Experience of the Rospotrebnadzor Administration in the Republic of Tatarstan in the Prevention of Internal epidemiological Risks During the Preparation and Holding of the FIFA World Cup-2018

Objective of the study was to describe the organization of epidemiological surveillance over internal risks associated with the intensification of natural-focal diseases in the Republic of Tatarstan, analysis of the measures taken to prevent natural focal diseases during the preparation and holding of the FIFA World Cup-2018. Materials and methods. The data from surveys and forecasts as regards the numbers of small mouse-like rodents as carriers and arthropod vectors of natural-focal diseases, epizootic and epidemiological situation reports in the Republic of Tatarstan and information on infectious and parasitic disease morbidity rates in the Republic of Tatarstan, presented by the Center of Hygiene and Epidemiology in the Republic of Tatarstan over 2015-2018 were utilized for analysis. Results and conclusions. The natural conditions of the Republic of Tatarstan are favorable for the circulation of pathogens of natural-focal diseases, which carriers are mammals (primarily small rodents) and birds, and vectors - blood-sucking arthropods: Ixodidae ticks, mosquitoes. The results of circulation monitoring of natural focal infection pathogens in the ambient environment made it possible to conclude that during the FIFA World Cup-2018, the epidemic risk of occurrence of natural-focal diseases would remain high. Considering the existing and forecasted internal risks, priorities were identified in the organization of preventive measures aimed at minimizing epidemiological risks in relation to natural-focal infections during the preparation and holding of the FIFA World Cup 2018. The chosen preventive strategy made it possible to prevent the infection with natural-focal infectious diseases among the population and ensure a stable epidemiological situation during the FIFA World Cup-2018

Provision of Biological Safety in the Territory of the Republic of Tatarstan during Preparation and Holding of FIFA World Cup-2018 in Kazan

Objective – assessment of effectiveness of the measures for biological safety provision at potentially hazardous facilities in the territory of the Republic of Tatarstan in the process of preparation and holding of FIFA World Cup-2018 in Kazan. Materials and methods. Regulatory-legal acts covering the requirements to the provision of biological safety during the work with pathogenic biological agents, international guidelines and documents determining inter-agency collaboration between the Rospotrebnadzor Administration in the Republic of Tatarstan and other departments and inter-agency task forces (Office of the Federal Security Bureau of Russia in the Republic of Tatarstan, Counter-Terrorism Commission in the Republic of Tatarstan, etc) were studied. Results and discussion. Considered were managerial-methodological approaches and matters of inter-agency cooperation on biological safety provision during preparation and holding of FIFA World Cup-2018 in Kazan. Biological safety was examined through the prism of its provision while working with pathogenic biological agents at potentially hazardous biological facilities and  counterterrorism integrity of the objects. The guiding, directive document in the performance of the complex of measures on biological safety provision and inter-agency collaboration was the Order of the President of the Russian Federation dated May 09, 2017 No 202 “On peculiarities of application of reinforced security measures during holding of FIFA World Cup-2018 and FIFA Confederations Cup-2017 in Russia”. As the result of the measures conducted, biological safety, including counter-terrorism security of potentially hazardous biological objects and sanitary-epidemiological welfare, was fully provided

Integrated solution for patients of a very high cardiovascular risk. Final results

Secondary prevention should be actively implemented at all stages of treatment and rehabilitation of patients after acute coronary syndrome (ACS). The integration of remote monitoring of patients with the transfer of vital and laboratory data into clinical practice seems promising.Aim. To evaluate the clinical and patient-centered effectiveness of the original 12-month combined face-to-face and telecare program in patients with recent ACS.Material and methods. For the present analysis the data from 84 (out of 100) patients (median age, 56 (50;61) years, 70 males) was used. These patients had to have hypertension and/or type 2 diabetes and an ACS with percutaneous revascularization within 12 months. Their low-density lipoprotein cholesterol (LDL-C) had to be above 2,4 mmol/L. Telehealth program supplemented routine care. A program contained electronic self-control diaries for blood pressure (BP) and lipid profile, and teleconsulting service (text chat). Mandatory face-to-face visits were carried out at 3 and 12 months after the enrollment. The primary end point was ∆LDL-C. Additional clinical and patient-specific endpoints were evaluated.Results. At the 12-month visit, there was a significant decrease in LDL-C by 1,6 (-2,3;-0,9) mmol/L. Besides the initial LDL-C value, the decrease in LDL-C was associated with the proper adherence to keeping diaries of BP and lipid profile (β=0,7), and the number of text messages sent by the doctor in the 1st month after the enrollment (β=0,04). In more adherent patients, the ∆LDL-C was greater by 0,49 mmol/L (95% CI (-1,2; -0,1)) after adjustment for abovementioned covariates. In 35 patients (42%), target LDL-C was achieved, in 60 patients (71%) — a decrease ≥1 mmol/l. Other lipids also have changed for the better. Moreover, adherent patients were twice as likely to achieve the target LDL-C (OR 2,2; 95% CI (0,6; 3,8)) than non-adherent ones. A decrease in office systolic BP by 5,8 mm Hg was shown (p=0,03). The number of physician-to-patient messages exceeded those from patients to physician (median 143 and 111 per patient for 12 months, respectively). The quality of life has improved, but only in terms of emotions. Satisfaction with the program remained high at all timepoints of the study.Conclusion. Our study showed the effectiveness of the integrated care in ACS patients with the telehealth tool included. Commitment to BP self-monitoring, as well as active consultative support at the first stages of rehabilitation, contributes to additional dynamic control of lipid profile, timely correction of lipid-lowering therapy with the achievement of the target LDL-C level. Most of the patients did not experience any difficulties in using the program and are ready to recommend integrated approach to other peers

Integrated solution for very high cardiovascular risk patients. Rationale and design of a pilot study

Coronary artery disease (CAD) is the most common cardiovascular disease and the leading cause of morbidity and mortality. Acute coronary syndrome (ACS) as an abrupt destabilization of CAD, multiplies the risk of cardiovascular events. To reduce the incidence of recurrent cardiovascular events, timely tackling potentially reversible risk factors such as hypertension and/or hyperglycemia is imperative. However, a solid basis for a secondary prevention lies in the treatment of dyslipidemia and begins in the first hours of hospital admission. Despite considerable evidence regarding the efficacy and safety of lipid-lowering therapy, averagely only one third of patients maintain control of lipids. The main challenges are low adherence, poor continuity of medical care, and the lack of an ambulatory routine follow-up. Telehealth solutions are believed to address these barriers and may be considered as an add-on to in-person patient care. Telemonitoring of vital and laboratory parameters, remote patient counseling can be introduced into routine care delivery. Telemedicine shows promise for fostering better clinical effect, and provides health-related quality of life improvement.It is planned to conduct a pilot observational study aimed to create and to test an integrated solution, i.e. telemonitoring and remote counseling in patients of very high cardiovascular risk with ACS followed by myocardial revascularization. The goal is to determine the clinical effectiveness, i.e achievement of target values of blood pressure, lipid profile and glycemia, and patient-centeredness of this approach

An integrated approach for very high cardiovascular risk patients. Intermediate results

The main objective of secondary prevention measures is to modify key risk factors such as hypertension (HTN) and dyslipidemia in patients with established cardiovascular diseases. Its proper implementation improves both short- and long-term outcomes. Telehealth technologies contributes to faster achievement of target levels and better control of key risk factors.Aim. To establish a comprehensive personalized follow-up framework for patients recovered from an acute coronary syndrome (ACS) that integrates telehealth software and to test its clinical and patient-centered efficacy.Material and methods. The three-month follow-up data of 50 patients (50% of planned enrollees; median age, 57 years [53; 61]; males, 84%) who suffered ACS with myocardial revascularization and low-density lipoprotein cholesterol (LDL-C) at least 2,5 mmol/L at admission. We introduced the simple and save telehealth software for home BP monitoring and lipid profiling. The basic demographic, clinical and laboratory characteristics of patients were described, as well as the changes lipid profile, office and home BP over this period was analyzed. The primary endpoint was a change in LDL-C after 3 months. In addition, we also focused on pharmacological therapy and its dynamics, as well as on remote counseling and patient’ experience with the mobile application.Results. Three months after inclusion, we have noted significant decrease of total cholesterol (-1,67 mmol/L, p<0,0001) and triglycerides (-0,48 mmol/L, p<0,0001). LDL-C changes were also significant (-1,49 mmol/L, adjusted for age, sex and lipid-lowering therapy; p<0,0001) and was associated only with the baseline LDL-C levels (R2=-0,521, p<0,0001). Thirty-nine (78%) patients achieved at least 1 mmol/L drop of LDL-C. Nine of them reached target LDL-C <1,4 mmol/L (and/or a decrease of 50% from baseline). Both high-density lipoprotein cholesterol (-0,48 mmol/l, p=0,348), office and home BP remained mostly unchanged. The proportion of patients with target office BP levels was almost the same (χ2=3,06, p=0,08). Patients who were recommended combined lipid-lowering therapy with cholesterol absorption inhibitor (ezetimibe) were more likely to achieve target LDL-C (χ2=10,95; p=0,003) than those with single agent (67% versus 17%, p=0,003). No differences were found in subgroups of patients in LDL-C reduction. In each patient an average of 15 remote consultations have been performed (from 1 to 54 per patient per 3 moths). Investigators have had to send reminders to 22 patients regarding the need for regular home BP monitoring. The majority of patients treated telehealth software as easy-to-use and user-friendly.Conclusion. According to the 3-month follow-up of patients after ACS who used the framework integrated with telemonitoring and remote counseling, a positive trend in reducing atherogenic lipid levels was demonstrated, but not in office BP. Only a fifth of patients reached the target LDL-C, but the vast majority had target BP. Despite the fact that the program is convenient to use, almost half of participants require additional reminders from physician on self-monitoring

Experience of using multielectrode catheter systems to perform radiofrequency renal sympathetic denervation in patients with resistant hypertension: immediate procedural effects

Aim. To investigate the baseline characteristics of patients with resistant hypertension (HTN) undergoing radiofrequency renal sympathetic denervation (RD) and to determine immediate procedural effects.Material and methods. During 2018-2019, two series of radiofrequency RD procedures were performed in patients with true resistant HTN using balloon-type (bipolar ablation) or spiral-type (unipolar ablation) multielectorde catheters. The basic demographic, clinical and laboratory characteristics of included patients were assessed. A comparative analysis of two groups was carried out depending on the type of catheter used. Dynamics of office systolic blood pressure (SBP) were assessed as ∆ between the two following timepoints: at screening and at hospital discharge. The safety of radiofrequency RD was assessed. Multiple linear regression was used to determine the factors associated with the ∆ of office SBP after radiofrequency RD.Results. A total of 48 patients taking 4 (4;6) antihypertensive drugs were sequentially included. Radiofrequency RD was performed with a balloon-type catheter in 27 patients (mean age, 56±12 years old; 12 males) and with a spiral-type catheter in 21 patients (50±14 years old; 8 males). Radiofrequency RD was significantly longer in the spiral catheter group than in balloon one (110 versus 60 minutes, p<0,001), as was the mean number of RF applications (24 versus 12, p=0,002). None of the patients had acute kidney injury after RD (creatinine ∆, -0,6 µmol/L; 95% CI [-3,97; 2,78]). A total of 4 patients had complications (3 femoral arterial pseudoaneurisms, one renal arterial dissection), all of which did not affect the average length of hospital stay (from 4 to 5 days). At discharge, there was a pronounced decrease in office SBP (adjusted for baseline characteristics) with the mean of -26 mm Hg (95% CI [-29; -23]). There were following main factors associated with the office SBP ∆: smoking status (positive), baseline office SBP (positive), and blood glucose (negative).Conclusion. Radiofrequency RD using multielectode catheters is characterized by favorable short-term hemodynamic effects. We have found novel potential predictors of these effects. Further research will focus on testing initial hypotheses in the long term

Clinical features and genetic risk factors in the development of ischemic stroke

Aim: to study the clinical features of the progredient and crisis course of the cerebrovascular process complicated by ischemic stroke, with genetic associations of gene polymorphisms. Methods. A molecular-genetic analysis of the distribution of alleles and genotypes: (ACE (rs1799752), FGB (rs1800790), F5 (rs6025), F7 (rs6046), F12 (rs1801020), GP1BA (rs2243093), GPIIIa (rs5918), SERPINE1 (rs1799768), MTHFR (rs1801133), CYP11B2 (rs1799998), P0N1 (rs662), P0N2 (rs1801282), NOS2 (rs2297518), N0S3 (rs1799983), PDE4D (rs966221, rs2910829), HIF1 a (rs11549465, rs11549467), LTA(rs 909253), ALOX5AP (rs4769874), TUB (rs4578424).) - was conducted for each of the studied polymorphic regions of genes in groups of patients with stroke having different clinical manifestations. Results. The analysis of clinical features, the state of brachiocephalic arteries in patients with chronic cerebrovascular pathology complicated by stroke was carried out. Groups based on the nature of stenosis of brachiocephalic arteries, the pathogenetic subtype of stroke, and molecular genetic analysis, revealed that the allele of the С gene of the GP1BA gene is more common in the group of patients with occlusion of the BCA and severe hemodynamic stenosis (24%) than in the group of patients with hemodynamically insignificant stenosis (8%) (OR = 3.385,95% Cl = 1.118-10.248, p = 0.03). It was found that the allele D of the ACE gene is more common in the group of patients with cardioembolic stroke (67%) compared with patients with atherothrombotic stroke (38%) (OR = 3.333,95% Cl = 1.174-9.464, p = 0.026).Цель. Изучить клинические особенности прогредиентного и кризового течения цереброваскулярного процесса, осложненного ишемическим инсультом, с генетическими ассоциациями полиморфизмов генов. Методы. Проведен молекулярно-генетический анализ распределения аллелей и генотипов (АСЕ (rs1799752), FGB (rs1800790), F5 (rs6025), F7 (rs6046), F12 (rs1801020), GP1BA (rs2243093), GPIIIa (rs5918), SERPINE1 (rs1799768), MTHFR (rs1801133), CYP11B2 (rs1799998), P0N1 (rs662), P0N2 (rs1801282), N0S2 (rs2297518), N0S3 (rs1799983), PDE4D (rs966221, rs2910829), HIF1 a (rs11549465, rs11549467), LTA (rs909253), AL0X5AP (rs4769874), TUB (rs4578424).) для каждого из исследуемых полиморфных участков генов в группах больных с инсультом, имеющих различные клинические проявления. Результаты. Проведен анализ клинических особенностей, состояния брахиоцефальных артерий у пациентов с хронической цереброваскулярной патологией, осложненной инсультом. Выделены группы по характеру стенозирования брахиоцефальных артерий, по патогенетическому подтипу инсульта, проведен молекулярно-генетический анализ, в ходе которого выявлено, что аллель С гена GP1ВА чаще встречается в группе пациентов с окклюзией БЦА и выраженным гемодинамическим стенозом (24%) по сравнению с группой пациентов с гемодинамически незначительным стенозом (8%) (ОШ=3,385,95%ДИ=1,118-10,248, р=0,03). Обнаружено, что аллель D гена АСЕ чаще встречается в группе пациентов с кардиоэмболическим инсультом (67%) по сравнению с пациентами с атеротромботическим инсультом (38%) (0Ш=3,333,95% ДИ=1,174-9,464, р=0,026)

Способ получения рекомбинантных антител, продуцируемых клеточной линией, трансдуцированной рекомбинантными аденовирусами

Objectives. To develop a technology for obtaining recombinant antibodies in a suspension culture of human HEK293 cells using transduction with recombinant adenovirus serotype 5 (rAd5) carrying genes expressing heavy and light chains of antibodies on the example of two broadspectrum anti-influenza antibodies 27F3 and CR9114.Methods. Ad5-27F3-H, Ad5-CR9114-H, and Ad5-27F3-L recombinant adenoviruses carrying the 27F3 antibody heavy chain gene, CR9114 antibody heavy chain gene, and 27F3 light chain gene, respectively, were generated using the AdEasy™ Adenoviral vector system. To accumulate preparative amounts of recombinant r27F3 and rCR9114 antibodies, the HEK293 suspension cell line was transduced with recombinant adenoviruses carrying genes for heavy and light chains of antibodies. The cells were cultured in a wave-type bioreactor. Chromatography was used to purify recombinant antibodies from the culture medium. After analyzing the molecular weights of purified antibodies using protein electrophoresis, their ability to interact with influenza A and B viruses was analyzed using the Western blot technique, while their ability to neutralize influenza A and B viruses was evaluated using the virus neutralization assay.Results. A method for the accumulation and purification of recombinant r27F3 and CR9114 antibodies from the culture medium of a suspension culture of human cells following transduction with its recombinant adenoviruses carrying the genes for heavy and light chains of these antibodies was developed. The ability of the r27F3 antibody to interact with and neutralize influenza A viruses of group 1 (except influenza A virus subtype H2) and group 2 was shown. The ability of the rCR9114 antibody to interact with influenza A viruses of group 1 and influenza B viruses, as well as to neutralize influenza A viruses of group 1, was demonstrated.Conclusions. A technology for obtaining recombinant antibodies in a suspension culture of HEK293 cells using transduction with recombinant adenoviruses carrying genes expressing heavy and light chains of antibodies was developed along with a confirmation of their specificity.Цели. Разработать технологию получения рекомбинантных антител в суспензионной культуре клеток человека HEK293 с помощью трансдукции рекомбинантными аденовирусами человека пятого серотипа, несущими гены, экспрессирующие тяжелые и легкие цепи антител, на примере двух противогриппозных антител широкого спектра действия 27F3 и CR9114.Методы. Рекомбинантные аденовирусы Ad5-27F3-H, Ad5-CR9114-H и Ad5-27F3-L, несущие ген тяжелой цепи антитела 27F3, ген тяжелой цепи антитела CR9114 и ген легкой цепи 27F3, были получены с помощью набора AdEasy™ Adenoviral vector system. Для накопления препаративных количеств рекомбинантных антител r27F3 и rCR9114 суспензионную клеточную линию HEK293 трансдуцировали рекомбинантными аденовирусами, несущими гены тяжелых и легких цепей антител, и культивировали клетки в биореакторе волнового типа. Рекомбинантные антитела очищали из культуральной жидкости хроматографическим методом. Молекулярную массу полученных антител анализировали с помощью белкового электрофореза, их способность взаимодействовать с вирусами гриппа А и В методом вестерн-блот анализа, а способность нейтрализовать вирусы гриппа А и В с помощью реакции вирус-нейтрализации.Результаты. Отработана методика накопления и очистки рекомбинантных антител r27F3 и CR9114 из культуральной жидкости суспензионной культуры клеток человека после трансдукции ее рекомбинантными аденовирусами, несущими гены тяжелых и легких цепей этих антител. Показана способность антитела r27F3 взаимодействовать с вирусами гриппа А подгруппы 1 (кроме вируса грипп А субтипа H2) и подгруппы 2 и нейтрализовать их. Показана способность антитела rCR9114 взаимодействовать с вирусами гриппа А подгруппы 1 и вирусами гриппа В, а также нейтрализовать вирусы гриппа А подгруппы 1.Выводы. Отработана технология получения рекомбинантных антител в суспензионной культуре клеток HEK293 с помощью трансдукции рекомбинантными аденовирусами, несущими гены, экспрессирующие тяжелые и легкие цепи антител, и показана их специфичность

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.