A Common Genetic Variant Risk Score is Associated with Drug-Induced QT Prolongation and Torsade de Pointes Risk: A Pilot Study.

Background -Drug-induced QT interval prolongation, a risk factor for life-threatening ventricular arrhythmias, is a potential side effect of many marketed and withdrawn medications. The contribution of common genetic variants previously associated with baseline QT interval to drug-induced QT prolongation and arrhythmias is not known. Methods -We tested the hypothesis that a weighted combination of common genetic variants contributing to QT interval at baseline, identified through genome-wide association studies, can predict individual response to multiple QT-prolonging drugs. Genetic analysis of 22 subjects was performed in a secondary analysis of a randomized, double-blind, placebo-controlled, cross-over trial of 3 QT-prolonging drugs with 15 time-matched QT and plasma drug concentration measurements. Subjects received single doses of dofetilide, quinidine, ranolazine and placebo. The outcome was the correlation between a genetic QT score comprising 61 common genetic variants and the slope of an individual subject's drug-induced increase in heart rate corrected QT (QTc) vs. drug concentration. Results -The genetic QT score was correlated with drug-induced QTc prolongation. Among white subjects, genetic QT score explained 30% of the variability in response to dofetilide (r = 0.55 [95% CI, 0.09-0.81], P = 0.02), 23% in response to quinidine (r = 0.48 [95% CI, -0.03 to 0.79], P = 0.06) and 27% in response to ranolazine (r = 0.52 [95% CI, 0.05 to 0.80], P = 0.03). Furthermore, the genetic QT score was a significant predictor of drug-induced torsade de pointes in an independent sample of 216 cases compared to 771 controls (r(2) = 12%, P = 1x10(-7)). Conclusions -We demonstrate that a genetic QT score comprising 61 common genetic variants explains a significant proportion of the variability in drug-induced QT prolongation and is a significant predictor of drug-induced torsade de pointes. These findings highlight an opportunity for recent genetic discoveries to improve individualized risk-benefit assessment for pharmacologic therapies. Replication of these findings in larger samples is needed to more precisely estimate variance explained and to establish the individual variants that drive these effects. Clinical Trial Registration - http://clinicaltrials.gov Unique identifier: NCT01873950

THE MANAGEMENT OF TRANSFORMATIONS OF UNIVERSITY PROCESSES BY PLANTATION AND REALIZATION OF BALANCED SYSTEM OF INDICATORS ON THE BASE OF COLLABORATION TECHNOLOGY

В статье рассмотрен метод управления стратегией высшего учебного заведения. Метод базируется на использовании сбалансированной системы показателей как технологии, помогающей представить стратегию организации в виде взаимосвязанных индикаторов деятельности. Это позволяет измерить эффективность выбранной стратегии и ход ее реализации. Авторами подробно рассматриваются все этапы внедрения и реализации ССП, начиная со стратегического анализа вуза, заканчивая формированием отчетов о выполнении стратегии и предоставлении их для анализа со стороны руководства. Также акцентируется внимание на том, что на этапе формирования стратегии ряд бизнес-процессов организации подлежит изменению, и в интересах любой организации проводить эти изменения в управляемых условиях. Работа вуза происходит с использованием технологий Web 2.0., что нашло свое отражение и в работе над построением сбалансированной системы показателей, а также в дальнейшей поддержке работ по выполнению и анализу стратегии. В статье отражены последние достижения в области внедрения сбалансированной системы показателей в одном из коммерческих вузов Москвы, опыт которого может быть полезен как образовательным учреждениям, так и любым предприятиям и организациям, в которых внедряется процессный подход, а также работа которых строится с использованием коллаборативных технологий.The article is repulsed supreme achievements in the field of plantation of balanced system of indicators in Moscow commercial university. This experience could be useful for educational institutes and any organizations, infusing process approach and using collaboration technologies

Experience of application VOSviewer software in epidemiological studies on the example of analysis scientific publication in medical text databases

In article reviewed main function VOSviewer software and possibility of their practical application in epidemiological studies. Graded publication activity on poliovirus infection activity on poliovirus infection in the period of 1879-2020, interpreted data of the resulting cartograms.В статье рассмотрены основные функции программного средства VOSviewer и возможность их практического применения в эпидемиологических исследованиях. Произведена оценка публикационной активности по вопросам полиовирусной инфекции в период 1879-2020 гг., интерпретированы данные полученных картограм

Матриксные металлопротеиназы и их ингибиторы

Metalloproteinase was discovered by Gross and Lapierre in 1962 for the first time. Since then, more than 20 enzymes of this family have been characterized, and their functions have been studied in detail. Metalloproteinases take part in blood pressure regulation, the cell matrix extension and remodeling, anesthesia, multiple sclerosis, blood coagulation, wound healing, tumor transformation and metastasis, etc. This review covers structure of matrix metalloproteinases, their mechanism of action, as well as MMP's endogenous and exogenous inhibitors. A special place is occupied by analysis of approaches to matrix metalloproteinases synthetic inhibitors and their activity. This review demonstrates the perspectivity of new selective matrix metalloproteinase inhibitors design.В 1962 г. Gross J и Lapierre C впервые была обнаружена металлопротеиназа. С тех пор было охарактеризовано более 20 ферментов этого семейства, а также подробно изучены их функции. Металлопротеиназы учавствуют в регуляции кровяного давления, развитии и ремоделировании клеточного матрикса, обезболивании, рассеянном склерозе, процессе свертывания крови, заживления ран, в процессах опухолевой трансформации и метастазирования и др. Настоящий обзор посвящён рассмотрению представлений о структуре матриксных металлопротеиназ, механизме их действия, а так же эндогенным и экзогенным ингибиторам матриксных металлопротеиназ. Особый акцент сделан на анализе подходов к дизайну синтетических ингибиторов матриксных металлопротеиназ и их активности. Представленный обзор демонстрирует перспективность конструирования новых селективных ингибиторов матриксных металлопротеиназ

The relationship between fertility and lifespan in humans

Evolutionary theories of aging predict a trade-off between fertility and lifespan, where increased lifespan comes at the cost of reduced fertility. Support for this prediction has been obtained from various sources. However, which genes underlie this relationship is unknown. To assess it, we first analyzed the association of fertility with age at menarche and menopause, and with mortality in 3,575 married female participants of the Rotterdam Study. In addition, we conducted a candidate gene study where 1,664 single nucleotide polymorphisms (SNPs) in 25 candidate genes were analyzed in relation to number of children as a measure of fertility. SNPs that associated with fertility were analyzed for association with mortality. We observed no associations between fertility and age at menarche (p = 0.38) and menopause (p = 0.07). In contrast, fertility was associated with mortality. Women with two to three children had significantly lower mortality (hazard ratio (HR), 0.82; 95% confidence interval (95% CI), 0.69–0.97) compared to women with no children. No such benefit was observed for women with four or more children, who had a similar mortality risk (HR, 0.93; 95% CI, 0.76–1.13) as women with no children. The analysis of candidate genes revealed four genes that influence fertility after correction for multiple testing: CGB/LHB gene cluster (p = 0.0036), FSHR (p = 0.023), FST (p = 0.023), and INHBA (p = 0.021). However, none of the independent SNPs in these genes predicted mortality. In conclusion, women who bear two to three children live longer than those who bear none or many children, but this relationship was not mediated by the candidate genes analyzed in this study

Defects, Dopants and Sodium Mobility in Na₂MnSiO₄

Sodium manganese orthosilicate, Na2MnSiO4, is a promising positive electrode material in rechargeable sodium ion batteries. Atomistic scale simulations are used to study the defects, doping behaviour and sodium migration paths in Na2MnSiO4. The most favourable intrinsic defect type is the cation anti-site (0.44 eV/defect), in which, Na and Mn exchange their positions. The second most favourable defect energy process is found to be the Na Frenkel (1.60 eV/defect) indicating that Na diffusion is assisted by the formation of Na vacancies via the vacancy mechanism. Long range sodium paths via vacancy mechanism were constructed and it is confirmed that the lowest activation energy (0.81 eV) migration path is three dimensional with zig-zag pattern. Subvalent doping by Al on the Si site is energetically favourable suggesting that this defect engineering stratergy to increase the Na content in Na2MnSiO4 warrants experimental verification