Phenotyping of severe asthma in a clinical context

Severe asthma is a chronic heterogeneous inflammatory disease characterized by several clinical phenotypes and molecular endotypes. Although it affects a relatively small proportion of the asthma population (approximately 4%-10%), with an even smaller proportion of these having severe uncontrolled eosinophilic asthma, it accounts for > 50% of the costs attributed to the disease. Despite the availability of modern medicines and improvements in certain outcomes, severe asthma is still a cause of mortality. Although it is known that severe asthma is driven by type 2 inflammation in most cases, and we now have the possibility to use specific biological therapies targeting this particular type of inflammation, many patients are still suboptimally controlled due to the heterogenous nature of this disease with its multiple subphenotypes. There is, therefore, an unmet need to characterize and classify these patients with a view to improve therapy and reduce costs on a global scale. Furthermore, selection of the most appropriate biologic and the best clinical outcomes and biomarkers with which to monitor response to therapy, are still issues of debate and the subject of ongoing research. Three clinical severe asthma studies are included in this thesis, the overall aim of which was to provide an increased understanding of the clinical features and treatment effects associated with the different sub-phenotypes of severe asthma. A specific focus was also to validate different clinical outcomes and assess their importance for the management of asthma. The three studies address these aims in different ways including an epidemiological investigation (Paper I), a pharmacological assessment of the drugs used to treat asthma as well as their side effects and relationship with asthma severity (Paper II) and a clinical intervention applied in a “real-life” setting, including a preliminary meta-analysis with the objective to develop a new method for assessment of response to therapy (Paper III). Several important observations were made in Paper I. The results of this study revealed differences in clinical characteristics, lifestyle factors and treatment patterns among severe asthmatics in Europe, confirming the heterogeneity of this disease. Moreover, the severe asthma definition in current guidelines did not correspond to the characteristics of real-world severe asthmatics, and the definitions also differed between countries. Finally, Paper I emphasized the importance of harmonizing severe asthma registries throughout Europe, and the need for long-term follow-up of this group of patients. In Paper II was done analysis of data from 478 well characterized asthmatics and 98 healthy controls in the U-BIOPRED study. Paper II shows that severe asthmatics have significant suppression of androgens and cortisol compared to patients with mild-to-moderate asthma and healthy control according to extensive analysis of urinary endogenous and exogenous steroids. This suppression is more pronounced in women compared to men. Moreover, the data show that this adrenal suppression is depended on the level of treatment with exogenous corticosteroids. Thus, our results provide support to the hypothesis that this relative deficiency in androgen levels during steroid treatment that is disproportional greater in women compared to men may partly explain gender differences in the severity of asthma and prevalence. Finally, our study supports that reduction of high dose inhaled corticosteroids (ICS), and especially the taper of oral corticosteroids (OCS) should be a clinical goal in order to reduce the side effects of corticosteroids. In Paper III, we modified a quantitative algorithm that was originally developed in a European collaboration to assess response to therapy and evaluate efficacy, and then tested this strategy in patients with severe asthma undergoing treatment with the biologic mepolizumab. The method was able to quantify response to an expensive biological treatment and identify four groups with different degrees of response to mepolizumab: super response, substantial response, sufficient response, and non-response. The super responder group had the greatest improvement in lung function, asthma quality of life questionnaire, asthma control questionnaire and the highest reductions in exacerbations and OCS use, whereas the nonresponders lost asthma control, discontinued mepolizumab treatment and switched to other biologics. This new, quantitative algorithm was shown to provide a more individualized assessment of treatment response and identified non-responders in need of revised treatment. Further, this method can be implemented in clinical practice for greater precision in early clinical decision-making regarding the use of biological therapy. In conclusion, the three clinical studies included in the thesis have contributed to an increased understanding of the clinical phenotypes of severe asthma. The experiences accumulated during this work allow for some general implications. For example, longitudinal, prospective studies carried out in a real-world setting are important for evaluation of response to treatment with new drugs since the differing responses of well-characterized and phenotyped patients can reveal clinical sub-phenotypes and their relationship to underlying molecular mechanisms. The utility of different clinical outcomes could be validated and their importance for asthma management assessed. Clinical studies also provide an opportunity to investigate requirements for improved management and care of severe asthmatics. Patient-centred research contributes to a better understanding of patient needs, and thereby facilitates refined assessment of clinical response to treatment

GOVERNANCE IN UKRAINE: MYTH OR REALITY?

The paper under discussion covers the importance of governance at the present stage of economic development in Ukraine. This study may contribute to understanding the governance systems in countries under very different laws and adopting very different board models. In order to integrate social and economic interests of all subjects of economy there is a need of developing the theory and practice of governance. So the definition of the word of governance was given in the article. The OECD principles of governance which should be introduced in the Ukrainian practice of administration and management are defined in it. Its key idea is to introduce a preconditions, characteristics and levels conceptual model of governance in the world and the opportunities for its introduction in Ukraine. The theoretical approach to the problem is based on structurally functional and genetic methods of cognition. The data obtained are given to illustrate the necessity of diagnosis of the governance level  by calculating all indices of governance indicator in Ukraine. It will define bases for further development of the state. The material presented can open new prospects for further research studies. It seems to be interesting to those who work in the field of governance, public administration and management

Концептуально-фреймовий аналіз квазісинонімічного ряду кіберсету ПОРУШНИК СИСТЕМИ. (THE CONCEPTUAL FRAME ANALYSIS OF QUASISYNONYMIC GROUP OF CYBERSET SYSTEM BURGLAR.)

У статті висвітлено дослідження аналізу квазісинонімічного ряду кіберсету ПОРУШНИК СИСТЕМИ (hacker, cracker, phreaker). Звернуто увагу на аналіз значення зазначених комп’ютерних неологізмів та порівнювання їх лексико-семантичних варіантів (ЛСВ). Сконструйовано слоти предметного та акціонального фреймів в межах даного кіберсету. Представлено таблицю кількісних параметрів слотової подібності та розбіжності комп’ютерних неологізмів hacker, cracker та phreaker, які входять до складу кіберсету ПОРУШНИК СИСТЕМИ. Визначено слоти у яких виявляється точна та неточна синонімія. Окреслено та досліджено явище квазісинонімії в межах представленого кіберсету. Визначено домінанту цього кіберсету, яка може замінити будь-який із комп’ютерних неологізмів у широкому лінгвістичному контексті) (The article deals with the research of analysis of quasisynonymic group of cyberset SYSTEM BURGLAR (hacker, cracker, phreaker). Attention has been devoted to the analysis of the above mentioned computer neologisms definitions and the comparison of their lexico-semantic variants. Slots of objected and actional frames have been constructed in the given cyberset. The table of similarity and difference of slots parameters of the computer neologisms hacker, cracker and phreaker make up the cyberset SYSTEM BURGLAR has also been presented. Slots with the exact and non-exact synonymy have been defined. It has also been described and studied the phenomenon of quasisynonymy in the given cyberset. The dominant of the given cyberset has been identified and it can substitute any of the computer neologisms in the wide linguistic context.

Methods and tools for protection of enterprise goodwill

Ділова репутація підприємства як важливий нематеріальний актив підприємства набуває все більшого значення у конкурентній боротьбі за покупця. Вона формується досить тривалий час – кілька десятків років однак, втратити її можна миттєво, за кілька хвилин. Зважаючи на цінність ділової репутації як важливої характеристики будь-яких відносин, зокрема і ділових, питання її збереження є досить актуальним. У статті розглянуто методи та інструменти, які дозволяють зберегти та захистити ділову репутацію підприємства від різних негативних факторів зовнішнього і внутрішнього середовищ, а також різних видів кризових ситуацій. Беручи до уваги те, що кризові ситуації на підприємстві зустрічаються досить часто, більшість керівників підприємств не вміють адекватно відреагувати на них не знають, яким чином управляти комунікаціями під час виникнення кризи та зберегти довірливі відносини з діловими партнерами та іншими групами громадськості.Enterprise goodwill as an essential intangible asset of the enterprise becomes increasingly important in the competition for customers. It is formed for a long time – even several decades, however, it can be instantly lost in a few minutes. Paying attention to the importance of goodwill as an essential feature of any relationship, including business, the issue preservation is very actual. Methods and tools that allow saving and protecting the goodwill of the enterprise from various negative internal and external factors and various types of crisis situations are examined in this article. Considering that the crisis situations in the company are common, most managers do not know how to respond to them or how to manage communications during a crisis and keep good relations with business partners and other society groups. This article studies two types of crises – crises caused by man-made accidents, disasters, etc. and crisis situations by spreading negative information against the company by its competitors. As a special case it has been investigated features of protection company reputation in the virtual environment of the Internet. It is marked the most common methods of protecting the reputation of the enterprise, legal and preventive methods and techniques of black public relations (PR)

Cyclic visualization of the respiratory stages in teaching human physiology to english-speaking students

In the course of Human Physiology, students of different specialties learn cyclic processes reflecting the work of the cardiovascular, respiratory, female reproductive systems and sleep as well. Visualization of the cyclic processes is essential for better understanding of the organization and functioning of these systems and finding pathological deviations with formation of defective cycles. The objective of the work is to analyze the application of the visualization of the respiratory stages into the educational process. Dynamics of the physiological processes at various stages of respiration with the help of schematic visual figures allows effective formation of the students’ systemic understanding of the respiratory system functions and its interrelations with the cardiovascular system.  These enable to apply the acquired theoretical knowledge while solving clinical situational tasks and formation of professional competence

The significance of epigenetic mechanisms of physiological adaptation to hypoxia in the search for key points of influence on hypoxia-dependent pathological processes

. Epigenetics is a term in biology referring to heritable traits that do not involve changes in the underlying DNA sequence of the organism. Cancer and stem cell research have gradually focused attention on these genome modifications. The molecular basis of epigenetics involves modifications of DNA and the chromatin proteins associated with it. Recent data suggests that epigenetics plays a crucial role in the development of many processes, including physiological reactions. Increasingly, researchers are detecting links between epigenetics and a number of diseases. Epigenomic modifications are reversible chromatin rearrangements that modulate gene expression without changing DNA sequences and provide variability in the transcriptional activity of individual genes, the course of the cell cycle, DNA replication and repair, and imprinting phenomena. Despite significant progress in the identification of adaptive genomic signals that are closely related to the physiological characteristics of “hypoxia tolerance” in high-altitude populations, many questions regarding the fundamental biological processes underlying such adaptation remain unanswered. The study of the mechanisms of adaptation to hypoxia in the ontogeny process acquires special importance in the view of the potential therapeutic and preventive effect of natural environmental factors

Sex related peculiarities of the adrenal tissue response on the hypobaric hypoxia at the altered duration of photoperiod in immature rats

This study showed the sex related dependence of the reaction of proteolytic processes in tissues of the adrenal glands of male and female immature rats held in systemic intermittent hypobaric hypoxia and constant lighting. The modelling of hypobaric hypoxia combined with a varying length of the photoperiod (natural duration of photoperiod and constant lighting) causes a different changes of the proteolysis in the tissues of the adrenal glands of the male and female immature rats with varying intensity depending on the sex of animals and duration of photoperiod. Sex differences in the response of tissue proteolysis indicators in the main organ of adaptation process in immature animals indicate a genetic-dependent peculiarities of reactivity of the response mechanisms of the body on the action of environmental factors at their isolated and combined impact

Specific characteristics of tissue reaction of the adrenal glands hypobaric hypoxia action according to altered photoperiod duration in immature female rats

Peculiarities of the reaction of indices of proteolytic and fibrinolytic processes to hypobaric hypoxia under conditions of its independent use and hypoxic preconditioning changes, stimulated by influence of constant light, in the the adrenal glands tissues in immature female rats have been studied. It has been established that modeling of the pineal gland hypofunction by means of a constant illumination significantly influences upon the character of changes proteolysis and fibrinolysis processes in the adrenal glands tissues of immature female rats, caused by systemic hypobaric hypoxia at a combined use of the indicated influences. Hypoxic preconditioning of influences of constant lighting does not compensate shifts in biochemical indices, stimulated by altered photoperiod duration