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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.

Aim. To study the parameters of 24-hour blood pressure monitoring in patients with polycythemia vera and to determine their informational value for the diagnosis of heart damage.Materials and methods. Blood pressure parameters were monitored daily in 63 patients with I–IIB stage polycythemia vera and 52 healthy individuals to determine the occurrence of their pathological types. The sensitivity and specificity of the studied parameters were evaluated using ROC analysis for early diagnosis of heart damage in polycythemia patients. The obtained information was processed in Statistica 25.0.Results. An analysis of blood pressure load showed that 47.6%, 30.1% and 34.9% of polycythemia patients suffer from systolic arterial hypertension (p = 0.012), daytime diastolic arterial hypertension (p = 0.03), and nocturnal diastolic arterial hypertension (p = 0.001), respectively. In comparison with healthy individuals, polycythemia patients experienced a higher variability of systolic (ppp = 0.014), more frequently. In 69.8% of polycythemia patients, pathological types of 24-hour blood pressure profile – with either insufficient or excessive nocturnal reduction – were observed. Informative parameters of heart damage in polycythemia patients were found to include blood pressure load, minimum daytime systolic and diastolic blood pressure, and the rate of nocturnal decrease in diastolic pressure.Conclusions. (1) Systolic-diastolic arterial hypertension was detected in half of polycythemia patients, with pathological types of 24-hour blood pressure profile observed in the majority of patients. (2) The parameters of 24-hour blood pressure monitoring can be used for early diagnosis of heart damage in patients with polycythemia vera.

The aim of the study was to assess the incidence and clinical features of headache associated with the use of granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization or neutropenia treatment among oncohematological patients and bone marrow donors.Material and methods. A prospective observational uncontrolled study included 39 participants: 20 bone marrow donors (group 1) and 19 oncohematological patients (group 2). We evaluated the incidence and clinical features of headache after subcutaneous administration of G-CSF (filgrastim) at doses of 5 to 10 μg/kg for 2 to 5 days.Results. Headache occurred in bone marrow donors more often compared to patients with hematological malignancies (78.9% vs 35.0%; p = 0.006). There were no significant differences in the time of headache onset, its duration, intensity, features, and localization between two groups. Gender, age, dose of G-CSF, and duration of its use were not associated with headache development in both groups.Conclusion. Headache occurs more often in bone marrow donors than in patients with hematological malignancies. The phenotype of headache associated with G-CSF exposure is not drug-specific and requires further studies on its semiotics.

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 relaxation of the shear elasticity of high-entropy bulk metallic glasses (HEBMGs) in the initial (as-quenched) and relaxed (aged) states is studied by electromagnetic-acoustic transformation. The experimental results are used to determine the temperature dependences of the changes in the molar concentration of defects and the enthalpy of their formation. The isochronous kinetics of changing the molar enthalpy of HEBMGs is shown to be calculated using independent data on the change in the molar concentration of defects.

A method for calculating the fragility of high-entropy bulk metallic glasses using the data on shear elasticity relaxation in the supercooled liquid range is suggested and verified.

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.

A method is proposed to calculate the temperature dependence of the unrelaxed shear modulus of high-entropy bulk metallic glasses from differential scanning calorimetry data. The results obtained by this method are shown to be in good agreement with the results of specially performed precision measurements of the unrelaxed shear modulus.

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.

The paper deals with an optimal control problem for the simplest version of a “reduced” linear impulsive continuity equation. The latter is introduced in our recent papers as a model of dynamical ensembles enduring jumps, or impulsive ODEs having a probabilistic uncertainty in the initial data. The model, addressed in the manuscript, is, in fact, equivalent to the mentioned impulsive one, while it is stated within the usual, continuous setup. The price for this reduction is the appearance of an integral constraint on control, which makes the problem non-standard.

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.

On the basis of the Interstitialcy theory, we suggest a quantitative explanation of density changes occurring upon structural relaxation and crystallization of metallic glasses.

High-precision measurements of the shear modulus of polycrystalline indium from room temperature to the melting temperature T m and molecular statics computer simulation have been performed. It has been found that interstitial defects are intensely generated near T m in a dumbbell (split) configuration and their concentration can exceed the concentration of vacancies.

We consider a class of complementarity hybrid systems performed by measure differential equations subject to “mixed constraints” on the measure and one-sided limits of the state (prior to and just after the jump). In such systems, vector Borel measures play the role of control inputs/slack variables. We try to understand the asymptotic behavior of solutions to the complementarity problem, namely, look for a constructive representation of the closure of the trajectory funnel. As we invent, a desired representation follows from a particular approximation of solutions and can be described in terms of a specific singular space-time transformation of measure-driven processes. The developed mathematical setup is naturally applied to modeling of Lagrangian systems controlled by instantaneous blocking/releasing a part of its degrees of freedom.

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.

A relationship between thermal effects and relaxation of the high-frequency shear modulus upon heat treatment of bulk Zr48(Cu5/6Ag1/6)44Al8 metallic glass is found. This relationship is attributed to the relaxation of a interstitial-type defect system frozen-in from the melt upon glass production. Calorimetric data show that thermal effects occurring on heating include heat release below the glass transition temperature, heat absorption above it and heat release caused by crystallization. The equation derived within the Interstitialcy theory can be used to calculate the shear modulus relaxation using the calorimetric data. The obtained results are used to trace the defect concentration as functions of temperature and thermal prehistory.

Epstein-Barr virus (EBV) - the etiological agent of a number of human benign and malignant tumors including infectious mononucleosis (IM), Burkitt lymphoma (BL), Hodgkin (HL) and non-Hodgkin (NLH) lymphomas, nasopharyngeal carcinoma (NPC), and many other tumors. Latent membrane protein 1 (LMPl) encoded by the gene of the same name (LMP I) is the main oncoprotein of EBV. LMP1 is a transmembrane protein capable of activating many signaling pathways and transcription factors of the cells, which leads to its transformation. Molecular analysis of LMP1 of various clinical origins identified many variants with different types of amino acid mutations that influence its biological activity. Since the role of LMPl in the development of NPC is still not fully understood, it is important to find out how LMPl samples from patients with EBV-associated form of NPC differ from those of patients with other tumors also located in the oral cavity (OTOC), but not associated with this virus. Unlike most investigations conducted in endemic regions, the present work is intended to compare the genetic structure and the transforming activity of LMPl variants from NPC and OTOC patients has been carried out in a non-endemic region of Russia, where NPC is rarely diagnosed. The obtained data show structural and functional similarities of LMP1 variants in the two groups of patients and, accordingly, a genetic relationship of EBV strains persisting in these patients. Our work suggests that in non-endemic regions any EBV strain with any structure of LMP1 may become the etiologic agent of NPC. However, based on modem concepts, the cancer can occur only if EBV-infected persons have a unique pattern of HLA associated with a high sensitivity to the development of NPC combined with exposure to harmful environmental factors (chemical or physical carcinogens) and lifestyle.

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.

It is well known that the Epstein-Barr virus (EBV) is a widespread infection in the human population. Typically, infection occurs in early childhood without serious consequences for infected people. At the same time, a secondary infection with an additional EBV strain occurs quite often. During the in vitro cultivation of peripheral blood lymphocytes from persons infected with multiple strains of the virus, only one of these strains with higher transforming potential becomes dominant, while the others are eliminated. Under certain conditions, such a highly transforming EBV strain apparently is able to be the etiologic agent of EBVassociated diseases. To find out the range of highly transforming EBV strains prevalent among Russians, cell lines from patients with EBV-associated and non-associated tumors, as well as healthy individuals, were established. The structural analysis of the latent membrane protein 1 gene (LMP1), a key oncogene of the virus, isolated from established cell lines and peripheral blood lymphocytes of blood donors was carried out, and data obtained were compared with the respective data for LMP1 isolates, amplified from cell lines established from African and Japanese patients with Burkitt's lymphoma. The data obtained show a genetic relationship between Russian LMP1 isolates regardless the fact whether they come from patients with tumors or healthy individuals and differ significantly from LMP1 isolates from Burkitt's lymphoma patients. Thus, the results of the study suggest that in nonendemic region for EBV-associated pathology, Russia, any strain of EBV with any structure of LMP1 with concomitant effect of additional factors may become an etiologic agent for EBV-associated neoplasia.

The role of Epstein-Barr virus (EBV), ubiquitous lymphotropic human herpesvirus 4, in etiology of nasopharyngeal carcinoma (NPC) has not been completely clarified. The mechanism of carcinogenesis in this disease (closely associated with EBV) is also unclear. The aim of the present study was to compare the structure of the LMP1 oncogene of EBV in isolates of the virus obtained from patients with two types of oral cavity tumors, including (a) associated (NPC) and (b) not associated (other tumors of the same anatomical region, OTOC) with EBV. A comparative analysis of the deductive C-terminal amino acid sequences of the LMP1 variants was carried out based on the LMP1 sequence data from samples of the tumor, blood, and oropharynx lavages from patients with NPC and OTOC. It was demonstrated that, in the compared groups of patients, all structural characteristics of LMP1 were close, and existing differences between the compared parameters were statistically insignificant. Thus, it was demonstrated for the first time that genetically related EBV strains with structurally similar LMP1 variants persist in patients with NPC and OTOC in Russia, which most likely reflects the polymorphism of EBV strains that circulate in the population. Based on the data obtained, it is possible to assume that the risk of the occurrence of NPC in NPC non-endemic world regions (including Russia) depends not so much on the EBV strain (and on the variant of the LMP1 that it contains) as on the genetic predisposition to the disease of individuals infected by this virus and the effect of other (still unknown) agents.

In this paper, a linear dynamic system is considered under Lp-constraint on control. We establish the existence of the limit shape of reachable sets as time goes to infinity. Asymptotic formulas are obtained for reachable sets and their shapes. The results throw a bridge between the cases of geometric bounds on control and constraints on the total impulse of control, and create a unified picture of the structure of the limit shapes of reachable sets.