[Effectiveness and safety of biological therapy in patients with severe asthma in a real clinical practice].

AIM: To assess effectiveness and safety of biological therapy in patients with severe asthma during 5 yr follow-up. MATERIALS AND METHODS: We recruited 129 adult outpatients (29% males) aged 18-81 yrs with severe asthma were followed up during 5 yrs and were examined for every 3-6 months. Eighty five patients were treated by conventional therapy (ICS/LABA ± tiotropium, montelukast, OCS) only and 44 pts additionally received biologicals (оmalizumab - 9 pts, мepolizumab - 8 pts, benralizumab - 11 pts, dupilumab - 16 pts). Pulmonary function tests were measured by dry spirometer (2120, Vitalograph Ltd., UK). Eosinophil count in blood was assessed by automatic haemoanalyser. Fraction of exhaled nitric oxide was measured by a chemiluminescence analyzer (LR4100; Logan Research, UK). Asthma control and quality of life were assessed by using Russian versions of ACQ-5 and SGRQ. RESULTS: The use of biologicals led to a more significant reduction of exacerbations and OCS use, improvement of lung function, asthma control and quality of life, decrease of eosinophil and fraction of exhaled nitric oxide than conventional therapy of severe asthma (p<0.05). Systemic side effects were not registered, frequency of local adverse reactions (edema, hyperemia and itching at injection site) was 14%. CONCLUSION: Long-term use of biologicals added to conventional therapy in patients with severe asthma is characterized by high effectiveness and favorable safety profile.

[Burden and management of severe asthma in Russia: results from international observational study].

AIM: To assess clinical and demographic characteristics of severe asthma (SA) patients and their management in Russian Federation. MATERIALS AND METHODS: This publication provides data for Russian part of population of the international observational study. In Phase I, retrospective analysis of medical records of patients with SA was performed with assessment of clinical and demographic data, medical history, comorbidities, treatment approaches and healthcare utilization. Phase II was a cross-sectional collection of patient-reported outcomes: level of asthma control assessed by ACT (Asthma Control Test) and health-related quality of life (HRQoL) measured using the EQ-5D-5L questionnaire. Phase I patients were enrolled into Phase II if they signed a written consent form. RESULTS: A total of 315 patients were included in Phase I of the study, 106 (33.6%) of them entered Phase II. Majority of study participants were either obese (n=103; 39.8%) or overweight (n=94; 36.3%). The most common comorbidities were cardiovascular diseases (n=217; 71.4%), followed by chronic respiratory diseases (n=198; 68.8%). There were 268 (85.1%) patients who had at least one exacerbation during last 12 months. Data for blood eosinophil count were available in 176 patients; 81.3% of them (n=143) had only one test in the last 12 months. The mean (SD) last available blood eosinophil count was 161.2 (181.2) cells/mm3. Serum Immunoglobulin E (IgE) value was known for 88 patients, and the mean (SD) last measured IgE value was 254.3 (249.7) ng/mL. Only 4.7% of Phase II participants had ACT scores indicative of controlled asthma (>20). As much as 74.5% had scores ≤15 suggesting uncontrolled disease. Most patients also had impaired HRQoL. CONCLUSION: Most SA patients had poor disease control with frequent exacerbations and high number of comorbidities. Blood eosinophils and IgE level measurements were not evaluated routinely which might be a barrier for appropriate phenotyping and treatment selection.

[New clinical guidelines for COPD - a paradigm shift: A review].

Chronic obstructive pulmonary disease is now one of the most common noncommunicable diseases and the main causes of morbidity, disability and mortality in the world. In recent years, new approaches to epidemiology, diagnosis, classification (categorization), evaluation of phenotypes, as well as characterization and assessment of the severity of сhronic obstructive pulmonary disease exacerbations have emerged. Modern approaches to starting and subsequent drug therapy have changed significantly. This is largely due to the results of recently conducted major clinical trials, demonstrated high efficacy of triple fixed combinations, including inhaled glucocorticosteroids, long-acting beta-agonists and long-acting anticholinergic drugs. The use of non-medication methods (smoking cessation, physical activity and respiratory rehabilitation) and modern approaches to the treatment of respiratory failure and antibiotic therapy remain important. In terms of their significance, all these updates have a significant impact on real clinical practice and can be considered as a novel paradigm of the approaches to the diagnosis and management of this disease.

[Problems and opportunities to improve diagnosis of asthma and chronic obstructive pulmonary disease in Russia: resolution of advisory board].

Asthma and chronic obstructive pulmonary disease remain major problems of medicine, and still there is need to improve the level and quality of diagnosis of these diseases. Primary care physicians (general practitioners, therapists) should be involved widely and actively in this process. To simplify the diagnosis, special questionnaires have been developed, they can be used in a real clinical practice. Only this approach will bring statistical data closer to the true prevalence of these diseases and improve quality of their treatment.

The Effect of COVID-19 on Long-Term Cardiac Function in Patients With Chronic Heart Failure.

Aim      To evaluate functional changes in the heart in the long-term following COVID-19 in patients with chronic heart failure (CHF).Material and methods  Case reports of 54 patients aged 69.1±9.7 years who had COVID-19 from January 2021 through January 2022 and had been previously diagnosed with NYHA functional class II-III CHF were studied. Two comparison groups were isolated: HF with LV EF >50 % (n=39) and <50 % (n=15). Echocardiography was used to evaluate changes in LV EF and pulmonary artery systolic pressure (PASP) 5-6 months following COVID-19.Results In all CHF patients after COVID-19 at 5.8 months on average, LV EF decreased (median difference, 2.5 %; 95 % confidence interval (CI): 6.99×10-5- 4.99) and PASP increased (median difference, 8 mm Hg; 95 % CI: 4.5-12.9). In the HF group with LV EF <50 %, the decrease in EF was greater than in the group with LV EF >50 % (6.9 and 0.7 %, respectively; p=0.037); furthermore, the CHF phenotype did not influence the change in PASP (p=0.4). The one-factor regression analysis showed that the dynamics of LV EF decrease was significantly influenced by the baseline decrease in LV EF, whereas the change in PASP was influenced by the dynamics of LV EF decrease, presence of dyslipidemia, and statin treatment. Furthermore, the multifactorial analysis showed that prognostically significant factors for long-term changes in LV EF following COVID-19 were male gender (odds ratio (OR), 5.92; 95 % CI: 1.31-26.75; p=0.014), LV EF at baseline <50 % (OR, 0.88; 95 % CI: 0.8-0.96; p<0.001); changes in PASP depended on the presence of dyslipidemia (OR, 0.08; 95 % CI: 0.01-0.84; p=0.018).Conclusion      This study showed that COVID-19 in the long term can influence the course of CHF; in this process, HF patients with EF <50 % have progression of systolic dysfunction and PASP, whereas patients with EF >50 % have an isolated increase in PASP.

[Combine therapy as a modern approach to treatment of allergic rhinitis].

Allergic rhinitis (AR) is one the most common allergic diseases affecting from 10 to 40% of the population in different countries, including Russia. AR is a risk factor of bronchial asthma, other upper airway disease and may decrease patient quality of life, their productivity, increase probability of occupational traumatism, depression and anxiety. AR also presents a substantial economic burden. The rationale to use fixed dose combination of intranasal steroids and topical H1 antihistamines includes suboptimal control of symptoms by monotherapy, its complementary pharmacologic activity and the results of clinical trials. This review focused on fixed dose combination of intranasal mometasone furoate and olopataine. Double blind placebo-controlled and open clinical trials have confirmed that this combination decreased severity of nasal and ocular symptoms of seasonal and perennial AR, improved patient quality of life and had a good tolerability. Its efficacy was higher than those of monotherapy. Fast onset of action and sustainable effect on symptoms (during 1 yr) may improve adherence patients to the treatment and control of symptoms of AR.

Necessary conditions for STDP-based pattern recognition learning in a memristive spiking neural network.

This work is aimed to study experimental and theoretical approaches for searching effective local training rules for unsupervised pattern recognition by high-performance memristor-based Spiking Neural Networks (SNNs). First, the possibility of weight change using Spike-Timing-Dependent Plasticity (STDP) is demonstrated with a pair of hardware analog neurons connected through a (CoFeB)x(LiNbO3)1-x nanocomposite memristor. Next, the learning convergence to a solution of binary clusterization task is analyzed in a wide range of memristive STDP parameters for a single-layer fully connected feedforward SNN. The memristive STDP behavior supplying convergence in this simple task is shown also to provide it in the handwritten digit recognition domain by the more complex SNN architecture with a Winner-Take-All competition between neurons. To investigate basic conditions necessary for training convergence, an original probabilistic generative model of a rate-based single-layer network with independent or competing neurons is built and thoroughly analyzed. The main result is a statement of "correlation growth-anticorrelation decay" principle which prompts near-optimal policy to configure model parameters. This principle is in line with requiring the binary clusterization convergence which can be defined as the necessary condition for optimal learning and used as the simple benchmark for tuning parameters of various neural network realizations with population-rate information coding. At last, a heuristic algorithm is described to experimentally find out the convergence conditions in a memristive SNN, including robustness to a device variability. Due to the generality of the proposed approach, it can be applied to a wide range of memristors and neurons of software- or hardware-based rate-coding single-layer SNNs when searching for local rules that ensure their unsupervised learning convergence in a pattern recognition task domain.

Correction to: Evolutionarily novel genes are expressed in transgenic fish tumors and their orthologs are involved in development of progressive traits in humans.

[This corrects the article DOI: 10.1186/s13027-019-0262-5.].

[Diagnosis and treatment of hereditary angioedema with normal C1-inhibitor level].

Hereditary angioedema (HAE) with normal C1-inhibitor level is a rare potentially life-threatening disorder with autosomal dominant inheritance which was first described in 2000. Its clinical presentation is similar to HAE with C1-deficiency. The review is summarized data about its prevalence, mechanisms, genetics and diagnostic criteria. Different subtypes and treatment options (on demand, short term and long-term prophylaxis) are discussed. We describe family clinical cases of 2 female patients with normal C1-inhibitor and plasminogen gene mutation. Their features were late diagnosis (in 10 and 25 years after the onset of symptoms), family history (similar genetic mutation in 3 female members of the same family, including 1-asymtomatic) and combination of face, tongue, larynx and abdominal angioedema in patient and her sibling.

Self-adaptive STDP-based learning of a spiking neuron with nanocomposite memristive weights.

Neuromorphic systems consisting of artificial neurons and memristive synapses could provide a much better performance and a significantly more energy-efficient approach to the implementation of different types of neural network algorithms than traditional hardware with the Von-Neumann architecture. However, the memristive weight adjustment in the formal neuromorphic networks by the standard back-propagation techniques suffers from poor device-to-device reproducibility. One of the most promising approaches to overcome this problem is to use local learning rules for spiking neuromorphic architectures which potentially could be adaptive to the variability issue mentioned above. Different kinds of local rules for learning spiking systems are mostly realized on a bio-inspired spike-time-dependent plasticity (STDP) mechanism, which is an improved type of classical Hebbian learning. Whereas the STDP-like mechanism has already been shown to emerge naturally in memristive devices, the demonstration of its self-adaptive learning property, potentially overcoming the variability problem, is more challenging and has yet to be reported. Here we experimentally demonstrate an STDP-based learning protocol that ensures self-adaptation of the memristor resistive states, after only a very few spikes, and makes the plasticity sensitive only to the input signal configuration, but neither to the initial state of the devices nor their device-to-device variability. Then, it is shown that the self-adaptive learning of a spiking neuron with memristive weights on rate-coded patterns could also be realized with hardware-based STDP rules. The experiments have been carried out with nanocomposite-based (Co40Fe40B20) х (LiNbO3-y )100-х memristive structures, but their results are believed to be applicable to a wide range of memristive devices. All the experimental data were supported and extended by numerical simulations. There is a hope that the obtained results pave the way for building up reliable spiking neuromorphic systems composed of partially unreliable analog memristive elements, with a more complex architecture and the capability of unsupervised learning.

Evolutionarily novel genes are expressed in transgenic fish tumors and their orthologs are involved in development of progressive traits in humans.

ABSTRACT: Earlier we suggested a new hypothesis of the possible evolutionary role of hereditary tumors (Kozlov, Evolution by tumor Neofunctionalization, 2014), and described a new class of genes - tumor specifically expressed, evolutionarily novel (TSEEN) genes - that are predicted by this hypothesis (Kozlov, Infect Agents Cancer 11:34, 2016). In this paper we studied evolutionarily novel genes expressed in fish tumors after regression, as a model of evolving organs. As evolutionarily novel genes may not yet have organismal functions, we studied the acquisition of new gene functions by comparing fish evolutionarily novel genes with their human orthologs. We found that many genes involved in development of progressive traits in humans (lung, mammary gland, placenta, ventricular septum, etc.) originated in fish and are expressed in fish tumors and tumors after regression. These findings support a possible evolutionary role of hereditary tumors, and in particular the hypothesis of evolution by tumor neofunctionalization. RESEARCH HIGHLIGHTS: Earlier we described a new class of genes that are tumor-specifically expressed and evolutionarily novel (TSEEN). As the functions of TSEEN genes are often uncertain, we decided to study TSEEN genes of fishes so that we could trace the appearance of their new functions in higher vertebrates. We found that many human genes which are involved in development of progressive traits (placenta development, mammary gland and lung development etc.,) originated in fishes and are expressed in fish tumors.

Solvothermal synthesis of Sm3+-doped Fe3O4 nanoparticles.

Magnetic iron oxide nanoparticles doped with samarium were prepared by solvothermal polyol method. An introduction of 2,2'-bipyridine during the synthesis reduces the particle diameter to about 9nm in average. The difference in physical and magnetic properties of the samples prepared with and without capping agent was outlined on the basis of complex characterization by a number of experimental techniques. The characteristics of resulted product make it suitable for biomedical applications, for instance, as a contrast agent for MRI.

[THE PREVALENCE OF RESPIRATORY SYMPTOMS AMONG RESIDENTS OF THE RUSSIAN FAR NORTH].

Aim: To study the frequency of respiratory symptoms among the reindeer herders of the Yamal region in the Far North of Russia. We conducted a cross-sectional study of the occurrence of respiratory symptoms among 500 subjects of the tundra Nenets population (28.1% of the adult Nenets population in the district), of which 38.3% were men and 61.7% women (average age 40.1 years). All patients were matched for age and occupation. Medical examination was carried out by a pulmonologist with the use of the GARD questionnaire (WHO, 2004) and spirometry. Spirometry was performed with a SpiroUSB device (UK) according to a unified standard and the criteria of ATS/ERS 2005. The frequency of respiratory symptoms among the tundra population was estimated at 71.8%. Cough with expectoration and dyspnea were found in 22.8% of the respondents. 70.0% of the examined subjects worked in the cold, 33% were exposed to the open flame at home, and 34.4% smoked. Respiratory symptoms developed in 16.3% of those working in the cold and in 37% exposed to open fire. The combination of such complaints as cough and sputum production occurred in smokers twice as frequently as in non-smokers (54.1%) (p<0.01).The combination of such complaints as cough and sputum production was twice as likely note in his those who smoked (54.1% vs 20.2%) (p<0.01). The combination of these problems dyspnea was three times more common in the smokers (23,3%vs 7,3%) (p<0.001). At presence at patients of such a factor as work in the cold and the absence of other only 16.3% of them have respiratory symptoms. When using at home the open flame and the absence of other factors leading up 37.0% of the individuals with symptoms of chronic bronchitis. Cough, sputum and dyspnea are formed only among 26.3% of the smokers face when smoking is the only risk factor. If the surveyed residents of all three negative factors respiratory symptoms met at 62.1%. Disorders of respiratory function according to spirometry were not observed in none of the study participants. Respiratory symptoms developed in 62.1% of the subjects exposed to all three risk factors. External respiration indices remain normal in all he examine subjects. It is concluded that residents of the Far North frequently suffer respiratory symptoms without disorders in the external respiratory function. In most cases they associated with three factors (work in the cold, exposure to open fire at home, and smoking). Compensatory stimulation of lung functions may create additional difficulties for diagnostics of bronchial obstruction.

[Severe asthma: Characteristics of patients in clinical practice].

AIM: To provide clinical characteristics of severe asthma (SA) patients encountered in clinical practice. SUBJECTS AND METHODS: A cross-sectional cohort study was performed to cover 119 outpatients aged 22-82 years. SA was diagnosed according to the ERS/ATS criteria (2014). Spirometry and bronchodilator reversibility testing were carried out; fractional exhaled nitric oxide (FeNO) was measured; inhalant allergen hypersensitivity (skin prick and blood specific IgE testing) and peripheral blood eosinophil counts were estimated. Asthma control and asthma-related quality of life were assessed. RESULTS: 77% of the patients were found to have allergic asthma; in this case, house dust mites were leading allergens in the spectrum of sensitization. 82% of the patients were observed to have uncontrolled asthma and 76% had incompletely reversible bronchial obstruction. The airway eosinophilic inflammation markers (FeNO more than 25 ppb and eosinophil counts of more than 150 cells/µ) were elevated in 63% of the patients. Good compliance was noted in 61% of the patients. There were 27% of active smokers who had lower lung function and FeNO levels. The smokers showed a low compliance with inhaled glucocorticosteroid treatment. SA was concurrent with chronic obstructive pulmonary disease in 37% of the cases. CONCLUSION: SA is a heterogeneous disease. Traditional treatment is not always effective, as many patients, despite their treatment, have uncontrolled SA and continuously increased markers of airways eosinophilic inflammation. Monoclonal antibody therapy may promote success in treating this cohort of patients.

Host-dependent serum specificity to the V3 domain of HIV-1.

The previous studies of anti-HIV-1 humoral immune response have found the stable individual structural bias in the antibody production that reflects the changes in the immune functional network caused by HIV-1. The correlation between antigen structure, in particular the V3 domain of HIV-1, and the serum specificity to the structure remains unclear. To clarify the role of host individual factors in the serum specificity, we used the slightly modified HIV-1 serotyping methodological approach for the sera of the patients infected with HIV-1 with a different level of genetic similarity. Substantial discrepancy between serum specificities and antigen structure was found. Patients infected with HIV-1 carrying similar and identical V3 sequences had significantly different serum specificities. The opposite situation was often observed as well. The results of the study suggest that the influence of the V3 loop structure in the development of humoral immune response to the V3 loop is substantially modified in a patient-specific manner.

Glycogen-forming function of hepatocytes in the rat regenerating cirrhotic liver after a partial hepatectomy.

Rat liver punctate biopsies were used for cytofluorimetric determinations of the content of glycogen and its fractions in hepatocytes, and also for microchemical measurements of the activity of glucose-6-phosphatase, glycogen phosphorylase, and glycogen synthase, in liver tissue with cirrhosis produced by carbon tetrachloride (CCl4) poisoning, during regeneration of the liver after the cessation of poisoning and after a partial resection of the cirrhosed liver. The liver cirrhosis was shown to be characterized by an accumulation of glycogen (predominantly of its metabolically less active fraction) in hepatocytes and by a decrease in the activities of the glycogenolytic enzymes in the liver parenchyma. On the cessation of poisoning, there was a partial or complete return to normal levels of the glycogen metabolism parameters. Some of them returned to normal more quickly if a partial hepatectomy was performed after the cessation of poisoning.

Quantitative analysis of glycogen content in hepatocytes of portal and central lobule zones of normal human liver and in patients with chronic hepatitis of different etiology.

Glycogen content was determined in hepatocytes of different lobule zones of the normal human liver (23 patients without any liver pathology) and the liver of patients with chronic viral B hepatitis (30 patients) and chronic alcohol hepatitis (28 patients). All the patients were males and aged between 17-50 years. Quantitative analysis of the glycogen content in hepatocytes of portal and central lobule zones was carried out in sections of the human liver (material of functional biopsies) stained with PAS-reaction. The measurements were carried out using an image analyser 'Magiscan' which allows combined cytophotometric analysis of a substance in cells and determination of the cell localization in tissue. The results showed significant differences of the glycogen content in different lobule zones in the normal liver and in the liver in chronic viral and alcohol hepatitis. Ratios of glycogen content in hepatocytes of the portal and the central zones of liver lobule were 1.128 +/- 0.004 and 1.061 +/- 0.003 in normal human liver, and liver of patients with chronic viral hepatitis respectively, i.e. the glycogen content in hepatocytes of the portal lobule zone was much higher than in the central lobule zone in the normal liver and in the liver of patients with chronic viral B hepatitis. The ratio in patients with chronic alcohol hepatitis was less than 1.0 (0.930 +/- 0.003), i.e. a significantly higher glycogen content was found in hepatocytes of the central liver lobule zone. Possible mechanisms of this phenomenon are discussed. Thus, the pattern of the glycogen content in hepatocytes of different lobule zones can be used as an indicator of etiology of chronic hepatitis.