Predictors of Long-Term Outcomes after Surgical Myocardial Revascularization

High mortality from cardiovascular diseases (CVD) requires improved approaches to the treatment of this socially significant pathology. Wide implementation of surgical myocardial revascularization makes it possible to improve significantly both life quality and expectancy in patients with coronary heart disease. The aim of this work was to analyze the literature on the impact of preoperative, operative and postoperative factors on the long-term prognosis after coronary artery bypass grafting (CABG). The review refers to both recent and earlier informative works. The target groups for this article are therapists, cardiologists, rehabilitologists, who work with patients in the short and long term after CABG. Data of Russian and foreign literature show that the long-term prognosis after CABG is largely determined by preoperative factors, in particular – age, set of cardiovascular risk factors (RF) and comorbidity, specifically – severity of coronary and systemic atherosclerosis, incident cardiovascular complications, structural and functional state of the heart. In the aggregate these factors reflect the cumulative effect and further potential of actual cardiovascular RFs, affect longterm risk of adverse events, and determine the therapeutic targets of secondary prevention. Priority of arterial conduits and completeness of revascularization are the main operative factors that determine the course of the long-term period after CABG. Among the postoperative factors, the efficiency of secondary CVD prevention is of paramount importance, in particular – achievement of target RF levels, compensation of cardiac and extracardiac pathology, adherence to the long-term medical therapy, known to improve outcomes based on specific comorbidity. Efficiency of secondary CVD prevention largely depends on patient's health attitudes, the key influence on which beyond attending physician can be provided by participation in rehabilitation programs, teaching patients the meaning and essentials of lifestyle modification and cardiovascular RFs’ control

Development of a three-level model of early rehabilitation in Perm kray

The article deals with the concept and the content of the technology of early rehabilitation and carries out a retrospective analysis of its development in the Russian Federation and abroad. The authors present the experience of organizing the system of early rehabilitation services in Perm Kray as a three-level model. At the macro-level, the model describes the content and the specificity of realization of the mechanisms of interdepartmental cooperation and highlights the problems and perspectives of their realization. The meso-level deals with the organization of activity of the services of early rehabilitation in institutions of various departments and agencies.В статье представлен опыт организации системы ранней помощи в Пермском крае, сложившейся в виде трехуровневой модели.

ДИАГНОСТИЧЕСКИЕ КРИТЕРИИ ПОРОГОВЫХ ЗНАЧЕНИЙ ФРАКЦИОННОЙ АНИЗОТРОПИИ В ОЦЕНКЕ РИСКА КОГНИТИВНЫХ НАРУШЕНИЙ У ПАЦИЕНТОВ С ДИСЦИРКУЛЯТОРНОЙ ПАТОЛОГИЕЙ ГОЛОВНОГО МОЗГА

As a consequence of the cerebral tracts’ damages, encephalopathy comes with cognitive disorders. Diffusion-tensor MRI is a cerebral tracts’ integrity quantitative measurement method. The main purpose of the study was to develop criteria of cerebral tracts integrity using DT-MRI to predict vascular dementia, to find threshold CFA level in liable tracts to measure dementia risk. DT-MR results were compared with neuropsychological tests of subjects with diagnosed encephalopathy. Identified statistically significant (р<0,005) FA decrease in three regions for those subjects with cognitive impairment: front sections of corona radiata, inferior longitudinal fasciculi and anterior horn of internal capsule. Threshold FA level calculated for these 3 region of interests, they can be predictors of the risk of cognitive disorders for subjects with diagnosed encephalopathy.У пациентов с дисциркуляторной энцефалопатией (ДЭ) отмечаются частые проявления расстройств когнитивной сферы, что является следствием органического поражения головного мозга. Методика диффузионно-тензорной магнитно-резонансной томографии (ДТ-МРТ) позволяет производить количественную оценку целостности проводящих путей. Цель исследования: разработать прогностические критерии изменений белого вещества головного мозга при ДЭ, выявить пороговые значения фракционной анизотропии, способные стать предикторами когнитивных нарушений (КН). Произведено сопоставление результатов ДТ-МРТ с данными нейропсихологического тестирования у пациентов с ДЭ. У пациентов с КН отмечалось статистически достоверное (р<0,005) снижение коэффициента фракционной анизотропии (КФА) в трактах передних отделов лучистого венца (лобные доли), в нижнем продольном пучке (височные доли) и в переднем бедре внутренней капсулы. Рассчитаны пороговые значения КФА в данных областях, являющиеся предикторами КН, что дает возможность определить вероятность риска их развития у пациентов с ДЭ. Количественный анализ изменений в структурах мозга, отвечающих за когнитивную функцию, является актуальным для прогнозирования вероятности наступления у пациентов сосудистой деменции

Systematic dissection of biases in whole-exome and whole-genome sequencing reveals major determinants of coding sequence coverage

Advantages and diagnostic effectiveness of the two most widely used resequencing approaches, whole exome (WES) and whole genome (WGS) sequencing, are often debated. WES dominated large-scale resequencing projects because of lower cost and easier data storage and processing. Rapid development of 3(rd) generation sequencing methods and novel exome sequencing kits predicate the need for a robust statistical framework allowing informative and easy performance comparison of the emerging methods. In our study we developed a set of statistical tools to systematically assess coverage of coding regions provided by several modern WES platforms, as well as PCR-free WGS. We identified a substantial problem in most previously published comparisons which did not account for mappability limitations of short reads. Using regression analysis and simple machine learning, as well as several novel metrics of coverage evenness, we analyzed the contribution from the major determinants of CDS coverage. Contrary to a common view, most of the observed bias in modern WES stems from mappability limitations of short reads and exome probe design rather than sequence composition. We also identified the similar to 500kb region of human exome that could not be effectively characterized using short read technology and should receive special attention during variant analysis. Using our novel metrics of sequencing coverage, we identified main determinants of WES and WGS performance. Overall, our study points out avenues for improvement of enrichment-based methods and development of novel approaches that would maximize variant discovery at optimal cost

О ВЛИЯНИИ МАЛЫХ И СРЕДНИХ ДОЗ РАДИАЦИИ НА СТРУКТУРУ ПРОВОДЯЩИХ ПУТЕЙ ГОЛОВНОГО МОЗГА У ЛИКВИДАТОРОВ ПОСЛЕДСТВИЙ АВАРИИ НА ЧАЭС В ОТДАЛЕННОМ ПЕРИОДЕ (ПО ДАННЫМ ВЫСОКОПОЛЬНОЙ РУТИННОЙ И ДИФФУЗИОННО-ТЕНЗОРНОЙ МАГНИТНО-РЕЗОНАНСНОЙ ТОМОГРАФИИ)

To evaluate correlation between brain structural damages and radiation exposure level for the Chernobyl nuclear power plant accident liquidators, routine and diffusion tensor magnetic resonance imaging methods are efficient to visualize and evaluate those damages; it is also important to compare magnetic resonance imaging data of liquidators with results, received for people of the same age and the same stage of cerebral vascular disease (the discirculatory encephalopathy of I and II stage), but who did not participate in the Chernobyl accident liquidation and did not suffer from other liquidation factors and radiation catastrophe aftermaths. As a result, the Chernobyl accident liquidators group (49 subjects) and group of control (50 subjects) were examined with routine magnetic resonance imaging methods and standard protocols. In addition, the innovative method of diffusion tensor magnetic resonance imaging was applied to examine 11 cerebral tracts, bilaterally (22 tracts in both hemispheres) for every subject of the research. It was for the first time when diffusion tensor magnetic resonance imaging was applied to conduct visual analysis of polymorphic brain changes for the Chernobyl accident liquidators and special research conducted to find correlation between fractional anisotropy coefficient and radiation exposure for these patients. The results of diffusion tensor magnetic resonance imaging indicated no statistically significant (p > 0,05) difference in the level of cerebral morphological changes and between average fraction anisotropy coefficient value in any cerebral tract for both sub-groups of liquidators with different level of irradiation: 28 subjects, who were exposed by low and very low radiation doses (0–100 micro-Sv, sub-group A) and 21 subjects, who were exposed by mean radiation doses (100–1000 micro-Sv, sub-group B). However, comparing diffusion tensor magnetic resonance imaging results of control group and liquidators group, statistically significant (p < 0,05) reduction of average fraction anisotropy coefficient was detected in frontal and temporal lobes. It proves significant micro-structural damages of mentioned brain areas caused by different factors of the Chernobyl accident liquidation.Цель работы – определить зависимость структурных изменений головного мозга ликвидаторов последствий аварии на Чернобыльской АЭС от полученной ими дозы облучения с помощью рутинной и диффузионно-тензорной магнитно-резонансной томографии; сравнить полученные данные с данными исследования лиц, не участвовавших в ликвидации аварии на Чернобыльской АЭС.Результаты: пациентам-ликвидаторам последствий аварии на Чернобыльской АЭС (49 человек) и пациентам контрольной группы (50 человек), не имеющим в анамнезе факторов профессионального облучения, выполнена высокопольная магнитно-резонансная томография с применением стандартных протоколов. Группы были равнозначными по возрасту и количеству пациентов с I и II степенями дисциркуляторной энцефалопатии. С помощью инновационной методики – диффузионно-тензорной магнитно-резонансной томографии – обследованы проводящие пути головного мозга пациентов обеих групп, всего 11 трактов, взятых билатерально (всего по 22 тракта в обоих полушариях).Заключение: в настоящей работе при использовании высокопольной рутинной магнитно-резонансной томографии впервые проведен визуальный анализ полиморфных изменений головного мозга для ликвидаторов последствий аварии на Чернобыльской АЭС с добавлением методики диффузионнотензорной магнитно-резонансной томографии; изучена связь выявленных изменений с полученной дозой радиации. При сравнении пациентов-ликвидаторов подгруппы А (28 человек, получивших очень малые дозы (до 10 мЗв) и малые дозы радиации (10–100 мЗв)) и пациентов подгруппы Б (21 человек, получивших средние дозы 100 мЗв – 1Зв) не отмечалось различий в степени морфологических изменений головного мозга, выявляемых при рутинной магнитно-резонансной томографии. При выполнении методики диффузионно-тензорной магнитно-резонансной томографии статистически значимого (p > 0,05) снижения коэффициента фракционной анизотропии в основных структурах головного мозга у пациентов данных подгрупп также выявлено не было. Однако, по сравнению с контрольной группой, у ликвидаторов отмечено достоверное снижение фракционной анизотропии в лобных и височных долях, что свидетельствует о микроструктурных изменениях данных зон под воздействием различных факторов при ликвидации последствий аварии и более тяжелом течении дисциркуляторной энцефалопатии у данного контингента больных

Profile of subpopulation composition of regulatory T lymphocytes and intestinal microbiota in patients with irritable bowel syndrome

The following specificcharacteristics of the composition of intestinal microbiota in patients with irritable bowel syndrome (IBS) were identified using a metagenomic analysis (16 S rRNA): 1) an increase in the representation of Actinobacteria, including Bifidobacterium spp., Firmicutes, including representatives of Streptococcaceae (Streptococcus), Lachnosperaceae (Dorea), Veillonellaceae (Dialister), Proteobacteria (Enterobacteriaceae and Desulfovibrionaceae families); 2) a decrease in the population of Bacteroidetes, including representatives of the families Prevotellacea (Prevotella spp.), Bacteroidaceae (Bacteroides spp.). Firmicutes belonging to the families Clostridiaceae and Ruminococcaceae (Fecalibacterium spp.).Flow cytometry in the study of the subpopulation composition of T regulatory (Treg) lymphocytes in patients with IBS revealed an increase in the number of CD45R0+CD62L+ central memory cells (CM), which can regulate the processes of maturation and differentiation of lymphocytes in lymphoid tissue. A decrease in the expression of exonucleases CD39 and CD73 was detected, which can have a significant effect on their activity. A reduction in effector memory cells (EM) Treg was observed.Changes in the expression level of exonucleases CD39 and CD73 were inversely correlated with the content of Proteobacteria and the representation of the genera Bifidobacterium spp. and Faecalibacterium spp. The content of СЫ Treg was directly correlated with the content of Dorea spp.The results may be indicative of impairment in the processes of Treg differentiation, which are closely related to changes in key components of intestinal microbiocenosis in IBS

Derivatives of 9-phosphorylated acridine as butyrylcholinesterase inhibitors with antioxidant activity and the ability to inhibit β-amyloid self-aggregation: potential therapeutic agents for Alzheimer’s disease

We investigated the inhibitory activities of novel 9-phosphoryl-9,10-dihydroacridines and 9-phosphorylacridines against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CES). We also studied the abilities of the new compounds to interfere with the self-aggregation of β-amyloid (Aβ42) in the thioflavin test as well as their antioxidant activities in the ABTS and FRAP assays. We used molecular docking, molecular dynamics simulations, and quantum-chemical calculations to explain experimental results. All new compounds weakly inhibited AChE and off-target CES. Dihydroacridines with aryl substituents in the phosphoryl moiety inhibited BChE; the most active were the dibenzyloxy derivative 1d and its diphenethyl bioisostere 1e (IC50 = 2.90 ± 0.23 µM and 3.22 ± 0.25 µM, respectively). Only one acridine, 2d, an analog of dihydroacridine, 1d, was an effective BChE inhibitor (IC50 = 6.90 ± 0.55 μM), consistent with docking results. Dihydroacridines inhibited Aβ42 self-aggregation; 1d and 1e were the most active (58.9% ± 4.7% and 46.9% ± 4.2%, respectively). All dihydroacridines 1 demonstrated high ABTS•+-scavenging and iron-reducing activities comparable to Trolox, but acridines 2 were almost inactive. Observed features were well explained by quantum-chemical calculations. ADMET parameters calculated for all compounds predicted favorable intestinal absorption, good blood–brain barrier permeability, and low cardiac toxicity. Overall, the best results were obtained for two dihydroacridine derivatives 1d and 1e with dibenzyloxy and diphenethyl substituents in the phosphoryl moiety. These compounds displayed high inhibition of BChE activity and Aβ42 self-aggregation, high antioxidant activity, and favorable predicted ADMET profiles. Therefore, we consider 1d and 1e as lead compounds for further in-depth studies as potential anti-AD preparations. Copyright © 2023 Makhaeva, Kovaleva, Rudakova, Boltneva, Lushchekina, Astakhova, Timokhina, Serebryakova, Shchepochkin, Averkov, Utepova, Demina, Radchenko, Palyulin, Fisenko, Bachurin, Chupakhin, Charushin and Richardson.122041400110-4; FFSN-2021-0005; Alternatives Research and Development Foundation, ARDF; University of Michigan, U-M; Russian Foundation for Basic Research, РФФИ: 19-29-08037; Russian Science Foundation, RSFThis research was partly supported by grant # 22-13-00298 of the Russian Science Foundation and IPAC RAS State Targets Project # FFSN-2021-0005; quantum-chemical calculations were supported the IBCP RAS State Targets Project # 122041400110-4. The synthesis of the compounds was financially supported by the Russian Foundation for Basic Research (research project # 19-29-08037). Support for RR’s contributions to the computer modeling components of the work was provided in part by a grant from the Alternatives Research and Development Foundation (ARDF) and an Mcubed grant from the University of Michigan