTS: In CVHB and CVHC patients leukocytic infiltrates (LI) of the liver present primarily with T-lymphocytes (CD3+), NKT cells (CD3+CD16+CD56+), NK cells (CD16+CD56+), T-regulatory lymphocytes (CD4+CD25+), cytotoxic T-lymphocytes (CD8+). Cytotoxic lymphocytes (CD8+) and NK cells (CD16+CD56+) detected in hepatic LI of patients with chronic viral hepatitis are similar in composition with cells in hepatic tissue infiltrates in autoimmune hepatitis. We are the first to detect the complex of T-regulatory cells (CD4+CD25+) in hepatic parenchyma of these patients. This complex suppresses cellular immune response in virus elimination and damaged tissues and supports development of persistent viral infection with autoimmune component. CONCLUSION: The complex of T-regulatory cells (CD4+CD25+) isolated in hepatic LI evidences for existence of a morphofunctional base for autoimmune manifestations in the presence of persistent viral infection.

[Markers of intestinal infection agents in patients with acute viral hepatitis with cholestatic syndrome].

AIM: To study the pathogenetic role of agents of the most common intestinal infections in the development of cholestatic syndrome in patients with acute viral hepatitis. MATERIAL AND METHODS: We investigated 97 patients with acute viral hepatitis (AVH), 112 blood donors and 165 patients with acute bacterial intestinal infections (ABII). O-antigens of the major causative agents of infections in feces and serum (CIC) and the presence of antishigatoxic CIC in the serum were found. RESULTS: It is first shown a high incidence of O-antigens of Salmonella, Yersinia, Helicobacter, Shigella and Campylobacter in 81.4% of patients with AVH, more frequent and prolonged their detection in patients with the syndrome of cholestasis, higher total O-antigenic load, the frequent identification of mixed-antigens, high levels of LII in comparison with patients without AVH cholestasis and with acute intestinal infections patients. One-third of patients with AVH revealed antishigatoxic CIC in blood serum, which is lower than in patients with ABII. CONCLUSION: The findings suggest the importance of intestinal infections agents in the development and maintenance of inflammation in the liver, the prognostic value of identifying markers in patients with AVH, especially with the syndrome of cholestasis.

[Lymphocyte subpopulation composition in hepatic tissue and autoimmune manifestations in viral hepatitis].

This work had the aim to study the role of disbalance of inflammatory procytokines, lymphocyte subpopulation composition in peripheral blood, and cell populations of hepatic tissue in pathogenesis of viral hepatitis. A total of 159 patients with chronic hepatitis B and C were examined. They proved to exhibit signs of autoimmune processes (ASMA, ANA, AMA, anti-LKM-1, RF, CG) and cytokine (IL-1b, TNFa) disbalance. The number of lymphocytes expressing HLADR+ was shown to increase and CD+ lymphocyte to decrease in proportion to the severity of periportal necrosis, portal inflammation, intralobular degeneration and fibrosis compared with healthy donors. Hepatic biopsies contained T-regulatory cell complex (CD4+ CD25+). These data give evidence of the morphofunctional basis for autoimmune manifestations in patients with persistent viral hepatitis infection.