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Diabetes mellitus, a well-known risk of cardiovascular disease (CVD), in patients with type 2 diabetes mellitus (DM2) Hyperglycemia has been found to be an increased risk of coronary heart disease and mortality. In real clinical practice, physicians are faced with the problem of choice when prescribing new hypoglycemic drugs in patients with type 2 diabetes and high cardiovascular risk. Modern possibilities and approaches to the treatment of DM2 have contributed to the creation of a promising class of hypoglycemic drugs that block renal glucose reabsorption - inhibitors of the sodium-glucose cotransporter type 2 (iSGLT-2). The unique mechanism of SGLT2 inhibition not only improves glycemic control, but also has cardio- and nephroprotective effects in patients with DM2 and at high cardiovascular risk. According to current recommendations, when choosing the tactics of treating patients with DM2 and the presence of risk factors for cardiovascular diseases or confirmed atherosclerotic cardiovascular diseases, preference is given to GLP-1 and/or iSGLT-2 receptor agonists in combination with the first-line drug, metformin. This article presents the main results of the efficacy and safety of ertugliflozin in a number of clinical studies and its beneficial effect not only on glycemic control, but also on cardio- and nephroprotective effects. The article also reflects the key results of an extensive program of randomized clinical trials VERTIS (acronym for eValuation of ERTugliflozinefficacy and Safety; evaluation of the efficacy and safety of ertugliflozin): including patients with type 2 diabetes and established atherosclerotic cardiovascular disease (VERTIS CV), with type 2 diabetes and CKD 3rd stage (VERTIS RENAL), as well as VERTIS MONO, VERTIS MET, VERTIS SITA, VERTIS SU and VERTIS FACTORIAL.

Inflammation plays a key role in the development and progression of type 2 diabetes (T2DM), a disease characterized by peripheral insulin resistance and systemic glucolipotoxicity. The main source of inflammation in the early stages of the disease is visceral adipose tissue (VT). Macrophages are innate immune cells that are present in all peripheral tissues, including VT. Violation of the response of VT (MT) macrophages to changes in the microenvironment underlies aberrant inflammation and the development of local and systemic insulin resistance. The inflammatory activation of macrophages is regulated at several levels: stimulation of cell surface receptors, intracellular signaling, transcription, and metabolic levels. Which are activated by the transformation of macrophages along the pro-inflammatory or anti-inflammatory pathways. Such polarization of macrophages in modern immunology is divided into classical anti-inflammatory M1 polarization and alternative anti-inflammatory M2 polarization of macrophages. The M1 / M2 ratio of macrophages in the process of inflammation ensures the resolution of inflammation at different stages of its development. The review considers the main mechanisms involved in VT inflammation and the development of insulin resistance in T2DM, supported with the participation of immunocompetent cells, M1 / M2, as well as growth factors and humoral immunity factors secreted during this process.

Introduction. The long-term event-free survival of patients with high-risk neuroblastoma (NB) receiving intensive complex therapy according to current russian standard do not exceed 40 %. Also, there is no standard tactics in patients with primary resistant and relapsed disease, most of them die due to disease progression. While, anti-GD2 immunotherapy (IT) proved to be effective in patients with high-risk NB, in Russian Federation this method is not generally available. There are currently two pilot studies ongoing in Raisa Gorbacheva Memorial Institute aimed to evaluate the effectiveness of anti-GD2 antibodies in high-risk NB patients.Aim of the study – describing a single-center experience of anti-GD2 IT in primary high-risk NB patients and patients with primary resistant and relapsed disease.Materials and methods. A total of 20 patients received anti-GD2 antibodies, 16 of them were included into pilot trials. The median age at IT initiation was 5 (3–17) years. In 13 cases the therapy was initiated in patients with high-risk disease after auto-HSCT, in 3 cases – in patients with 1st systemic relapse of primary resistant disease after 2nd-line therapy and haplo-HSCT, in 1 case – in patient with 2nd chemosensitive relapse after haplo-HSCT. Also, 3 patients with progressive chemoresistant disease received anti-GD2 antibodies as monotherapy (n = 1) or in combination with chemotherapy (n = 2) as salvage regimen.Results. Patients receiving anti-GD2 antibodies after auto-HSCT retain response to therapy in 11 of 13 cases with a median follow-up period of 15 (6–27) months, in 2 cases there was disease progression during or immediately after IT cessation. Both patients with disease progression responded well to salvage therapy. Two of 3 haplo-HSCT recipients with prior good response to 2nd-line therapy are currently in remission 16 and 36 months past haplo-HSCT, one patient progressed 55 months after transplantation. A patient with 2nd late relapse after haplo-HSCT currently maintains remission on IT. Both patients with chemorefractory progressive disease did not respond to IT and died due to disease progression. IT was characterized by acceptable toxicity. In most cases it was complicated by Gr 1–2 fever, rash or neuropathic pain effectively controlled by supportive therapy. However, three patients had signs of neurotoxicity requiring therapy termination in one case.Conclusion. Dinutuximab beta IT is characterized by acceptable toxicity. With a median follow-up of 18 (6–59) months the majority (14 of 17) patients receiving anti-GD2 antibodies as maintenance therapy after auto- or allogeneic HSCT retain response. However, we did not observe any response in patients with progressive chemorefractory disease.

The article presents a clinical case of a 25-year-old patient with progressive diffuse B-cell lymphoma with lesions of the S2 nerve root, accompanied by pain syndrome that is not relieved by systemic multimodal analgesia using opioids, antiepileptic and non-steroidal anti-inflammatory drugs. Polyneuropathy, secondary immunodeficiency, thrombocytopenia grade IV refractory to platelet concentrate transfusion, Guillain-Barre syndrome, impaired the somatic status and intensified the pain syndrome. Local anesthetics epidural port was successfully implanted to improve quality of analgesia. As a result of prolonged epidural infusion of 0.2% ropivacaine with titration rate from 4 to 7 ml/hour depending on the severity of the pain syndrome, that significantly improved patients quality of life was achieved by reducing the intensity of pain and increasing duration of night sleep. In the early postoperative and long-term follow-up periods (14 days), there were no hemorrhagic and infectious complications associated with the use of the epidural port.

Aim: the study was aimed to develop a reagent kit for the real-time RT-PCR diagnostics of virus causing COVID-19.Materials and Methods.Three target sites were chosen in the genome SARS-CoV-2. The testing included 220 samples, 48 artificially created positive samples (made from patients’ biomaterial) and 172 clinical samples (scrapes from nasal and pharyngeal cavities, bronchoalveolar lavage, expectoration, endotracheal/nasopharyngeal aspirate, feces, post-mortem material), obtained from two medical centers. Preliminary, the obtained biomaterial was analyzed with a reagent kit of comparison. The evaluation was performed with a confidential interval CI 95%. The calculation of CI for the sensitivity and specificity was made based on the distribution of χ2.Results.The authors developed a technology of novel coronavirus infection (COVID-19) real-time RT-PCR diagnostics for the application in practical healthcare and proposed the variants of testing at all the stages (preanalytical, analytical, and post-analytical, including automated results processing). The proposed reagent kit meets the requirements of the World Health Organization and the Ministry of Healthcare of the Russian Federation. The study results demonstrated high sensitivity and specificity. The sensitivity was 100% (95% CI) 95.6–100%; the specificity was 100% (95% CI) 96.7–100%.Conclusion.The proposed reagent kit was registered in the RF as a medical product; the registration certificate No. RZN 2020/9948 dated 01.04.2020. The application of the reagent kit in network laboratories will provide patients with access to testing for the virus causing COVID-19 and contribute to quick differential diagnostics, improvement of pandemic control, and accurate statistics on the spread of the virus.

The prevalence of T2D is steadily increasing annually, which resulted in an active search for a way to control the disease. The last decade has seen a rise in the number of new groups of glucose-lowering drugs, which not only proved effective in the management of hyperglycemia and safe against hypoglycemia, but also joined the ranks of the drugs of the first-line therapy. Among them is incretin-active agents - type 4 dipeptidyl peptidases inhibitors (IDPP-4, glyptines). Sitagliptin was the world's first approved IDPP-4, and began to be used successfully in Russia since 2007. The review presents data on the efficacy, safety (including cardiac safety) of sitagliptin use and accumulated experience of its use in the treatment of patients with type 2 diabetes.

Oncological diseases are the main causes of death in the world. Modern treatment of cancer patients contributes to an increase in survival rate due to strong chemotherapeutic drugs, the use of which is accompanied by toxic effects on cardiomyocytes. The main manifestations of cardiotoxicity are left ventricular dysfunction, myocardial ischemia, thromboembolic complications, chronic heart failure. As a result, the risk of cardiovascular mortality may be higher than the risk of death from the tumor process. An important task of oncologists and cardiologists is the early diagnosis of cardiotoxic complications in order to start treatment in time and reduce mortality from cardiovascular pathology in cancer patients.

The article is devoted to the role of self-monitoring of the level of glycemia in achieving the goals of treatment in patients with diabetes mellitus. The dependence between the compensation of carbohydrate metabolism and the level of motivation of the trained patient for the control of glycemia is shown, the necessity of regular self-monitoring of glycemia by the patient is grounded. The main methods and means used for self-monitoring of glycemia are given and their characteristics are given. The importance of teaching patients to self-control methods as a measure of preventing the occurrence of complications of diabetes mellitus is substantiated. Comparative data on the prevalence of complications in patients, both not using self-monitoring, and conducting it, are given. Teaching patients proper glycemic control with portable glucometers is an important and indispensable component of diabetes therapy.

The paper suggests a framework of control synthesis (feedback) for differential systems driven by nonlinear impulses. We propose a simple but relevant notion of control synthesis and a related concept of sampling solution. For extremal problems stated for input-polynomial systems, we fix two connected issues: establish the dynamic programming principle, including the characterization of the value function and verification theorem (sufficient optimality condition), and design an optimal synthesis procedure. Finally, we discuss a different, to some extent “dual” to the verification theorem, issue — a sufficient condition for non-optimality, — which performs an application of the control synthesis to discarding non-optimal extrema of the impulsive maximum principle.

Modern representation of self-monitoring blood glucose can be characterised by new technologies introduced in recent years, including tools to identify trends and patterns of glycaemia (PatternAlert ). These technologies simplify self-monitoring and help avoid errors in the interpretation of blood glucose levels in patients. This study examines the primary trends in the management and control of diabetes, as well as the strengths and weaknesses of the control of glycated haemoglobin (HbA1c). In addition, this study raises broader questions on self-control in patients with diabetes mellitus, which are beyond the issues of the normalisation of blood glucose levels.

The article investigates the value of canagliflozin in the management of type 2 diabetes mellitus from the perspective of a clinically-based patient-centred approach. It focusses on the outcomes of a 52-week double-blind, active-controlled study. The results of this clinical trial demonstrate that canagliflozin, which provides significant weight loss ability, improves the quality of life and satisfaction with physical and emotional health in patients with diabetes compared with sitagliptin.

It has been shown for 24 metallic alloys that temperature dependences of the relative changes of the shear moduli in the glassy and crystalline states below the glass transition are nearly equal, provided that structural relaxation is absent. This behavior supports the idea that the shear elasticities of glass and its crystalline counterpart are intrinsically interrelated, in agreement with the Interstitialcy theory.

Aim. To study the effect of antiviral therapy (AVT) on some cardiac hemodynamic parameters in patients with chronic viral hepatitis (CVH).Material and methods. Segmental systolic and diastolic functions of the ventricles as well as global diastolic function were evaluated in 25 patients with CVH by pulsed tissue Doppler mapping and by the method of Doppler echocardiography, respectively. The blood flow speed and diameter of blood vessels in liver were determined by ultrasound Doppler. Cardiac hemodynamics was examined in all patients before and after AVT with interferon in combination with ribavirin with formation of persistent virological response. Healthy people (n=19) were included into control group.Results. Reduction in atrial and ventricular sizes, decrease in left ventricular mass, improvement of systolic function of both ventricles, as well as diastolic function of the left ventricle were found in patients with CVH after specific treatment. Reduction in hepatic arterial and portal blood flow speed and a total number of heart rhythm disorders were also observed. Therefore AVT in patients with CVH shows a positive impact on cardiac hemodynamics. Medium-strength correlation (r=0.31; pConclusion. Patients with CVH that do not receive AVT have worse prognosis and indicators of cardiac hemodynamics in comparison with patients who receive specific AVT.

The paper is concerned with a nonlinear optimal impulsive control problem with trajectories of bounded variation. Vector Lebesgue-Stieltjes measures play the part of controls. Studied were state and mixed constraints in the conventional and fast times, as well as joint conditions for trajectory and impulsive control. A method of reduction to the classical problem of optimal control was developed relying on the discontinuous time reparameterization. The original and reduced problems were established to be equivalent.

An optimal control problem is considered for a system described by a differential equation with measures; a certain constraint is imposed on the total variation of controlmeasure. Involving the method of discontinuous time reparameterization, an interpretation is performed for the procedures of weak control variation in an auxiliary reduced problem, and new refinement methods are developed for impulsive processes. An example is provided.

End of XX - beginning of XXI century. were characterized by a rapid increase in the incidence of type 2 diabetes mellitus, which is caused by overeating, an increase in the number of refined products, obesity, a decrease in physical activity, and an increase in life expectancy. Worldwide, the number of people with diabetes is over 100 million. In Europe, the cost of treating diabetes and its complications, according to experts, is 5.8% of the total medical budget

We consider an optimal control problem for an impulsive hybrid dynamic system, where jumps of a trajectory may occur only at the moments of hitting a given closed set. A time reparameterization technique is applied to reduce the original problem to the one with bounded controls. We show that the reparameterized problem is equivalent to optimization in a class of generalized solutions to the impulsive hybrid system. Necessary conditions for optimality of generalized control processes are obtained by interpreting the Maximum Principle in the reduced problem.

Iodine deficiency disorders are one of the most common problems in thyroidology and endocrinology. Due to the vulnerability to reduced consumption of iodine, a special interest in the study of the effects of iodine deficiency and its prevention are pregnant and lactating women, patients of reproductive age and children is shown.

The Epstein-Barr virus, widespread herpesvirus among the population of the planet, is also the etiologic agent for a number of malignancies. One of the oncoproteins encoded by the virus, the latent membrane protein 1 (LMP1I), through activation of the complex signaling pathways is involved in the processes of cell immortalization and transformation. The goal of this work was to study the level of the EBV infection in Russian population and LMP1 polymorphism in patients with benign and malignant EBV-associated diseases and healthy virus carriers. Studies have shown that by the age of 5-9 years the percentage of the infected persons and the level of antibody titers reaches almost the maximum values. With the age, virus specific antibody titers are decreased (with a high percentage of infected persons) and increased again in groups of older persons. The analysis of the nucleotide sequences of the gene LMP1 translated in amino acid (aa) sequences unexpectedly revealed the dominance a low divergent variant LMP1 B95.8A not only in healthy individuals but also in patients with all forms of EBV-associated diseases. Highly divergent variants Ch1 and Med +, containing a deletion of 10 aa, and characterized by elevated transforming activity more often were detected in the tumor tissue samples than in the blood samples/mouth washes of the same patients. Detection of highly transforming variant LMP1 Ch1 in blood samples of healthy individuals indicates that this analog of Chinese variant Cao may persist in any population and is not necessarily associated with the occurrence of the EBV-associated disorders.

An algorithm for polyhedral approximation of the reachable set of impulsive dynamic control systems is designed. The boundary points of the reachable set are determined by recursively generating and solving a family of auxiliary optimal impulsive control problems with state-linear objective functional. The impulsive control problem is solved with an algorithm that implicitly reduces the problem an ordinary optimal control problem. The reduced problem thus obtained is solved with an algorithm based on local approximations of the reachable set.

The discrete problem of optimal control with mixed constraints was considered from the standpoint of numerical solution. Computational methods are usually based on solving a series of improvement problems. The nonlinear discrete problem and that of nonlinear functional improvement for the variational system were compared. A procedure for constructing an admissible control process improving the original problem from the solution of the reduced problem was described.

The terminal functional of a general control system is refined by studying an analogous problem for a variational system and regularization. A sequential refinement method is designed by combining the local approximation of the reachability set and reduction. The corresponding algorithm has relaxation properties. An illustrative example is given.

The Epstein–Barr virus (EBV) represents an etiological agent for a number of human benign and malignant tumors. One of the EBV encoded proteins, the latent membrane protein 1 (LMP1), is involved in activation of many signaling pathways and transcription factors leading EBV infected cells to immortalization and transformation. It’s well known that almost all worlds’ population is infected with EBV. As usually, infection occurs during early childhood without serious consequences for infected people. At the same time a secondary infection by additional EBV strain(s) occurs quite often. During the in vitro cultivation of peripheral blood lymphocyte from persons infected with multiple strains of the virus, only one of them having LMP1 oncogene with highest transforming potential becomes dominant while the others are eliminated. To figure out whether pattern of LMP1 expressions reflects the origin of EBV strains, six cell lines from patients with tumors, associated and not-associated with the virus and healthy individuals were established. The nucleotide and deductive amino acid (a.a.) sequences of LMP1 isolates tested were analyzed and compared with those of LMP1 isolates obtained from eight cell lines of African and Japanese EBV-associated Burkitt’s lymphomas (BL) origin. As the result, in four out of six cell lines of Russian origin (2 from patients with lymphoid pathology and 2 from PBLs of blood donors) the low divergent LMP1 B95.8/A variant characterized by a low transforming activity and a small number of a.a. substitutions was detected. For other two cell lines originated from EBV-associated patient with nasopharyngeal carcinoma and not virus-associated Hodgkin’s lymphoma patient the LMP1Med- and LMP1China1 variants, characterized by a larger set of mutations and high transforming potential, were found. Low divergent LMP1 variants (B95.8 or B95.8/A) were observed for 13 of 15 LMP1 samples from PBLs of Russian blood donors; in 2 donors highly divergent China1 and NC LMP1 variants were also detected. Among eight cell lines of BL origin three lines were the sources of the prototype EBV strain B95.8 (Jijoye, P3HR1, Raji). From other five cell lines (Daudi, Namalva, Ag 876, NC37 and Akata) LMP1 variants Med- and China1, characterized by a significant number of mutations and high transforming capacity were obtained. Genetic relationship between LMP1 isolates from cell lines of Russian and BL origin were analyzed by the phylogenetic tree. It follows from the constructed tree that cell lines of Russian and BL lymphoma origin formed two separate clusters located at the tree a distance from each other, indicating genetic proximity for respective groups of cell lines. The data obtained complemented with the results of our previous studies suggest that among Russians represented by cancer patients and healthy individuals, EBV strains with predominantly low transforming capacity of LMP1 are persisting. These findings are likely can explain the non-endemic nature of the EBV-associated pathologies in Russia.On the other hand, one can speculate that in African countries which are endemic for BL highly oncogenic strains of EBV are dominated, the indirect confirmation of what is the detection in cell lines of BL origin LMP1 isolates having high transforming activity. The results of this study let us also to suggest that LMP1 expression pattern in non-endemic region like Russia does not reflect the type of malignancy but rather reflect their geographic origin.

The investigation was undertaken to study the molecular characteristics of Epstein-Barr virus (EBV) LMP1 gene samples amplified from the tumor and intact tissues of patients with EBV-negative forms of gastric carcinoma (GC). The genetic structure of these samples determined by their sequencing was compared with that of the gene samples isolated from the cells of oropharyngeal washing specimens from the same patients with GC, as well as peripheral blood lymphocytes of patients with infectious mononucleosis (IM) and blood donors. The findings suggest that the samples of tumor tissue LMP1 from patients with GC have higher divergence than those from patients with IM and blood donors although no specific variants of the gene for GC were found. Comparison of LMP1 sequences from tumor tissue and cells of oropharyngeal washing specimens from the same patients with EBV-negative GC revealed the common LMP1 variant in 2 cases while they differed in 3 cases. The findings are an initial step in studying the role of EBV in the carcinogenesis of EBV-negative GC that is likely to be established by investigations on representative clinical material, by applying the up-to-date technologies.

To elucidate the role of some viral and cellular proteins in the occurrence and development of HERV-K-associated germ-cell tumors (GCT), reverse-transcription polymerase chain reaction using specific primers has been employed to study the transcription of the protein Rec HERV-K and the possible interaction of the protein Rec(cORF), that has transforming properties, and the cellular protein PLZF, that is a negative regulator of cell division, in human GCT tissues, in the testicular parenchyma adjacent to a tumor, and in the normal testicular tissues. It was shown that there was expression of Rec(cORF) of mRNA, rather than cellular PLZF in all malignant GCT tissues, this led to the conclusion that no interaction occured between the Rec HERV-K and PLZF proteins in the GCT cells. At the same time co-expression of Rec and PLZF protein was first revealed at the level of transcription in the testicular parenchyma adjacent to a tumor that exhibited carcinoma in situ cells. By taking into account that the protein Rec HERV-K has transforming activity and it is presumed to be Implicated in the development of GCT, the authors discuss a possible role in the Rec HERV-K/HTDV and cellular PLZF interaction in the pathogenesis of GST at the early stages of its genesis.

To study fractional composition of red cell membrane (RCM) lipids in patients with severe iron-deficiency anemia (IDA) complicated by myocardiodystrophy prior to treatment and after 1-month combined treatment with sorbifer and mildronate.Fatty acid composition of RCM lipids was studied in 12 patients with severe chronic posthemorrhagic IDA complicated by myocardiodystrophy and in 15 healthy subjects. Extraction of lipids from blood red cells and methylation of fatty acids were performed according to K.M. Sinyak et al. (1976). Relative content of fatty acids was determined at chromatography.The study detected increased content of saturated fatty acids, especially palmitic and decreased content of unsaturated fatty acids especially fraction of omega6-polyunsaturated fatty acids: arachidonic and gamma-linolenic.Sorbifer in combination with mildronate improved fatty acid composition of blood red cells in patients with iron-deficiency anemia.

Epstein-Barr virus (EBV) is an etiological agent of a number of benign and malignant human diseases, such as infectious mononucleosis (IM), Hodgkin's lymphoma (HL), and non-Hodgkin's lymphoma (NHL). EBV latent membrane protein 1 (LMP1) gene (recognized as a viral oncoprotein) of various clinical and geographical origin was found to have different types of amino acid mutations affecting its biological activity. Since there was no information on the strain differences in LMP1 of EBV persisting in Russia, the authors made a sequence analysis of LMP1 samples amplified from the biological materials of Russian patients with IM, HL, and NHL and healthy individuals. The studies have shown that LMP1 variants of Russian origin are a mixed heterogeneous group containing both the earlier characterized and presumably new genetic variants. Among the point amino avid substitutions, the mutations S366T, F106Y, 185L, and E328Q associated with the enhanced transforming activity of a LMP1 molecule and its reduced cytotoxicity. There was no specific association between the certain Russian variants of LMP1 and the specific forms of the disease (IM, HL, and NHL).

The samples of tumor biopsy, blood, and saliva from 10 patients with Hodgkin's disease, 10 patients with non-Hodgkin's lymphoma, and the blood samples of 20 donors were tested by polymerase chain reaction (PCR) for standard (wild) B95-8 and Cao-like (deleted) variants of the LMP1 gene. The paraffin sections of most PCR-tested tumors were also investigated by immunohistochemistry using the monoclonal antibodies S12 or 7D7 to detect the expression of the standard or Cao-like variants of LMP1 protein, respectively. It is suggested that Eptein-Barr virus (EBV) that contains the above deletion is not crucial for the development of the study lymphoproliferative malignancies. The fact that in some cases there is the Cao-like variant of LMP1 in the tumor biopsy specimen and its standard variant LMP1-B95-8 in the biological fluids of the same patient is very likely to suggest that the patient is infected with both types of the virus or there is genetic mutation(s) of EBV during viral carcinogenesis preceding or accompanying the development of a tumor.