[The effect of etiopathogenetic therapy of COVID-19 on the severity of the disease: results of a multicenter double-blind placebo-controlled randomized trial].

AIM: The search for etiopathogenetic agents to prevent the development of severe and extremely severe COVID-19 remains relevant. A placebo-controlled randomized clinical trial was conducted to evaluate the efficacy and safety of the antibody-based biological drug (Raphamin). MATERIALS AND METHODS: 785 outpatients 18-75 y.o. with laboratory confirmed mild COVID-19 were included within 24 hours from the disease onset. 771 patients were randomized to the group Raphamin (n=382) and the Placebo group (n=389). The study drug/placebo was prescribed for 5 days. The rate of progression to a more severe degree of COVID-19 by day 28 as well as the time to sustained clinical recovery and the frequency of hospitalization were evaluated. Safety was assessed taking into account adverse events, vital signs and laboratory parameters. RESULTS: The number of cases of progression to a more severe degree of COVID-19 in participants receiving Raphamin was 59 (15.5%) [52 (14.6%)] versus placebo - 89 (22.9%) [85 (23.7%)], ITT and [PP] analysis data are presented. The odds ratio between groups was OR=0.6157 [OR=0.5494], 95% confidence interval 0.4276-0.8866 [0.3750-0.8048], which meant a reduction in the chance of progression to a more severe degree by 38.4% [45.1%] or 1.48 [1.62] times; p=0.0088 [p=0.0019]. The time to sustained recovery in the Raphamin group was 4.5±2.4 [4.6±2.4] days, versus placebo - 5.8±4.7 [6.0±4.8] days; p=0.0025 [p=0.0036]. No adverse events with a certain relationship were registered. CONCLUSION: Raphamin reduces the risk of progression to a more severe degree of the COVID-19 and significantly shortens the duration of clinical symptoms.

[The experience of reforming primary health care in conditions of demographic trends of average population age increasing].

The article presents experience of reforming of primary health care in the Belgorod Oblast in 2016-2019. In the course of reforming the original organizational model of interaction between doctors and patients developed and implemented. The measures were applied to strengthen the material-technical base and personnel potential of primary medical care. The offices of General Practitioners were arranged within step accessibility for patients. The continuous training of family physicians was organized at the workplace. The unified regional medical information system was developed and implemented enabling corporate conference communication, remote consultations, population feedback and remote arrangement of making appointment with physician. The differentiated approach to medical personnel remuneration of labor was brought on the basis of key performance indices that permitted to increase their salary and quality of work. As a result of the reforms, the percentage of people covered by family physicians dispensary observation increased by 13%, number of emergency calls decreased by 3.3% and number of calls because of illness reduced by 17%. The mortality rate of people older than able-bodied age began to decrease and population life expectancy reached prognosticated numbers of 74 years in 2019.

[Pharmacoepidemiological research of COVID-19 in the Russian Federation EGIDA-2020].

AIM: An analysis of coronavirus infection in Russia and evaluation of different AVT regimens effectiveness. MATERIALS AND METHODS: The study involved a retrospective analysis of 1082 patient records with laboratory-confirmed COVID-19 in 17 regions of Russia. The number of men and women was equal, mean age 48.718.1 (median 50). Patients with moderate COVID-19 (85%) versus mild COVID-19 (15%) were characterized by higher age (median 54 vs 21 years; p0.001), higher body mass index (27.8 vs 23.4; p0.001), prevalence of chronic diseases (75.3% vs 8.5%; p0.001), including circulatory system diseases (37.8%). Moderate COVID-19 characterized higher intoxication (10.86.1 vs 4.22.7 days; p0.001) and catarrhal symptoms duration (10.25.4 vs 6.14.1 days; p0.001). RESULTS: During hospitalization 92% of the patients received AVT, 77% antibiotics, and 16% corticosteroids. Umifenovir therapy resulted in a significant reduction of intoxication (8.75.5 vs 11.75.5 days; p0.001) and catarrhal symptoms duration (8.85.1 vs 12.04.9 days; p0.001) compared to the group without AVT. The usage of INF reduced intoxication symptoms compared with the group without AVT (8.97.5 vs 11.75.5; p0.05). Therapy with hydroxychloroquine, imidazolylethanamide pentandioic acid, and lopinavir + ritonavir combination did not affect the course of COVID-19. Most of adverse reactions were related to antibiotics. CONCLUSION: Umifenovir therapy and inclusion of interferon in AVT regimens was associated improvement in the clinical manifestation of the disease among patients.

[The experience of reforming primary health care in conditions of increasing of population average age].

The article presents the experience of reforming primary health care in Belgorod Oblast in 2016-2019. In the process of reforming, the original organizational model of new interaction pattern "family doctor - patient - family members", was developed and implemented. The measures were taken to strengthen material-technical base and manpower potential of primary medical care. The general practitioners offices were positioned within "step accessibility" for patients. The continuous training of family doctors was organized at the workplace. The unified regional medical information system was developed and implemented enabling corporate conference communications, remote consultations, public feedback and remote arrangement of visits of patients to physician. The differentiated approach to remuneration of medical personnel was implemented using key performance indices that permitted to increase salaries and work quality. As a result of the reforms, the percentage of patients under supervision of family doctors increased up to 13%, the number of medical emergency calls decreased up to 3.3% and the number of calls because of illness decreased up to 17%. The mortality of population older than able-bodied age began to decrease and life expectancy reached relevant 74 years in 2019.

Multidrug-Resistant Hypervirulent Klebsiella pneumoniae Found Persisting Silently in Infant Gut Microbiota.

Since the spread of multidrug-resistant Klebsiella pneumoniae (MDRKP) strains is considered as a challenge for patients with weakened or suppressed immunity, the emergence of isolates carrying determinants of hypervirulent phenotypes in addition may become a serious problem even for healthy individuals. The aim of this study is an investigation of the nonoutbreak K. pneumoniae emergence occurred in early 2017 at a maternity hospital of Kazan, Russia. Ten bacterial isolates demonstrating multiple drug resistance phenotypes were collected from eight healthy full-term breastfed neonates, observed at the maternity hospital of Kazan, Russia. All the infants and their mothers were dismissed without symptoms or complaints, in a satisfactory condition. Whole-genome shotgun (WGS) sequencing was performed with the purpose to track down a possible spread source(s) and obtain detailed information about resistance determinants and pathogenic potential of the collected isolates. Microdilution tests have confirmed production of extended-spectrum ß-lactamases (ESBL) and their resistance to aminoglycoside, ß-lactam, fluoroquinolone, sulfonamide, nitrofurantoin, trimethoprim, and fosfomycin antibiotics and Klebsiella phage. The WGS analysis has revealed the genes that are resistant to aminoglycosides, fluoroquinolones, macrolides, sulfonamides, chloramphenicols, tetracyclines, and trimethoprim and ESBL determinants. The pangenome analysis had split the isolates into two phylogenetic clades. The first group, a more heterogeneous clade, was represented by 5 isolates with 4 different in silico multilocus sequence types (MLSTs). The second group contained 5 isolates from infants born vaginally with the single MLST ST23, positive for genes corresponding to hypervirulent phenotypes: yersiniabactin, aerobactin, salmochelin, colibactin, hypermucoid determinants, and specific alleles of K- and O-antigens. The source of the MDRKP spread was not defined. Infected infants have shown no developed disease symptoms.

THE SEARCH OF COMPOUNDS WITH ANTIAGGREGATION ACTIVITY AMONG S-ESTERS OF THIOSULFONIC ACIDS.

According to the current understanding, the hyperactivation of platelets may lead to increased intravascular coagulation and thrombosis. Today a relevant issue is the search for new anti-thrombotic agents that are able to modulate the activity of platelet receptors, thus, influence the processes of activation and aggregation of platelets. The aim of this study was to investigate the effects of newly synthesized thiosulfonate derivatives on platelet aggregation. The activity of the compounds was tested in vitro using platelet-rich plasma. As a result of the screening test, structural formulas of four agents with high antiaggregative activity were established. These compounds inhibited ADP- and collagen-induced platelet aggregation in a dose-dependent manner. Two of these compounds were shown to be more effective inhibitors of aggregation induced by ADP (IC50 - 8-10 µM), as well as collagen (IC50 - 1.5-2.0 µM).

[ENTEROTOXIGENICITY OF STAPHYLOCOCCUS AUREUS STRAINS, ISOLATED FROM BREAST MILK OF WOMEN, FEEDING CHILDREN WITH INFECTIOUS PATHOLOGY].

AIM: Determination of enterotoxigenicity and ability to synthesize TSST-1 in S. aureus strains, isolated from breast milk of women, feeding children with infectious pathology. MATERIALS AND METHODS: 35 S. aureus strains, isolated from breast milk of women feeding children with varying infectious pathology in hospitals and as outpatients were studied for the presence of staphylococci enterotoxins (SE) of types A and B and toxic shock syndrome toxin (TSST-1). Determination of SEA, SEB and TSST-1 was carried out by enzyme immunoassay. RESULTS: Toxins were detected in 94.2% of S. aureus strains. SEB was synthesized by 86.7%, SEA--34.3%, TSST-1--42.8% of S. aureus strains. Toxins were detected with equal frequencies in healthy women and women with inflammatory diseases of breasts. Differences in frequency of colonization of intestines of children receiving breast milk, infected with toxigenic and non-toxigenic staphylococci strains was not detected. CONCLUSION: A high frequency of occurrence of enterotoxins and TSST-1 in S. aureus, isolated from breast milk of the mother during infectious pathology in the child was discovered. Enterotoxigenic strains can be detected in breast milk in healthy women. Study of the role of breast milk, infected with S. aureus, producing SEA, SEB And TSST-1 in development of child pathology is necessary.

[Frequency of occurrence of ivyC and pliC lysozyme inhibitors genes in clinical klebsiella strains].

AIM: Chromosomal ivyC and plasmid pliC lysozyme inhibitor genes frequency of occurrence detection in klebsiella strains of various origins. MATERIALS AND METHODS: 129 strains were studied including K. pneumoniae (n= 115) and K. oxytoca (n=14). Klebsiella strains were divided into 2 groups: group 1 - 62 strains (39 isolated in Kazan and 23 strains isolated from children with klebsiella infection in Moscow). Kazan strains were presented by isolates from young children receiving in-patient treatment regarding klebsiella (n=8), respiratory (n= 17), rotavirus (n=5) and purulent-inflammation infection ofnewborns (n=9). Group 2 (n=67) was composed of strains isolated from children that had received outpatient treatment regarding intestine dysbacteriosis in Kazan (n=37) and Moscow (n=30). ivyC and pliC gene detection was carried out by PCR (N.B. Perunova et al., 2012). RESULTS: Chromosomal ivyC gene determinants were isolated in 40.3% of cases (52 strains of 129), plasmid pliC gene - 6.9% (9 of 129). ivyC gene frequency of occurrence in klebsiella strains isolated from 39 ill children of Kazan was 46.6% of cases (18 of 39), in Moscow clinical strains - 95.5% (22 of 23) cases, wherein 6 strains had ivyC and pliC genes at the same time. Dysbiosis intestine strains had chromosomal ivyC gene at the frequency of 61.2% (41 of 67), 1 strain additionally had pliC gene. CONCLUSION: . The presence of ivyC and pliC lysozyme inhibitor genes in klebsiella clinical strains provides bacteria with selective advantages in various biotopes in the process of bacterial colonization of mucous membrane.

Upregulation of IFN-γ and IL-12 is associated with a milder form of hantavirus hemorrhagic fever with renal syndrome.

Hantavirus hemorrhagic fever with renal syndrome (HFRS) is a zoonotic disease characterized by acute onset, fever, malaise, and back pain. As the disease progresses, hemorrhagic disturbances and kidney dysfunctions predominate. The examination of tissue collected postmortem supports the premise that virus replication is not responsible for this pathology; therefore, it is widely believed that virus-induced immune responses lead to the clinical manifestations associated with HFRS. The overproduction of inflammatory cytokines is commonly reported in subjects with HFRS and has given rise to the hypothesis that a so-called "cytokine storm" may play a pivotal role in the pathogenesis of this disease. Currently, supportive care remains the only effective treatment for HFRS. Our data show that serum levels of interferon (IFN)-γ, interleukin (IL)-10, CCL2, and IL-12 are upregulated in HFRS cases when compared to healthy controls and the level of upregulation is dependent on the phase and severity of the disease. Furthermore, we observed an association between the mild form of the disease and elevated serum levels of IFN-γ and IL-12. Collectively, these observations suggest that the administration of exogenous IFN-γ and IL-12 may provide antiviral benefits for the treatment of HFRS and, thus, warrants further investigations.

[Species composition and antibiotic resistance of lactobacillus in infants].

AIM: To study species composition and antibiotic resistance of indigenous bacteria from Lactobacillus genus in infants. MATERIALS AND METHODS: Twenty-six strains of lactobacilli isolated from feces of infants living in Kazan. Species membership of lactobacilli was determined using PCR with primers for identification of 7 species of lactobacilli: L. acidophilus, L. plantarum, L. rhamnosus, L. delbrueckii, L. casei, L. paracasei, and L. zeae. Susceptibility to antibiotics was determined by indicator paper discs method. RESULTS. In breastfed infants L. fermentum and L. rhamnosus dominated, whereas in artificially fed infants colonization with L. casei and L. paracasei was characteristic. L.acidophilus, L. plantarum, and L. zeae were not detected in infants. In 6 cases isolates could be identified only to genus characteristic. Lactobacilli were polyresistant and had from 8 to 15 markers of resistance. All strains were resistant to ciprofloxacin, co-trimoxazole, ceftriaxone, nitroxoline, metronidazole, furazolidone, and 95% of strains were resistant to vancomycin. In 60-70% of cases lactobacilli were susceptible to penicillin, linezolid, erythromycin and lyncomycin. CONCLUSION: Regional features of species composition and antibiotic resistance of lactobacilli in infants depending on type of feeding were revealed.

Effect of long-term constant illumination of female rats on the parameters of brain development in their 40-day-old progeny.

We studied the progeny from female rats exposed to constant illumination for 1 month and mated with intact males 14 days after this exposure. At the age of 40 days, the progeny from experimental rats differed from the control by lower body weight, thickness of the adrenal cortex, and diameter of convoluted seminal tubules. The weight of the brain was similar in both groups. The thickness of the cortex in the parietal lobe, and especially, in the frontoparietal lobe was decreased; the neuronal density in these lobes (layers II and V) was reduced. In layer II and V neurons of the parietal lobe, the size of neuronal nuclei reduced, the concentration of RNA and activities of NADH and NADPH dehydrogenases in the cytoplasm were considerably increased. Elevated concentration of lipids was found in layer I of cerebral and cerebellar cortex and in the white matter, which attests to higher myelinization degree compared to the control.

[Influence of maternal microflora on the composition of infants' intestinal microcenosis during breastfeeding].

Composition of intestinal microflora in 38 breastfed infants and their mothers was studied. Microflora of mothers' breast milk was studied also. In all 38 (100%) infants as well as 29 (76.3%) mothers abnormalities in normal intestinal microflora composition were detected. In 50% of cases milk of breastfeeding mothers was contaminated with bacteria without clinical symptoms of infection. Staphylococcus epidermidis predominated between bacteria. In 31.6% of pairs "mother-infant" identical bacterial species were detected in breastmilk and infant's intestine with detection rate highest for S. aureus. It was concluded that improvement of bacteriological examination and preventive measures for breastfeeding mothers and their children is necessary.

[Drug resistance of Staphylococcus aureus strains, isolated from children with intestinal dysbacteriosis]. / Lekarstvennaia ustochivost' shtammov Staphylococcus aureus, vydelennykh u dete s disbakteriozom kishechnika.

The level of antibiotic-sensitivity of 73 S. aureus strains isolated from children with dysbacteriosis of the large intestine in an outpatient clinic was determined. The isolation rate of polyresistant strains was 44%. Methicillin-resistant S. aureus (MRSA) were isolated from 25 children (34.2%). 60% of MRSA strains could not be typed with the international set of phages. Among the strains capable of being lyzed by the phages the representatives of phage groups 3 and 4 prevailed. All MRSA strains were sensitive to vancomycin, 84-88% of the strains were sensitive to chloroamphenicol, rifampicin, spiramycin and neomycin, 80% of the strains were sensitive to fusidin and phosphomycin. The level of sensitivity of methicillin-sensitive S. aureus strains (MSSA) to different groups of antistaphylococcal antibiotics was higher. 36-64% of MRSA strains and 21-27% of MSSA strains were resistant to the action of curative bacteriophages. The suppression of obligate microflora was the risk factor in the development of staphylococcal infection of the gastrointestinal tract in children.

[The frequency of staphylococcal colonization of the intestines in children with the manifestations of dysbacteriosis]. / Chastota kolonizatsii stafilokokkami kishechnika u detei s iavleniiami disbakterioza.

In 2100 children of different age groups the microbiocenosis of the large intestine was studied. The study revealed that the colonization of the mucous membrane of the large intestine with staphylococci developed in 30% of children with intestinal dysbacteriosis. Young children were mainly affected (91%). The prevailing species among isolated staphylococci was S. aureus (86%), capable of persistence in the intestine (30.9%). In children non typing S. aureus strains mainly circulated (70%), and among phage-typing strains isolates of phage group III prevailed (70.2%). The colonization of the intestine with coagulase-negative staphylococci was possible (14%). Microecological intestinal disturbances in children of different age groups were characterized by different degrees of changes in normal microflora with the prevalence of opportunistic microorganisms in the microbial picture.

[Evaluation of the incidence of congenital developmental defects in newborn infants based on an analysis of archival documentation]. / Otsenka rasprostranennosti vrozhdennykh porokov razvitiia u novorozhdennykh na osnove analiza arkhivnoi dokumentatsii.

Incidence of congenital malformations in the newborn was analyzed on the basis of the medical archives, thus the possibility of using the obtained data for genetic monitoring being established.

Retro- and prospective evaluation of dynamics of some mutational events.

The dynamics of some mutational events were studied in a Siberian town with a chemical industry. Retro- and prospective evaluations of the frequency of spontaneous abortions, multiple congenital malformations, and Down syndrome were carried out. Mutational components of these endpoints were summarized and provisionally termed "units of mutational events" (UME). The results show that the frequencies of UME have not changed in 14 years.

[Assortative mating in the population of a modern city]. / Brachnaia assortativnost' v naselenii sovremennogo goroda.

An investigation of the population of modern Siberian city Angarsk was carried out. The sample consisted of 13746 individuals in the age interval from 21 to 60 years old. The population comprises more than 40 nationalities. The percentage of Russians, Ukrainians, Buryats, Byelorussians and Tatars in this population is 86.37, 5.35, 1.91, 1.65 and 1.46, respectively. The incidence of other nationalities does not exceed 1%. Analysis of the distances of birth places for married couples demonstrated the predominance of those in which husband and wife had come from different administrative regions of the country. This implies a significant impact of migration on formation of the new city population. A new qualitative approach to the assessing of assortative mating considering the nationality is presented and it is discovered that assortative mating on the basis of national belonging takes place in all the nationalities taken into analysis: in Russians, Ukrainians, Buryats, Byelorussians and Tatars.

[Dynamic evaluation of the incidence of hereditary pathology by an accounting of spontaneous abortions and congenital developmental defects]. / Otsenka dinamiki chastoty nasledstvennoi patologii po uchetu spontannykh abortov i vrozhdennykh porokov razvitiia.

A new method is suggested to control the mutation process in man by the dynamics of hereditary pathology frequency. The paper presents data on registration of spontaneous abortions, congenital malformations, Down's syndrome and perinatal death in Angarsk for 10 years (1971-1980). No changes are found in the frequencies of these data. The dynamic analysis of hereditary pathology "units" of mutation origin for 10 years did not show any time trend.