Properties of the VT1-0 titanium surface modified by a pulsed ion beam

The physicomechanical properties of the VT1-0 titanium surface modified by a pulsed carbon ion beam at a pulse duration of 80 ns, an energy of 200 keV, a current density of 120 A/cm2, an energy density of 1.92 J/cm2, and various numbers of pulses (four regimes) are studied. Irradiation by the beam leads to hardening of a 1.8-μm-thick surface layer in titanium, a decrease in the hydrogen sorption rate, a decrease in the grain size, and the formation of twins

Right heart condition in patients with COVID-19 pneumonia

Aim. To assess right heart condition in patients with coronavirus disease 2019 (COVID-19) pneumonia.Material and methods. One hundred and five patients with COVID-19 pneumonia were divided into 3 groups depending on the involvement of lung parenchyma: group I — 0-25%, II — 25-50%, III — 50-75%. The clinical status of patients was assessed using the NEWS2 and SHOKS-COVID scales. A complete blood count and biochemical blood tests were performed to determine the level of N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin I. Echocardiography was performed to assess the right heart structural, hemodynamic and functional parameters.Results. In patients with COVID-19 pneumonia, with an increase in lung parenchyma involvement, the intensity of systemic inflammatory response increased: C-reactive protein, group I — (4 [1,9; 35] mg/l), in III — (70,5 [33; 144] mg/l) (pI-III=0,012); myocardial stress marker level increased: NT-proBNP, group I — 77 [48; 150] ng/l, group III — 165 [100; 287] ng/l (pI-III=0,047). The dependence of NT-proBNP on C-reactive protein level was revealed (r=0,335, p=0,03). Intergroup comparison did not reveal significant differences between the main right heart functional parameters: TAPSE, Tei index (PW and TDI), FAC of the right ventricle (RV) (p>0,05). However, differences in the tricuspid annular peaks were found as follows: group I — 0,14 [0,12; 0,14] m/s, group II — 0,14 [0,12; 0,15] m/s, group III — 0,16 [0,14; 0,17] m/s (pI-II=0,012, pI-III=0,014) and RV global longitudinal strain: group I — 19,63±7,72%, group III — 27,4±5,93% (pI-III=0,014). The relationship between the RV global longitudinal strain and SHOKS-COVID score was confirmed (r=0,381; p=0,024).Conclusion. Patients with COVID-19 pneumonia showed no signs of right heart dysfunction. The development of RV hyperfunction was noted. Most likely, this is a compensatory mechanism in response to acute RV afterload. NT-proBNP increase under conditions of an inflammatory response may indicate myocardial stress. The results obtained allow to expand our understanding of the right heart condition in patients with COVID-19 pneumonia

Thermodynamic and kinetic basis for recognition and repair of 8-oxoguanine in DNA by human 8-oxoguanine-DNA glycosylase

We have used a stepwise increase in ligand complexity approach to estimate the relative contributions of the nucleotide units of DNA containing 7,8-dihydro-8-oxoguanine (oxoG) to its total affinity for human 8-oxoguanine DNA glycosylase (OGG1) and construct thermodynamic models of the enzyme interaction with cognate and non-cognate DNA. Non-specific OGG1 interactions with 10–13 nt pairs within its DNA-binding cleft provides approximately 5 orders of magnitude of its affinity for DNA (ΔG° approximately −6.7 kcal/mol). The relative contribution of the oxoG unit of DNA (ΔG° approximately −3.3 kcal/mol) together with other specific interactions (ΔG° approximately −0.7 kcal/mol) provide approximately 3 orders of magnitude of the affinity. Formation of the Michaelis complex of OGG1 with the cognate DNA cannot account for the major part of the enzyme specificity, which lies in the kcat term instead; the rate increases by 6–7 orders of magnitude for cognate DNA as compared with non-cognate one. The kcat values for substrates of different sequences correlate with the DNA twist, while the KM values correlate with ΔG° of the DNA fragments surrounding the lesion (position from −6 to +6). The functions for predicting the KM and kcat values for different sequences containing oxoG were found

Germ Warfare in a Microbial Mat Community: CRISPRs Provide Insights into the Co-Evolution of Host and Viral Genomes

CRISPR arrays and associated cas genes are widespread in bacteria and archaea and confer acquired resistance to viruses. To examine viral immunity in the context of naturally evolving microbial populations we analyzed genomic data from two thermophilic Synechococcus isolates (Syn OS-A and Syn OS-B′) as well as a prokaryotic metagenome and viral metagenome derived from microbial mats in hotsprings at Yellowstone National Park. Two distinct CRISPR types, distinguished by the repeat sequence, are found in both the Syn OS-A and Syn OS-B′ genomes. The genome of Syn OS-A contains a third CRISPR type with a distinct repeat sequence, which is not found in Syn OS-B′, but appears to be shared with other microorganisms that inhabit the mat. The CRISPR repeats identified in the microbial metagenome are highly conserved, while the spacer sequences (hereafter referred to as “viritopes” to emphasize their critical role in viral immunity) were mostly unique and had no high identity matches when searched against GenBank. Searching the viritopes against the viral metagenome, however, yielded several matches with high similarity some of which were within a gene identified as a likely viral lysozyme/lysin protein. Analysis of viral metagenome sequences corresponding to this lysozyme/lysin protein revealed several mutations all of which translate into silent or conservative mutations which are unlikely to affect protein function, but may help the virus evade the host CRISPR resistance mechanism. These results demonstrate the varied challenges presented by a natural virus population, and support the notion that the CRISPR/viritope system must be able to adapt quickly to provide host immunity. The ability of metagenomics to track population-level variation in viritope sequences allows for a culture-independent method for evaluating the fast co-evolution of host and viral genomes and its consequence on the structuring of complex microbial communities

Combined Transfer of Human VEGF165 and HGF Genes Renders Potent Angiogenic Effect in Ischemic Skeletal Muscle

Increased interest in development of combined gene therapy emerges from results of recent clinical trials that indicate good safety yet unexpected low efficacy of “single-gene” administration. Multiple studies showed that vascular endothelial growth factor 165 aminoacid form (VEGF165) and hepatocyte growth factor (HGF) can be used for induction of angiogenesis in ischemic myocardium and skeletal muscle. Gene transfer system composed of a novel cytomegalovirus-based (CMV) plasmid vector and codon-optimized human VEGF165 and HGF genes combined with intramuscular low-voltage electroporation was developed and tested in vitro and in vivo. Studies in HEK293T cell culture, murine skeletal muscle explants and ELISA of tissue homogenates showed efficacy of constructed plasmids. Functional activity of angiogenic proteins secreted by HEK293T after transfection by induction of tube formation in human umbilical vein endothelial cell (HUVEC) culture. HUVEC cells were used for in vitro experiments to assay the putative signaling pathways to be responsible for combined administration effect one of which could be the ERK1/2 pathway. In vivo tests of VEGF165 and HGF genes co-transfer were conceived in mouse model of hind limb ischemia. Intramuscular administration of plasmid encoding either VEGF165 or HGF gene resulted in increased perfusion compared to empty vector administration. Mice injected with a mixture of two plasmids (VEGF165+HGF) showed significant increase in perfusion compared to single plasmid injection. These findings were supported by increased CD31+ capillary and SMA+ vessel density in animals that received combined VEGF165 and HGF gene therapy compared to single gene therapy. Results of the study suggest that co-transfer of VEGF and HGF genes renders a robust angiogenic effect in ischemic skeletal muscle and may present interest as a potential therapeutic combination for treatment of ischemic disorders

Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. Methods: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Findings: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. Interpretation: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Funding: Sanofi and Regeneron Pharmaceuticals

Сравнительный анализ применения тоцилизумаба при тяжелых COVID-19-ассоциированных пневмониях у пациентов разных возрастных групп

According to accumulated clinical data, one of the causes of severe damage to lung epithelial cells associated with SARS-CoV-2 (2019-nCoV) is an acute, timely underestimated "cytokine storm" (cytokine cascade, hypercytokinaemia) with characteristic signs of an expressed hyper-inflammatory syndrome with subsequent polyorganic failure. The study presents the results of the analysis of the effectiveness of tocilizumab therapy (TCZ) in patients (n = 181) of different age groups with developed pneumonia caused by SARS-CoV-2. The aim of the study was to evaluate the effectiveness of TCZ therapy in patients of different age groups with developed pneumonia in the frame of COVID-19. Methods. Patients (n = 181) with community-acquired pneumonia caused by coronavirus SARS-CoV-2 are included in a one-center, non-randomized, prospective study to evaluate the effectiveness of TCZ therapy conducted at the State Public Health Institution "City Clinical Hospital No.52" of the Moscow City Health Department. Patients were divided into 3 age subgroups – up to 50 years, 50–70 years and over 70 years. Patients with community-acquired SARS-CoV-2-induced pneumonia receiving non-invasive oxygen support and patients who had artificial lung ventilation (ALV) were given a single dose of 400 mg of TCZ in addition to basic therapy. Results. There are no significant differences between age groups in the severity of pneumonia according to the data of the computed tomography (CT), however, a more severe condition and a higher mortality rate (p < 0.001) were reliably observed in patients over 70 age compared to the other age groups. After TCZ treatment in patients of each age group, the severity of the condition assessed on the National Early Warning Score (NEWS2) has been significantly reduced compared to the baseline. Conclusion. According to the data of the pilot study the efficacy and safety of TCZ in patients of all presented age groups with COVID-associated pulmonary tissue lesion and signs of "cytokine storm" was demonstrated. At the same time, patients up to 50 years after the therapy of TCZ managed to achieve greater clinical efficiency compared to patients in other groups. According to the severity of the state and laboratory criteria, the lowest clinical efficacy of TCZ therapy was observed in patients over 70 years of age; as a consequence, the highest mortality rate was observed in the same group. At the same time, the TCZ therapy has not had a positive impact on the change of laboratory values and the severity of the disease in case of unfavorable outcome. Согласно накопленным клиническим данным, одной из причин тяжелых повреждений клеток эпителия легких, ассоциированных с SARS-CoV-2 (2019-nCoV), является острый, вовремя недооцененный синдром «цитокинового шторма» (цитокиновый каскад, гиперцитокинемия) с характерными признаками выраженного гипервоспалительного синдрома с последующей полиорганной недоста - точностью. В работе представлены результаты анализа эффективности терапии тоцилизумабом (ТЦЗ) у пациентов (n = 181) разных возрастных групп с развившейся пневмонией в рамках COVID-19. Целью исследования явилась оценка эффективности терапии ТЦЗ у пациентов разных возрастных групп с развившейся пневмонией, вызванной SARS-CoV-2. Материалы и методы. В одноцентровом нерандомизированном проспективном исследовании оценки эффективности терапии ТЦЗ, проведенном на базе Государственного бюд жетного учреждения здравоохранения «Городская клиническая больница № 52» Департамента здравоохранения города Мос - квы, приняли участие пациенты (n = 181) с внебольничной пневмонией, вызванной коронавирусом SARS-CoV-2. Больные были распределены в 3 возрастные подгруппы: до 50 лет, 50–70 лет, старше 70 лет. Пациентам с внебольничной пневмонией, вызванной SARS-CoV-2, получающим неинвазивную кислородную поддержку, и больным, у которых проводилась искусственная вентиляция легких (ИВЛ), в до полнение к основной терапии назначен ТЦЗ однократно в дозе 400 мг. Результаты. Достоверных различий между возрастными группами по тяжести пневмонии по данным компьютерной томографии (КТ) не выявлено, однако отмечено достоверно более тяжелое состояние и более высокий уровень смертности (p < 0,001) у больных старше 70 лет по сравнению с остальными возрастными группами. После терапии ТЦЗ у больных каждой из возрастных групп тяжесть состояния, оцененная по шкале National Early Warning Score (NEWS2), достоверно снизилась по сравнению с исходными показателями. Заключение. По данным пилотного исследования продемонстрирована эффективность и безопасность применения ТЦЗ у пациентов всех представленных возрастных групп с COVID-ассоциированным повреждением легочной ткани и признаками «цитокинового шторма». При этом у пациентов до 50 лет после терапии ТЦЗ удалось добиться бόльшей клинической эффективности по сравнению с больными остальных групп. По степени тяжести состояния и лабораторным критериям самая низкая клиническая эффективность терапии ТЦЗ отмечена у пациентов старше 70 лет; как следствие, в этой же группе отмечен самый высокий уровень смертности. При этом в случае неблагоприятного исхода терапия ТЦЗ не оказывала положительного влияния на изменение лабораторных показателей и степень тяжести заболевания.

DIRECTIONS OF USEING ELECTRONIC MEANS IN TEACHING SCIENTIFIC STYLE OF SPEECH

The article notes that the modern human cognitive activity related to the implementation of information processes, by means of information and communication technologies. The author identifies three main areas of use of electronic media in teaching scientific style of speech. These include: 1) work with electronic textbooks; 2) search of the scientific literature in electronic libraries; 3) use computer software for content analysis of scientific texts. The analysis of these areas is done. It stated that the introduction in the educational process should be accompanied by electronic means creating specialized audiences and providing them with modern equipment