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Rutin contents in biological samples of blood plasma, cardiomyocytes, and mitochondria of cardiomyocytes in rats after administration of Primula veris L. dense herbal extract were determined using a quantitative HPLC method. The optimum conditions for quantitative determination of rutin were KH2PO4 buffer (50 mM, pH 4.6), 82:18% (v/v) aqueous to organic phase ratio, 30°C, detection at 205 nm, flow rate 1 mL/min, 12 MPa pressure in chromatographic system, and retention time 6 – 6.5 min. Rutin was found to enter the blood and distribute into the heart, in which its concentration was 5.34 times higher than in blood, and to penetrate mitochondria, in which its concentration was 1.7 times higher than in plasma and 3.18 times lower than in the heart.

It is important to control the levels of specific IgG against SARS-CoV-2 to ensure the timely monitoring of immunity in patients with COVID-19. Yet it is unclear what antibody levels protect against new infection and how long the protection is maintained. The study was aimed to assess the dynamic changes in the levels of IgG against SARS-CoV-2 by the two-year controlled observation. Healthy individuals (n = 70), COVID-19 survivors (n = 42), and people vaccinated with Sputnik V (n = 43) were enrolled. They were followed-up from April 2020 to April 2022. Serum IgG levels were defined (n = 312) using immunochip and the commercially available test system. Significance of differences was estimated using the Mann–Whitney U test for р ≤ 0.05. IgG levels in the disease survivors (median 97.1; 95% CI: 80–162 BAU/mL) and vaccinated individuals (103.1; 78–139 BAU/mL) were significantly higher than in healthy people (4.3; 4.1–4.5 BAU/mL). Intensity of immune response significantly increased after vaccination of the disease survivors (up to 1023; 657–1191 BAU/mL) or administration of booster dose to vaccinated individuals (413; 213–545 BAU/mL). In elderly convalescents (60+), IgG levels were significantly higher, and in vaccinated people these were significantly lower, than in people under the age of 60. IgG levels decreased faster in vaccinated individuals (after 3–4 months), than in the disease survivors, and stabilized at

A Phosphorescence Analysis (PHOSPHAN)-based test system was developed for simultaneous detection of thyroid-stimulating hormone (TSH) and free thyroxin (fT4), the markers of thyroid function, in dried human blood samples. The immunoassay was performed at the bottom of polystyrene 96-well microplate wells covered with analyte-specific microarrays (0.35 mm in diameter). The detection system consisted of polystyrene nanoparticles (46 ± 14 nm in diameter) with incorporated long luminescent Eu(III) chelate complexes (1960 molecules/particle). Fluorescence intensity was measured in time-resolved mode (TRF). Analytical parameter values and possible limitations of this experimental system were investigated. The system allowed the simultaneous detection of high-molecular-weight and low-molecular-weight compounds in clinically relevant concentration ranges, from 2.0 to 50 pmol/L for free T4, and 0.8 to 50 µIU for TSH. The sensitivity of the analysis was 1.0 ± 0.2 pmol/L (fT4) and 0.3 ± 0.1 µIU/mL (TSH), which corresponded to the detection thresholds of 3 × 10–18 mol T4 and 0.9 × 10–9 IU TSH. The test determined correctly the TSH and T4 concentrations in standard samples used in quality assessment programs, as well as the thyroid status of the patients included in the investigation (n = 48). Results of hormone detection in dried blood spots with our experimental test system correlated well with the results of hormone detection in serum samples using commercial kits (r = 0.9730 for TSH and r = 0.8585 for fT4). The main drawback of the system was associated with high variability of measurement results (up to 20%), which limits the possibility of its application for the quantification of the hormones level in patient blood. We believe that this system can be useful for detecting thyroid disorders both in the existing programs of neonatal screening for congenital hypothyroidism and in mass screening surveys in risk groups of the adult population, for example, in ecologically unfavorable regions.

Aim. To assess efficacy and toxicity of ibrutinib monotherapy in patients with relapsed/refractory mantle cell lymphoma (MCL). Materials & Methods. In this group of patients ibrutinib has been used since April 2016. Ibrutinib administration criteria were the age > 18 years and the confirmed MCL diagnosis with nuclear hyperexpression of cyclin D1 and t(11;14) (q13;q32) translocation. Poor physical status, pancytopenia, infectious complications (except for life-threatening conditions), blastoid variant, and the number of previous treatment lines were not regarded as contraindications to ibrutinib therapy. Oral ibrutinib was administered once a day at a dose of 560 mg before progression and until intolerable toxicity was observed. Results. From April 20, 2016 to April 6, 2018 ibrutinib therapy was provided to 42 patients with relapsed/refractory MCL. The median age was 69 years (range 40-81); 64 % of patients were men; ECOG > 2 was registered in 14 % of patients; 38 % of patients had blastoid variant; the median number of previous treatment lines was 2 (range 1-11). The overall response rate was 85 % (35 % were in complete remission); 57 % (24/42) of patients remain on ibrutinib treatment for the period of 4-667 days. The median event-free survival (EFS) was 365 days (95% confidence interval was 31-698 days). The median overall survival was not achieved. In blastoid variant the median EFS was 92 days, in the alternative group the median was not achieved and EFS was 76 % for 12 months (p < 0.001). In the majority of cases ibrutinib was well tolerated by patients. The most common complications were myalgia and muscle cramps (57 % cases), diarrhea (46 %, and grade 3 in 5 % cases), hemorrhagic complications (63 %, all of them of grade 1-2), and arrhythmia (7 %). Infectious complications were reported in 31 % of patients. In one case the start of ibrutinib treatment appeared to be problematic due to neutropenia of grade 4. Relative dose intensity was > 98 % (range 91.6-100 %). In 10 (24 %) patients ibrutinib treatment had to be adjusted (dose reduction or treatment interruption) due to toxicity and planned surgeries. None of ibrutinib recipients had to completely discontinue ibrutinib therapy due to complications. Conclusion. These data on the use of ibrutinib in actual clinical practice are comparable with the results of international multicenter studies (PCYC-1104, SPARK, and RAY). Reduced toxicity profile and rather high speed of antitumor response allow for ibrutinib administration in cases of poor physical status, low blood count, and even infectious complications. However, some adverse effects are manifested not earlier than after 6-month treatment, which calls for continuous monitoring, especially when preparing for surgeries.

Background High interest in chronic heart failure (CHF) is accounted for by its high incidence, poor prognosis, growing number of hospital admissions due to the heart failure relapse, and inadequate treatment. These facts necessitate a search for new pharmacological agents for the CHF correction. Herbal medicinal products appear to be very promising as they have a noticeable therapeutic effect and tend to be more harmless in comparison to the most of synthesized medications. Purpose Our aim was to study the composition of the Primula veris L. solid herbal extract (PVSHE) and its effects on the myocardial contractile function in animals with experimental CHF. Study design The study design involved the identification of the raw material composition of the P. veris L. extract. For the experimental part of our research, we used the model of CHF to elucidate the cardioprotective properties of PVSHE. Methods The active extract constituents were isolated by thin-layer chromatography and column chromatography; the extract components were identified by high-performance liquid chromatography, ultraviolet spectroscopy (UVS), and nuclear magnetic resonance spectroscopy (NMRS). To model CHF, L-isoproterenol at a dose of 2.5 mg/kg was intraperitoneally injected to the experimental rats twice a day for 21 days. Cardiac output was assessed with the loading test, adrenoreactivity test, and maximum isometric loading test; CHF markers adrenomedullin and copeptin were detected in blood plasma with ELISA kit for adrenomedullin and copeptin (Coud-Clone Corp., USA). Results P. veris L. solid herbal extract contains flavonoid aglycons (apigenin, quercetine, kaemferol), flavonoid glycosides (cinarozid, rutin, hyperozid), as well as polymethoxylated flavonoids acting as chemotaxonomic markers for the genus Primula (8-methoxy-flavone; 3′,4′methylenedioxy-5′-methoxyflavone). The substance 3′,4′methylenedioxy-5′-methoxyflavone has been isolated from the primrose herb for the first time. We showed that the PVSHE has a cardioprotective effect when it was administered at a dose of 30 mg/kg in the experimental CHF, as evidenced by a lower number of animal death, lower level of CHF markers in the blood plasma of the experimental animals, the higher increase in rate of myocardial contraction and relaxation, the higher level of left ventricular pressure (LVP) and of maximum intensity of structural performance (MISP), as compared to the control group. Conclusion P. veris L. solid herbal extract contains flavonoid aglycons, flavonoid glycosides, and polymethoxylated flavonoids. The herbal agent increases the myocardial contractility in experimental CHF.

Perishable food is food which shelf life’s duration is not more than 5 days. Therefore, extending the shelf life of perishable products is necessary. This action is needed, for example, for the transportation of products over long distances and their further sale. Food spoilage can be caused by microorganisms, enzymes or improper storage. Lower temperatures and preservatives are often used to increase the shelf life, and the preservatives can be chemically synthesized or natural. The aim of the article is to find ways to extend the shelf life of semi-finished potatoes using natural preservatives. Moreover, it is aimed at finding ways using natural preservatives. The research is carried out on the potato salad example. The graphs and tables show the results of the experiments. The results showed that 6% vinegar is the most suitable for extending the shelf life of semi-finished potatoes., Скоропортящиеся продукты - продукты, срок хранения которых не превышает 5 дней. Поэтому продление сроков годности скоропортящейся продукции является необходимым. Это нужно, например, для транспортирования продукции на дальние расстояния и ее дальнейшей реализации. Порча продуктов может быть вызвана с помощью микроорганизмов, различных ферментов или неправильного хранения. Для увеличения срока годности часто служат пониженные температуры и консерванты, причем консерванты могут быть химически синтезированными или же натуральными. Цель статьи - найти способы продлить срок хранения картофельного полуфабриката с использованием натуральных консервантов. Исследование проводится на примере картофельного салата. На графиках и в таблицах представлены результаты экспериментов. Результаты показали, что уксус 6% наиболее пригоден для продления срока годности картофельного полуфабриката., Journal of Agriculture and Environment, Выпуск 1 (17) 2021, Page 5

Background Heart failure (HF) is a well-recognized public health concern and imposes high economic and societal costs. Decision analytic models exist for evaluating the economic ramifications associated with HF. Despite this, studies that appraise these modelling approaches for augmenting best-practice decisions remain scarce. Objective Our objective was to conduct a systematic literature review (SLR) of published economic models for the management of HF and describe their general and methodological features. Methods This SLR employed a combination of relevant search terms associated with HF, which were used in a number of databases, including MEDLINE, Embase, the National Health Service Economic Evaluation Database, Cost-Effectiveness Analysis Registry, ScHARR Health Utilities Database and Cochrane Library Database. A number of model features (i.e. model structure, specification, outcomes assessed, scenario and sensitivity analysis, key model drivers) were extracted and subsequently summarized. Results Of 64 publications retained, a selection of modelling approaches were identified, including Markov (n = 28), trial-based analytic (n = 22), discrete-event simulation (n = 6), survival analytic (n = 7) and decision-tree modelling (n = 1) approaches. The bulk of publications employed either a cost-utility (n = 27) or cost-effectiveness (n = 36) analysis and evaluated more than one study outcome, which typically included overall costs (n = 59), incremental cost-effectiveness ratios (n = 55), life-years gained (n = 48) and willingness-to-pay thresholds (n = 37). Most publications focused on patients with chronic HF (n = 40) and used New York Heart Association (NYHA) disease classifications to categorize patients and determine disease severity. Few (n = 19) publications documented the use of hospitalization states for modelling patient outcomes and associated costs. A quality assessment of the included publications revealed most articles demonstrated reasonable methodological value. Conclusions We identified numerous decision analytic modelling approaches for evaluating the cost effectiveness of pharmacologic treatments in HF. A Markov cohort model approach was most commonly used, and most models relied on NYHA classes as a proxy of HF severity, disease progression and prognosis. Electronic supplementary material The online version of this article (10.1007/s40273-018-0755-x) contains supplementary material, which is available to authorized users.

Experimental chronic heart failure (CHF), caused by intraperitoneal administration of L-isoproterenol (2.5 mg/kg twice a day for 21 days), promotes uncoupling of respiration and oxidative phosphorylation in rat cardiac mitochondria. The rate of mitochondrial oxygen consumption in the metabolic state V3 by Chance in animals with CHF decreased by 53.3% (p < 0.05) with malate (as an oxidation substrate feeding complex I of the electron transport chain (ETC)), by 70.6% (p < 0.05) with succinate (complex II substrate) and by 63.6% (p < 0.05) when malate and succinate were added simultaneously. The respiratory control ratio (RCR) of mitochondria from CHF rats demonstrated a significant decrease for complex I substrate (2.3-fold), complex II substrate (2.5-fold) and 2.6-fold in the case of simultaneous addition of complex I and II substrates and 2.6 times as compared to cardiac mitochondria of intact animals. Mitochondrial dysfunction in experimental CHF is evidently associated with the development of oxidative stress: the malondialdehyde (MDA) content in the group of CHF rats was higher by 54.7% (p < 0.05), as compared with intact animals. The activity of superoxide dismutase (SOD) and catalase was lower by 17.5% (p < 0.05), and by 18.4%, respectively, than in the intact group. Administration of the Primula veris solid herbal extract (PVSHE) attenuated the development of mitochondrial dysfunction in rats with experimental CHF as evidenced by an increase in the V3 respiration using complex I (77.2%; p < 0.05), complex II (114.6%; p < 0.05) substrates and a 1.7- and 2-fold increase in the RCR value (p < 0.05) determined versus negative control with complex I and complex II substrates, respectively. Under these conditions the MDA concentration was lower by 15.7% (p < 0.05), while SOD activity was higher by 56.3% (p < 0.05).

Were studied endothelioprotective and antiaggregant properties of Primula veris L. solid herbal extract (PVSHE) in animals under experimental chronic heart failure (CHF) caused by isoproterenol administration in a dose of 2,5 mg / kg twice a day for 21 days. It was shown that in the control group of animals with CHF, the introduction of acetylcholine increased by 21,2 %, while the non-selective NO-synthase inhibitor L-NAME reduced the rate of blood flow in the carotid artery of rats by 27,5 %, which was less than the same values in the intact group: 45,2 % and -46,8 %, respectively (p < 0,05). The introduction of acetylcholine caused an increase in the rate of blood flow in the carotid artery in rats with CHF who received PVSHE at a dose of 30 mg / kg by 43,4 % and mildronate at a dose of 50 mg / kg - by 43,8 %, which was significantly higher than in animals of the control group (p < 0,05). The non-selective inhibitor of NO-synthase L-NAME reduced blood flow in the animals with CHF receiving study medications: -40,4 % and -39,5 % (p < 0,05), respectively It was found that the rate and degree of aggregation of platelets was higher in rats with CHF than in intact animals (29,6 % / min versus 20,6 % / min and 27,3 % vs. 18,8 %, p < 0,05, respectively ). In rats with CHF receiving PVSHE, the rate of blood flow in the carotid artery was 20% / min, mildronate -23,2 % / min, the degree of aggregation was 19 % and 21,9 %, respectively which was significantly lower in comparison with animals of the control group (p < 0,05). It was found that the level of von Willebrand factor (vW) was higher in animals with CHF than in the intact group by 91,1 % (p < 0.05) and significantly lower in animals with CHF who received PVSHE by 31,4 % (p < 0,05) and mildronate 21,2 % relative to the control group of rats (p < 0,05). The obtained data testify to the endothelioprotective and antiaggregant effect of the PVSHE comparable to the comparative preparation mildronate.

Experimental chronic heart failure (CHF), caused by administration of L-isoproterenol (2.5 mg/kg twice a day intraperitoneally for 21 days), promotes uncoupling of respiration and oxidative phosphorylation. The rate of mitochondrial oxygen consumption in the metabolic state V3 by Chance in animals with CHF decreased by 53.3% (p0.05) with malate using (as an oxidation substrate feeding сomplex I of the electron transport chain (ETC)), by 70.6% (p0.05) with succinate using (сomplex II substrate) and by 63.6% (p0.05) when malate and succinate were added simultaneously. The respiratory control ratio significantly decreased 2.3 times for сomplex I, 2.5 for сomplex II, and 2.6 times for the simultaneous operation of two respiratory chain complexes in mitochondria of CHF rats compared to intact animals. Mitochondrial dysfunction in experimental CHF is evidently due to the development of oxidative stress. It was revealed that the content of malonic dialdehyde (MDA) in the group of rats with experimental CHF was higher by 54.7% (p0.05), as compared with intact animals. The activity of superoxide dismutase (SOD) and catalase was lower by 17.5% (p0.05), and by 18.4%, respectively than in the intact group. The dense extract from herba of Primula veris L. (DEHPV) 30 mg/kg limits the development of mitochondrial dysfunction in rats with experimental CHF, as evidenced by an increase in the role of V3 respiration for the first and second respiratory chain complexes in 1.7 (p0.05) and 2.0 times (p0.05), respectively, the ratio of respiratory control (RCR) - 1.7 times (p0.05) for сomplex I and 2 times (p0.05) for сomplex II compared with the negative control. The concentration of MDA was by 15.7% (p0.05), lower and the activity of SOD was by 56.3% (p0.05) higher.Pokazano, chto éksperimental'naia khronicheskaia serdechnaia nedostatochnost' (KhSN), vyzvannaia vvedeniem L-izoproterenola v doze 2,5 mg/kg dvazhdy v sutki vnutribriushinno v techenie 21 dnia, sposobstvuet razobshcheniiu dykhaniia i okislitel'nogo fosforilirovaniia v mitokhondriiakh kletok serdtsa, na chto ukazyvaet snizhenie skorosti potrebleniia kisloroda v metabolicheskom sostoianii V3 po Chansu u zhivotnykh s KhSN na 53,3% (p0,05) pri ispol'zovanii malata (substrata okisleniia kompleksa I tsepi perenosa élektronov (TsPÉ)), na 70,6% (p0,05) – suktsinata (substrata kompleksa II TsPÉ) i na 63,6% (p0,05) pri ikh odnovremennom primenenii. Koéffitsient dykhatel'nogo kontrolia (KDK) dostoverno snizhalsia v 2,3 raza dlia kompleksa I, v 2,5 – dlia kompleksa II i v 2,6 raza pri odnovremennoĭ rabote dvukh kompleksov dykhatel'noĭ tsepi u krys s éksperimental'noĭ KhSN po sravneniiu s intaktnymi zhivotnymi. Mitokhondrial'naia disfunktsiia pri éksperimental'noĭ KhSN, ochevidno, obuslovlena razvitiem oksidativnogo stressa. Vyiavleno, chto soderzhanie malonovogo dial'degida (MDA) v gruppe krys s éksperimental'noĭ KhSN, bylo vyshe na 54,7% (p0,05) po sravneniiu s pokazateliami intaktnykh zhivotnykh. Pri étom summarnaia aktivnost' superoksiddismutazy (SOD) v kontrol'noĭ gruppe byla na 17,5% (p0,05), katalazy – na 18,4% nizhe po sravneniiu s intaktnoĭ gruppoĭ. Gustoĭ ékstrakt iz travy pervotsveta vesennego (GÉTPV) ogranichivaet razvitie mitokhondrial'noĭ disfunktsii u krys s éksperimental'noĭ KhSN, o chem svidetel'stvuet povyshenie V3 dlia pervogo i vtorogo kompleksov dykhatel'noĭ tsepi na 77,2 (p0,05) i 114,6% (p0,05) sootvetstvenno, KDK – v 1,7 raza (p0,05) dlia kompleksa I i v 2 raza (p0,05) dlia kompleksa II po sravneniiu s negativnym kontrolem. Pri étom kontsentratsiia MDA byla na 15,7% (p0,05) nizhe, a summarnaia aktivnost' SOD na 56,3% (p0,05) vyshe.

Eu(III) chelate-bonded polymer nanoparticles were used as phosphorescent labels to develop a highly sensitive phosphorescence analysis (PHOSPHANTM) for detection of human thyroid stimulating hormone (TSH). The phosphorescence was recorded in a time-resolved mode from microzones (microarrays) that were printed on the bottoms of the wells of standard polystyrene microplates. TSH was detected in paper discs (3.2 mm in diameter) that were punched from capillary blood that was dried on filter paper. The basic analytical and functional characteristics of this new method were similar to those of the commercial reagent kit for TSH detection in dried blood spots from newborns. Both methods made it possible to correctly detect the hormone concentration in the range of 0–250 μIU/mL blood. The analytical sensitivity of the Eu(III) nanoparticle label was 0.46 ± 0.1 μIU/mL (corresponded to approximately 17 fmol/L), which was comparable with the most sensitive assays. The matrix effect was insignificant. The coefficient of the variation of the results (up to 20%) was higher than in the commercial kit. This highly sensitive new test system could be integrated into PHOSPHAN-based multiplex tests to aid in simultaneous detection of markers for several congenital disorders in newborns.

We studied the effect of thick extract of Primula veris herb on blood pressure and heart rate in rats with stress-induced hypertension. A dose-dependent decrease in BP and HR was registered which was most pronounced in the stressed animals receiving thick extract of Primula veris herb at a dose of 60 mg / kg.

Various decision analytic models exist for evaluating the cost-effectiveness of pharmacological interventions for heart failure (HF). Despite this, studies that explore drivers influencing these modeling approaches remain scarce. Through a systematic review of the literature, the present study sought to identify model drivers that emerge from economic evaluations of HF pharmacological interventions. Among the 72 cost effectiveness papers evaluating HF drug interventions, the most frequently identified, top 5 ranked model drivers impacting the incremental cost-effectiveness ratio (ICER) were cost of treatment and utility, identified in 10% of studies, respectively. Other drivers that emerged as top 5 ranked drivers in > 5% of studies included treatment effect on mortality (or cardiovascular mortality), duration of treatment, and baseline cardiovascular mortality. Model drivers reported at the top of tornado diagrams were treatment effect on mortality or on cardiovascular mortality. Collectively, these observations highlight the key importance of treatment effect in driving cost-effectiveness models for HF. Electronic supplementary material The online version of this article (10.1007/s41669-019-00173-y) contains supplementary material, which is available to authorized users.

Migration of people with different ethnic and cultural origins observed during past decade worldwide resulted in the introduction of national beverages into food markets. In this study, we have investigated and critically appraised properties and marketing potential of the Kyrgyz-Kazakh beverage Maksim. This national non-alcoholic beverage is produced by mixed fermentation of milk in the presence of fried cereal such as barley, proso millet, oats, and corn. Pure cultures of lactic acid bacteria are used as a leaven for fermentation. Maksim is used as a thirst-quenching and tonic beverage. It could be also considered as functional food. While being dense, it serves as an excellent source of nutrients, fiber, vitamins, microelements, and other biologically active ingredients that offer health benefits that extend beyond basic nutrition. However, this beverage is not recommended for those affected by gluten sensitivity disorders. Here, we reviewed a number of different national beverages, assess physico-chemical properties of Maksym, and evaluate marketing strategies for the introduction of this beverage to Russian food markets. Although being unfamiliar to most of Russian consumers, this beverage is of interest due to its nutritional and thirst-quenching properties, and that a better advertisement strategies are needed to advance this healthy drink to food market. These strategies could include tasting, explanation of production process, historical and cultural origins of this beverage to general public.

We have developed a technology for the production of polymeric nanoparticles containing the incorporated phosphorescent label (europium ions–naphthoyltrifluoroacetone complexes) and streptavidin that is covalently bound on the surface. The aggregation-stable biospecific nanoparticles (40–60 nm in diameter) include up to 2000 molecular tags/particle and retain biological activity and stable phosphorescence for at least 20 months. They can be used in phosphorescence analysis (PHOSPHANTM)-based biochip technology as an effective detector system to record phosphorescence from microzones (microarrays) printed on the well bottoms of standard polystyrene microplates. The creation of a dense monolayer on the surface of a microzone requires up to 108 particles/microarray, or 109 particles/mm2 of area; this is in good agreement with theoretical estimates. The detection limit is as low as 300–400 phosphorescent nanoparticles per a microzone with an area of ~0.1 mm2. It has been demonstrated in the model of thyroid stimulating hormone (TSH) detection in filter paper dried blood that the newly developed detector system is five times more sensitive than the conventional methods of multiplex PHOSPHAN (with Pt-coproporphyrin phosphorescent label) and lanthanide immune fluoroassay (with fluorescent Eu3+ chelate complexes registered in the enhancement solution). The sensitivity of phosphorescent nanoparticle-based detector system is as low as 6.8 × 105 molecules/1.5 μL sample, which corresponds to a TSH concentration of 1.5 × 10–14 M.

Alemdar Karamanov is the creator of a special kind of religious symphony, which was formed during his mature musical period. Religious subject matter provided the foundation for: his symphonic macro-cycles “Sovershyshasya” [“It is Finished”] in ten movements, inspired by the four Gospels, “Byst’” [“That Which Shall Be”] consisting of six symphonies, based on the Book of Revelation, and the Third Piano Concerto, “Ave Мaria.” The inluence of the religious source material on the composer’s music formulates the conceptual invariant of his religious musical compositions. It is deined by the presence of a religious title and a religious program, the creation of his personal symbolic language, the usage of traditional rhetorical Baroque igures and symbols a la Bach, Biblical semantics interpretations of separate instruments, a semantic rendition of form as a “constructive” analogue to a religious program, the inluence of the principle of construction of the religious source on the form of the composition, as well as the uniication of symphonies into macro-cycles capable of embodying the scale, diversity and integrity of the religious sources. Keywords: Alemdar Karamanov, religious symphony, cycles of symphonies “Soversyshasya,” “Byst,” Piano Concerto “Ave Maria”, symphony-revelation

Introduction. Currently tourist activity management is in need of creating special conditions for the development of integrated management tools based on the general information and analytical base. Material and methods. The creation of architecture and the content of geoinformation and hybrid information systems are oriented at the usage of the Integrated Tourist Spaces Management (ITSM) to set up a specific claim related to the features of management model. The authors created the concept of tourist space. The information and the analytical system are used to create the information model of tourist space. Information support development of ITSM system is a sort of a hybrid system: an expert system constructed on the basis of GIS. Results and conclusions. By means of GIS collecting, storage, analysis and graphic visualization of spatial data and the related information on the objects presented in an expert system is provided. The offered approach leads to the formation of an information system and the analytical maintenance of not only human decision-making, but it also promotes the creation of new tourist products based on more and more differentiated inquiries of clients or a ratio of the price and quality (from the point of view of satisfaction of inquiries).

Background. Ibrutinib became available for patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) in Russia in the end of 2015 based on the results of phase 2 study by M. Wang from MD Anderson Cancer Center (NEJM 2013, Blood 2015). However, pts in routine clinical practice tend to differ significantly from the patients selected for clinical trials, which may lead to poorer results in off study treated patients. Aim. To assess efficacy and toxicity of ibrutinib monotherapy in pts with R/R MCL in routine community clinical practice outside of clinical trials. Materials & Methods. We analyzed the charts of all pts with R/R MCL who started ibrutinib from April 2016 to July 2019 in 7 Moscow's hospitals. The following criteria were used to initiate ibrutinib monotherapy: the age > 18 years, confirmed MCL diagnosis with nuclear hyperexpression of cyclin D1 and/or presence of the t(11;14)(q13;q32); symptomatic relapse or failure to achieve at least PR with a prior regimen. Poor physical status, pancytopenia grade 3-4, infectious complications (except for life-threatening conditions), blastoid variant and the number of previous treatment lines were not regarded as contraindications to ibrutinib therapy. Patients with CNS involvement were excluded from this analysis. Ibrutinib was administered once a day at a dose of 560 mg until progression or intolerable toxicity. Response to therapy was assessed every 2-3 months utilizing CT scan, PET/CT and bone marrow examination were required to confirm CR. Results. 54 pts with R/R MCL received ibrutinib monotherapy between April 2016 and July 2019. 26 pts (48%) were refractory to a prior therapy. The median age was 68 years (range 40-81); 69% of pts were men; ECOG > 2 in 22% of pts. 15 pts (28%) underwent a repeated biopsy before starting ibrutinib. 23 pts (43%) had an aggressive variant of MCL: either blastoid morphology (13/54 at diagnosis and 5/54 after repeated biopsy) or classical morphology with Ki-67>40% (4/54 at diagnosis and 1/54 after repeated biopsy). The median number of previous treatment lines was 2 (1-11). The response was evaluated in 53/54 pts. ORR was 81%, CR rate was 30% in the whole group. Pts with aggressive variants of MCL (group 1) had ORR of 65%, CR rate of 7%. In the group with classical morphology and Ki-67≤40% (group 2) ORR and CR rates were 93% and 47%. 2 pts with a response to therapy stopped ibrutinib early on their own accord, without signs of toxicity above gr.1. The median EFS for all pts was 394 days (95% CI: 261-526). In group 1 the median EFS was 173 days (95% CI: 112-234), in the group 2 the median EFS was 759 days (95% CI: 521-996, p The most common complications were myalgia and muscle cramps (60%, all gr.1-2), diarrhea (gr.1-2 in 58% and gr.3 in 4%); hemorrhagic complications (65%, all gr. 1-2); skin, nail toxicity and a rash (15%, all gr.1-2) and arrhythmia (9%). Infections were reported in 30% of pts (gr.3 in 6%). Skin/nails toxicity developed mainly after 6 months of ibrutinib intake. In 14 (26 %) pts ibrutinib treatment had to be adjusted (dose reduction or treatment interruption for 3-10 days) due to toxicity and planned surgeries. 4 pts (9%) required dose reduction from 560 to 420 mg. None of ibrutinib recipients had to completely discontinue ibrutinib therapy due to complications (with exception of 2 patients who stopped taking ibrutinib on their own). None of the patients received alloSCT. Conclusion. These data on the use of ibrutinib in actual clinical practice are comparable with the results of international multicenter studies (PCYC-1104, SPARK, and RAY). Favorable toxicity profile and rather short time to antitumor response allow for ibrutinib administration in cases of poor performance status due to disease, low blood count, and even infectious complications. Ibrutinib monotherapy results in the durable disease control in 93% of patients with non-blastoid MCL with the median EFS 25 months, but only 65% with blastoid type with the median EFS 6 months. However, some adverse effects are manifested not earlier than after 6-month treatment, which calls for continuous monitoring, especially when preparing for surgeries. Figure Disclosures Vorobyev: AstraZeneca: Consultancy; Abbvie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Sanofi: Consultancy. Ptushkin:JSC GENERIUM: Research Funding; Alexion Pharmaceuticals, Inc:: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; AbbVie: Consultancy.

The tradeoff between parental effort and mating effort in male animals may be mediated by testosterone (T). The pattern of association between T and paternal care in birds is consistent with this hypothesis, while it is poorly studied and not universal for mammals. We used the correlation approach to test two predictions of T-mediated tradeoff hypothesis for a biparental vole, Microtus mandarinus: (1) that T levels in males decrease from before pair formation to after birth of the first litter and (2) that paternal responsiveness of males negatively correlates with their T levels. T concentrations were measured in fecal samples collected before pairing and then immediately before behavioral testing on day 5 after birth of the first litter. Both nonpaternal and low paternal males had high initial T that decreased after birth of pups, though the decrease was only significant in low paternal males. In highly paternal males, the initial T was low and did not change after birth. Our results support the predictions of T-mediated tradeoff hypothesis and reveal individual variation in hormone–behavior relationship.