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UDC 616.5-007.23-036.12-076-078.088.7
ANALYSIS OF ATOPIC DERMATITIS AND ECZEMA RESISTANT FORMS ASSOCIATION WITH THE EXPRESSION OF XENOBIOTIC BIOTRANSFORMATION GENES IN THE SKIN OF
PATIENTS
Milkoto N.A., Rudenkova T. V., Kostiuk S.A., Pankratov O.V., Poluyan O.S., Shimanskaya I.G., Hlinkina T.V.
State Educational Establishment "Belarusian Medical Academy of Postgraduate Education ",
The Republic of Belarus, Minsk
ABSTRACT
As a result of the studies, a reliable association of the course of atopic dermatitis and eczema (resistant, often long-term relapsing, continuously-relapsing) with an increase in the expression levels of xenobiotic biotransformation genes (UGT1A7, HMOX2, BLVRA, CCL13, APOBR, ABCC2, GSTP1) in the skin was determined. The data obtained during the studies allow us to recommend the use of a method for assessing the expression levels of xenobiotic biotransformation genes in skin scrapings, based on real-time PCR, for early diagnosis and an objective choice of treatment tactics in patients suffering from resistant, often long-term, continuously-relapsing forms of atopic dermatitis and eczema.
Keywords: atopic dermatitis, eczema, resistant forms, xenobiotic biotransformation genes, expression level
Introduction
Skin atopy (atopic dermatitis (AD) and eczema) is a chronic inflammatory disease that occurs, in most cases, in early childhood in individuals with a hereditary predisposition to other atopic, usually respiratory diseases, which has a relapsing course with age-related localization and morphology of foci of inflammation, characterized by itching and due to hypersensitivity to both specific (allergenic) and nonspecific irritants [1].
Eczema is an acute or chronic relapsing allergic skin disease that forms under the influence of exogenous and endogenous trigger factors; it is characterized by the appearance of a polymorphous light eruption, an acute inflammatory reaction caused by serous inflammation of the skin, and severe itching [2].
The Nomenclature committee of the European Academy of Allergy and Clinical Immunology (EAACI) classified AD and eczema as allergic reactions in the classification system of hypersensitivity reactions by biological significance [3].
With the development of AD and eczema, a violation of the barrier functions of the skin occurs, with the involvement of immune mechanisms in the pathological process, the deterioration in the metabolism of biologically active substances in the skin. The course of the disease is accompanied by a change in the qualitative and quantitative composition of microflora, a redistribution of the activity of the xenobiotic transformation system [4, 5, 6].
Establishing a list of objective markers (clinical-anamnestic and/or molecular-genetic) for a standardized assessment of changes in the skin of patients with AD and eczema is an urgent task in the diagnosis and choice of treatment tactics for patients with resistant forms of the disease. The study and comprehensive analysis of clinical and anamnestic data, normalized expression of genes that control the
processes of biotransformation of xenobiotics in the skin of patients with AD and eczema will make it possible to establish the presence of a possible association between these markers and the presence of a resistant form of the course of the disease in a patient, which will make it possible to identify objective diagnostic criteria.
The objective of the study is to identify possible associations of objective diagnostic criteria (clinical-anamnestic and/or molecular-genetic) for standardized assessment and correction of changes in the skin of patients with AD and eczema, based on the study and comprehensive analysis of clinical-anamnestic data, levels of normalized gene expression, controlling the processes of biotransformation of xenobiotics in the skin of patients with AD and eczema.
Material and methods. The main study group included 107 patients: group 1 - 79 patients with atopic dermatitis (L20.0 - L20.9); group 2 - 28 patients with eczema (L30.0 - L30.9). The control group (group 3) included 30 apparently healthy individuals. The age of the patients in the main study group was 27 (18/59) years; in the control group - 29 (18/62) years old.
At the time of examination and taking of biological material, all patients of the main group were in a state of exacerbation of the skin process. Anamnesis was collected and analyzed in all patients, including the timing and causes of exacerbation of the clinical symptoms of the disease.
The main methods of clinical and instrumental examination of patients were the following: examination of patients and collection of anamnestic data, visual assessment using the SCORAD rating scale, confirmed by photo documentation, dermatoscopy [7].
To determine the levels of normalized expression of genes for biotransformation of xenobiotics, scrapings of deep layers of affected skin areas of patients with atopic dermatitis and eczema were used as biological material; scrapings of the deep layers of
the skin of practically healthy individuals were taken from the elbow folds. The determination of the levels of normalized expression of genes UGT1A 7, HMOX2, BLVRA, CCL13, APOBR, ABCC2, GSTP1 was carried out according to the previously described methods [8].
Statistical processing of the obtained results was carried out using the computer program "Statistica 10".
The analysis used nonparametric methods of statistical analysis, one-way and multivariate analysis. Results and discussion.
When collecting the anamnesis data, the following indicators were characterized: the duration of the course of the disease, the frequency of exacerbations, the presence of concomitant diseases, the use of drugs (Table 1).
Table 1
Patient history data, based on the analysis of personalized questionnaires (n=107)
Indicator Number of patients
Group 1 (n=79) Group 2 (n=28)
n % n %
Duration of the disease up to 1 year 2 2,53 2 7,1
1-5 years 10 12,66 5 17,86
5-10 years 29 36,7 12 42,86
10-20 years 27 34,18 6 21,43
more than 20 years 11 13,08 3 10,71
Number of exacerbations per year 1-2 17 21,52 6 21,43
2-4 41 51,89 15 53,57
4-6 21 26,58 7 25,0
Concomitant diseases associated with atopy 6 8,41 4 14,29
not associated with atopy 3 4,67 2 7,14
Use of external means mono-corticosteroids 37 48,60 13 46,43
corticosteroids + antibiotics 15 20,56 8 28,57
corticosteroids + antiseptics 6 8,41 4 25,0
calcineurin inhibitors 4 6,54 2 71,43
emollients 25 33,64 8 28,57
During the examination of patients according to the SCORAD scale, the prevalence of the skin process,
the intensity of clinical manifestations and subjective symptoms were assessed (Table 2).
Table 2
Number of patients
Indicator Степень выраженности симптомов Group 1 (n=79) Group 2 (n=28)
n % n %
5-40 15 18,69 6 21,43
Prevalence of the skin process 40-80 64 81,31 22 78,57
80-100 - - - -
1 - - - -
erythema 2 10 13,08 9 32,14
3 68 86,92 19 67,86
1 63 80,37 17 60,71
edema/papule 2 16 19,63 11 39,29
3 - - - -
1 43 54,21 17 60,71
crusts/oozing 2 11 14,02 7 25,0
Intensity of the clinical 3 0 0,00 4 14,29
manifestations 1 48 61,68 9 32,14
excoriations 2 19 24,30 15 53,57
3 3 4,67 3 4,67
1 13 17,76 9 32,14
lichenification 2 51 65,42 16 57,14
3 12 15,89 3 4,67
1 10 13,08 8 28,57
dry skin 2 56 71,96 18 64,29
3 11 14,95 2 7,14
1-4 4 6,54 2 7,14
itching 5-7 64 82,24 20 71,43
Subjective symptoms 8-10 8 10,28 6 21,43
sleep disturbance 1-4 3 4,67 7 25,0
5-7 69 88,79 18 64,29
8-10 5 6,54 3 4,67
During dermatoscopy, the following parameters examining patients of the main study group are were assessed: morphology, location of vascular presented in Table 3. structures, peeling patterns, color. The results of
Table 3
Results of dermatoscopy in patients with AD and eczema (n=107)_
Indicator Number of patients
Group 1 (n=79) Group 2 (n=28)
n % n %
Morphology Microvesicles 15 19,63 21 75,0
Micropapules 19 25,23 19 67,86
Normal vessels 19 25,23 16 57,14
Point vessels 59 74,77 22 78,57
Location of vascular structures Homogeneous 25 31,78 4 14,29
Heterogeneous 55 70,09 24 85,71
Peeling patterns Absent - - - -
Follicular 15 18,69 4 14,29
Non-follicular 66 83,18 24 85,71
Yellow crusts 37 46,73 23 82,14
Yellow scaly crusts 30 38,32 18 64,29
White scaly crusts 36 33,64 6 21,43
Colour Normal 23 29,91 3 10,71
Hot pink 52 66,36 18 64,29
Red 3 4,67 7 25,0
After analysis of clinical-anamnestic data and results of dermatoscopy among patients with AD, a severe course of AD was revealed in 11.39% of cases (n = 9) - these are patients in whom the SCORAD index was more than 50 and the dermatoscopic index was more than 10 [9]. In 73.42% of cases (n = 58), the patients had a moderate-severe course of AD - patients in whom the SCORAD index was 30-50 and the dermatoscopic index was 5-10. In 15.19% of cases (n = 12), the patients had a mild course of AD - patients in whom the SCORAD index was less than 30 and the dermatoscopic index was less than 5.
Among the patients of group 2, the study revealed in 7.14% of cases (n = 2) a severe course of eczema -patients in whom the SCORAD index was more than 50 and the dermatoscopic index was more than 10. In 67.85% of cases (n = 19) - a moderate-severe course of the disease was established -- patients in whom the SCORAD index was 30-50 and the dermatoscopic index was 5-10. In 25% of cases (n = 7), patients had a mild course of eczema, the SCORAD index was less than 30 and the dermatoscopic index was less than 5 (Table 4).
Table 4
Distribution of patients due to the severity of the disease according to the results
Number of detected cases
Severity of the disease Group 1 (n=79) Group 2 (n=28)
n % n %
Severe form 9 11,39 2 7,14
Moderate to severe form 58 73,42 19 67,85
Light form 12 15,19 7 25,0
Among patients with severe and moderately severe forms of AD (n = 67), a resistant form of the disease was found in 46.27% (n = 31) of cases. In these patients, the disease was difficult to treat; single lesions persisted 6 weeks after the treatment. An often long-term relapsing form of the disease, in which exacerbations occurred 4 or more times a year, was
found in 29 (43.28%) patients with severe and moderately severe forms of AD (n = 67). Also, among this group of patients, 9.09% (n = 6) cases of continuously-relapsing course were identified - these are patients with a severe form of the disease, in whom, based on the anamnesis, according to the patient, there was no stable remission within 6 months (Table 5).
Table 5
Note - * p <0.05, in comparison with the indicators of patients in the control group
The frequency of detection of resistant and relapsing forms of AD and eczema in patients with severe and
Number of detected cases
Disease form Group 1 (n=67) Group 2 (n=21)
n % n %
Resistant forms 31 46,27 11 52,38
Often long-term relapsing forms 29 43,28 8 38,09
Continuously-relapsing forms 6 9,09 2 9,52
Among patients with severe and moderately severe forms of eczema (n = 21), a resistant form of the disease was established in 52.38% (n = 11) of cases. An often long-term relapsing form of the disease (exacerbations 4 or more times a year) was found in 8 (38.09%) patients. Continuously-relapsing course of eczema was detected in 9.52% of cases (n = 2) (Table 5).
When analyzing the expression level of genes for biotransformation of xenobiotics in patients of the main
(patients with AD and eczema) and control groups, statistically significant differences were revealed in the expression of genes HMOX2 (p = 0.016), BLVRA (p = 0.021) (Table 6), in patients with AD and eczema, a higher expression of these genes was noted compared in patients in the control group. There were no significant differences in the levels of normalized expression of the studied genes between patients in group 1 and group 2.
Table 6
Values of the percentage of the level of normalized expression of genes for biotransformation of
Gene normalized expression level (NEL), Me (min.. .max) (%) P
Group 1 (n=79) Group 2 (n=28) Main group (n= 107) Control group (n=30)
UGT1A7 0,07 (0.8,02) 0,03 (0.6,74) 0,04 (0.8,02) 0,007 (0.0,01) 0,059
HMOX2 0,005 (0.42,04) 0,001 (0.37,22) 0,001 (0.42,04)* 0 0,016
BLVRA 0,019 (0.83,51) 0,014 (0.78,25) 0,016 (0.83,51)* 0 0,021
CCL13 9,01 (0.61,13) 7,69 (0.57,46) 8,13 (0.61,13) 3,64 (0.12,33) 0,072
APOBR 0,014 (0.49,31) 0,011 (0.47,19) 0,012 (0.49,31) 0 0,054
ABCC2 3,12 (0.63,29) 2,77 (0.60,07) 2,91 (0.63,29) 2,35 (0.7,80) 0,270
GSTP1 13,07 (0.43,53) 11,45 (0.40,27) 12,59 (0.43,53) 17,74 (0.29,12) 0,061
ABCG2 0,1 (0.38,42) 0,087 (0.35,86) 0,09 (0.38,42) 0 0,077
GSTM1 0,091 (0.6,16) 0,057 (0.5,42) 0,079 (0.6,16) 0,14 (0.1,13) 0,315
Due to the high frequency of lack of expression of the genes UGT1A7 (64,49%), HMOX2 (63,55%), BLVRA (59,81%), CCL13 (63,33%), APOBR (79,44%), GSTM1 (71,5%) in patients of the main
At the same time, the frequency of detecting the expression of the genes UGT1A7, HMOX2, BLVRA, CCL13, APOBR, GSTM1 was significantly higher in the group of patients with AD and eczema (p<0.05).
The analysis of the relationship between the detection in a patient of a resistant, often long-term relapsing or continuously-relapsing form of the disease
study group, during further statistical analysis, these genes were considered as nominal (the absolute and relative number of patients with the presence/absence of expression of these genes was estimated) (Table 7).
and the frequency of detection of expression of genes for biotransformation of xenobiotics (NEL of 2 or more genes > 0) was carried out using contingency tables and the Pearson x2 test (Table 8). The analysis revealed significant associations between resistant, often long-term relapsing or continuously-relapsing forms of the disease and the frequency of detecting expression of
Table 7
Analysis of the frequency of detecting the expression of genes for biotransformation of xenobiotics _in the skin of patients in the main and control groups__
Gene Patients with a gene expression, n (%) P
Main group (n=107) Control group (n=30)
UGT1A 7>0 38 (35,51) 8 (26,67) 0,021
HMOX2>0 39 (36,45) 0 (0) 0,004
BLVRA>0 43 (40,19) 0 (0) 0,005
CCL13» 73 (68,22) 11 (36,67) 0,011
APOBR» 22 (20,56) 0 (0) 0,004
GSTM1>0 23 (21,50) 4 (13,33) 0,033
genes for biotransformation of xenobiotics (NEL of 2 or more genes > 0) (p<0.05).
Table 8
The results of the analysis of the presence of a relationship between the form of the disease and the frequency of detecting the expression of genes for biotransformation of xenobiotics
Disease form Value x2, p
Group 1 Group 2
x2 P x2 p
Resistant forms 44,72 0,003 21,26 0,004
Often long-term relapsing forms 39,51 0,006 25,17 0,001
Continuously-relapsing forms 58,22 <0,001 26,33 <0,001
Next, the authors analyzed the relationship between the levels of normalized expression of genes for biotransformation of xenobiotics (UGT1A7, HMOX2, BLVRA, CCL13, APOBR, ABCC2, GSTP1, ABCG2, GSTM1) and various forms of the course of the disease in examined patients with AD and eczema. According to the course of the disease, the patients were divided into 4 subgroups:
1. subgroup 1 - patients with a resistant form (the disease was difficult to treat, single lesions persisted 6 weeks after the treatment) - n=42
2. subgroup 2 - patients with often long-term relapsing form of the disease (exacerbations 4 or more times a year) - n=37
3. subgroup 3 - patients with a continuously-relapsing course of the disease (according to the history
Association of expression of genes with a resistant for
data, there was no stable remission for 6 months or more) - n=8.
4. subgroup 4 - patients with the usual course of the disease - n=20.
For the genes UGT1A7, HMOX2, BLVRA, CCL13, APOBR, GSTM1 the trait was considered nominal, due to the high frequency of their absence in the samples. Based on the results of the univariate analysis, it can be concluded that the chance of a patient having a resistant form of AD and eczema is significantly higher in the presence of expression of the genes UGT1A7 (p=0.042), HMOX2 (p=0.021), BLVRA (p=0.003) (Table 9). For other genes, no effect of the level of normalized expression for the presence of epidermal atrophy (p> 0.05) was found.
Table 9
r biotransformation of xenobiotics of AD and eczema
Gene Subgroup 1 -resistant form (n=42) Subgroup 4 -normal form (n=20) P
UGT1A7>0, n (%) 25 (59,52) 3 (15,00) 0,042
HM0X2>0, n (%) 28 (66,67) 5 (25,00) 0,021
BLVRA>0, n (%) 30 (71,43) 4 (20,00) 0,003
CCL13>0, n (%) 24 (57,14) 9 (45,00) 0,061
APOBR>0, n (%) 7 (16,67) 3 (15,00) 0,074
GSTM1>0, n (%) 9 (21,43) 4 (20,00) 0,063
ABCC2, Me (min.. .max) 3,22 (0...63,29) 1,25 (0.31,44) 0,071
GSTP1, Me (min.max) 10,07 (0.43,53) 8,52 (0.29,43) 0,063
ABCG2, Me (min.. .max) 0,11 (0.38,42) 0,04 (0.20,61) 0,054
Further, the criterion of the presence or absence of often long-term relapsing forms of the disease in patients (exacerbations 4 or more times a year) was used as a ranking factor. According to the results of statistical analysis, it can be concluded that the chance
of a patient having often long-term relapsing forms of AD or eczema is significantly higher when the expression of the CCL13 gene is detected (p=0.011) (Table 10).
Association of expression of genes for biotransformation of xenobiotics
Table 10
Gene Subgroup 2 - often long-term relapsing form (n=37) Subgroup 4 - normal form (n=20) P
UGT1A 7>0, n (%) 8 (21,62) 3 (15,00) 0,56
HM0X2>0, n (%) 5 (13,51) 5 (25,00) 0,31
BLVRA>0, n (%) 7 (18,92) 4 (20,00) 0,76
CCL13>0, n (%) 36 (97,30) 9 (45,00) 0,011
APOBR>0, n (%) 5 (13,51) 3 (15,00) 0,44
GSTM1», n (%) 8 (21,62) 4 (20,00) 0,83
ABCC2, Me (min.max) 2,87 (0.52,75) 1,25 (0.31,44) 0,071
GSTP1, Me (min.max) 8,56 (0.36,11) 8,52 (0.29,43) 0,063
ABCG2, Me (min.max) 0,27 (0.21,44) 0,04 (0.20,61) 0,054
Further, the criterion of the presence or absence of a continuously-relapsing course of the disease in patients was used as a ranking factor (according to the anamnesis, there was no stable remission for 6 months or more). According to the results of statistical analysis, it can be concluded that the chance of a patient with a
continuously-relapsing form of AD or eczema is significantly higher when the APOBR gene expression is detected (p=0.012) and the level of normalized expression of the ABCC2 gene is more than 32% (p=0.042) (Table 11).
Association of expression of genes for biotransformation of xenobiotics
Table 11
Gene Subgroup 2 - often long-term relapsing form (n=37) Subgroup 4 - normal form (n=20) P
UGT1A7», n (%) 2 (25,00) 3 (15,00) 0,27
HMOX2X), n (%) 1 (12,50) 5 (25,00) 0,21
BLVRA>0, n (%) 2 (25,00) 4 (20,00) 0,63
CCL13>0, n (%) 4 (50,00) 9 (45,00) 0,31
APOBR>0, n (%) 7 (87,50) 3 (15,00) 0,012
GSTM1>0, n (%) 2 (25,00) 4 (20,00) 0,33
ABCC2, Me (min.max) 25,19 (20,71.63,29) 1,25 (0.31,44) 0,042
GSTP1, Me (min.max) 7,21 (0.32,55) 8,52 (0.29,43) 0,080
ABCG2, Me (min.max) 0,07 (0.27,69) 0,04 (0.20,61) 0,072
Conclusions. In the course of the studies, a reliable association of the form of the course of AD and eczema (resistant, often long-term relapsing, continuously-relapsing) was determined with the identification of the expression of genes for biotransformation of xenobiotics in the skin of patients. It was found that the presence of a resistant form of AD and eczema in a patient is associated with the expression of the genes UGT1A7 (p=0.042), HMOX2 (p=0.021), BLVRA (p=0.003); often long-term relapsing form - with expression of the CCL13 gene (p=0.011); continuously-relapsing form - with expression of the APOBR gene (p=0.012) and the detection of the level of normalized expression of the ABCC2 gene is more than 32% (p=0.042). The data obtained in the course of the study make it possible to recommend the use of a method for assessing the expression levels of genes for biotransformation of xenobiotics in skin scrapings, based on real-time PCR, for early diagnosis and an objective choice of treatment tactics in patients suffering from resistant, often long-term relapsing, continuously-relapsing forms of AD and eczema.
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2.Okhlopkov V.A. Federal Clinical Guidelines for the Management of Patients with Eczema. Moscow, 2013, 18 p.
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4.Gushchin I. S. Epidermal Barrier and Allergy. Rossiyskiy allergologicheskiy zhurnal - Russian Allergy Journal, 2007, no. 2, pp. 3-16.
5.Grice E. A. et al. Topographical and Temporal Diversity of the Human Skin Microbiome. Science, 2009, no. 324 (5931), pp. 1190-1192.
6.Pease, J. E. Chemokines and Their Receptors in Allergic Disease. The Journal of Allergy and Clinical Immunology, 2006, no. 118, pp. 305-318.
7.Shimanskaya, I. G., Kostiuk, S. A., Rudenkova, T. V., Milkoto, N. A., Solovej, O. M. Clinical Characteristics and Some Biochemical Blood Parameters in Patients with Atopic Dermatitis and Eczema. Dermatovenerologiya. Kosmetologiya -Dermatovenerology. Kosmetology, 2018, vol. 4, no 4. - pp. 401-412.
8.Rudenkova T. V., Kostiuk S. A., Milkoto N. A., Shimanskaya I. G. Development of a Method for Determining the Expression Levels of Xenobiotic Biotransformation Genes in the Skin of Patients.
Dermatovenerologiya. Kosmetologiya -
Dermatovenerology. Kosmetology, 2019, vol. 5, no. 4, pp. 357-367.
9.Milkoto N.A. Comprehensive Analysis of Clinical-Anamnestic Data and Results of Molecular-Genetic Identification of Dermatophytes, Yeast, Malaseisia in Patients with Atopic Dermatitis and Eczema. Yevraziyskiy soyuz uchenykh - Eurasian Union of Scientists, 2019, no. 9, vol. 66, pp. 12-21.
10.Rudenkova Tatyana Vladimirovna - Leading Researcher of the PCR Diagnostics Group of the Research Laboratory of the State Educational Establishment "Belarusian Medical Academy of Postgraduate Education", Candidate of Biological Sciences;
Address: Minsk, 3 P. Brovki St., building 3.
Tel.: 265-35-82.
Kostiuk Svetlana Andreevna - Chief Researcher of the PCR Diagnostics Group of the Research Laboratory of the State Educational Establishment
"Belarusian Medical Academy of Postgraduate Education", Doctor of Medical Sciences, Professor;
Address: Minsk, 3 P. Brovki St., building 3.
Tel.: 265-35-82.
Shimanskaya Irina Grigorievna - Candidate of Medical Sciences; Associate Professor
Pankratov Oleg Valentinovich - Head of the Department of Dermatovenereology and Cosmetology of the State Educational Establishment "Belarusian Medical Academy of Postgraduate Education"; Doctor of Medical Sciences, Professor;
Address: Minsk, 3 P. Brovki St., building 3.
Tel.: 372-74-40.
Milkoto Nadezhda Alekseevna - Senior Lecturer of the Department of Dermatovenereology and Cosmetology of the State Educational Establishment "Belarusian Medical Academy of Postgraduate Education";
Address: Minsk, 3 P. Brovki St., building 3.
Tel.: 222-89-12.
АНАЛИЗ ПОЛИТИКИ В ОБЛАСТИ ПОСЛЕВУЗОВСКОГО ОБУЧЕНИЯ ВРАЧЕЙ В БОЛГАРИИ
Светлана Радева, д.оз
СБАГАЛ „Проф. д-р Д. Стаматов", гр. Варна, България Проф. д-р Лора Георгиева,д.м
Катедра по социальной медицине и организации здравоохранения,
Медицинский университет Варна
ANALYSIS OF THE POLICY IN THE FIELD OF POSTGRADUATE TRAINING
OF DOCTORS IN BULGARIA
Radeva Svetlana
Specialized hospital of obstetrics and gynecolog for active treatment „D-r D. Stamatov",
Varna Georgieva Lora
Department of Social Medicine and Healthcare Organization,
Medical University of Varna
ABSTRACT
Health workers and the provision of doctors to the population require a thorough analysis of needs, which primarily depend on processes and trends at the European level that exert pressure and affect the sustainability of national health systems. Resource planning in Bulgaria depends on:
1. the processes of changing the state system and related long-term health care reform. Processes at the national level directly form managerial, economic and legal problems in the development of the national system of clinical specialization of doctors. In recent years, the medical profession has lost its prestige, as a result of the long-term underestimation of expert human capital in the health care system as a whole, and the process of acquiring a clinical specialty by doctors.
2. influence of the macro environment. The main problem is the demographic trend of the aging population in Europe, but other factors should be taken into account, such as working conditions in the health systems of member countries and the mobility of health managers. National health policy on the main cause of migration-the acquisition of a clinical specialty by doctors should traditionally follow the best management practices in our country and in other European countries, combined with the capabilities that today's generation has-technological support for medical practice, e-health and telemedicine. This, in turn, requires a transition to the next stage of development of the system of clinical specialization, regulation of new forms of medical training and qualification of doctors, adequate structures and funding.
It is necessary to take measures to transform the models of training and specialty acquisition in accordance with the changing socio-economic environment, constantly developing social relations related to professional implementation and international requirements for the quality of medical training, specialization and medical care of the population.
