MACHINE LEARNING ALGORITHMS IMPLEMENTATION IN THE HEALTHCARE SYSTEM AS A PROSPECTIVE AREA FOR SCIENCE, HEALTHCARE, AND BUSINESS

Relevance. The current state of medicine is imperfect as in every other field. Some main discrete problems may be separated in diagnostics and disease management. Biomedical data operation difficulties are a serious limiting factor in solving crucial healthcare problems, represented in the statistically significant groups of diseases. Accumulation of life science data creates as possibilities as challenges to effectively utilize it in clinical practice. Machine learning-based tools are necessary for the generation of new insights and the discovery of new hidden patterns especially on big datasets. AI-based decisions may be successfully utilized for diagnosis of diseases, monitoring of general health, prediction of risks, treatment solutions, and biomedical knowledge generation. Objective. To analyze the potential of machine learning algorithms in healthcare on exact existing problems and make a forecast of their development in near future. Method. An analytical review of the literature on keywords from the scientometric databases Scopus, PubMed, Wiley. Search depth 7 years from 2013 to 2020. Results. Analyzing the current general state of the healthcare system we separated the most relevant problems linked to diagnostics, treatment, and systemic management: diagnostics errors, delayed diagnostics (including during emergencies), overdiagnosis, bureaucracy, communication issues, and "handoff" difficulties. We examined details of the convenient decision-making process in the clinical environment in order to define exact points which may be significantly improved by AI-based decisions, among them: diagnosis of diseases, monitoring of general health, prediction of risks, treatment solutions, and biomedical knowledge generation. We defined machine learning algorithms as a prospective tool for disease diagnostics and management, as well as for new utilizable insights generation and big data processing. Conclusion. Machine learning is a group of technologies that can become a cornerstone for dealing with various medical problems. But still, we have some problems to solve before the intense implementation of such tools in the healthcare system.

CORRELATION OF GLYCOSYLATED HEMOGLOBIN LEVELS WITH AUDITORY AND VISUAL REACTION TIME IN DIABETICS

Relevance. Diabetes mellitus is a group of metabolic disorders wherein hyperglycemia occurs either due to lack of insulin secretion and/or reduced insulin sensitivity of the tissues. One of the commonest complications of diabetes is neuropathy and its severity will depend on how long and how high the hyperglycemia has been prevalent. Chronic hyperglycemia in diabetes affects the peripheral nerves and slows psychomotor responses in persons who do not have proper glycemic control. This decreased psychomotor response because improper glycemic control affects the reaction time in diabetics. Objective: to assess and compare the auditory and visual reaction time in group-1 and group-2 diabetics and to correlate it with glycosylated hemoglobin (HbA1c) levels in both the groups. Methods. The study was conducted on 60 subjects aged between 40-50 years after obtaining the permission of the ethical committee of our institution. The group consisted of 60 well-controlled diabetic patients (HbA1c < 7%) with a history of diabetes for 1-10 years attending the medical OPD of Basaveshwar teaching and general hospital, Gulbarga. Diabetics with HbA1c 5-6% were grouped as group-1 and those with HbA1c 6-7% as group 2. The visual reaction time for a green and red light and auditory reaction time for tone and click sound were measured by using reaction time apparatus 2x4, Anand agencies Pune. HbA1c was done by the micro-column method. Results. The visual and auditory reaction time of diabetics with HbA1c 5-6% was faster as compared to the diabetics with HbA1c 6-7% with P< 0.001 and a statistically significant positive correlation was found between HbA1c levels and the visual and auditory reaction time. Conclusion. Poor glycemic control slows psychomotor responses and thus affects the visual and auditory reaction time.

CLINICAL AND MICROBIOLOGICAL SUBSTANTIATION OF TOPICAL APPLICATION OF SORPTION HYDROPHILIC/HYDROPHOBIC COMPOSITION BASED ON NANOSILICA IN THE TREATMENT OF PATIENTS WITH BURNS

Relevance.One of the promising methods of treatment of patients with burns is the local use of sorption agents with antimicrobial properties. Objective: experimental study of antimicrobial properties and clinical evaluation of the effectiveness of local use of a new sorption composition based on nanosilica in the complex treatment of patients with burns. Materials and methods. The suggested sorption nanocomposition included highly dispersed silicon dioxide, polymethylsiloxane, decamethoxine, metronidazole. The experimental study involved the study of the antimicrobial properties of the sorption nanocomposition and antimicrobial agents which are part of it. The clinical material consisted of the results of examination of 42 patients with IIab-III degree burns with an area of 10-30% of the body surface. Depending on the tactics of local treatment, patients were divided into 2 groups: after early necrectomy, xenodermoplasty, the wound surface of the patients in the main group (n = 20) was treated with a solution of decamethoxine in combination with the same sorption powder. Treatment in the comparison group (n = 22) was similar except the use of sorption drugs. The examination included visual inspection of the injured area in combination with microbiological monitoring of the wound contents on the 3rd,7th,14th day. Results. The obtained results confirmed the sufficient antimicrobial potential of the studied sorption nanocomposition, the properties of which are not inferior to the existing antiseptics for museum and clinical strains of microorganisms and fungi. Signs of a more favorable wound healing process of the patients in the main group were observed: faster wound cleaning, less inflammatory reactions and much shorter preparation of wounds for grafting. Conclusions. The obtained results convincingly indicate the effectiveness of a multicomponent composite based on nanosilica with antimicrobial components in a comprehensive treatment of patients with burns.

ECOLOGICAL AND HYGIENIC ASSESSMENT OF NEW PESTICIDES FOR GRAIN CEREALS CHEMICAL PROTECTION

Relevance. The use of pesticides in the national economy is to destroy or inhibit the growth of harmful plants and to protect crops from pathogens requires a mandatory assessment of their environmental hygienic hazard. Objective of our study is to assess the hazards of three new pesticides for cereal grains protection: amicarbazone from the chemical class of triazolinone compounds, bicyclopyrone from the class of tricetones and pydiflumetofen from the class of carboxamides, in terms of ecotoxicity and environmental behavior. Materials and methods. Hazard assessment of amicarbazone, bicyclopyrone and pydiflumetofen was performed on the basis of data sources on their physico-chemical characteristics, toxicometry parameters for different species of living things and indicators of environmental behavior. For potential hazards integral assess for terrestrial ecosystems an ecotox was calculated taking into account mammalian toxicity, persistence and maximum rate consumption. To identify the limiting section of migration, the mathematical modeling was performed in the systems "soil-water", "soil-plants" and "soil-atmospheric air". Results. Amicarbazone has been shown to be extremely toxic to algae and highly toxic to higher aquatic plants (HAP) (hazard class I), moderately toxic (class IV) to mammals, mildly toxic (class III) to birds, soil mesofauna and invertebrates, virtually non-toxic to bees and fish; bicyclopyrone - extremely toxic to HAP (class I) and moderately toxic (class II) to the most sensitive algae, mildly toxic (class III) to birds, fish and invertebrates and virtually non-toxic to other terrestrial fauna; pydiflumetofen is highly toxic (class I) to fish and invertebrates, moderately toxic (class II) to algae and HAP, virtually non-toxic to all terrestrial biota. Pydiflumetofen has been shown to be a highly resistant and poorly mobile in soil; amicarbazone is stable and mobile; bicyclopyrone is highly resistant in laboratory experiments and moderately stable in field experiments, its mobility varies in a wide range: from very mobile to less mobile in some soils. The danger for terrestrial biocenoses of all studied pesticides under different soil and climatic conditions is lower by (1–5) orders of magnitude in comparison with DDT; the lowest is the ecotoxicity of bicyclopyrone, the highest – pydiflumetofen. All test substances are highly stable in water. The leading section of their migration in environment is the system "soil – water of ponds" and in case of pydiflumetofen – "soil – plants" as well.

THE RELATIONSHIP BETWEEN PLACENTAL GROWTH RATES AND THE BIRTH WEIGHT IN DICHORIONIC DIAMNIOTIC TWINS

Relevance. Birth weight is one of the main indicators of intrauterine fetal development. The condition of the placenta reflects the influence of the maternal environment on the fetus. It is important to find out which placental growth parameters significantly affect the mass of dichorionic diamniotic (DHDA) twins. Objective: to investigate the relationship between indicators of placental growth and birth weight of dichorionic diamniotic twins. Materials and methods. One hundred thirty-five DCDA twin pairs were studied during 2016-2020: 68 pairs were opposite-sex, 32 – same-sex females and 35 – same-sex males. The gestational age ranged from 29 to 39.5 weeks, averaging 36,4 ± V1,74 weeks. The influence of such parameters as maximum and minimum placental diameters, as well as perimeter, area, circularity (Circ), roundness, thickness, mass (PM), volume (V), displacement of the umbilical cord insertion site from the placental disc centre along its maximum (XCD) and the minimum axis (YCD). Results. A strong positive correlation was found between PM and birth weight in the whole cohort of DCDA twins (r = 0.7059, p < 0.0001). It was strongest in the same-sex female group (r = 0.7886, p < 0.0001), then in the opposite-sex pairs (r = 0.7093, p < 0.0001), slightly weaker – in the same-sex male couples (r = 0.6065, p < 0.0001). The birth weight and PM correlated with almost all indicators that characterize the placental shape. The strongest correlation was with V (rV_BW = 0.66, p < 0.0001; rV_PM = 0.59, p < 0.0001) and the area*Circ (rS*Circ_BW = 0.64; p < 0.0001; rS*Circ_PM = 0.62; p < 0.0001). The multiple regression analysis of the effect of different morphometric parameters of the placentas on the birth weight has demonstrated the statistical significance of the following parameters: XCD, PM, V, YCD and Circ. The general regression model for the whole DCDA group: birth weight = 2242,3 + 0,8*МП + V – 10,0* XCD (R2 = 0,7002). Similar equations were calculated for different types of DCDA tweens. Thus, morphometric measures account for the 67-85% variances of the birth weight of the DCDA tweens. Conclusion. In the DCDA pairs, placental mass strongly positively correlated with birth weight. Both indicators are in strong relationship with V and their area*Circ. The closer the placental shape is to the circle, the higher its functional ability. Deterioration of the latter may be due to the far fixation of the umbilical cord from the center of the placental disc. The displacement along the maximum axis has a stronger impact comparing to the displacement relative to the minimum axis. The multiple regression analysis has revealed that statistical significance had XCD and PM or V in the whole types of twins. Proposed models demonstrate that 67-85% of the variability of birth weight may be accounted for by the three or four simple placental measures

ACTIVITY OF ANGIOTENSIN-CONVERSING ENZYME-2 IN ACUTE PULMONARY INFLAMMATION

Relevance. Angiotensin converting enzyme-2 (ACE2), which is the gateway to coronavirus, is also an important component of the tissue renin-angiotensin system with a number of anti-inflammatory effects. It is known that ACE2 is expressed in the lungs of patients with coronavirus pneumonia, but it is not clear how this depends on the stages of development and the severity of inflammation. Objective: to establish the effect of acute inflammation on pulmonary expression of angiotensin-converting enzyme-2. Material and methods. In Wistar rats (n=20), in compliance with bioethical standards, a sterile nylon thread 2.5 cm long and 0.2 mm thick to a depth of 2.5 cm was introduced into the trachea. The animals were observed and removed from the experiment at 7, 14, 21 and 28 days, microscopic and immunohistochemical (monoclonal antibodies against ACE2; clone 4G5.1; EMD Millipore Corporation; Temecula, CA US) studies were performed. Results. The microscopic picture of the lungs indicated the development of acute bronchopulmonary inflammation during the first week, the formation of peribronchial and alveolar abscesses in the second week with the onset of resolution of bronchopneumonia with the organization of abscesses in the third week and the development of diffuse fibrosis of the parenchyma and vascular hyalinosis in the fourth week of observation. The exudative phase of acute inflammation was accompanied by inhibition of ACE2 activity in bronchial epithelial cells, type II alveolocytes and vascular endothelium. With the transition of inflammation to the stage of proliferation and fibrosis, ACE2 activity was restored. Conclusion. The detected phase change in ACE2 activity can cause a wavy recurrent course of coronavirus infection, since an increase in the amount of ACE2 protein during attenuation of acute inflammation contributes to an increase in target cell infection.

EFFECT OF PARENTERAL INFLUENZA VACCINATION ON THE CELL COMPOSITION AND ITS MICROBIOTA OF THE OROPHARYNGEAL SECRETION IN PATIENTS WITH CHRONIC INFLAMMATORY DISEASES OF THE UPPER RESPIRATORY TRACT

Relevance. Until recently, the issues of changes in immunological and microbiological parameters of the oropharynx in vaccinated against viral infections remain insufficiently covered. Objective: to determine the effect of parenteral influenza vaccination on the cellular and microbial composition of the oropharyngeal secretion in patients with chronic inflammatory diseases of the upper respiratory tract with the presence of anamnestic antibodies to vaccine strains of viruses. Materials and methods. Oropharyngeal secretion samples of 18 patients with chronic inflammatory diseases of the upper respiratory tract studied before and 3, 12, and 36 weeks after vaccination with inactivated split influenza vaccine. As control 25 donors were used. The cell composition of the sediment was determined. A microbiological study of the oropharyngeal secretion was performed. Results. At 3 and 12 weeks after vaccination, vaccinated patients significantly changed the relative rates of entry into the oropharyngeal secretion of lymphocytes and the composition of its microbiota while maintaining its total number. After 36 weeks, the cell composition and the representation of pathogenic and opportunistic microflora practically returned to baseline with a significant increase in the total microbiota. Conclusions. Parenteral administration of inactivated split vaccine to persons with chronic inflammatory diseases of the upper respiratory tract with the presence in the blood of anamnestic antibodies to vaccine strains of viruses is accompanied by a simultaneous temporary increase in lymphocyte representation with a simultaneous decrease in the number of transfusion microflora in the oropharyngeal secretion.

EVALUATION OF THE THERAPEUTIC EFFECT OF THE COMBINED USE OF CRYOPRESERVED PLACENTA EXTRACT AND DICLOFENAC SODIUM IN EXPERIMENTAL RHEUMATOID ARTHRITIS BY HEMATOLOGICAL PARAMETERS

Relevance. Cryopreserved placenta extract (CPE) increase the resistance of the mucous membrane of the gastrointestinal tract to the damaging effects of nonsteroidal anti-inflammatory drugs. Preventive administration of CPE can reduce the ulcerogenic effect of meloxicam, ibuprofen, diclofenac sodium (DS) and others. There is evidence of CPE's own anti-inflammatory activity, which can be successfully combined with the pharmacological properties of nonsteroidal anti-inflammatory drugs, while improving their safety profile. Objective: to characterize the therapeutic activity of the combined use of CPE and DS according to hematological parameters in the model of experimental rheumatoid arthritis (RA). Materials and methods. Studies were performed on 28 nonlinear laboratory rats. The rats were divided into 4 groups: I (n = 7) – intact rats; II (n = 7) – rats with experimental RA; ІІІ (n = 7) – rats with experimental RA, treated with DN; IV (n = 7) – rats with experimental RA, treated with DN and CPE. Adjuvant arthritis was modeled by subplantar administration of complete Freund's adjuvant. Treatment was performed from 14 to 28 days. CPE was administered on days 14, 17, 20, 23 and 26, and DS – daily. Blood tests were performed on day 28 of the experiment. Results. The combined use of CPE and DS is accompanied by a more pronounced leveling of inflammatory signs by hematological parameters – erythrocyte clotting rate decreased by 72.2% (p<0.001), and the number of leukocytes decreased by 54.81% (p<0.001) relative to rats with adjuvant arthritis without treatment. There was a leveling of signs of anemia of chronic inflammation – the level of hemoglobin and erythrocytes increased (p<0,001) by 17.6% and 36.8%, respectively, relative to rats with adjuvant arthritis without treatment. Conclusions. The combined use of CPE and DS is superior in therapeutic activity to monotherapy with this nonsteroidal anti-inflammatory drug of experimental rheumatoid arthritis.

THE RESULTS OF THE SEARCH FOR LABORATORY SIGNS OF AUTOIMMUNE REACTIONS TO CEREBRAL AND EXTRACEREBRAL AUTOANTIGENS IN CHILDREN WITH AUTISM SPECTRUM DISORDERS ASSOCIATED WITH GENETIC DEFICIENCY OF THE FOLATE CYCLE

Relevance. The results of five meta-analyzes of randomized controlled clinical trials indicate an association between genetic deficiency of the folate cycle (GDFC) and autism spectrum disorders (ASD) in children. Autoimmune mechanisms play a special role in the pathogenesis of encephalopathy in children with ASD associated with GDFC. Objective: to study the structure of autoimmune reactions in children with ASD associated with GDFC, according to the accumulated evidence base and to identify associations of laboratory signs of autoimmunity and microorganisms to improve understanding of encephalopathy pathogenesis and diagnostic, monitoring and treatment algorithms. Materials and methods. The medical data of 225 children aged 2 to 9 years with GDFC, who had clinical manifestations of ASD (183 boys and 42 girls) were retrospectively analyzed. The diagnosis of ASD was made by child psychiatrists according to the criteria DSM-IV-TR (Diagnostic and Statistical Manual of mental disorders) and ICD-10 (The International Statistical Classification of Diseases and Related Health Problems) (study group; SG). The control group (CG) included 51 clinically healthy children (37 boys and 14 girls) of similar age and gender distribution who did not suffer from GDFC and ASD. Pathogenic polymorphic variants of folate cycle genes were determined by PCR with restriction (Sinevo, Ukraine). Autoantibodies to autoantigens of CNS subcortical ganglion neurons in blood serum were determined using a Cunningham panel (Moleculera Labs, Inc, USA). Serum autoantibodies to neurons of the mesolimbic system of the brain were identified by ELISA (MDI Limbach Berlin GmbH, Germany). Autoimmunization to myelin was assessed by serum autoantibody titer to basic myelin protein (ELISA) and signs of neutrophil and CD8+ T-lymphocyte sensitization to hemispheric white matter autoantigens (cell-based assay; department of neuroimmunology at the Neurosurgery Institute; Ukraine). Serum autoantibodies to nuclei of connective tissue cells and striated muscle proteins were determined by western blot analysis (Sinevo, Ukraine). To determine the significance of the differences between the indicators in the observation groups, we used the Student's parametric T-test with the confidence probability p and the nonparametric criterion – the number of signs Z according to Urbach Yu.V. The odds ratio (OR) and the 95% confidence interval (95% CI) were used to study the associations between the studied indicators. The study was performed as a fragment of research work commissioned by the Ministry of Health of Ukraine (№ state registration 0121U107940). Research. Positive results of the Cunningham panel occurred in 32%, laboratory signs of autoimmunization to neurons of the mesolimbic system – 36%, myelin of white matter of the hemispheres – 43%, nuclei autoantigens of connective tissue cells – 53%, proteins of striated muscles – 48% of cases among children SG (in general – 68% of cases; p < 0.05; Z < Z0.05). Serological signs of autoimmunization to autoantigens of the subcortical ganglia of the cerebral hemispheres were associated with Streptococcus pyogenes and Borrelia, to neurons of the mesolimbic system – EBV, HHV-6, HHV-7, Toxoplasma and TTV, to CNS myelin – EBV, HHV-6, HHV-7, Borrelia and TTV, to the nuclei of connective tissue cells and striated muscles – EBV, HHV-6, HHV-7, Borrelia and TTV. Conclusions. In children with ASD associated with GDFC laboratory sings of microbial-induced autoimmunity to a number of cerebral and extracerebral autoantigens has been evaluated, which affects the mental and physical health of patients and is a potential target for effective therapeutic interventions.

MOLECULAR-GENETIC ASPECTS OF KABUKI MAKEUP SYNDROME. Review

Relevance. Kabuki Makeup Syndrome (KS) is a rare monogenic genetic disease characterized by multiple malformations. The phenotype includes specific facial features, skeletal and dermatoglyphic abnormalities, mental retardation, short stature. Most cases are associated with de novo mutations in the KMT2D and KMD6A genes. However, in 25% of patients with KS, the genetic basis remains unknown, which indicates the genetic heterogeneity of the disease and encourages further accumulation of clinical experience in KS. The article summarizes current data on the molecular geneticі aspects of the development of Kabuki Makeup Syndrome and describes its own clinical case of Kabuki Makeup Syndrome Type I. Objective: to summarize the data on modern molecular-genetic aspects of the development of Kabuki makeup syndrome on the example of a clinical case. Materials and methods. Analysis of scientific publications in the international electronic scientometric database Scopus, PubMed by keywords. Search depth – 15 years (2007-2021). The clinical case of Kabuki Makeup Syndrome from our own practice. Clinical and genealogical, molecular-genetic, cytogenetic, instrumental research methods. Results. According to current data, the development of Kabuki Makeup Syndrome is due to mutations in the KMT2D (MLL2) gene, which belongs to the genes that control embryogenesis. KMT2D functions as a promoter of the expression of other genes and the KDM6A gene; encodes a large multidomain protein that interacts with the SET1/COMPASS complex. KDM6A is a cofactor physically associated with the KMT2D-COMPASS complex and exhibits demethylase activity in histone 3. Gene mutations KMT2D and KDM6A associated with KS lead to a lack of functioning of the corresponding enzyme, which leads to impaired methylation of histones and active genes in many organs and tissues of the body. Depending on the type of mutation in the KMT2D and KMD6A genes, there are two types of Kabuki Makeup Syndrome. KS type 1 with autosomal dominant type of inheritance due to pathogenic mutations in the KMT2D gene in a heterozygous state on chromosome 12q13.12. 70% of patients have KS1. Type 2 KS is an X-linked disease that develops as a result of a heterozygous pathogenic mutation in the KDM6 gene. In most cases, KS mutations are sporadic, but families with parent-to-child transmission have been described. In patients with phenotypic signs of KS pathogenic mutations are detected in 75% of cases. Pathogenic mutations in the KMT2D gene can be detected in mosaic form, and the carrier can pass this mutation on to offspring. Pathogenic mutations have not been described in phenotypically healthy people. Here is our own observation. The girl with a combined congenital heart defect and multiple stigmas of dysembryogenesis was born at 36 weeks with a weight of 2930, 49 cm long, on the Apgar scale 8/8 points from the third planned pregnancy in parents who already had an older healthy boy. In connection with multiple malformations, the girl underwent a syndromic diagnosis using the program "Face2gene"; Kabuki Makeup Syndrome is suspected. Molecular genetic analysis revealed a pathogenic mutation (c.11884C>T) (p.Gln3962*) in the KMT2D gene, which is associated with autosomal dominant Kabuki Makeup Syndrome of type 1 (MedGen UID: 893727). Conclusions. Kabuki Makeup Syndrome has clinical and molecular polymorphisms. Most of the registered KMT2D mutations occur de novo and occur in episodic cases. The described case demonstrates the molecular-positive Kabuki Makeup Syndrome of type I. The identified variant c.11884C>T(p.Gln3962*) in the KMT2D gene is associated with the autosomal dominant Kabuki Makeup Syndrome (MedGen UID: 893727). Verification of the diagnosis of the disease and prevention of KS in siblings is based on the results of molecular genetic analysis. The prognosis of this disease depends on the severity of heart disease and intellectual impairment. Early diagnosis determines the type and timing of therapeutic interventions, is crucial for medical and genetic counseling of the family.