Crowd-technology in the selection of personnel

In article is examined the crowdsourcing technology and the technology based on its principles a crowd-recruiting as instruments of staff recruitment in the organization. The presented technologies are new effective tools large-scale by geographical coverage and number of participants of selection of the employees who are really interested in work with this organization. Crowd-technologies, which are based on "the phenomenon of the crowd" can not only greatly speed up the solution of important problems for the company, but also significantly reduce costs. Was designed the methodology of introduction of crowdsourcing technology at staff recruitment in the organization Because of introduction of this methodology is assumed optimization of costs of the personnel, thanks to improvement of staff recruitment by means of crowd-technologies (crowdsourcing, crowd-recruiting, crowd-staffing), namely: increase of qualitative structure of the personnel and reduction of staff turnover thanks to what will be seen labor productivity growth.peer-reviewe

Pharmacoeconomic evaluation of the tixagevimab and cilgavimab combination using for pre-exposure prophylaxis of COVID-19

Aim. To evaluate pharmacoeconomic feasibility using of the tixagevimab and cilgavimab combination for pre-exposure prophylaxis of COVID-19 in immunocompromised patients. Materials and methods. Cost-effectiveness of tixagevimab and cilgavimab in persons 12 years old who weigh 40 kg and have either a history of allergy that prevents their vaccination against COVID-19 or moderate or immunocompromised was assessed based on PROVENT phase III study results. The quantity of life years or quality-adjusted life years gained was calculated. Direct medical cost associated with prophylaxis of COVID-19, treatment of infected patients and those experiencing long COVID post infection were assessed. Results were compared with wiliness-to-pay threshold, measured as tripled gross domestic product per capita and equal to 2.69 mln RUB in 2022. Results. Pre-exposure prophylaxis of COVID-19 results in additional 0.0287 life years or 0.0247 quality-adjusted life years. The cost of additional life year gained is equal to 1.12 mln RUB, the cost of additional quality-adjusted life years is 1.30 mln RUB. Both costs of additional life year and cost of quality-adjusted life years appeared to be significantly less compared to wiliness-to-pay threshold. Conclusion. Pre-exposure prophylaxis of COVID-19 with combination of tixagevimab and cilgavimab is economically feasible and may be recommended for wide use in Russian healthcare system

Suppression of hepatitis b virus by a combined activity of CRISPR/Cas9 and HBx proteins

Chronic hepatitis B is a severe liver disease associated with persistent infection with hepatitis B virus. According to recent estimations, 250 million people in the world are chronically infected, including 3 million chronically infected people in Russia. Antiviral therapeutics (nucleos(t)ide analogues and PEGylated interferon) suppress viral transcription and replication, but do not eliminate the virus from infected cells. The key reason for HBV persistency is a stable form of the viral genome (covalently closed circular DNA, cccDNA) that exists as a minichromosome protected from novel cccDNA-targeting therapeutics. Novel therapeutic approaches aimed at elimination or inactivation of cccDNA are urgently needed. CRISPR/Cas9 systems induce double strand breaks in target sites of DNA sequences. Experiments with CRISPR/Cas9 demonstrated high antiviral activity and efficient cleavage of cccDNA, but a small part of cccDNA pool remains intact. One of the main reasons of incomplete cccDNA elimination might be the structural organization of cccDNA, which persists in a heterochromatinized, very compacted form and is not be accessible to CRISPR/Cas9 systems. Viral protein HBx unwinds cccDNA and regulates cccDNA epigenetically by recruiting transcription-remodeling factors. In this work, we analyzed effects of CRISPR/Cas9 in combination with an HBxencoding plasmid or plasmids encoding mutant forms of HBx (HBxMut, which does not interact with pro-apoptotic factors Bcl-2 и Bcl-xL, and HBxNesm is localized exclusively in the nucleus and does not generate reactive oxygen species and double strand breaks in the genome). We showed that HBx improves CRISPR/Cas9 efficiency, decreasing pregenomic RNA transcription level over 98%. Moreover, we analyzed optimal ratios of plasmids encoding CRISPR/ Cas9 and HBx proteins for better antiviral efficacy. Furthermore, we discovered that HBx proteins do not have an effect on proliferation and viability of the transfected cells. In conclusion, CRISPR/Cas9 with HBx proteins exhibit high antiviral effect

Клинико-экономический анализ применения комбинации «тиксагевимаб + цилгавимаб» для терапии коронавирусной инфекции COVID-19

Objective: to evaluate the pharmacoeconomic feasibility of using monoclonal antibodies or their combinations vs standard therapy in patients with mild and moderate-severe COVID-19 in order to prevent the severe course of the disease.Material and methods. The decision tree and Markov models for calculation of costs and outcomes were used for patients with COVID-19 and post-COVID-19 syndrome, respectively. The cost-effectiveness of tixagevimab and cilgavimab was evaluated in persons ≥18 years old not vaccinated against COVID-19 with a high risk of progression to severe COVID-19. Effectiveness and safety of tixagevimab and cilgavimab combination was assessed based on TACKLE phase III study results. The quantities of life years gained (LYG) and quality-adjusted life years (QALY) were calculated. Results were compared with the wiliness-to-pay threshold measured as tripled gross domestic product per capita according the World Health Organization recommendations.Results. Treatment of COVID-19 with tixagevimab and cilgavimab results in additional 0.2657 LIGs or 0.2255 QALYs. The cost of 1 LIG was 213,4 thousand rubles, the cost of 1 QALY was 251,5 thousand rubles. Both costs of LIG and QALY appeared to be significantly less compared to the wiliness-to-pay threshold equal to 3.09 million rubles in 2022.Conclusion. Treatment of mild and moderate-severe COVID-19 is economically feasible and may be recommended for wide use in the Russian healthcare system.Цель: анализ клинико-экономической эффективности терапии моноклональными антителами или их комбинациями в сравнении со стандартной терапией у пациентов с легким или среднетяжелым течением COVID-19 для профилактики развития тяжелого течения заболевания.Материал и методы. С помощью моделей древа решений и Маркова, разработанных для моделирования затрат и исходов на этапе лечения активной фазы заболевания и в случае развития постковидного синдрома соответственно, определяли затратную эффективность комбинации «тиксагевимаб + цилгавимаб» у пациентов с COVID-19 старше 18 лет, которые ранее не были вакцинированы против COVID-19 и относились к группе высокого риска развития тяжелого течения заболевания. Клиническую эффективность и безопасность комбинации «тиксагевимаб + цилгавимаб» оценивали на основании исследования фазы III TACKLE. Рассчитывали количество сохраненных лет жизни (англ. life years gained, LYG), а также количество лет жизни с поправкой на качество (англ. qualityadjusted life years, QALY). Результаты сравнивали с порогом готовности платить (ПГП), определенным согласно рекомендациям Всемирной организации здравоохранения как троекратный внутренний валовый продукт на душу населения.Результаты. Терапия COVID-19 комбинацией «тиксагевимаб + цилгавимаб» дает дополнительные 0,2657 LYG или 0,2255 QALY. При этом стоимость 1 LYG составила 213,4 тыс. руб., стоимость 1 QALY – 251,5 тыс. руб. Оба показателя оказались значительно ниже ПГП, составившего 3,09 млн руб. в 2022 г.Заключение. Применение комбинации «тиксагевимаб + цилгавимаб» у пациентов с легким и среднетяжелым течением COVID-19 является экономически целесообразным и может быть рекомендовано в условиях российской системы здравоохранения

Hepatitis B virus and site-specific nucleases: effects of genetic modifications in CRISPR/Cas9 on antiviral activity

Chronic hepatitis B is a severe liver disease caused by persistent infection of hepatitis B virus in human hepatocytes. Chronic hepatitis B is one of the most common diseases in the world. According to recent estimations, more than 250 million people are chronically infected and more than 1 million of people die annually due to consequences of chronic hepatitis B: liver cirrhosis and hepatocellular carcinoma. The key factor of hepatitis B virus persistency is a special form of viral genome called circular covalently closed DNA. Current therapeutics suppress viral replication but have no effect on circular covalently closed DNA as it exists in the nuclei of hepatocytes as a minichromosome and is not accessible for therapeutics. Commonly, viral reactivation occurs after cessation of treatment. Therefore, duration of antiviral treatment is supposed to be indefinitely long. One of the most promising approaches to target circular covalently closed DNA is the technology of site-specific nucleases CRISPR/Cas9 from Streptococcus pyogenes. A short guide RNA recruits an SpCas9 protein to the viral genome and induces generation of DNA double strand breaks. However, there are several limitations of CRISPR/Cas9 hampering translation of this technology into the clinic. First, efficacy of CRISPR/Cas9 needs to be improved. Second, CRISPR/Cas9-mediated off-target mutagenesis represents a menacing problem which has to be addressed. To overcome these limitations, several approaches have been devised to improve CRISPR/Cas9 activity (modification of guide RNAs) and reduce off-target mutagenesis (a Cas9 protein with enhanced specificity, eSpCas9). In this study, we compared antiviral activity of a classic SpCas9 with an eSpCas9 system as well as analyzed effects of gRNAs modification on anti-HBV effects. Here, we demonstrated that SpCas9 has the highest antiviral potency, reducing transcription and replication of HBV over 90%. Hepatitis B virus covalently closed circular DNA declined over 90% post CRISPR/Cas9 transfection. Although it was previously shown that modified guide RNAs increase nucleolytic activity of CRISPR/Cas9, our results indicated that this modification impairs antiviral activity of CRISPR/Cas9. To conclude, CRISPR/Cas9 effectively suppress viral replication and transcription per se. Described modifications do not potentiate antiviral activity of CRISPR/Cas9 system and should not be used for development of future therapeutics. The best strategy to improve CRISPR/Cas9 efficacy is to design new highly effective guide RNAs

Состояние и перспективы терапии хронического гепатита С у детей в Российской Федерации

Aim. To determine the number of children with chronic hepatitis C in the Russian Federation, including, who have received antiviral treatment, taking into account their age, the genotype of the virus, as well as the therapy regimens used.Materials and methods. The analysis of specially developed statistical reporting forms was carried out, the filling of which was carried out in September 2020 by specialists from 268 medical organizations from 37 constituent entities of the Russian Federation, which are part of 8 federal districts.Results. In September 2020, 2,160 children with chronic hepatitis C virus infection aged 0 to 17 years were under observation in 268 medical organizations, including 50.7% females and 49.3% of males. The number of children in the age group from 12 to 17 years was 42.9%, from 6 to 11 years – 34.5%, from 3 to 5 years – 16.2% and from 0 to 2 years – 6.4%. The genotype of the virus was determined in 1388 (64.3%) children. The proportion of children with genotype 1 was 58.6%, with genotype 3 – 37.2%, with genotype 2 – 4%. Only 141 (8.8%) children with chronic hepatitis C virus infection have been received antiviral therapy. 1465 (91.2%) children were not treated, but 153 (9.5%) of them received therapy earlier, without achieving a sustained virological response. Direct-acting antiviral agents treatment was carried out to 120 children (85.1%), of whom glecaprevir + pibrentasvir was received by 85 children (70.8%) in 20 regions, sofosbuvir + ledipasvir – 14 children (11.7%) in 6 regions, sofosbuvir – 14 children (11.7%) in 6 regions, daklatasvir – 7 children (5.8%) in 4 regions. Children are removed from dispensary observation after achieving a stable virological response in accordance with the current regulatory documents in 26 regions of the Russian Federation (70.3%).Conclusion. In 2020, less than 10% of children under management received antiviral therapy for chronic hepatitis C virus infection in the Russian Federation. It is necessary to approve the state program for the treatment of viral hepatitis, one of the directions of which should be the provision of all children with chronic hepatitis C virus infection with modern highly effective antiviral drugs. It is also necessary to conduct clinical trials to assess the safety and efficacy of direct-acting antiviral agents for children with chronic hepatitis C virus infection in order to ensure the possibility of their earlier prescription.Цель. Установить количество детей, больных хроническим гепатитом С, в Российской Федерации, в том числе получивших противовирусное лечение, с учетом их возраста, генотипа вируса, а также используемых схем терапии.Материалы и методы. Проведен анализ специально разработанных статистических отчетных форм, заполнение которых осуществлялось в сентябре 2020 г. специалистами 268 медицинских организаций из 37 субъектов РФ, входящих в состав 8 федеральных округов.Результаты. В сентябре 2020 г. в 268 медицинских организациях под наблюдением находились 2160 детей с хроническим гепатитом С в возрасте от 0 до 17 лет, в том числе 50,7% женского и 49,3% мужского пола. Количество детей в возрастной группе от 12 до 17 лет включительно составило 42,9%, от 6 до 11 лет – 34,5%, от 3 до 5 лет – 16,2% и от 0 до 2 лет – 6,4%. Генотип вируса был определен у 1388 (64,3%) детей. Доля детей с генотипом 1 составила 58,6%, с генотипом 3 – 37,2%, с генотипом 2 – 4%. Противовирусную терапию получал 141 (8,8%) ребенок. Лечение 1465 (91,2%) детей не проводилось, однако было отмечено, что 153 (9,5%) из них получали терапию ранее, без достижения устойчивого вирусологического ответа. Лечение препаратами прямого противовирусного действия проводилось 120 детям (85,1%), из них глекапревир + пибрентасвир получали 85 детей (70,8%) в 20 регионах, софосбувир + ледипасвир – 14 детей (11,7%) в 6 регионах, софосбувир – 14 детей (11,7%) в 6 регионах, даклатасвир – 7 детей (5,8%) в 4 регионах. В 26 регионах РФ (70,3%) дети снимались с наблюдения после достижения устойчивого вирусологического ответа в соответствии с действующими нормативными документами.Заключение. Противовирусную терапию хронического гепатита С в РФ в 2020 г. получали менее 10% детей, находившихся под наблюдением. Необходимо утверждение долгосрочной государственной программы лечения вирусных гепатитов, одним из направлений которой должно стать обеспечение всех детей с хроническим гепатитом С современными высокоэффективными противовирусными препаратами. Также необходимо проведение клинических исследований в РФ для оценки безопасности и эффективности препаратов прямого противовирусного действия у детей с хроническим гепатитом С с целью обеспечения возможности их более раннего назначения

Clinical Practice Guidelines of the Russian Society for the Study of the Liver, the Russian Gastroenterological Association, the National Scientific Society of Infectious Disease Specialists for the Diagnosis and Treatment of Chronic Hepatitis C

Аim: diagnosis and treatment algorithms in the clinical recommendations intended for general practitioners, gastroenterologists, infectious disease specialists, hepatologists on the of chronic hepatitis C are presented.Summary. Chronic viral hepatitis C is a socially significant infection, the incidence of which in the Russian Federation remains significantly high. Over the past 10 years, great progress has been made in the treatment of hepatitis C — direct acting antiviral drugs have appeared. The spectrum of their effectiveness allows to achieve a sustained virological response in more than 90 % of cases, even in groups that were not previously considered even as candidates for therapy or were difficult to treat — patients receiving renal replacement therapy, after liver transplantation (or other organs), at the stage of decompensated liver cirrhosis, HIV co-infected, etc. Interferons are excluded from the recommendations due to their low effectiveness and a wide range of adverse events. The indications for the treatment have been expanded, namely, the fact of confirmation of viral replication. The terms of dispensary observation of patients without cirrhosis of the liver have been reduced (up to 12 weeks after the end of therapy). Also, these recommendations present approaches to active screening of hepatitis in risk groups, preventive and rehabilitation measures after the end of treatment.Conclusion. Great success has been achieved in the treatment of chronic hepatitis C. In most cases, eradication of viral HCV infection is a real task even in patients at the stage of cirrhosis of the liver, with impaired renal function, HIV co-infection, after solid organs transplantation

Characteristics of hepatitis C virus resistance in an international cohort after a decade of direct-acting antivirals

Background & Aims: Direct-acting antiviral (DAA) regimens provide a cure in >95% of patients with chronic HCV infection. However, in some patients in whom therapy fails, resistance-associated substitutions (RASs) can develop, limiting retreatment options and risking onward resistant virus transmission. In this study, we evaluated RAS prevalence and distribution, including novel NS5A RASs and clinical factors associated with RAS selection, among patients who experienced DAA treatment failure. Methods: SHARED is an international consortium of clinicians and scientists studying HCV drug resistance. HCV sequence linked metadata from 3,355 patients were collected from 22 countries. NS3, NS5A, and NS5B RASs in virologic failures, including novel NS5A substitutions, were examined. Associations of clinical and demographic characteristics with RAS selection were investigated. Results: The frequency of RASs increased from its natural prevalence following DAA exposure: 37% to 60% in NS3, 29% to 80% in NS5A, 15% to 22% in NS5B for sofosbuvir, and 24% to 37% in NS5B for dasabuvir. Among 730 virologic failures, most were treated with first-generation DAAs, 94% had drug resistance in ≥1 DAA class: 31% single-class resistance, 42% dual-class resistance (predominantly against protease and NS5A inhibitors), and 21% triple-class resistance. Distinct patterns containing ≥2 highly resistant RASs were common. New potential NS5A RASs and adaptive changes were identified in genotypes 1a, 3, and 4. Following DAA failure, RAS selection was more frequent in older people with cirrhosis and those infected with genotypes 1b and 4. Conclusions: Drug resistance in HCV is frequent after DAA treatment failure. Previously unrecognized substitutions continue to emerge and remain uncharacterized. Lay summary: Although direct-acting antiviral medications effectively cure hepatitis C in most patients, sometimes treatment selects for resistant viruses, causing antiviral drugs to be either ineffective or only partially effective. Multidrug resistance is common in patients for whom DAA treatment fails. Older patients and patients with advanced liver diseases are more likely to select drug-resistant viruses. Collective efforts from international communities and governments are needed to develop an optimal approach to managing drug resistance and preventing the transmission of resistant viruses

Analysis and Forecasting of Viral Hepatitis A Morbidity in the Russian Federation Using the Wald’s Schedule

Objective of the study was to conduct the analysis and develop the method of forecasting of viral hepatitis A (VHA) incidence using Wald’s schedule. Materials and methods. The work is based on official statistical data of the Rospotrebnadzor on the VHA morbidity rates in the Russian Federation and Moscow city between 2010 and 2016. Results and discussion. It is established that in the overall incidence of VHA cases in the Russian Federation over the period of 2010–2016, 67.7 % were registered among adults and 32.3 % – among children; as for the incidence among adults in Moscow, it accounted for 79.8 %, and for children – 20.2 %. To assess epidemiological situation on VHA, forecasting approach using Wald’s schedule was put forward. Based on the results of the analysis conducted, the threshold values for morbidity rates among adult population in Moscow stood at 38 cases, fluctuations in mean values ranged from 48 to 63 cases. It is shown that the total minimum and maximum levels of morbidity among adult population in 2017 would account for 180 and 624 cases, respectively. Forecast of incidence among children is determined on an accrual basis: minimum monthly level – 7 cases, maximum – 17. Monthly growth of infection is 0.9 cases. It is revealed that possible cumulative minimum and maximum morbidity rates among children would amount to 84 and 204 cases in 2017, respectively. The proposed method of Wald’s schedule for VHA incidence forecasting will allow for determining both monthly minimum and maximum rates of infection for the upcoming period and provide for timely planning of anti-epidemic measures