Aim. To study the impact of comorbidities on health-related quality of life (QoL) in patients with asthma, and their interaction with disease control.

Materials and methods. We interviewed and examined 360 patients with mild-to-moderate asthma, aged 18 to 62 years, who received standard basic therapy. The examined patients were divided into 2 groups: without concomitant diseases (n=193) and with comorbid conditions (n=167). QoL and the state of the emotional sphere were assessed using the SF-36, AQLQ, HADS questionnaires. The level of asthma control was determined by the ACT questionnaire. The lung function was assessed by means of spirometry

Results. Chronic rhinosinusitis, atopic conditions, obesity or overweight, gastroesophageal reflux disease, diseases of the hormonal system were noted among the most frequent comorbidities. Out of 167 asthma patients with comorbidities, 107 had one, and 60 had two or more comorbid conditions. Analysis of the overall QoL according to the SF-36 questionnaire showed a decrease in physical activity in patients with comorbidities. When analyzing specific QoL according to the AQLQ questionnaire, a significant difference was found in the “Activity” domain, the level of which was lower in the group of patients with comorbidity. Calculation of the odds ratio (OR) showed that the presence of comorbid conditions in a patient with asthma increases the likelihood of a decrease in QoL in the domain of physical activity by 2.7 times, and in the presence of two or more concomitant diseases – by 8.4 times.

Conclusion. The presence of comorbid pathology reduces the physical functioning and general activity of patients with asthma. The chances of a decrease in QoL in the domain of physical activity increase many times in the presence of two or more comorbid conditions. The addition of concomitant diseases eliminates the influence of the emotional state and, in particular, anxiety, on general health, vitality, and the role of physical problems in limiting the life of asthma patients.

Aim. Study of the features of renal blood flow and correction of its disorders in COPD patients at different stages of the formation of chronic cor pulmonale (CCP).

Materials and methods. Examination of 38 patients with COPD complicated by CCP (26 men and 12 women) was carried out, mean age was 61.9±0.56 years, smoking history was 29.6±2.9 pack/years. The complex treatment included Perindopril (Servier, France) for 6th months. The patients were divided into two groups: group 1 included 20 patients with COPD with compensated CCP, group 2 included 18 patients with decompensated CCP.

Results. During treatment in group 1, patients showed normalization of end-diastolic velocity in the interlobar renal arteries (Wilcoxon T-test, p=0.01), pulsation and resistance indices (Wilcoxon T-test, p=0.01), systolic-diastolic ratio of speeds (Wilcoxon T-test, p=0.001). By the end of the observation, the functional capacity of the right ventricle (RV) in patients of group 1 practically did not differ from that of healthy individuals (Mann-Whitney U Test, p=0.1). The left ventricle (LV) ejection fraction increased (Wilcoxon T-test, p=0.1), no signs of diastolic dysfunction were detected. There was a decrease in total peripheral vascular resistance (TPVR) (Student's t-test, p=0.01). An improvement in renal function was observed (Wilcoxon T-test, p=0.001). In patients of group 2, after treatment, there was a significant increase in end-diastolic velocity (Wilcoxon T-test, p=0.02) and a decrease in vascular resistance in the renal arteries (Wilcoxon T-test, p=0.02). A decrease in systolic pressure in the pulmonary artery was revealed (Student's t-test, p=0.01), indicators of diastolic and systolic right ventricle function improved (Wilcoxon T-test, p=0.01). There was an improvement in the contractility of the left ventricle, a decrease in total peripheral vascular resistance. Glomerular filtration rate improved after treatment (Wilcoxon T-test, p=0.01), but did not return to normal (Mann-Whitney U Test, p=0.01).

Conclusion. The use of perindopril in COPD patients with compensated CCP leads to the normalization of pulmonary, intracardiac, renal hemodynamics and improvement of these parameters in COPD patients with decompensated CCP.

Introduction. The pathogenesis of most chronic nonspecific lung diseases (CNSLD) in children is based on a long-term inflammatory process, often leading to the formation of pulmonary fibrosis in the structurally altered tissue, which requires dynamic monitoring of patients, including the study of lung function.

Aim. To assess the indicators of the lung function in children with chronic bronchopulmonary pathology accompanied by pulmonary fibrosis.

Materials and methods. 84 children with CNSLD were examined. The main group consisted of 45 children with CNSLD with pulmonary fibrosis (bronchopulmonary dysplasia, congenital malformations of the lungs, chronic bronchitis, and post pneumonia fibrosis). The comparison group consisted of 39 children with CNSLD without pulmonary fibrosis. The average age of children in the study groups was 9,3±0,48 years. The patients underwent multispiral computed tomography of the lungs with a virtual bronchoscopy program and intravenous bolus contrast enhancement. Evaluation of lung function was carried out by spirometry.

Results. In patients in remission, the average values of the ventilation capacity of the lungs in both groups were within the predicted values. However, in patients with fibrotic changes, pulmonary dysfunction was detected 2 times more often than in children with CNSLD without pulmonary fibrosis (35.5% and 15.4%, respectively, p<0.05). Restrictive ventilation disorders were diagnosed only in the group of patients with pulmonary fibrosis. In children with pulmonary fibrosis, the risk of reduced ventilation capacity is significantly higher than in children with CNSLD without pulmonary fibrosis (OR=3.04, 95% CI 1.049–8.78).

Conclusion. The data obtained can serve as a prerequisite for further development of predicting the nature of the course of the disease, identifying “risk groups” for the development of fibrotic changes for a personalized approach to the treatment and follow-up of patients with CNSLD.

Introduction. In silico methods make it possible to detect low molecular weight ligands with a high affinity for a protein, but cannot answer the question of whether the ligand is its agonist or antagonist.

Aim. Use of a virtual modification of the TRPM8 agonist menthol to solve this problem.

Materials and methods. The structure of menthol was modified using the PyMol computer simulation program, removing the hydroxy group in the meta position and adding two new hydroxy groups in the ortho positions. To identify the features of the docking of menthol and its modified derivative in the TRPM8 molecular pocket, the Galaxy7TM virtual molecular laboratory service was used, which allows to determine which amino acid residues the ligand interacts with by using flexible intermolecular docking methods.

Results. Menthol and its modified derivative form stable complexes with TRPM8, but the hydrogen bonds of the hydroxyl groups of the ligands occur with different amino acid residues.

Conclusion. Using in silico methods, it was possible to modify the structure of menthol and obtain a ligand that binds to TRPM8 differently than natural. The modified ligand does not bind to the key amino acid of the TRPM8 active site, tyrosine 745, and therefore should exhibit antagonist properties. The proposed strategy is universal, will accelerate the search for ligands to various proteins and will facilitate the accelerated search for potential drugs by in silico methods.

Introduction. Tobacco smoking is the most dangerous and significant risk factor for diseases of the circulatory system and an increase in premature mortality

Aim. To study the gender aspects of the prevalence of smoking in connection with the sex and age characteristics and the level of education of patients with diseases of the circulatory system.

Materials and methods. A total of 422 people were interviewed (267 women and 155 men). Sample – target spontaneous filling; the questionnaire was filled out in paper form at an outpatient appointment.

Results. Among the surveyed patients with diseases of the circulatory system, the fact of smoking was confirmed by 29% of men and 6.4% of women. The most common image of a smoking person is a man aged 30-49 years (in this group, 55.6% smoke). Smoking is widespread among men aged 50 and older (every fourth smokes). Among women, the most susceptible to smoking is the age group of 30-49 years (15.3% smokers). Typical quitters include men aged 50-69 (58%) and women aged 30-49 (15.3%). The absence of the habit of smoking tobacco is most characteristic of the generation under the age of 29 years. According to the educational level, men with incomplete secondary and secondary education are susceptible to smoking (47.4% and 34.9%, respectively). Among men with secondary, secondary specialized and higher education, the share of those who quit smoking was relatively high (51.2%, 59.3% and 50%, respectively). The prevalence of tobacco smoking among women compared to men by educational groups is significantly lower: among people with secondary education – by 5.7 times (6.1% vs. 34.9%), with secondary specialized education – by 2.4 times (7.8% vs. 18.6%), with higher education – 5.2 times (5.6% vs. 29.4%).

Conclusion. The data obtained update the development of programs for the prevention of smoking among patients with diseases of the circulatory system, taking into account gender, age and educational groups.

Aim. To develop a new method for quantitative evaluation of digital data of chest CT images of patients with sarcoidosis, to evaluate the diagnostic significance of the obtained quantitative indicators in comparison with functional pulmonary tests.

Materials and methods. Healthy individuals (n=21) and patients with pulmonary sarcoidosis (n=101), divided into 5 groups according to J.G.Scadding classification, were examined. The lung function was assessed according to the data of spirometry, body plethysmography and the study of the lung diffusion capacity. All examined patients underwent a two-stage computed tomography of the lungs in the inspiratory and expiratory phases with the measurement in 3 density ranges.

Results. The values of the obtained quantitative indicators, determined by the new method of CT-densitovolumetry, differed from the control group both in the general group of patients with sarcoidosis and in individual groups according to the J.G.Scadding classification. Correlations were found between radiometric measurements and lung function parameters. In patients with sarcoidosis, a larger volume of poorly ventilated sections was determined in comparison with the healthy group.

Conclusion. The new method of CT-densitovolumetry makes it possible to quantify the entire volume of lung tissue in the area of tomographic coverage, the obtained results can be used as a useful tool in predicting the course of the disease and the response to ongoing therapy.

Aim. To assess the prognostic significance of hematological parameters of endogenous intoxication syndrome at the stage of routing patients with pneumonia associated with COVID-19.

Materials and methods. 146 case histories of patients were analyzed, divided into 2 groups: patients who were referred for treatment to intensive care units based on the results of routing in the admission and diagnostic department (ADD) and patients referred for treatment to pulmonology departments. Upon admission of patients to the hospital, according to the case histories at the stage of ADD, an assessment of the clinical blood test was made, the calculation of hematological indicators of intoxication. Based on the data obtained, a ROC analysis was performed to determine the prognostic significance of hematological indicators of intoxication.

Results. In patients who were in intensive care units, at the stage of sorting in the ADD, the concentration of leukocytes and the percentage of neutrophils were higher by 25.9 and 16.2%, respectively, in comparison with patients referred for treatment to the pulmonology departments, however, the percentage of lymphocytes and the quantitative concentration of erythrocytes was lower by 26.6 and 8.3%, respectively. The integral indicator of intoxication in patients in intensive care was higher by 38.6%, the leukocyte index of intoxication by 74.3% and the index of the ratio of neutrophils to lymphocytes by 81.5%. In patients of the same group, the index of the ratio of neutrophils to monocytes was lower by 28.7%, the index of the ratio of lymphocytes to monocytes by 44.9%. The sensitivity of the integral indicator of intoxication was 73.3%, the specificity was 51.2%; in the leukocyte index of intoxication – 57.3 and 51.2%, respectively; the sensitivity of the index of the ratio of neutrophils to monocytes was 57.3%, the specificity was 59.1%; the same figures for the index of the ratio of neutrophils to lymphocytes were 68 and 60%, respectively.

Conclusion. It can be concluded that there is a rather high clinical prognostic value in the routing of patients with community-acquired pneumonia caused by COVID- 19 at the stage of initial examination in the ADD, such hematological parameters of intoxication as the integral index of intoxication and the index of the ratio of neutrophils to lymphocytes. We believe that hematological indicators of intoxication can complement prognostic scales and be used as another criterion in determining the routing of patients in ADD.

Introduction. Community-acquired pneumonia (CAP) is associated with the development of anemia and its clinical manifestations: hypoxemia and hypoxia, which complicates the course of the disease and leads to the development of adverse pregnancy outcomes. The studies are lack of a comparative description of the main laboratory signs of anemia in pregnant women with COVID-19-associated and bacterial CAP, which has a theoretical and applied significance.

Aim. To carry out a comparative analysis of the clinical indicators of red blood in pregnant women with COVID- 19-associated and bacterial CAP.

Materials and methods. 140 pregnant women were studied in the third trimester of pregnancy, of which 100 participants had CAP of moderate severity (main group) and with uncomplicated pregnancy – 40 (comparison group). The main group included 47 pregnant women with bacterial CAP and 53 participants with COVID-19-associated CAP. All pregnant women were comparable in age and duration of pregnancy. Bacteriological studies of sputum, detection of SARS-Cov-2 RNA in swabs from the oropharynx and nasopharynx by PCR, microscopy of peripheral blood smears, and a clinical blood test were performed.

Results. In pregnant women with COVID-19-associated CAP, compared with pregnant women with bacterial CAP, a number of differences were revealed in laboratory parameters that determine the development of anemia: the total number of erythrocytes was reduced by 1.22 times (p<0.001) and hemoglobin concentration by 1.1 times (p<0.05), the percentage of echinocytes was increased by 1.14 times (p<0.05) and degenerative forms of erythrocytes by 1.16 times (p<0.05).

Conclusion. In pregnant women with COVID-19-associated CAP, compared with pregnant women with bacterial CAP, significant changes in the number and morphological composition of erythrocytes, hemoglobin concentration were revealed, indicating a high risk of developing anemia and concomitant hypoxemia and hypoxia, which adversely affects the course of the disease and leads to development of pregnancy complications.

Introduction. The pandemic of the novel coronavirus infection COVID-19 (NCI) has posed a number of questions for humanity, starting with the impact of the infection on the ability of fetation in a couple, pregnancy outcomes, its complications, and ending with the impact on the health of future generations, including the reproductive one.

Aim. To analyze the register of pregnant women and newborns in the Amur Region with NCI to identify immediate complications of pregnancy and the neonatal period.

Materials and methods. An analysis was made of the registry of pregnant women (n=966) with NCI, newborns from mothers with NCI (n=111) and infected from family members (n=21) in the period from May 1, 2020 to January 1, 2022. A general clinical study of pregnant women and newborns was performed, as well as an analysis of the vaccination of women registered for pregnancy in 2022. Standard statistical data processing methods were used.

Results. 966 women were registered who underwent NCI during pregnancy, which accounted for 6.13% of all births, of which in 2020 – 16.9%, in 2021 –83%. In the Amur Region, the maternal mortality rate, as in the Russian Federation, increased during the pandemic and amounted to 38.2 in 2020, and 68.1 per 100 000 population in 2021; particularly from COVID-19 in 2020 – 12.8, in 2021 – 40.9 per 100 thousand population. At the same time, 17.8% had an asymptomatic course of the disease, 63.4% had a mild course, 17.7% had a moderate course, and 11.14% had a severe course with pathological changes in the lungs. The risk of lung tissue damage was increased by infection in the third trimester of pregnancy (RR – 1.73; 95% CI: 1.04-2.9), age over 30 years (RR – 1.24; 95% CI: 1.01-1 .53), overweight (RR –1.8; 95% CI: 1.5–2.14), and obesity (RR – 1.53: 95% CI: 1.2–1.8). The risk of developing complications of pregnancy significantly increased in women with pathological changes in the lungs (moderate and severe course), in comparison with pregnant women with mild NCI. It was found that 14.4% of newborns from mothers with NCI were born prematurely, 3.6% – in moderate asphyxia. The vertical transmission path was not registered in any case. In 33% of children infected in the neonatal period, NCI proceeded in the moderate, in 67% – in mild severity. Only one in three pregnant women are currently vaccinated. Of these, at the stage of preconception preparation, 77%, during pregnancy – 23%.

Conclusion. NCI is a factor in the severe course of the disease and the development of pregnancy complications in women with pathological changes in the lungs, which increases the risk of maternal and infant mortality.

Aim. To evaluate the mechanisms of regulation of blood flow in the uterine arteries during the formation of chronic placental insufficiency caused by an exacerbation of cytomegalovirus infection (CMVI) in the second trimester of pregnancy.

Materials and methods. The concentration of IL-1β, IFN-γ, IL-4, IL-2 and the systolic-diastolic ratio (SDR) in the right (RUA) and left uterine arteries (LUA) were determined in 90 women in the second trimester of pregnancy, uncomplicated and complicated by exacerbation of CMVI. Retrospectively, 2 groups were distinguished. Group 1 (control) was represented by 30 women with CMV-seronegative physiological pregnancy, group 2 (main) included 60 patients with acute phase of chronic CMVI and consisted of subgroups 1 and 2. Subgroup 1 included 30 women with exacerbation of CMVI, initiating the development of chronic compensated placental insufficiency (CCPI), subgroup 2 − 30 patients with acute phase of chronic CMVI, leading to the formation of chronic subcompensated placental insufficiency (CSPI) in the third trimester of gestation.

Results. In women of the 1st group in the blood serum, the concentration of IL-1β (Me [Q1- Q3]) was 18.0 [13.4-36.3] pg/mL, IFN-γ − 134.4 [114.2-151.3] pg/mL, IL-4 − 26.2 [20.3-51.3] pg/mL and IL-2 − 27.9 [18.2-38.0] pg/mL; SDR in RUA – 1.95 [1.87-2.30] relative units and SDR in LUA – 1.84 [1.73-2.25] relative units. In patients of subgroup 1, in comparison with the control one, the concentration of IL-1β increased to 87.3 [55.6-98.2] pg/mL (p=0.000001), IFN-γ − up to 237.3 [191.4-318.6] pg/mL (p=0.000001) and IL-2 − up to 77.1 [58.6-92.3] pg/mL (p=0.000001) in the absence of statistically significant changes IL-4 level. There was an increase in SDR in RUA up to 2.45 [2.35-3.46] relative units (p=0.000001) and SDR in LUA up to 2.80 [2.31-3.05] relative units (p=0.000001). In subgroup 2, in comparison with subgroup 1, higher values of IL-1β were recorded (1.67 times, p=0.000001), IFN-γ (1.38 times, p=0.000015), IL-2 (1.36 times, p=0.00808), SDR in RUA (by 1.35 times, p=0.0105) and SDR in the LUA (by 1.08 times, p=0.0307), as well as a decrease in the level of IL-4 (by 1.84 times, p=0.000002). In women of subgroup 1, there was a direct relationship between the level of IL-1β, IFN-γ, IL-2 and SDR in the RUA (r=0.54, p<0.01; r=0.74, p<0.001 and r=0.58, p<0.001, respectively). The correlation between IFN-γ and SDR in the LUA was determined (r=0.40; p<0.05). In subgroup 2, there was a relationship between IL-4 and SDR in RUA (r=-0.59; p<0.001), as well as IL-2 and SDR in RUA (r=0.39; p<0.05). A correlation was recorded between the concentration of IL-1β, IFN-γ, IL-2 and the SDR value in the LUA (r=0.39, p<0.05; r=0.58, p<0.001 and r=0.57, p<0.001, respectively).

Conclusion. Exacerbation of CMVI in women in the second trimester of gestation, leading to the formation of CSPI, in contrast to a similar viral infection that initiates the development of CCPI in the third trimester of pregnancy, is characterized by a more pronounced activation of the systemic inflammatory response, an increase in resistance to blood flow, as well as differences in immuno-hemodynamic relationships that determine the maintenance of vascular tone in the basin of the right and left uterine arteries.

Aim. Demonstration of clinical observation of EVALI from the personal practice of the authors.

Materials and methods. A brief review of the literature on the effects of e-liquids on the human respiratory system is presented. Clinical observation of this pathology is given.

Results. Patient H., 19 years old, was admitted to the Thoracic Surgery Department with complaints of shortness of breath, cough with hemoptysis. On computer tomography in lung parenchyma, infiltrates are found in all fields with extensive ground glass areas. Fibrobronchoscopy revealed in the lumen of the bronchi a small amount of hemorrhagic “crusts” and hemorrhagic exudate, catarrhal-hemorrhagic endobronchitis. The patient is a fan of electronic cigarettes, which was not immediately paid attention to. A differential diagnosis was made with Goodpasture's syndrome, idiopathic pulmonary hemosiderosis, systemic lupus erythematosus with lung involvement, and ANCA-associated vasculitis. Since there was nephropathy and there were negative immunological findings of other diseases, a diagnosis of Goodpasture's syndrome was made. A kidney biopsy was not performed. The rapid positive dynamics from hormonal therapy and the absence of relapses and progression raised doubts about this diagnosis. After the disease, the patient refused to take electronic cigarettes. The anamnesis was again addressed, where there were indications of the abuse of electronic cigarettes, after frequent use of which a detailed clinical picture of the disease appeared, the diagnosis of Goodpasture's syndrome was withdrawn, lung damage was regarded as a manifestation of EVALI.

Conclusion. Confirmation of the negative impact of electronic smoking systems is the described clinical case, indicating lung damage in humans and difficulties in the differential diagnosis of EVALI syndrome.

The division of the mediastinum into specific departments is necessary for targeted differential diagnosis of mediastinal masses in imaging studies and planning biopsies and surgical procedures. The majority of radiological classifications are based on arbitrary marks that are conventionally labeled on a lateral chest radiograph. At present, the use of multislice computed tomography (MSCT) with a wide range of post-processing of axial tomographic images has become the gold standard for visualization of diseases of the chest organs. A new scheme based on cross-sectional imaging during MSCT has been developed by the International Thymic Malignancy Interest Group (ITMIG) and adopted as the standard. Using the example of diagnosing some solid formations (own clinical and radiological observations), this article sets out various classifications of the mediastinal sections according to the radiograph of the lungs in the lateral projection, which are the place of priority localization of a number of pathological formations, which greatly simplifies the identification of this pathology.

Introduction. Chronic respiratory diseases are one of the most common types of non-communicable diseases and are an important problem of our time. The induction of oxidative stress, chronic inflammation and hypoxia, which underlie the pathogenesis of chronic diseases of the bronchopulmonary system, can be determined at the cellular and molecular level by impaired mitochondrial functioning.

Aim. This review is devoted to the prospects for assessing the functional state of mitochondria as a fine indicator of the course of chronic respiratory diseases.

Results. The data of domestic and foreign sources on the most important parameters of mitochondrial functioning in normal and chronic bronchopulmonary pathology were analyzed. It has been shown that mitochondria are highly sensitive to changes in both exogenous and endogenous homeostasis. Functional parameters of mitochondria, the level of mitochondrial reactive oxygen species, mitochondrial membrane potential, and fatty acid composition of mitochondrial membranes can be used as diagnostic and prognostic criteria for chronic respiratory diseases. The data presented in the review indicate the need for further studies of the functional state of mitochondria in chronic bronchopulmonary pathology.

Introduction. Cardiovascular diseases remain the leading cause of death, both in Russia and in most other countries, and the problem of cardiovascular disorders in patients with COVID-19 is currently extremely important.

Aim. To summarize the literature data on patterns of development of cardiovascular disorders in patients with COVID-19.

Results. The article presents a literature review of the PubMed and Google Scholar databases on the patterns of development of cardiovascular disorders in patients with COVID-19. The pathogenetic relationship of the viral spike S-protein with angiotensin-converting enzyme 2 in the mechanisms of regulation of the cardiovascular and immune systems was shown. The role of pro-inflammatory cytokines in the formation of inflammation and fibrosis in cardiovascular pathology has been determined. The changes in the cardiovascular system against the background of COVID-19 were demonstrated. The basic principles of the interaction of the SARS-CoV-2 virus with endotheliocytes and cardiomyocytes, the mechanisms of inflammatory reactions that underlie the development of cardiovascular pathology in COVID-19 are described.

Conclusion. An analysis of current data regarding damage to the cardiovascular system in COVID-19 led to the conclusion that, despite considerable achievements in this field of research, many aspects are not fully understood and require further study. The practical significance of this review is determined in the identification of potential therapeutic targets for the prevention of complications in COVID-19, as well as in expanding the possibilities of diagnosing SARS-CoV-2. Probably the crucial importance to reduce complications, as well as associated mortality, is the development of an effective method for modulating the immune response.

In this lecture, we discussed methods and approaches to the diagnosis of small airways dysfunction, such as multiple breath nitrogen washout test, impulse oscillometry, as well as the calculation of poorly communicating fraction (PCF) as the ratio of total lung capacity to alveolar volume. The detection of the small airways dysfunction with the help of the diagnostic tools listed above makes it possible to establish functional disorders of the respiratory system in the early stages of bronchopulmonary diseases, when the results of traditional pulmonary functional tests remain within normal values. Thus, a well-standardized and the most accessible method for detecting the peripheral airways dysfunction is body plethysmography, which is used to diagnose the presence of “air trappings”. However, in the early stages of bronchopulmonary diseases, the possibilities of this method are limited. The lecture focuses primarily on the results of our own researches which were performed on patients who have suffered from a novel coronavirus infection complicated by viral pneumonia. Spirometry, body plethysmography, diffusion test, impulse oscillometry, multiple breath nitrogen washout test were conducted, and PCF index was calculated in all patients included in this analysis. The description of the PCF index, the method of its calculation, the range of normal values, as well as the possibilities of application in clinical practice are given for the first time in the Russian literature. The approaches to assessing the dysfunction of the small airways described in the lecture are not widely used at present, however, we hope that the knowledge that is currently being applied in scientific laboratories will gradually be introduced into routine clinical practice.