General dynamics of the URT microbiome and microbial signs of recovery in COVID-19 patients.

COVID-19 is caused by an airborne virus, SARS-CoV-2. The upper respiratory tract (URT) is, therefore, the first system to endure the attack. Inhabited by an assemblage of microbial communities, a healthy URT wards off the invasion. However, once invaded, it becomes destabilised, which could be crucial to the establishment and progression of the infection. We examined 696 URT samples collected from 285 COVID-19 patients at three time-points throughout their hospital stay and 100 URT samples from 100 healthy controls. We used 16S ribosomal RNA sequencing to evaluate the abundance of various bacterial taxa, α-diversity, and ß-diversity of the URT microbiome. Ordinary least squares regression was used to establish associations between the variables, with age, sex, and antibiotics as covariates. The URT microbiome in the COVID-19 patients was distinctively different from that of healthy controls. In COVID-19 patients, the abundance of 16 genera was significantly reduced. A total of 47 genera were specific to patients, whereas only 2 were unique to controls. The URT samples collected at admission differed more from the control than from the samples collected at later stages of treatment. The following four genera originally depleted in the patients grew significantly by the end of treatment: Fusobacterium, Haemophilus, Neisseria, and Stenotrophomonas. Our findings strongly suggest that SARS-CoV-2 caused significant changes in the URT microbiome, including the emergence of numerous atypical taxa. These findings may indicate increased instability of the URT microbiome in COVID-19 patients. In the course of the treatment, the microbial composition of the URT of COVID-19 patients tended toward that of controls. These microbial changes may be interpreted as markers of recovery.

Safety and immunogenicity of GamEvac-Combi, a heterologous VSV- and Ad5-vectored Ebola vaccine: An open phase I/II trial in healthy adults in Russia.

Ebola hemorrhagic fever, also known as Ebola virus disease or EVD, is one of the most dangerous viral diseases in humans and animals. In this open-label, dose-escalation clinical trial, we assessed the safety, side effects, and immunogenicity of a novel, heterologous prime-boost vaccine against Ebola, which was administered in 2 doses to 84 healthy adults of both sexes between 18 and 55 years. The vaccine consists of live-attenuated recombinant vesicular stomatitis virus (VSV) and adenovirus serotype-5 (Ad5) expressing Ebola envelope glycoprotein. The most common adverse event was pain at the injection site, although no serious adverse events were reported. The vaccine did not significantly impact blood, urine, and immune indices. Seroconversion rate was 100 %. Antigen-specific IgG geometric mean titer at day 42 was 3,277 (95 % confidence interval 2,401-4,473) in volunteers immunized at full dose. Neutralizing antibodies were detected in 93.1 % of volunteers immunized at full dose, with geometric mean titer 20. Antigen-specific response in peripheral blood mononuclear cells was also detected in 100 % of participants, as well as in CD4+ and CD8+ T cells in 82.8 % and 58.6 % of participants vaccinated at full dose, respectively. The data indicate that the vaccine is safe and induces strong humoral and cellular immune response in up to 100 % of healthy adult volunteers, and provide a rationale for testing efficacy in Phase III trials. Indeed, the strong immune response to the vaccine may elicit long-term protection. This trial was registered with grls.rosminzdrav.ru (No. 495*), and with zakupki.gov.ru (No. 0373100043215000055).

[ZIKA FEVER: CLINICAL, EPIDEMIOLOGICAL, LABORATORY, AND DIAGNOSTIC ASPECTS].

The authors overview data on the prevalence of Zika fever with reference to biological properties of the causative agent, epidemiological process, pathogenesis, and clinical symptoms of the disease. Special attention is given to the identification of the virus in pregnant women, microcephaly in the babies born by Zika-infected women, algorithm of laboratory diagnostics, and measures needed to prevent and control mosquitoes that spread viruses.

Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium.

Hemizygous deletion of a 1.5- to 3-megabase region on chromosome 22 causes 22q11.2 deletion syndrome (22q11DS), which constitutes one of the strongest genetic risks for schizophrenia. Mouse models of 22q11DS have abnormal short-term synaptic plasticity that contributes to working-memory deficiencies similar to those in schizophrenia. We screened mutant mice carrying hemizygous deletions of 22q11DS genes and identified haploinsufficiency of Mrpl40 (mitochondrial large ribosomal subunit protein 40) as a contributor to abnormal short-term potentiation (STP), a major form of short-term synaptic plasticity. Two-photon imaging of the genetically encoded fluorescent calcium indicator GCaMP6, expressed in presynaptic cytosol or mitochondria, showed that Mrpl40 haploinsufficiency deregulates STP via impaired calcium extrusion from the mitochondrial matrix through the mitochondrial permeability transition pore. This led to abnormally high cytosolic calcium transients in presynaptic terminals and deficient working memory but did not affect long-term spatial memory. Thus, we propose that mitochondrial calcium deregulation is a novel pathogenic mechanism of cognitive deficiencies in schizophrenia.

[Zika virus infection: clinical and diagnostic aspects and organization of preventive measures].

The article presents modem data about Zika virus outbreak, the biological characteristics of the pathogen, vectors, the nature of the epidemic process, pathogenesis and diagnosis of infection. This infection has a high potential for epidemic spread because vectors are widely represented in the fauna of many climatic and geographic zones. It presents information on the main clinical manifestations of the disease. Particular attention is paid to the problem of congenital maiformations of the nervous system (microcephaly and others) detected in infants born to women infected with Zika virus. The basis of therapy in this disease constitute a pathogenic agent. The'package of, measures for the prevention of disease caused by Zika virus, including early identification and treatment of patients, as well as measures for the destruction of the virus vectors.

[Evacuation of contagious patients in the modern system of medical support].

Evacuation of contagious patients in the modern system. of medical support. The main problematic issues of organizing and conducting the evacuation of contagious patients are defined. A peculiarity of evacuation and healthcare delivery to contagious patients is the need for permanent complex of sanitary and anti-epidemic (preventive) measures aimed at preventing the spread of infectious diseases. Set out fundamental approaches to triage of infectious patients at different stages of medical evacuation, defined sorting group. The attention is focused on the clinical-and-syndrome principle infectious pathology diagnostics. The experience of the medical evacuation of infectious diseases in Afghanistan is analysed. The necessity of protecting the accompanying medical staff is showed. The possibilities, the benefits and how to use for the isolation of infectious patients and the evacuation of mobile autonomous units - the transport of insulating boxes are studied.

[EBOLA HEMORRHAGIC FEVER; ETIOLOGY, EPIDEMIOLOGY, PATHOGENESIS, AND CLINICAL SYMPTOMS].

The data on the prevalence of disease caused by Ebola virus, biological features of its pathogen, character of the epidemiological process, pathogenesis and clinical symptoms are presented. The disease is characterized by suppression of protective immunological mechanisms and systemic inflammatory reaction accounting for the lesions of vascular endothelium, hemostatic and immune systems. It eventually leads to polyorgan insufficiency and severe shock. Lethality amounts to 50%.

[Meningococcal disease: early clinical diagnosis and emergency care].

Late diagnosis of meningococcal disease leads to high mortality. Early diagnosis of its generalized forms plays a crucial role in the pre-hospital phase and mainly based on the clinical picture of the disease. In most cases, pre-hospital typical mistake is late diagnosis of meningococcal disease: We propose an algorithm of early diagnosis of generalized forms of the disease in order to reduce the number of diagnostic errors. Proper and timely diagnosis will enable the physician pre-hospital fully implement measures to provide emergency and urgent care in generalized meningococcal infection, leading to. a more.favourable course and a significant improvement in the outcomes of the disease in the course of further hospital treatment.

[EBOLA HEMORRHAGIC FEVER: DIAGNOSTICS, ETIOTROPIC AND PATHOGENETIC THERAPY, PREVENTION].

The data on diagnostics, etiotropic and pathogenetic therapy, prevention of Ebola hemorrhagic fever are presented including diagnostic algorithms for different clinical situations. Fundamentals of pathogenetic therapy are described. Various groups of medications used for antiviral therapy of conditions caused by Ebola virus are characterized. Experimental drugs at different stages of clinical studies are considered along with candidate vaccines being developed for the prevention of the disease.

[Treatment of Ebola virus disease].

Treatment of Ebola virus disease. The article presents data on the etiology, pathogenesis, clinical presentation, diagnosis and modern approaches to the treatment of Ebola haemorrhagic fever. This serious infectious disease with a high fatality rate is characterized by intoxication, severe haemorrhages, disseminated intravascular coagulation, and multiple organ failure with the development of severe shock. It is emphasized that the treatment of patients with Ebola should be conducted under strict anti-epidemic regime. Since there is currently no effective drugs against Ebola virus, the basis of modern treatment of this disease are pathogenic and symptomatic treatments. The main activities should be aimed at correcting violations homeostasis, blood volume deficiency, disorders of water and electrolyte balance, acid-base status osmolar and oncotic pressure shortfall of clotting factors and blood components. The treatment program should be drawn up taking into account the stage of the disease, the severity of the course and comorbidity.

[Ebola virus disease: clinical and diagnostic aspects and organization of treatment-and-prophylactic measures].

The article presents data about world spread of Ebola virus disease, biological characteristics of the pathogen, the laws of the epidemic process in this disease, its pathogenesis, clinical manifestations and diagnosis. Pointed out that the current anti-viral agents, effective for the Ebola virus, have not been developed. Timely performed pathogenetic therapy improves the prognosis of the disease. The basis of this therapy is infusion-detoxification activities and replenishment of losses, of electrolytes, as well as anti-inflammatory and anti-emetic drugs. The Armed Forces of the Russian Federation received the guidelines for preventive measure that can reduce Ebola virus disease transmission. Recommendations for emergency anti-epidemic commission consisted of representatives of the command, specialists and medical services and logistics, are given. Fundamentally important condition for the effective anti-epidemic measures is not only the constant readiness of medical personnel in the detection of disease EVD, but also the appropriate level of equipment of medical institutions of medical supplies and equipment.

[Perspective applications of multi-species probiotics in the prevention of antibiotic-associated diarrhea].

The problem of antibiotic-associated conditions is one of the most actual problems of clinical practice. The antibiotic-associated diarrhea is a multidisciplinary problem. Investigations of the small intestine microecological status and assessment of microflora at the patients receiving antibiotics testifies to dysbiosis existence. In article results of open-label investigation of a multispecies probiotic RioFlora Balance using for antibiotic-associated diarrhea prophylaxis in patients used antibacterial therapy are presented.

[Delivery of healthcare to patients with infectious diseases during the pre-hospital stage].

In the field infectious military hospital work with double-triple overcharge. It leads to reduction of health care to patients, requires the additional hospital departments or evacuation of contagious patients to other hospitals. That is why the pre-hospital care is of prime importance. According to modem concept the number of interim stages is minimal--1 stage--on site of definition of contagious patients (isolator of medical station of military unit) and 2 stage--infectious military hospital. Main measures of health care to contagious patients during the pre-hospital stage are early active detection of patients or suspected of having infection, early clinical diagnosis, medical sorting, delivery of emergency care, treatment in isolators in case of delay of evacuation and evacuation in infectious military hospital.

[Intestinal dysbiosis in liver cirrhosis].

Intestinal dysbiosis is revealed in 28.5% of patients with liver cirrhosis, mainly in classes B and C by Child-Pugh by the results of hydrogen breath test. It is established that revealed intestinal dysbiosis in patients with liver cirrhosis of viral etiology aggravates the course of the disease.

[Infection agents and irritable bowel syndrome].

The discussion concerns onset and pathogenesis of functional intestinal diseases. Current data are presented on association of functional intestinal diseases with different infectious agents with illustration on the model of postinfectious irritable colon syndrome (ICS). ICS-like conditions in patients who had previously intestinal infections are considered.

Epidemiological, clinical and viral determinants of the increased prevalence of high-risk human papillomavirus (HPV) infections in elderly women.

BACKGROUND: Population-based studies have reported a second peak of human papillomavirus (HPV) prevalence among women > 55 years, but reasons for this U-shaped HPV prevalence curve are poorly understood. OBJECTIVES: To analyse determinants of high-risk HPV (HR-HPV) infections among postmenopausal women. STUDY DESIGN AND METHODS: A cohort of 3,187 women was stratified into three age categories: i) youngest age group < 25 years (n = 1.103); ii) women between 26-55 years (n = 2.004), and iii) women > 55 years (n = 80), analysed for epidemiological, clinical and virological determinants of their HR-HPV infections. Real-time PCR was used for HPV genotyping, analysis of viral loads for HPV16, 18/45, 31, 33/52/58, 35 and 39, and load of integrated HPV16. RESULTS: Age-standardised prevalence of HR-HPV infections showed a second peak among women > 55 years, with a perfect U-shaped curve (R2 = 0.966). The factors explaining this increased HR-HPV prevalence among older women include: i) cohort effect, ii) higher viral loads for HR-HPV types with cubic model curve (R2 = 0.714) for HPV 16, iii) distinct shift (p = 0.0001) from multiple-type infections to single HR-HPV types, iv) transition from episomal to integrated HPV16 (p = 0.009), v) higher load of integrated HPV16 (p = 0.009), and, vi) higher proportion of incident infections, higher rate of viral persistence, and lower rate of HR-HPV clearance. CONCLUSIONS: These data suggest that in women who fail to eradicate their HR-HPV infection until menopause, selection of integrated viral clone has taken place, driving the process towards progressing disease. Consequent to this, most of the HR-HPV infections in women > 55 years were associated with high-grade CIN or invasive carcinoma.

Phosphatase and tensin homolog, deleted on chromosome 10 deficiency in brain causes defects in synaptic structure, transmission and plasticity, and myelination abnormalities.

The phosphatidylinositol 3-kinase (PI3K) signaling pathway modulates growth, proliferation and cell survival in diverse tissue types and plays specialized roles in the nervous system including influences on neuronal polarity, dendritic branching and synaptic plasticity. The tumor-suppressor phosphatase with tensin homology (PTEN) is the central negative regulator of the PI3K pathway. Germline PTEN mutations result in cancer predisposition, macrocephaly and benign hamartomas in many tissues, including Lhermitte-Duclos disease, a cerebellar growth disorder. Neurological abnormalities including autism, seizures and ataxia have been observed in association with inherited PTEN mutation with variable penetrance. It remains unclear how loss of PTEN activity contributes to neurological dysfunction. To explore the effects of Pten deficiency on neuronal structure and function, we analyzed several ultra-structural features of Pten-deficient neurons in Pten conditional knockout mice. Using Golgi stain to visualize full neuronal morphology, we observed that increased size of nuclei and somata in Pten-deficient neurons was accompanied by enlarged caliber of neuronal projections and increased dendritic spine density. Electron microscopic evaluation revealed enlarged abnormal synaptic structures in the cerebral cortex and cerebellum. Severe myelination defects included thickening and unraveling of the myelin sheath surrounding hypertrophic axons in the corpus callosum. Defects in myelination of axons of normal caliber were observed in the cerebellum, suggesting intrinsic abnormalities in Pten-deficient oligodendrocytes. We did not observe these abnormalities in wild-type or conditional Pten heterozygous mice. Moreover, conditional deletion of Pten drastically weakened synaptic transmission and synaptic plasticity at excitatory synapses between CA3 and CA1 pyramidal neurons in the hippocampus. These data suggest that Pten is involved in mechanisms that control development of neuronal and synaptic structures and subsequently synaptic function.

Factors predicting persistence of high-risk human papillomavirus (HPV) infections in women prospectively followed-up in three New Independent States (NIS) of the former Soviet Union.

BACKGROUND: We completed an analysis of the factors predicting the persistence of high risk (HR) HPV infections in women participating in a multicenter screening trial in three NIS countries. METHODS: The 543 baseline HR HPV-positive women included in this analysis are derived from a sub-cohort of 887 women who were prospectively followed-up for a mean of 21.6 months (range: 0.5-42.9) as a part of a multi-center screening study in three NIS countries (the NIS cohort study; n = 3,187 women). Of these 543 women, 273 showed persistent HR-HPV in serial Hybrid Capture II (HCII) testing during the follow-up (Group 1), whereas 270 women cleared their infection (Group 2). These two groups were compared with their epidemiological, clinical, and virological data (HCII, PCR) to disclose the factors predicting persistent HR-HPV infection. RESULTS: Women with persistent HR-HPV infections were significantly younger (27.3 yrs) than those who cleared their infection (29.1 yrs) (p = 0.006), and their follow-up time was shorter; 14.1 and 21 months, respectively (p = 0.0001). Both variables were treated as confounders in the multivariate analyses. Of the 66 recorded epidemiological variables, only being a current smoker proved to be an independent predictor (OR 1.693; 95% CI 1.114-2.573; p=0.014). Baseline colposcopy, biopsy or Pap smear did not predict HPV persistence, whereas an incident or persistent abnormal Pap during the follow-up were independent predictors in a multivariate model (p = 0.005), together with the high viral load (HCII RLU/CO at 100 pg/ml cut-off), and HR HPV positive PCR test (p = 0.0001). When all significant variables were entered in the regression model, only the follow-up time (OR 0.950, 95% CI 0.924-0.976; p = 0.0001) and HR-HPV positive PCR (OR 4.169, 95% CI 1.741-9.987; p = 0.001), remained independent predictors. CONCLUSIONS: While several factors were related to HR-HPV persistence in univariate analysis and when adjusted for age and follow-up time as confounders, the only independent predictors in the multivariate regression model were follow-up time and HR-HPV positive PCR. Clearly more data are needed on type-specific persistence and HPV integration as its predictors.

Clearance of high-risk human papillomavirus (HPV) DNA and PAP smear abnormalities in a cohort of women subjected to HPV screening in the New Independent States of the former Soviet Union (the NIS cohort study).

BACKGROUND: We analysed the temporal relationships of the clearance of human papillomavirus (HPV) DNA and cytological abnormalities in women participating in a screening study in three NIS countries. METHODS: The 274 patients included in this analysis were prospectively followed-up for 21.6 months (range: 0.5-42.9). All 274 women had abnormal PAP test (ASC-US or higher) and high-risk HPV-positive test (HCII) at baseline. Two groups were compared: 132 women who cleared both tests (Group 1), and 142 women who cleared either HPV or abnormal PAP test (Group 2). The first clearance during the follow-up, and the last visit clearance were modeled using life-table techniques, and the predictive factors were analysed using univariate (Kaplan-Meier) and multivariate (Cox) survival analysis. RESULTS: There was no difference in the mean clearance time for the abnormal PAP test (14.4 months; 0.7-40.5 and 12.6 months; 0.5-35.0) and high-risk HPV DNA (12.67 months; 0.6-33.5 and 10.8 months; 0.7-33.4) in Group 1 and Group 2 (Mann-Whitney: P = 0.107 and P = 0.082, respectively). Clearance times for HPV DNA and abnormal PAP test did not deviate from each other in either groups (Wilcoxon: P = 0.063 and P = 0.088). The monthly clearance rates for the abnormal PAP test are 1.32 and 1.38%, and those for the HPV DNA 1.62 and 1.61%, in Groups 1 and 2, respectively. Of the factors predicting the last visit clearance, the issues related to smoking are of particular interest. CONCLUSIONS: The clearance of high-risk HPV type and abnormal PAP test shows a close temporal relationship, the former preceding the latter, however, by an interval of 1.0-2.0 months.