Changes in Prescribing Antithrombotic Therapy in Patients with Atrial Fibrillation in the Multidisciplinary Hospital in Volgograd from 2012 to 2020

Aim. To study the frequency of prescribing antithrombotic agents in patients with non-valvular atrial fibrillation (AF) in real clinical practice, to evaluate changes of prescriptions from 2012 till 2020.Material and methods. The medical records of inpatients (Form 003/y) with the diagnosis AF, hospitalized in the cardiological department were analyzed. According to the inclusion criteria, the patients were over 18 years of age, established diagnosis of non-valvular AF. There were two exclusion criteria: congenital and acquired valvular heart disease and prosthetic heart valves. In retrospective analysis we have included 263 case histories in 2012, 502 ones in 2016 and 524 in 2020. CHA2DS2-VASc score was used for individual stroke risk assessment in AF. The rational use of the antithrombotic therapy was evaluated according with current clinical practice guidelines at analyzing moment.Results. During period of observation the frequency of antiplatelet therapy significantly decreased from 25,5% to 5,5% (р<0.001), decreased the frequency of administration of warfarin from 71,9% to 18,3% (р<0.001). The frequency of use of direct oral anticoagulants increased in 2020 compared to 2016 (р<0.001). For patients with a high risk of stroke anticoagulant therapy was administered in 71.8% of cases in 2012, 88.5% in 2016 and 92.5% in 2020. Before discharge from hospital majority of patients (72%) achieved a desired minimum international normalized ratio (INR) from 2.0 to 3.0 in 2012. In 2016 and 2020 an only 33% and 40.6% of patients achieved INR (2.0-3.0).Conclusion. Doctors have become more committed to following clinical guidelines during the period of the investigation. In 2020 antithrombotic therapy for atrial fibrillation was suitable according to current clinical guidelines

Efficacy and safety of the new oral anticoagulants in the treatment of venous thromboembolic complications: meta-analysis

Aim. Analysis of the efficacy and safety of the new oral anticoagulants (NOACs) in the management of venous thromboembolism (VTE).Material and methods. This meta-analysis of randomized controlled trials (RCTs) was made in accordance with the instructions “Preferred reporting items for systematic reviews and meta-analyses (PRISMA)”.Results. The meta-analysis included 5 RCTs. NOACs were as effective as vitamin K antagonists (VKAs) in preventing recurrent symptomatic VTE (RR=0.93; 95% CI 0.77-1.12; p=0.44). The incidence of recurrent thrombosis (RR=0.82; 95% CI 0.63-1.08; p=0.16) and deep vein thrombosis ± fatal or nonfatal pulmonary embolism (RR=1.06; 95% CI 0.81-1.40; p=0.66) was comparable in the groups of comparison. Meta-analysis of the safety of the NOACs suggested significant reduction of risk of major bleeding as compared with standard therapy (RR=0.54; 95% CI 0.42-0.69; р<0.00001). The incidence of all types of bleeding was significantly lower with NOACs (RR=0.70; 95% CI 0.51-0.95; p=0.02). All-cause mortality rate was comparable between the groups (RR=0.93; 95% CI 0.76-1.13; p=0.46).Conclusions. NOACs are as effective as the standard therapy, at that they are much safer in VTE treatment

Cutting Edge Geometry Effect on Plastic Deformation of Titanium Alloy

The paper presents experimental studies of ОТ4 titanium alloy machining with cutting edges of various geometry parameters. Experiments were performed at a low speed by the scheme of free cutting. Intensity of plastic shear strain was set for defining of cutting edge geometry effect on machining. Images of chip formed are shown. Estimation of strain magnitude was accomplished with digital image correlation method. Effect of rake angle and cutting edge angle has been studied. Depth of deformed layer and the area of the plastic strain is determine. Results showed that increasing the angle of the cutting edge inclination results in a change the mechanism of chip formation

Antibiotic Dosing in Chronic Kidney Disease

Infectious process is an important cause of morbidity and mortality among patients with chronic kidney disease. Prescription of antibacterial drugs should take into account the pharmacokinetic parameters of the medicine and the individual characteristics of the patient. Adequate antibiotic dosing is crucial for positive treatment outcome and minimisation of side effects. The aim of the study was to analyse scientific literature on factors affecting the dosing of antibacterials in patients with chronic kidney disease. Since most antibacterial medicines are eliminated by the kidneys, a decrease in glomerular filtration rate or kidney function should be followed by the dose adjustment in order to prevent the medicine accumulation and reduce the risk of side effects. Antibiotic dosing in such patients should be accompanied by kidney function assessment and be adjusted to ensure effective and safe treatment, as well as prevention of bacterial resistance. The review provides data on the dosing of some antibiotic groups (beta-lactams, aminoglycosides, fluoroquinolones) at different creatinine clearance rates. Extrarenal excretion of medicines does not usually require the dose adjustment in patients with chronic kidney disease

An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy

Drug-based strategies to overcome tumour resistance to radiotherapy (R-RT) remain limited by the single-agent toxicity of traditional radiosensitizers (for example, platinums) and a lack of targeted alternatives. In a screen for compounds that restore radiosensitivity in p53 mutant zebrafish while tolerated in non-irradiated wild-type animals, we identified the benzimidazole anthelmintic oxfendazole. Surprisingly, oxfendazole acts via the inhibition of IRAK1, a kinase thus far implicated in interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) immune responses. IRAK1 drives R-RT in a pathway involving IRAK4 and TRAF6 but not the IL-1R/TLR-IRAK adaptor MyD88. Rather than stimulating nuclear factor-κB, radiation-activated IRAK1 prevented apoptosis mediated by the PIDDosome complex (comprising PIDD, RAIDD and caspase-2). Countering this pathway with IRAK1 inhibitors suppressed R-RT in tumour models derived from cancers in which TP53 mutations predict R-RT. Moreover, IRAK1 inhibitors synergized with inhibitors of PIN1, a prolyl isomerase essential for IRAK1 activation in response to pathogens and, as shown here, in response to ionizing radiation. These data identify an IRAK1 radiation-response pathway as a rational chemoradiation therapy target

Prospects in Analytical Atomic Spectrometry

Tendencies in five main branches of atomic spectrometry (absorption, emission, mass, fluorescence and ionization spectrometry) are considered. The first three techniques are the most widespread and universal, with the best sensitivity attributed to atomic mass spectrometry. In the direct elemental analysis of solid samples, the leading roles are now conquered by laser-induced breakdown and laser ablation mass spectrometry, and the related techniques with transfer of the laser ablation products into inductively-coupled plasma. Advances in design of diode lasers and optical parametric oscillators promote developments in fluorescence and ionization spectrometry and also in absorption techniques where uses of optical cavities for increased effective absorption pathlength are expected to expand. Prospects for analytical instrumentation are seen in higher productivity, portability, miniaturization, incorporation of advanced software, automated sample preparation and transition to the multifunctional modular architecture. Steady progress and growth in applications of plasma- and laser-based methods are observed. An interest towards the absolute (standardless) analysis has revived, particularly in the emission spectrometry.Comment: Proofread copy with an added full reference list of 279 citations. A pdf version of the final published review may be requested from Alexander Bol'shakov <[email protected]

Individual quality of life: adaptive conjoint analysis as an alternative for direct weighting?

In the schedule for the evaluation of individual quality of life (SEIQoL) the weights for five individualized quality of life domains have been derived by judgment analysis and direct weighting (DW). We studied the feasibility and validity of adaptive conjoint analysis (ACA) as an alternative method to derive weights in 27 cancer patients and 20 patients with rheumatoid arthritis. Further, we assessed the convergence between direct weights and weights derived by ACA, and their correlation with global quality-of-life scores. All respondents finished the ACA task, but one in five respondents were upset about the ACA task. Further, the task was vulnerable to judgment ‘errors’, such as inconsistent answers. The agreement between the two weights was low. Both weighted index scores were strongly correlated to the unweighted index score. The relationships between the index score and scores on a visual analogue scale for global individual quality of life and global quality of life were similar whether or not the index score was calculated with DW weights, with ACA weights, or without using weights. We conclude that, because weights did not improve the correlation between the index score and global quality of life scores, it seems sufficient to use the unweighted index score as a measure for global individual quality of life

Эффективность и безопасность пероральных антикоагулянтов при венозных тромбоэмболических осложнениях: непрямые сравнения

Objective. The aim was to perform an indirect comparisons of the effectiveness and safety of new oral anticoagulants (NOACs) in the management of venous thromboembolism (VTE).Material and methods. In the absence of a head-to-head comparisons, indirect comparison was done using the method proposed by Butcher et al.Results. The indirect comparison included 5 RCTs. Apixaban, rivaroxaban and dabigatran were equally effective in preventing recurrent symptomatic VTE, deep vein thrombosis and pulmonary embolism. Dabigatran increased major bleeding risk compared to apixaban RR=2.36; 95% CI 1.15-4.82 and the risk major or clinical relevant non-major (CRNM) bleedings RR=1.43; 95% CI 1.06-1.93. Dabigatran and apixaban were associated with the significant lower risk of major and CRNM bleeding compared with rivaroxaban RR=1.49; 95% CI 1.17-1.91 and RR=2.13; 95% CI 1.66-2.74.Conclusions. There were no statistically significant differences between apixaban, dabigatran and rivaroxaban in effectiveness. Apixaban treatment associated with the most favorable safety profile of the NOACs.Цель исследования – провести сравнительный анализ эффективности и безопасности новых пероральных антикоагулянтов (ривароксабана, дабигатрана и апиксабана) со стандартной терапией венозных тромбоэмболических осложнений (ВТЭО).Материалы и методы. Проведены непрямые сравнения новых пероральных антикоагулянтов.Результаты. Для выполнения непрямого сравнения включено пять рандомизированных контролируемых испытаний (РКИ). Статистически достоверных различий между тремя новыми антикоагулянтами (ривароксабан, дабигатран, апиксабан) для исходов, оценивающих эффективность, включая ВТЭО, тромбоз глубоких вен и тромбоэмболию легочной артерии, не выявлено. Риск развития массивных кровотечений на фоне терапии дабигатраном выше, чем в случае назначения апиксабана ОР=2,36; 95% ДИ 1,15-4,82. В сравнении с дабигатраном апиксабан достоверно реже вызывает все клинически значимые кровотечения (ОР=1,43; 95% ДИ 1,06-1,93). При непрямом сравнении по конечной точке комбинации всех клинически значимых кровотечений ривароксабан уступает дабигатрану и апиксабану (ОР=1,49; 95% ДИ 1,17-1,91 и ОР=2,13; 95% ДИ 1,66-2,74 соответственно).Заключение. При сопоставимой эффективности ривароксабана, дабигатрана и апиксабана последний обладает более благоприятным профилем безопасности (по частоте геморрагических осложнений) из зарегистрированных в настоящее время препаратов данной группы

New Synthetic Thrombin Inhibitors: Molecular Design and Experimental Verification

BACKGROUND: The development of new anticoagulants is an important goal for the improvement of thromboses treatments. OBJECTIVES: The design, synthesis and experimental testing of new safe and effective small molecule direct thrombin inhibitors for intravenous administration. METHODS: Computer-aided molecular design of new thrombin inhibitors was performed using our original docking program SOL, which is based on the genetic algorithm of global energy minimization in the framework of a Merck Molecular Force Field. This program takes into account the effects of solvent. The designed molecules with the best scoring functions (calculated binding energies) were synthesized and their thrombin inhibitory activity evaluated experimentally in vitro using a chromogenic substrate in a buffer system and using a thrombin generation test in isolated plasma and in vivo using the newly developed model of hemodilution-induced hypercoagulation in rats. The acute toxicities of the most promising new thrombin inhibitors were evaluated in mice, and their stabilities in aqueous solutions were measured. RESULTS: New compounds that are both effective direct thrombin inhibitors (the best K(I) was <1 nM) and strong anticoagulants in plasma (an IC(50) in the thrombin generation assay of approximately 100 nM) were discovered. These compounds contain one of the following new residues as the basic fragment: isothiuronium, 4-aminopyridinium, or 2-aminothiazolinium. LD(50) values for the best new inhibitors ranged from 166.7 to >1111.1 mg/kg. A plasma-substituting solution supplemented with one of the new inhibitors prevented hypercoagulation in the rat model of hemodilution-induced hypercoagulation. Activities of the best new inhibitors in physiological saline (1 µM solutions) were stable after sterilization by autoclaving, and the inhibitors remained stable at long-term storage over more than 1.5 years at room temperature and at 4°C. CONCLUSIONS: The high efficacy, stability and low acute toxicity reveal that the inhibitors that were developed may be promising for potential medical applications