The use of targeted therapy lumacaftor/ivacaftor in patients with cystic fibrosis

Accepted, basic therapy of cystic fibrosis (CF), until recently, was symptomatic and aimed at slowing down pathological processes, mainly from the respiratory system and gastrointestinal tract, caused by a defect in the CFTR gene. New strategic opportunities have emerged since 2012 and are aimed at correcting a defect in a gene or its product. A mutation in the cystic fibrosis gene disrupts the function of the cystic fibrosis transmembrane conductance regulator protein (CFTR or CFTR in English transcription), which is located on the surface of the apical membrane of epithelial cells and functions as a chloride channel. The basic achievement for the new CF therapy was the discovery of small molecules that restore the processes of synthesis, transport to the membrane, or the  functioning of  the defective CFTR protein. The effectiveness of  drugs that restore CFTR function is related to the ability of the molecules to deliver an adequate amount of the CFTR protein to the surface of the epithelial cell and/or improve its functional activity. Among them, correctors and potentiators for pharmacological modulation of ion transport are distinguished in clinical practice. Correctors are medicinal substances that allow the mutant CFTR protein to pass through the system of intracellular quality control and take the correct location on the apical membrane (with class II mutations). The action of potentiators is aimed at restoring (activating) the function of the ion channel formed by the mutant CFTR protein (class III–IV mutations). The purpose of this article is to analyze the literature sources, the results of clinical trials on the use of CFTR modulators, including combinations of a potentiator and a corrector. Their effectiveness and safety were evaluated. Literature sources (20) are used and own clinical observation is given. A positive assessment of the action of the modulator, the combination of a potentiator and a corrector, its safety and good tolerability is given. In conclusion, the place and indications for prescribing drugs of this class, the number of patients in the Russian Federation in need of such treatment are determined

Влияние генотипа и микрофлоры дыхательных путей на функцию легких и нутритивный статус взрослых больных муковисцидозом при длительном наблюдении

In recent years, an increase in the number of patients with chronic infection with nonfermenting gram-negative bacteria (NFGNB) in adult patients with cystic fibrosis (CF) has increased. The genotype and phenotype characteristics, NFGNB structure, changes in sensitivity and the development of antibiotic resistance in adult patients have not been adequately studied.Aim. To determine the impact of genotype severity and Achromobacter xylosoxidans sensitivity to carbapenems on the functional and nutritional status of adult cystic fibrosis patients over a period 2016 – 2021.Materials. Retrospective analysis of genotypic and microbiological data from 54 adult CF patients and their effects on FEV1 and BMI over a period 2016 – 2021. Sputum cultures were confirmed by MALDI-TOF mass spectrometer. Depending on the severity of the mutation, the patients were divided into 2 groups: group 1 (“severe” genotype) – patients who had 2 mutations of class I – III; group 2 (“soft” genotype) – at least 1 class IV – VI mutation.Results. The group of patients with “mild” mutations had a higher BMI (kg / m2) than the group with severe mutations for a longer period of follow-up from 2018 – 2021 than in the group with severe mutations: BMI (2016) – 21.14 ± 3.55 / 19.28 ± 3.13 (p = 0.163); BMI (2017) – 21.27 ± 3.43 / 18.31 ± 2.05 (p = 0.123); BMI (2018) – 21.17 ± 4.00 / 18.80 ± 2.12 (p = 0.025); BMI (2019) – 21.01 ± 4.20 / 18.55 ± 2.53 (p = 0.049); BMI (2020) – 20.94 ± 4.12 / 18.41 ± 2.15 (p = 0.050). Age at diagnosis was 20.36 ± 2.18 years for “mild” genotypes and was higher (p = 0.042) than for “severe” genotypes (6.27 ± 1.53 years). All 7 patients who died (100%) were in the “severe” genotype group (23.3%). Functional status assessment showed no differences in FEV1 over 6 years between the “severe” and “mild” genotype groups: FEV1 (2016) – p = 0.51; FEV1 (2017) – p = 0.39; FEV1 (2018) – p = 0.51; FEV1 (2019) – p = 0.35; FEV1 (2020) – p = 0.48. Nonfermenting Gram-negative bacteria accounted for 49.9% of the isolated microorganisms. The group of carbapenem-resistant Achromobacter xylosoxidans lost the FEV1 level faster every year for 6 years (p < 0.05) compared to the group of the sensitive variant.Conclusion. In general, patients with the “mild” genotype have higher nutritional status and do not differ from patients with the “severe” genotype in terms of FEV1. The survival rate of patients with the “mild” genotype patients survival rate is higher, despite the later diagnosis and start of treatment. Development of carbаpenem resistance in Achromobacter xylosoxidans is associated with an unfavorable prognosis of the functional status decline.В последние годы отмечен рост числа взрослых пациентов, больных муковисцидозом (МВ), с хронической инфекцией неферментирующими грамотрицательными бактериями (НФГОБ). Однако особенности генотипа и фенотипа, структура НФГОБ, изменение чувствительности и развитие резистентности к антибактериальным препаратам у взрослых пациентов с МВ изучены недостаточно.Целью исследования являлось установление влияния тяжести генотипа и чувствительности штаммов Achromobacter xylosoxidans к карбапенемам на динамику функционального и нутритивного статуса у взрослых пациентов с МВ за период 2016–2021 гг.Материалы и методы. Проведен ретроспективный анализ генотипических, микробиологических данных взрослых пациентов с МВ (n = 54) за весь период наблюдения, рассмотрено их влияние на объем форсированного выдоха за 1-ю секунду (ОФВ1) и индекс массы тела (ИМТ) в динамике. Результаты культуральных посевов образцов мокроты подтверждены при помощи масс-спектрометра MALDI-TOF. В зависимости   от тяжести мутации пациенты распределены на 2 группы: 1-я («тяжелый» генотип) – больные, у которых выявлены 2 мутации I–III класса; 2-я («мягкий» генотип) – хотя бы 1 мутация IV–VI класса.Результаты. У пациентов 2-й группы («мягкий» генотип) при большем сроке динамического наблюдения (2018–2021) отмечен более высокий ИМТ по сравнению с таковым у лиц 1-й группы («тяжелые» мутации): 2016 г. – 21,14 ± 3,55 vs 19,28 ± 3,13 (p = 0,163); 2017 г. – 21,27 ± 3,43 vs 18,31 ± 2,05 (p = 0,123); 2018 г. – 21,17 ± 4,00 vs 18,80 ± 2,12 (p = 0,025); 2019 г. – 21,01 ± 4,20 vs 18,55 ± 2,53 (p = 0,049); 2020 г. – 20,94 ± 4,12 vs 18,41 ± 2,15 (p = 0,050) соответственно. Возраст установления диагноза у лиц с «мягким» генотипом составил 20,36 ± 2,18 года и был выше (p = 0,042) по сравнению с таковым у пациентов с «тяжелым» генотипом – 6,27 ± 1,53 года. У всех 7 (23,3 %) умерших пациентов отмечен «тяжелый» генотип. При оценке функционального статуса по уровню ОФВ1 у пациентов с «тяжелым» и «мягким» генотипами за весь период наблюдения достоверных различий не выявлено: 2016 г. – р = 0,51; 2017 г. – р = 0,39; 2018 г. – р = 0,51; 2019 г. – р = 0,35; 2020 г. – р = 0,48 соответственно. НФГОБ составили 49,9 % от всех выделенных изолятов. У пациентов, инфицированных резистентным к карбапенемам штаммом A. xylosoxidans, отмечено более быстрое ежегодное снижение ОФВ1 (p < 0,05) по сравнению с таковым у лиц, инфицированных чувствительным штаммом.Заключение. Таким образом, по результатам анализа у лиц с «мягким» генотипом в целом отмечен более высокий нутритивный статус. По уровню ОФВ1 у лиц с «мягким» генотипом различий в динамике по сравнению с таковыми показателями при «тяжелом» генотипе за весь период наблюдения не установлено. Отмечены также более высокая продолжительность жизни пациентов с «мягким» генотипом, несмотря на более поздний срок установления диагноза и старта терапии, развитие резистентности A. xylosoxidans к карбапенемам и неблагоприятный прогноз по динамике снижения функционального статуса

BASOPHILE ACTIVATION TEST FOR THE DIAGNOSTICS OF FUNGAL SENSITIZATION IN THE PATIENTS WITH CYSTIC FIBROSIS

Aspergillus fumigatus colonization in the patients with cystic fibrosis (CF) may cause sensitization against A. fumigatus and/or allergic bronchopulmonary aspergillosis (ABPA), which significantly worsens the course of underlying disease. At the present time, new diagnostic tests are searched for detection of fungal sensitization in these patients. The aim of this work was to evaluate an opportunity of application of basophile activation test with A. fumigatus allergen in vitro using flow cytometry, aiming for identification of fungal sensitization in the CF patients. The study included 190 patients with CF aged 1 to 37 years. All the patients underwent common allergy screening (skin tests with fungal allergens, determination of serum levels of total IgE and specific IgE for the fungal allergens), and mycological examination (microscopy and culture of respiratory substrates). Computed tomography of the chest was performed upon clinical indications. The basophil activation test with the A. fumigatus allergen was performed in 10 CF patients with ABPA, and 10 CF patients without ABPA, in addition to the standard allergological examination. Frequency of sensitization to A. fumigatus in the patients with cystic fibrosis was 27%, the incidence of allergic bronchopulmonary aspergillosis was 5.7%. The number of eosinophils, total IgE and specific IgE levels in CF patients with ABPA were significantly higher than in CF patients without ABPA. In blood of the ABPA patients we have identified 68.5 (52.5-81.5%) of basophilic leukocytes activated by A. fumigatus allergen, with a stimulation index of 17.07 (10.30-27.70). In appropriate comparison group, the stimulation index did not exceed 1.5 (p = 0.000). Direct positive correlation between the levels of specific IgE to A. fumigatus and the number of basophils activated by A. fumigatus allergens was revealed (r = 0.77; р < 0.05). FVC values and the body mass index in CF patients with ABPA were significantly lower when compared with the patients without fungal sensitization. Introduction of the basophil activation test, along with standard techniques, may enable a more differentiated assessment of ABPA development in CF patients. Timely detection of associations between A. fumigatus sensitization and clinical status of CF patients will facilitate early and effective administration of specific therapy

Technology for the development and use of electronic educational resources in the educational process of a university

Purpose of the study.  The aim of the work is to consider the possibility of improving the quality and accessibility of teaching and educational resources through the development and use of electronic educational resources (hereinafter referred to as EER) using the example of the module “System Design”. The article presents a solution to the problem that is of significant importance in the field of information technology implementation in education. The relevance of the research problem is determined by the fact that through the use of interactive tools in the learning process, users, as a rule, a student and an educator, can actively interact with these information tools. Interactivity implies the existence of conditions for educational dialogue, one of the participants of which is a means of informatization of education.Materials and methods.  To solve these tasks, the general scientific system approach was used as the main one, the basis of which is to consider educational facilities as systems functioning in a certain environment, as well as methods of analysis and comparison. The study was conducted in accordance with the pedagogical conditions of student learning and the methodological requirements for the educational product. We reviewed methodological recommendations on the use of e-learning in the educational process of the university, the main regulatory documents of distance education technologies in the implementation of additional professional programs, the Moodle distance learning system, guidelines for practical exercises, as well as reference materials on the Moodle system.Results.  The study revealed the problem of the use of electronic educational resources, their positive and somewhat negative impact on the goals and results of the educational process, as well as existing technologies for their creation. Based on the analysis of a variety of development technologies for various characteristics, a decision was made to use the LMS Moodle environment. The structure of the module “System Design” was developed, and this module was implemented in the LMS Moodle environment and tested in the educational process, it was revealed that the level of knowledge and skills mastering, as well as their possession is higher among students who studied on the electronic educational resource.Conclusion.  Thus, the results of the study allow us to recommend the introduction of electronic educational resources in the learning process. Since the use of the presented development will not interrupt the learning process in cases where the student can not attend classes, and also contributes to improving the formation of students’ competence level

Anticafe as a new cultural phenomenon. The conceptual content of the word

In this work there is the analysis of a new Russian cultural phenomenon — antikafe — and formulated an alternative definition that fully captures the essence of the phenomenon.В данной работе приведен анализ нового для России культурологического явления — антикафе — и сформулированы альтернативные определения, в полной мере отражающие суть данного явления

Анализ случаев COVID-19 у взрослых больных муковисцидозом в Санкт-Петербурге и Ленинградской области

March 11, 2020 WHO has declared the COVID-19 coronavirus pandemic. The European Society for Cystic Fibrosis (ECFS) has developed the ECFSCOVID- 19 surveillance program to collect information on the characteristics of COVID-19 in patients with cystic fibrosis (CF). CF centers in the Russian Federation also joined the ECFS study. The ECFS collected information only through national Registers. In our country, the national register of CF patients has existed since 2011, its data is included in the European Register. Тo analyze the prevalence and course of COVID-19 in adult CF patients in Saint-Petersburg and the Leningrad region.Methods. From 11.03.20 to 24.12.20, 10 cases of adult CF patients (4 women, 6 men) with COVID-19 were analyzed in Saint-Petersburg and the Leningrad region. At the beginning of the study, 56 adult CF patients lived in Saint-Petersburg and Leningrad Region. All patients were monitored remotely by telephone, in case of ARVI symptoms, disease exacerbation, a PCR smear was performed on SARS-CoV-2, therapy was prescribed remotely, and inpatient treatment was prescribed if indicated.Results. COVID-19 was diagnosed in 10 adult CF patients aged 21 to 43 years. Two patients (32-year-old male and 31-year-old female with severe mixed cystic fibrosis form) were hospitalized with polysegmental pneumonia. 8 people were treated on an outpatient basis. Only 1 outpatient patient aged 43 years had pronounced clinical manifestations of COVID-19, the condition was regarded as moderate, the remaining outpatient patients suffered from a mild ARI disease. All patients were treated with positive dynamics. During the period of this follow – up, 3 CF patients (2 men, 1 woman) died, the death cause was the respiratory failure progression. Clinical and radiological, repeated laboratory data for COVID-19 were not obtained. At the point of December 24, 2020 53 adult CF patients are alive.Conclusion. According to our data, the incidence of COVID-19 among adult CF patients in Saint-Petersburg and the Leningrad Region was 17.85%, which is a lower indicator than in the general population. The disease was rarely severe, and effective treatment was noted in outpatient settings. There were no deaths from COVID-19.11.03.20 Всемирной организацией здравоохранения объявлена пандемия коронавирусной инфекции (КИ) – COVID-19. Европейским обществом по муковисцидозу (МВ) (European Cystic Fibrosis Society – ECFS) разработана программа наблюдения ECFS-COVID-19 для сбора информации об особенностях течения COVID-19 у больных МВ. К исследованию ECFS присоединились и российские центры МВ. Сбор информации ECFS осуществлялся только через национальные регистры. Национальный регистр больных МВ Российской Федерации существует с 2011 г., его данные входят в Европейский регистр.Целью исследования явился анализ распространенности и течения COVID-19 у взрослых пациентов с МВ в Санкт-Петербурге и Ленинградской области (ЛО).Материалы и методы. Проанализированы данные взрослых больных МВ (n = 10: 4 женщины, 6 мужчин; возраст – 21–43 года) проживающих в Санкт-Петербурге и Ленинградской области, в период с 11.03.20 по 24.12.20 перенесших COVID-19. На начало исследования в Санкт-Петербурге и Ленинградской области проживали 56 взрослых больных МВ. Все пациенты находились на дистанционном (по телефону) наблюдении, при выявлении симптомов острой респираторной вирусной инфекции и обострении заболевания проводилось исследование назофарингеального мазка на SARS-CoV-2 методом полимеразной цепной реакции, дистанционно назначалась терапия, при наличии показаний – стационарное лечение.Результаты. С полисегментарной пневмонией госпитализированы 2 больных (1 мужчина 32 лет и 1 женщина 31 года) с МВ смешанной формы тяжелого течения, остальные 8 пациентов лечились амбулаторно. Только у 1 амбулаторного больного 43 лет отмечены выраженные клинические проявления COVID-19, состояние расценено как средней степени тяжести, остальные амбулаторные больные перенесли болезнь по типу острого респираторного заболевания легкой степени. У всех пациентов проведено лечение с положительной динамикой. За период наблюдения умерли 3 больных МВ (2 мужчин, 1 женщина), причиной смер- ти явилось прогрессирование дыхательной недостаточности, при этом рентгенологических и неоднократных лабораторных данных, подтверждающих новую КИ, не получено. На 24.12.20 живы 53 взрослых больных МВ.Заключение. Заболеваемость COVID-19 среди взрослых больных МВ, проживающих в Санкт-Петербурге и Ленинградской области, составила 17,85 % – меньше, чем в общей попу- ляции. В редких случаях болезнь протекала в тяжелой форме. Отмечается также эффективность лечения в амбулаторных условиях и отсутствие смертельных исходов от COVID-19