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The article offers the possibility to develop project management and reengineering of business processes due to the inclusion of Design Thinking techniques. The stages of process modeling invariant to the project context are highlighted. The comparison of traditional and proposed approaches is carried out. The uncertainty of the modern world and constantly changing conditions require the project team to be able to study business processes and the person in the business process directly in context. Design Thinking will remove or at least mitigate the uncertainty associated with the definition and understanding of the variability of the content of the project, will reveal the bottlenecks of business processes, will reveal the user's pain. Using an integrated approach involves the development of templates of a specific project artifact using Design Thinking techniques for projects of a specific type at a specific stage of the project life cycle. Descriptions of the proposed methods are given Guerrilla Ethnography, Video Ethnography, Customer Journey Map and Service Blueprint, Matrix of positive and negative experience, HMW, Current-Future-Barriers, The World Cafe. The design-based thinking approach is more flexible than the traditional linear step-by-step design process, helping to more actively identify and understand knowledge about potential and current problems, as well as their possible solutions. In addition, Design Thinking forms the project consciousness of the group. At the same time, the focus of creativity shifts to identifying the real needs of users and quickly launching a prototype to test the idea of changes embodied in the reengineering project.

Because of the constantly growing numbers of COVID-19 infections and deaths, attempts were undertaken to find drugs with anti-SARS-CoV-2 activity among ones already approved for other pathologies. In the framework of such attempts, in a number of in vitro, as well as in vivo, models it was shown that hydroxychloroquine (HCQ) has an effect against SARS-CoV-2. While there were not enough clinical data to support the use of HCQ, several countries including Russia have included HCQ in treatment protocols for infected patients and for prophylaxis. In the current non-randomized, observational study we evaluated the SARS-CoV-2 RNA in nasopharynx swabs from infected patients 7–10 days post symptoms with clinically mild disease and compared the viral RNA load dynamics between patients receiving HCQ (200 mg twice per day according to the Ministry of Health of Russian Federation treatment instructions, n = 33) and a control group without antiviral pharmacological therapy (n = 12). We found a statistically significant relationship between maximal RNA quantity and deterioration of patients’ medical conditions, and as well we confirmed arterial hypertension to be a risk factor for people with COVID-19. However, we showed that at the dose used in the study HCQ therapy neither shortened the viral shedding period nor reduced the virus RNA load.

Not so long ago, human resources were perceived as the main participant in business processes and as an integral part of the company's organizational capital. However, automation and the introduction of industrial technologies 4.0 replace people with programs, robots, chatbots, etc. But this does not mean that in the new era, human functions in the process will be reduced to a minimum. Goals focused on the implementation of new business tasks in the face of constant changes will require a person to work in a team, effectively use their competencies, be focused and successful, think outside the box and find original solutions, actively use the accumulated individual and collective intellectual capital. This will make the application of various techniques of the design thinking methodology an integral part of human activity in the company. The author gives an overview of the tools and techniques of design thinking, shows the features of their application. Highlights the specifics of organizing collective creative work and maintaining an atmosphere of trust and creativity. Provides a list of popular digital services for organizing teamwork. The development of the design thinking approach was achieved through the new methodology - Platform Innovation Kit, which is used for designing an ecosystem platform. Platform design canvases help startups and corporations launch and scale businesses on digital platforms.

The article discusses the features of teaching the course “Internet entrepreneurship”, supported by the Foundation for development of Internet initiatives in universities in Russia, Belarus, Kazakhstan. The Department of “Business Informatics” of the Financial University has been teaching students and postgraduates the basics of entrepreneurship on the Internet since 2015. The authors highlight the problems of teaching students technological entrepreneurship. The key participants in the process of training specialists whose competencies can be in demand in the digital world are identified. Recommendations for improving the effectiveness of the learning process are given. An important advantage of the approach to teaching the course” Internet entrepreneurship” is the integration of Lean Startup methodology and Design thinking. The authors developed cases and practical recommendations for the creation of digital services based on the Human-Centered Design. The article also describes the developed business game “Your profession in the field of IT”. The tasks of the business game describe necessary personal qualities and competencies of 8 popular IT professions: Consultant, Presales, Product Manager, Software Developer, Support Engineer, Tester, Project Manager, System Administrator. A portrait of a typical representative of the profession, the type of behaviour in a conflict situation, behavioural characteristics is constructed. The game uses psychological tests, checks subject area knowledge, identification of communication skills, logic. The result of the game is a set of competencies inherent to the IT profession competency, as well as a roadmap for learning and the pattern of career development.

Introduction Enhanced activation of endogenous fibrinolysis in ST-elevation myocardial infarction (STEMI) patients is the main cause of spontaneous reperfusion of the infarct-related artery (IRA) in the acute period. Whether this enhanced activation remains in the deferred period of myocardial infarction remains unclear. Purpose The main purpose of our work was to analyze the process of clot formation and endogenous fibrinolysis in patients with a history of myocardial infarction. Methods We included 51 patients with a history of myocardial infarction (median, 35 months). Of these patients, 19 had a spontaneous reperfusion of the IRA (SR group) during the index event, and 32 had a total occlusion of the IRA (occlusion group). We assessed parameters of clot formation and endogenous fibrinolysis using thromboelastometry and a thrombodynamics assay. We analyzed endothelial function using the flow-mediated dilation test (FMD). Results The process of clot formation was more active in the occlusion group than in the SR group. Thus, the initial, mean, and total clot velocity times were significantly higher in the occlusion group than in the SR group: 57.2 mcm/min vs. 60.25 mcm/min; 28,1 mcm/min vs. 31.9 mcm/min; and 28.7 mcm/min vs. 31.9 mcm/min, respectively; p Conclusion STEMI patients with occlusion of the IRA and those with spontaneous reperfusion remain different in clot formation and endothelial function even after many years. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported by the Russian Science Foundation grant

Background Inflammation plays a major role in atherosclerotic plaques' progression and was shown to be associated with the formation of hypoxic areas within the plaques. However, the data about the impact of hypoxia on atherosclerosis are contradictory, in part due to inadequacy of in vitro and animal models to reproduce faithfully the complexity of human atherosclerotic plaques. Purpose The aim of this study was to investigate the effect of hypoxia on immune status in the ex vivo system of human atherosclerotic plaques. Methods We collected 25 atherosclerotic plaques from patients undergoing carotid endarterectomy, cut plaques into ring-shaped slices and cultured them for 24 hours at the liquid/air interface on collagen sponges under hypoxic (2% O2) and normoxic (12% O2) conditions. After 24 hours we evaluated T-cell activation status within plaques according to the presence of membrane activation markers by means of multiparametric flow cytometry and the activity of cytokine production using xMAP technology. Results We found that CD8 T cells from human atherosclerotic plaques cultured under hypoxic conditions compared to normoxic conditions have a decreased expression of CD69 activation marker (42.7 [34.3; 50.9]% vs 53.8 [33.3; 63.3]%, n=10, p=0.047) and lower level of CD69 and HLA-DR coexpression (16.0 [10.5; 22.3] vs 22.6 [11.3; 28.2], n=10, p=0.02). CD4 T cells did not show any significant changes in expression of activation markers under hypoxia. Hypoxic conditions also resulted in a reduced IL-10 production (104.2 [53.8; 170.9] vs 235.2 [158.5; 335.3] pg/100 mg of tissue, n=20, p=0.0001) and increased VEGF production (116.1 [79.8; 253.5] vs 89.9 [71.1; 148.8] pg/100 mg of tissue, n=20, p=0.033). Conclusions Our results indicate that hypoxia causes a decrease in the activity of cytotoxic T cells and increases stimuli for angiogenesis within the human atherosclerotic plaques. The established ex vivo model of human atherosclerotic plaques culture under hypoxia enables further studies of the hypoxia impact on atherosclerosis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Russian Science Foundation grant

Background/Introduction Electrical storm (ES) is a potentially lethal state developing in 4–28% of ICD patients. Neuroaxial modulation (beta-blockers, deep sedation, epidural anesthesia, stellate ganglion blockade etc) is used to decrease arrhythmogenic predisposition of ventricular myocardium to trigger and maintain ventricular arrhythmias. Catheter renal arterial denervation (RDN) is recently described to prevent atrial fibrillation recurrence after pulmonary vein isolation. We used this procedure in addition to standard care to improve the results of ES treatment. Purpose This retrospective single-center case-series is aimed to analyze ES patient population and describe the effect of RDN on the in-hospital number of ventricular tachycardia (VT) episodes and ICD shocks and on the mid-term survival. Methods Pts admitted to the CCU for more than 3 sustained VT episodes or more than 3 appropriate ICD shocks during the 24h period in 2017–18 were enrolled into study. Demographic, echocardiographic, ICD check up, renal arteries anatomy and mid-term mortality/transplant data were retrospectively analyzed. Results Twelve pts (10 male, age 69,3±9,8 years; 2 female, age 72,0±8,5) were included. Nine pts (75%) had CAD, 3 pts (25%) – DCM. Echocardiography revealed LVEF 30±9%, and LV EDV – 216±38 ml. Time from ICD implantation to ES onset was from 4 mos to 13 yrs. In 2 pts RDN was performed after VT ablation, in 1 pt – both RDN and VT ablation were performed during the same procedure, in 4 pts – RDN was done prior to VT ablation and in 5 pts - without VT ablation. Mean number of ablations was 4,8 per artery. The power was 2 to 11 Wt and lesion duration was 90 sec. In 1 pt RF-balloon-based technology was used to achieve RDN. Dramatic decrease in the number of VT episodes (49c52 vs. 6±2) was found in 6/12 pts directly after RDN procedure. In-hospital rhythm control was accessed in 10/12 pts, 1 pt with DCM was transferred for heart transplant despite VT ablation and RDN. There were no RDN procedure related complications in this group of pts. During mean 22 mos of follow-up 2/11 pts needed repeat hospitalization due to ES recurrence (VT ablation and 2-chamber ICD to CRT-D upgrade, respectively, were performed), 2/11 died (1-probably arrhythmic death, 1-other cause), 1/11 was lost for follow up. Total efficacy of RDN after almost 2 years in this study was 50%. Mean LVEF increased to 38±7%. Conclusion(s) Catheter renal artery denervation is effective and safe additional procedure to treat ES patients. It allows decreasing the number of ICD shocks and decreases arrhythmogenic potential of ventricular myocardium. Prospective registry is warranted. Funding Acknowledgement Type of funding source: None

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded., Author summary People living with HIV infection and elderly HIV-uninfected persons have increased risk of developing atherosclerotic cardiovascular disease, and have increased numbers and/or proportions of CD8 T cells that express the vascular endothelium-homing receptor CX3CR1. Atherosclerotic plaques contain many activated CD8 T cells, which have been implicated in disease pathogenesis, yet the mechanisms driving T cell recruitment to and activation within plaques are not clear. Here we propose a model in which CX3CR1+ CD8 T cells promote endothelial dysfunction by the combined effects of CX3CL1, IL-15, and TNF. Persistent inflammation triggers endothelial cell activation and dysfunction in people living with HIV infection. Endothelial cell-derived CX3CL1 then directs the migration of CX3CR1+ T cells to the activated endothelium where IL-15 activates T cells to express TNF. TNF drives endothelial expression of CX3CL1 and IL-15, providing a feed-forward loop of activation. We provide evidence that these pathways are active in human atherosclerotic plaques and in the aortic endothelium of SIV/SHIV-infected rhesus macaques. We propose these mechanisms of T cell-induced endothelial damage are operative in traditional risk factor-associated atherosclerosis in the general population and are accelerated in people with HIV infection who live in a state of sustained chronic inflammation.

With the progress of COVID-19 studies, it became evident that SARS-CoV-2 infection is often associated with thrombotic complications. The goal of our present study was to evaluate which component of clot formation process including endothelial function, platelets aggregation and plasma coagulation, as well as endogenous fibrinolysis in patients with COVID-19 correlates with the severity of the disease. We prospectively included 58 patients with COVID-19 and 47 healthy volunteers as a control group that we recruited before the pandemic started. It turns out that plasma coagulation with subsequent platelet aggregation, but not endothelial function, correlates with the severity of the COVID-19. IL-6 blockade may play a beneficial role in COVID-19 induced coagulopathy.

Due to the urgent need to stop the spread of the COVID-19 attempts to find the drug with anti SARS-CoV-2 effects among ones already available on a market are actively being made. A number of in vitro as well as in vivo model animal studies have shown that widely used compound hydroxychloroquine (HCQ) is able to cause anti-viral effect on SARS-CoV-2. While there is no enough clinical data to support the use of HCQ, several countries including Russia have already approved HCQ as treatment and prophylactic option. In the current study we analyzed the dynamics of the SARS-CoV-2 RNA quantity change in nasopharynx swabs of infected patients in mild condition and compared that of patients receiving HCQ and receiving no antiviral pharmacological therapy. We found that most of the patients demonstrated gradual decrease in the number of SARS-CoV-2 RNA copies in the swab regardless of the HCQ receiving. Noteworthy that patients with RNA load higher than 106 copies were hospitalized due to condition deteriorating significantly more frequently compared to those with RNA load below 106 copies even with HCQ administration. In addition, the results of the current study indicate that recovering patients may produce viruses at least during 18 days from the onset of symptoms and HCQ therapy does not block or reduce it.

We present the results of an experimental study of the behavior of a colloidal plasma system formed by copper-coated and uncoated polymer particles under the action of laser irradiation. A comparative study of particle velocity distribution profiles depending on the power of the pushing laser was conducted. In the case of uncoated melamine-formaldehyde (MF) particles, we observed the well-known action of light pressure, causing shear stress in the colloidal plasma structure and leading to the occurrence of a laminar flow within the affected area. For the copper-coated MF particles, we revealed some additional patterns of behavior for the dust particles, i.e., kinetic temperature growth due to laser radiation absorption by the copper coating, as well as the appearance of chaotic particle motion. We believe that this happens due to the existence of defects in the coating, causing asymmetric heating of the particles, which in turn leads to chaotic deviations of the photophoretic force pushing the particles in different directions.

BACKGROUND In hypogonadotropic forms of delayed puberty (DP), hypophyseal follicle-stimulating (FSH) and luteinizing (LH) hormones, normally released with GnRH stimulation, are detected low. Since kisspeptin (KP) is a strong stimulant of GnRH neurons, it is considered to have a role in DP etiology. It may be hypothesized that abnormal plasma levels of KP are indicative of DP. The study aimed at evaluation and comparison of plasma KP levels in boys of pre-pubertal age, with normal puberty and diagnosed primary hypogonadotropic forms of DP. METHODS The study comprised 22 boys with verified hypogonadotropic DP (age 14-17 years), 25 boys with normal puberty (age 14-17 years), and 28 pre-pubertal boys (age 6-9 years). Triprorelin stimulation test was performed in DP patients. Plasma KP values were compared between three groups. RESULTS Statistically significant difference was found for the overall distribution of the plasma KP values across different groups (Kruskal-Wallis H=21.95, P

A proinflammatory dysregulation of cytokine release is associated with various diseases, in particular with those of infectious etiology, as well as with cardiovascular diseases (CVD). We showed earlier that cytokines are released in two forms, soluble and in association with extracellular vesicles (EVs). Here, we investigated the patterns of expression and clustering of soluble and EV-associated cytokines in patients with ST-elevation myocardial infarction (STEMI). We collected plasma samples from 48 volunteers without CVD and 62 patients with STEMI, separated soluble and EV fractions, and analyzed them for 33 cytokines using a multiplexed bead-based assay. We identified soluble and EV-associated cytokines that are upregulated in STEMI and form correlative clusters. Several clustered soluble cytokines were expressed almost exclusively in patients with STEMI. EV-associated cytokines were largely not affected by STEMI, except for pro-inflammatory cytokines IL-6, IL-18, and MIG, as well as anti-inflammatory IL-2 that were upregulated in a correlated fashion. Our results demonstrated that soluble cytokines in patients with STEMI are upregulated in a coordinated fashion in contrast to the mainly unaffected system of EV-associated cytokines. Identification of cytokine clusters affected differently by STEMI now permits investigation of their differential contributions to this pathology.

Cytotoxic CD4 T cells are linked to cardiovascular morbidities and accumulate in both human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infections, both of which are associated with increased risk of cardiovascular disease. In this report we identify CMV coinfection as a major driver of the cytotoxic phenotype – characterized by elevated CD57 expression and reduced CD28 expression – in circulating CD4 T cells from people living with HIV infection (PLWH) and investigate potential mechanisms linking this cell population to cardiovascular disease. We find that human CD57+ CD4 T cells express high levels of the costimulatory receptor CD2 and that CD2/LFA-3 costimulation results in a more robust and polyfunctional effector response to T cell receptor (TCR) signals, compared to CD28-mediated costimulation. CD57+ CD4 T cells also express the vascular endothelium-homing receptor CX3CR1 and migrate toward CX3CL1-expressing endothelial cells in vitro. IL-15 promotes the cytotoxic phenotype, elevates CX3CR1 expression, and enhances the trafficking of CD57+ CD4 T cells to endothelium, and may therefore be important in linking these cells to cardiovascular complications. Finally, we demonstrate the presence of activated CD57+ CD4 T cells and expression of CX3CL1 and LFA-3 in atherosclerotic plaque tissues from HIV-uninfected donors. Our findings are consistent with a model in which cytotoxic CD4 T cells contribute to cardiovascular disease in HIV/CMV coinfection and in atherosclerosis via CX3CR1-mediated trafficking and CD2/LFA-3-mediated costimulation. This study identifies several targets for therapeutic interventions and may help bridge the gap in understanding how CMV infection and immunity are linked to increased cardiovascular risk in PLWH.

Acute myocardial infarction (AMI) is associated with activation of various cells, including platelets that form monocyte–platelet complexes (MPCs). Here, we analysed MPC in vivo and in vitro and investigated the abilities of different monocyte subclasses to form MPC, the characteristics of the cells involved in MPC formation and MPC changes in AMI. We identified MPC by co-staining for platelet antigen CD41a and monocyte antigens CD14 and CD16. Platelet activation was evaluated from expression of phosphatidylserine as revealed by annexin V. Our results confirm published data and provide new information regarding the patterns of MPC in AMI patients. We found that the patterns of platelet aggregation with monocytes were different in AMI patients and controls: (1) in AMI patients, MPC formed by intermediate monocytes carry more platelets whereas in healthy controls more platelets aggregated with classical monocytes; (2) the numbers of MPC in AMI patients, being already higher than in controls, were further increased if these patients suffered various in-hospital complications; (3) on the basis of the CD41a fluorescence of the antibody-stained MPC, some of the aggregates seem to consist of monocytes and platelet-derived extracellular vesicles (EVs); (4) aggregation of monocytes with platelet EV occurred in in vitro experiments; and (5) these experiments demonstrated that monocytes from AMI patients aggregate with both platelets and platelet EVs more efficiently than do monocytes from controls. MPC in AMI patients may play an important role in this pathology.

Cytokines are soluble factors that mediate cell–cell communications in multicellular organisms. Recently, another system of cell–cell communication was discovered, which is mediated by extracellular vesicles (EVs). Here, we demonstrate that these two systems are not strictly separated, as many cytokines in vitro, ex vivo, and in vivo are released in EV-encapsulated forms and are capable of eliciting biological effects upon contact with sensitive cells. Association with EVs is not necessarily a property of a particular cytokine but rather of a biological system and can be changed upon system activation. EV-encapsulated cytokines were not detected by standard cytokine assays. Deciphering the regulatory mechanisms of EV-encapsulation will lead to a better understanding of cell–cell communications in health and disease.

Supplemental Digital Content is available in the text., Background: Thrombotic events are reduced with cangrelor, an intravenous P2Y12 inhibitor. We sought to characterize the timing, number, and type of early events (within 2 hours of randomization) in CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). Methods: CHAMPION PHOENIX was a double-blind, placebo-controlled trial that randomized patients undergoing percutaneous coronary intervention to cangrelor or clopidogrel. For this analysis, we evaluated the efficacy of cangrelor in the first 2 hours postrandomization with regards to the primary end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis). Sensitivity analyses were performed evaluating a secondary, post hoc end point (death, Society of Coronary Angiography and Intervention myocardial infarction, ischemia-driven revascularization, or Academic Research Consortium definite stent thrombosis). Results: The majority of events (63%) that occurred in the trial occurred within 2 hours of randomization. The most common early event was myocardial infarction; next were stent thrombosis, ischemia driven revascularization, and death. In the first 2 hours after randomization, cangrelor significantly decreased the primary composite end point compared with clopidogrel (4.1% versus 5.4%; hazard ratio, 0.76 [95% CI, 0.64–0.90], P=0.002). Similar findings were seen for the composite end point of death, Society of Coronary Angiography and Intervention myocardial infarction, ischemia-driven revascularization, or Academic Research Consortium stent thrombosis at 2 hours (0.9% versus 1.6%; hazard ratio, 0.57 [95% CI, 0.40–0.80], P=0.001). Between 2 and 48 hours, there was no difference in the primary composite end point (0.6% versus 0.5%; odds ratio, 1.17 [95% CI, 0.71–1.93]; P=0.53). Early (≤2 hours of randomization) GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate or severe bleeding events were infrequent, and there was no significant difference with cangrelor compared with clopidogrel (0.2% [n=10] versus 0.1% [n=4]; adjusted odds ratio, 1.41 [95% CI, 0.37–5.40]; P=0.62). Conclusions: The reductions in ischemic events and overall efficacy seen with cangrelor in CHAMPION PHOENIX occurred early and during the period of time in which patients were being actively treated with cangrelor. These findings provide evidence that supports the importance of potent platelet inhibition during percutaneous coronary intervention. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01156571.

Background and aims The mechanisms that drive atherosclerotic plaque progression and destabilization in humans remain largely unknown. Laboratory models are needed to study these mechanisms under controlled conditions. The aim of this study was to establish a new ex vivo model of human atherosclerotic plaques that preserves the main cell types in plaques and the extracellular components in the context of native cytoarchitecture. Methods Atherosclerotic plaques from carotid arteries of 28 patients undergoing carotid endarterectomy were dissected and cultured. At various time-points, samples were collected and analysed histologically. After enzymatic digestion, single cells were analysed with flow cytometry. Moreover, tissue cytokine production was evaluated. Results We optimised the plaque dissection protocol by cutting plaques into circular segments that we cultured on collagen rafts at the medium–air interface, thus keeping them well oxygenated. With this technique, the relative presence of T and B lymphocytes did not change significantly during culture, and the sizes of lymphocyte subsets remained stable after day 4 of culture. Macrophages, smooth muscle cells, and fibroblasts with collagen fibres, as well as T and B lymphocyte subsets and CD16 natural killer cells, remained largely preserved for 19 days of culture, with a continuous production of inflammatory cytokines and chemokines. Conclusions Our new model of ex vivo human atherosclerotic plaques, which preserves the main subsets of immune cells in the context of tissue cytoarchitecture, may be used to investigate important aspects of atherogenesis, in particular, the functions of immune cells under controlled laboratory conditions.

At present, the disposal of polymer and rubber waste, and especially automobile tires, is one of the most acute environmental problems. These types of waste pollute the environment both when they are stored at landfills and during subsequent disposal, especially if it is carried out in the form of incineration. Therefore, at present, much attention is paid to thermal methods of their processing. The results of the study of liquid product of pyrolysis of tires of Kuznetskecology+ LLC are presented in the work. During its distillation, the following fractures were obtained (the yield wt% is indicated in parentheses): petroleum (4), gasoline (21), kerosene (18), diesel (47), fuel oil (10), for which the refractive index was determined and a conclusion about their chemical composition was drawn. When analyzing the data obtained during the analysis of liquid pyrolysis product and its fractions, as well as on the basis of published data, possible chemical reactions occurring during vulcanized rubber pyrolysis are proposed. Research results show that pyrolysis products are valuable chemical raw materials that have great prospects for industrial use, including the production of synthetic motor fuels.

Supplemental Digital Content is available in the text., Background and Purpose: Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events. Methods: In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–30) or placebo added to aspirin (300–325 mg on day 1 followed by 75–100 mg daily for days 2–30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature. The primary end point was time to the occurrence of stroke or death within 30 days. Results: Of 11 016 randomized patients, 2351 (21.3%) patients had an ipsilateral atherosclerotic stenosis. After 30 days, a primary end point occurred in 92/1136 (8.1%) patients with ipsilateral stenosis randomized to ticagrelor and in 132/1215 (10.9%) randomized to placebo (hazard ratio 0.73 [95% CI, 0.56–0.96], P=0.023) resulting in a number needed to treat of 34 (95% CI, 19–171). In patients without ipsilateral stenosis, the corresponding event rate was 211/4387 (4.8%) and 230/4278 (5.4%), respectively (hazard ratio, 0.89 [95% CI, 0.74–1.08]; P=0.23, Pinteraction=0.245). Severe bleeding occurred in 4 (0.4%) and 3 (0.2%) patients with ipsilateral atherosclerotic stenosis on ticagrelor and on placebo, respectively (P=NS), and in 24 (0.5%) and 4 (0.1%), respectively, in 8665 patients without ipsilateral stenosis (hazard ratio=5.87 [95% CI, 2.04–16.9], P=0.001). Conclusions: In this exploratory analysis comparing ticagrelor added to aspirin to aspirin alone, we found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction but did identify a higher absolute risk and a greater absolute risk reduction of stroke or death at 30 days in patients with ipsilateral atherosclerosis stenosis than in those without. In this easily identified population, ticagrelor added to aspirin provided a clinically meaningful benefit with a number needed to treat of 34 (95% CI, 19–171). Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03354429.

The gaming industry is only approaching the stage of formalizing the monetization rules and methods. In business, there are already dozens of monetization ways, each of which has a different effect on both the company’s’ profits and the loyalty of its customers. Efficient layout of various monetization methods, based on the product provided within the gaming digital platform, can dramatically affect the financial characteristics of the enterprise. This article discusses the use of enterprise architecture modelling patterns to generate value propositions to customers of companies implementing game projects.

In the article the author substantiates the importance of the approach of project thinking in the training and education of future professionals for the digital economy. Development of entrepreneurial abilities, creative thinking, ability to work in a project team, to make decisions in unusual situations - all these important competencies must be obtained during the training of students at the University. The article presents the experience of design seminars, especially the use of popular tools of design thinking to create projects of Internet entrepreneurship, recommendations for the introduction of the approach of design thinking (DT) in engineering education. The author describes in detail one of his cases “Search for sources of ideas”. DT can redirect from the usual ways of judgment about the object to the unconventional solution. They help develop an innovation that is based on empathy for the pain of the consumer, including one that is still unconscious to prevent his hidden needs and create a breakthrough product for him. It is important to learn how to accept even the most ridiculous at first glance the ideas of their colleagues, which can trigger your best idea. In the case we used tools of design thinking, such as random stimulus technique, the technique of personal ideas, World cafe, “good and bad ideas”, etc. Each point of the case contains comments on how the new idea was developed, what difficulties arose with this or that tool, what ways we found to get the team out of the deadlocks.

The incorporation of glycemic index (GI) and glycemic load (GL) is a promising way to improve the accuracy of postprandial glycemic response (PPGR) prediction for personalized treatment of gestational diabetes (GDM). Our aim was to assess the prediction accuracy for PPGR prediction models with and without GI data in women with GDM and healthy pregnant women. The GI values were sourced from University of Sydney&rsquo, s database and assigned to a food database used in the mobile app DiaCompanion. Weekly continuous glucose monitoring (CGM) data for 124 pregnant women (90 GDM and 34 control) were analyzed together with records of 1489 food intakes. Pearson correlation (R) was used to quantify the accuracy of predicted PPGRs from the model relative to those obtained from CGM. The final model for incremental area under glucose curve (iAUC120) prediction chosen by stepwise multiple linear regression had an R of 0.705 when GI/GL was included among input variables and an R of 0.700 when GI/GL was not included. In linear regression with coefficients acquired using regularization methods, which was tested on the data of new patients, R was 0.584 for both models (with and without inclusion of GI/GL). In conclusion, the incorporation of GI and GL only slightly improved the accuracy of PPGR prediction models when used in remote monitoring.

In the digital economy, a person should not have a narrow specialization, but interdisciplinary knowledge and broad competences. Combinations of hard and soft skills, metacompetence and integrative thinking are important. Already today, organizations demand the competence of innovators and creative abilities, the ability to think outside the box and adapt to constantly changing conditions. Digital society, globalization of markets and network economy require new approaches to the study of customer preferences. This is only a few list of features that provide techniques and tools of Design Thinking. The article discusses the key features of design thinking in solving company problems. The experience of conducting a design study with the involvement of employees of the organization—customer (state service) is presented. The organization’s staff, together with design researchers, studied the process through the eyes of customers. Discussion of the results of observations allowed to identify problems and identify directions in improving the practice of providing services to the public. However, the main achievement of such collaboration is the involvement of government officials in the improvement process. In order for the digital transformation of the organization to be successfully implemented, employees must be ready for changes, understand the essence of the transformation. Regular carrying out of such design studies will change the culture of relations with the client, increase responsibility and interest in transformational changes. Design seminars, other new forms and approaches to the development of creative thinking, abilities to work in a team and make decisions in unusual situations are necessary for the growth of the competence potential of the organization’s personnel. Then she can have the right person at the right job at the right time, motivated for result and development.

The modern openness of the relationship between people and the transparency of borders makes the public service to adapt to the networked, interdependent society. Work with digital transformation in the public sector can be built on the principle of adaptability, based on the experience of other, more advanced sectors—banking, Telecom, e-commerce, etc., where the transformation is actively taking place. The author defines the principles of digital organization formation and the main steps of transformation of client experience in the sphere of public services on the basis of omnichannel. The basis for the implementation of digital principles should be changes in personnel management, including a focus on involvement, motivation, result orientation, team building, understanding of the client. However, is the society ready for those digital services for which the heads of state administration actively vote? The article presents the results of digital maturity assessment. Thus, the survey showed that citizens are not ready for the introduction of neurotechnologies and telemedicine, however, they are interested in the possibility of services based on identification tools (electronic passports, social cards, etc.), the transfer of most tasks to a mobile device, as well as virtual assistants, VR/AR. The possibilities of implementing the platform for the organization of targeted charitable assistance, monitoring the financing of social services and personalization of taxes are highly appreciated.

Background Brain-derived neurotrophic factor (BDNF) plays a crucial role in the neuronal networking and reorganization. BDNF levels are changed in neurological and psychiatric diseases. We assessed BDNF levels in patients with chronic primary insomnia (PI) and their association with the brain metabolism. Design and methods We assessed BDNF levels in 27 PI (DSM V criteria) patients (15 males, 56%) and in 14 controls (6 males, 43%). All subjects underwent 18fluorodeoxyglucose positron emission tomography (18F-FDG PET), brain PET with 13N-ammonium in the morning in wakefulness. Brain PET/CT scanning was performed 30 min. after administration of 250 MBq 18F-FDG. The PET images were statistically analyzed by 3D-SSP method (Z-score) using software package Cortex ID. Results There was no difference in BDNF level in PI patients and control group: 11.9 (8.5; 100) and 12.8 (10.1; 72.8) ng/ml, respectively (p=0,138). We found a weak association between BDNF level and brain metabolism in the left prefrontal medial lobe (ρ=0.57, p=0.02) and right parietal inferior lobe (ρ=0.52, p=0.039). However, there was no association between BDNF level and 13N-ammonium accumulation which indicate the activity of glutamate synthase. Conclusions Insomnia is not associated with the changes in BDNF levels compared to healthy control subjects, although the relation between brain metabolism and BDNF concentration requires further investigation. (The study was supported by the Grant of the President of Russian Federation for the Leading Scientific Schools of Russia NS-5508.2018.7 (agreement n 075-15-2019-161, 23.05.2019).

Background/Introduction Electrical storm (ES) is a potentially lethal state developing in 4–28% of ICD patients. Neuroaxial modulation (beta-blockers, deep sedation, epidural anesthesia, stellate ganglion blockade etc) is used to decrease arrhythmogenic predisposition of ventricular myocardium to trigger and maintain ventricular arrhythmias. Catheter renal arterial denervation (RDN) is recently described to prevent atrial fibrillation recurrence after pulmonary vein isolation. We used this procedure in addition to standard care to improve the results of ES treatment. Purpose This retrospective single-center case-series is aimed to analyze ES patient population and to describe the effect of RDN on the in-hospital number of ventricular tachycardia (VT) episodes and ICD shocks and on the mid-term survival. Methods Pts admitted to the CCU for more than 3 sustained VT episodes or more than 3 appropriate ICD shocks during the 24h period in 2017–18 were enrolled into study. Demographic, echocardiographic, ICD check up, renal arteries anatomy and mid-term mortality/transplant data were retrospectively analysed. Results Eleven pts (all male, age 69±9 years) were included. Seven pts (73%) had CAD, 3 pts (27%) – DCM. Echocardiography revealed LVEF 28±8%, and LV EDV - 226±91 ml. Time from ICD implantation to ES onset was from 4 mos to 13 yrs. In 5 pts RDN was performed without VT ablation, in 3 pts – prior to VT ablation, in 2 – after VT ablation and in 1 pt – both RDN and VT ablation were performed during the same procedure. Mean number of renal arteries was 2,5 per pt. Mean number of ablations was 4,8 per artery. The power was 2 to 11 Wt and lesion duration was 90 sec. Dramatic decrease in the number of VT episodes (49±52 vs. 6±2) was found in 6/11 pts directly after RDN procedure. In-hospital rhythm control was accessed in 10/11 pts, 1 pt with DCM was transferred for heart transplant due to recurrence of VT after VT ablation and RAD (excluded from survival analysis). There were no RDN procedure related complications in this group of pts. In mean 6 mos of follow-up 9/10 pts are free from ES recurrence, 1/10 was lost for the follow up. Conclusion(s) Catheter renal artery denervation is effective and safe additional procedure to treat ES patients. It allows to decrease the number of ICD shocks and stabilize arrhythmogenicity of ventricular myocardium. Larger multi-center randomized trials are warranted.

Background An association between productive cytomegalovirus infection and atherosclerosis was shown recently in several trials, including a previous study of ours. However, the mechanism involved in this association is still under investigation. Here, we addressed the interaction between productive cytomegalovirus infection and endothelial function in patients with ST-elevation myocardial infarction (STEMI). Methods We analyzed the presence of cytomegaloviral DNA in plasma and endothelial function in 33 patients with STEMI and 33 volunteers without cardiovascular diseases, using real-time polymerase chain reaction (PCR) and a noninvasive test of flow-mediated dilation. Results Both the frequency of presence and the load of cytomegaloviral DNA were higher in plasma of patients with STEMI than those in controls. This difference was independent of other cardiovascular risk factors (7.38 [1.36-40.07]; P = 0.02). The results of the flow-mediated dilation test were lower in patients in STEMI than in controls (5.0% [2.65%-3.09%] vs 12. %5 [7.5%-15.15%]; P = 0.004) and correlated negatively with the cytomegaloviral DNA load (Spearman R = −0.407; P = 0.019) independently of other cardiovascular risk factors. Conclusions Productive cytomegalovirus infection in patients with STEMI correlated negatively with endothelial function independently of other cardiovascular risk factors. The impact of cytomegalovirus on endothelial function may explain the role of cytomegalovirus in cardiovascular prognosis.

Background Cangrelor, an intravenous, reversible P2Y12 antagonist, is approved for use in patients undergoing percutaneous coronary intervention (PCI). Objectives This study sought to evaluate the efficacy and safety of cangrelor compared with clopidogrel in subgroups that did and did not receive glycoprotein IIb/IIIa inhibitors (GPIs). Methods This pooled, patient-level analysis of the 3 CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials analyzed all randomized patients who underwent PCI and received the study drug (n = 24,902). Only bailout/rescue GPI use was permitted, except in CHAMPION PCI, in which routine or bailout/rescue GPI use was at the site investigator’s discretion. The primary efficacy endpoint was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization. Results Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%). Despite variation in indications for GPIs, baseline characteristics were well balanced between the cangrelor and clopidogrel arms in subsets receiving and not receiving GPIs. Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms. Conclusions Cangrelor’s efficacy in reducing ischemic complications in patients undergoing PCI was maintained irrespective of GPI administration. GPI use was associated with substantially higher bleeding rates, regardless of the randomization to cangrelor or clopidogrel. (A Clinical Trial to Demonstrate the Efficacy of Cangrelor [PCI]: NCT00305162 ; Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition [PLATFORM]: NCT00385138 ; A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]: NCT01156571 )

Cytomegalovirus (CMV), a ubiquitous human pathogen that is never cleared from the host, has long been thought to be relatively innocuous in immunocompetent adults, but causes severe complications including blindness, end-organ disease, and death in newborns and in immunocompromised individuals, such as organ transplant recipients and those suffering from AIDS. Yet even in persons with intact immunity, CMV infection is associated with profound stimulation of immune and inflammatory pathways. Carriers of CMV infection also have an elevated risk of developing cardiovascular complications. In this review, we define the proposed mechanisms of how CMV contributes to cardiovascular disease (CVD), describe current approaches to target CMV, and discuss how these strategies may or may not alleviate cardiovascular complications in those with CMV infection. In addition, we discuss the special situation of CMV coinfection in people with HIV infection receiving antiretroviral therapy, and describe how these 2 viral infections may interact to potentiate CVD in this especially vulnerable population.

The paper is dedicated to analyzing the process of innovative product development in the chemical industry, elaborating a methodology for evaluating the efficiency of innovative projects common for this sector of the economy, and testing this methodology using the example of a project. First, the authors consider the specifics of the development process in which a new product is created in the chemical sector. The emphasis is laid on the product-process approach, and a brief characteristic of this approach is provided. Then the authors discuss the general methodology of product development in the chemical sector using investment analysis methods and a decision tree. Then the authors tested the methodology using the example of a Russian chemical enterprise realizing an innovative project on production of urea-formaldehyde concentrate, urea-formaldehyde resins, and phenol-formaldehyde resins. The results of the investment attractiveness of the project demonstrate that the net present value from the implemented project, given the risk factors, is higher than if the project was implemented with the basic initial conditions. The elaborated methodology allows us to evaluate investment projects in the context of uncertainty, and the result of its application is that more informed management decisions about investment projects in the chemical industry become possible.