[Clinical importance of evaluation of circulating miRNA expression and epicardial adipose tissue thickness as predictors of cardiovascular pathology in young patients with type 1 diabetes mellitus].

Cardiovascular disease (CVD) in type 1 diabetes mellitus (T1DM) is preceded by asymptomatic changes in the geometry of the heart. The only symptoms of the beginning of cardiac remodeling and concomitant predictors of an unfavorable cardiovascular prognosis are: thickening of epicardial fat (EAT), secreting a number of adipokines, and cardiospecific miRNAs. To improve the effectiveness of prevention of CVD in young patients with DM1, a search was made for structural-functional and epigenetic markers. AIM: To assess the state of the cardiovascular system according to MRI-heart with T1 mapping in T1DM without CVD. To reveal the relationship of epigenetic markers (circulating miR-126-5p, miR-21-5p) and adipokines with cardiovascular system in T1DM. Suggested personalized approach to patients with T1DM with initial manifestations of joint remodeling and/or exclusion of cardiospecific microRNA. MATERIALS AND METHODS: The study included 40 patients: 30 with T1DM (age 26.2±7.4 years), 10 without T1DM (26.4±8.2). The patients underwent a general clinical examination, bioimpedancemetry, electrocardiography, MRI of the heart with T1 mapping, determination of adiponectin, resistin, visfatin, NT-proBNP, miR-126-5p, miR-21-5p. RESULTS: Patients with T1DM had lower levels of cardioprotective miR-126-5p (p=0.046). According to MRI of the heart in T1DM, signs of vascular remodeling were revealed - thickening of the interventricular septum (p=0.001), posterior wall (p=0.012) and relative size of the walls (p=0.048) of the left ventricle, an increase in EAT density (p=0.001). Diffuse vascular fibrosis was found in 16% of patients from the T1DM group. Also, in T1DM, the expression of visfatin is increased (p=0.036) and adiponectin is reduced (p=0.043). CONCLUSION: Structural and functional changes in the cardiovascular system (including thickening of the EAT), shifts in miR-126-5p expression and adipokines profile are observed already at a young age in patients with T1DM. In T1DM, diffuse vascular fibrosis is detected in 16% of patients. The data obtained were used to identify the group increased risk of developing CVD in T1DM and served as the basis for determining the timing of the start of preventive therapy.

[Features of steroidogenesis and arterial hypertension in men in different types of "physiological" male hyperandrogenism].

AIM: To reveal the peculiarities of steroidogenesis and arterial hypertension in «physiological¼ hyperandrogenism in men. MATERIALS AND METHODS: One-stage simultaneous study. The groups of men with hyperandrogenism caused by increased total testosterone (n=34) and those with hyperandrogenism caused by increased dihydrotestosterone (DHT) (n=66) were compared. In determining the type of hyperandrogenism and allocating patients to groups, DHT and total testosterone levels were determined by enhanced chemiluminescence. Subgroups of men with and without arterial hypertension were compared in the group of patients with hyperandrogenism due to an increase in total testosterone. Body mass index, waist circumference, systolic and diastolic blood pressure, pulse, and LH, SBHG, estradiol, blood multisteroid levels by isotope dilution liquid chromatography/tandem mass spectrometry, glucose, blood lipid spectrum, uric acid, creatinine, renin, potassium, sodium, and blood chloride were assessed in all patients. Patients with arterial hypertension additionally underwent daily BP monitoring, albuminuria assessment, electrocardiography, ocular fundus examination. The baseline threshold level of significance was p<0.05. For multiple comparisons, the p significance level was calculated using the Bonferroni correction. RESULTS: Statistically significant differences were found in the levels of 17-hydroxypregnenolone, 17-hydroxyprogesterone, and androstenedione, which were higher in men with elevated levels of total testosterone. No statistically significant differences in other laboratory parameters were found. No cases of increased blood pressure were detected in the group of men with elevated DHT. In the group of men with elevated total testosterone, 23,5% of men with arterial hypertension without targetorgan lesions were identified, while hyperandrogenism was associated with 17,6% of cases. Arterial hypertension associated with hyperandrogenism was characterized by a rise in blood pressure in the early morning hours. Estradiol levels, while remaining within normal limits, were statistically significantly lower in patients with arterial hypertension compared with men with elevated testosterone but without hypertension. CONCLUSION: No cases of arterial hypertension were observed in «physiological¼ hyperandrogenism due to elevated DHT levels, whereas its incidence in «physiological¼ hyperandrogenism due to elevated total testosterone was 23,5%. The features of steroidogenesis were increased production of 17-hydroxypregnenolone, 17-hydroxyprogesterone, and androstenedione in men with testosterone hyperandrogenism and decreased estradiol production in patients with arterial hypertension compared with patients without testosterone hyperandrogenism.

A phase Ib/II dose expansion study of subcutaneous sasanlimab in patients with locally advanced or metastatic non-small-cell lung cancer and urothelial carcinoma.

BACKGROUND: Sasanlimab is an antibody to the programmed cell death protein 1 receptor. We report updated data of subcutaneous sasanlimab in non-small-cell lung cancer (NSCLC) and urothelial carcinoma dose expansion cohorts from a first-in-human phase Ib/II study. PATIENTS AND METHODS: Patients were ≥18 years of age with NSCLC or urothelial carcinoma, and no prior immunotherapies, who progressed on or were intolerant to systemic therapy, or for whom systemic therapy was refused or unavailable. Patients received subcutaneous sasanlimab at 300 mg every 4 weeks (q4w). Primary objectives were to evaluate safety, tolerability, and clinical efficacy by objective response rate (ORR). RESULTS: Sixty-eight and 38 patients with NSCLC and urothelial carcinoma, respectively, received subcutaneous sasanlimab. Overall, sasanlimab was well tolerated; 13.2% of patients experienced grade ≥3 treatment-related adverse events. Confirmed ORR was 16.4% and 18.4% in the NSCLC and urothelial carcinoma cohorts, respectively. ORR was generally higher in patients with high programmed death-ligand 1 (PD-L1) expression (≥25%) and high tumor mutational burden (TMB; >75%). In the NSCLC and urothelial carcinoma cohorts, median progression-free survival (PFS) was 3.7 and 2.9 months, respectively; corresponding median overall survival (OS) was 14.7 and 10.9 months. Overall, longer median PFS and OS correlated with high PD-L1 expression and high TMB. Longer median PFS and OS were also associated with T-cell inflamed gene signature in the urothelial carcinoma cohort. CONCLUSIONS: Subcutaneous sasanlimab at 300 mg q4w was well tolerated with promising clinical efficacy observed. Phase II and III clinical trials of sasanlimab are ongoing to validate clinical benefit. Subcutaneous sasanlimab may be a potential treatment option for patients with NSCLC or urothelial carcinoma.

[Adipokines and the cardiorespiratory system in young patients with type 1 diabetes mellitus].

Early screening of complications of diabetes mellitus (DM) is one of the priorities for public health. Most patients with type 1 diabetes mellitus (T1DM) are patients of working age. New strategies for the primary prevention of cardiovascular disease (CVD) are needed to prevent their early disability. AIM: To assess the predictive value of adipokines in relation to a personalized approach to the need for an in-depth examination of young patients with T1DM. MATERIALS AND METHODS: The study included 98 patients without CVD: 70 patients with T1DM (mean age 26.4±8.1 years) and 28 patients without DM (mean age 27±9 years). All patients underwent a general clinical examination, the levels of adipokines were determined, ergospirometry, echocardiography, and bioimpedancemetry were performed. RESULTS: Changes in the cardiorespiratory system in patients with T1DM were revealed, in comparison with persons without T1DM: anaerobic threshold was reached faster (p=0.001), maximum oxygen consumption was lower (p=0.048), metabolic equivalent was reduced (p=0.0001). Signs of myocardial remodeling were found in the T1DM group: there was an increase in the relative wall thickness (p=0.001), the posterior wall of the left ventricle (p=0.001), myocardial mass index (p=0.049), in comparison with persons without T1DM. Changes in the adipokines system were revealed: higher levels of resistin (p=0.002) and visfatin (p=0.001), lower level of adiponectin (p=0.040) in T1DM. A positive correlation was found between posterior wall of the left ventricle and visfatin (p=0.014) and a negative relationship between adiponectin and relative wall thickness (p=0.018) in T1DM. CONCLUSION: In T1DM, even at a young age, there are multifactorial changes in the heart, which can be detected even at the preclinical stage. The data obtained can be used to identify groups of patients at high risk of developing dangerous CVD in T1DM, which can form the basis for determining the timing of the start of preventive therapy.

PRE-WAR STATE OF INFORMATION PROVISION OF THE POPULATION OF SURVEILLANCE ZONES ON THE SAFETY OF NUCLEAR ENERGY FACILITIES. / DOVOIeNNYI STAN INFORMATsIINOGO ZABEZPEChENNIa NASELENNIa ZON SPOSTEREZhENNIa Z PYTAN' BEZPEKY OB'IeKTIV IaDERNOÏ ENERGETYKY.

OBJECTIVE: to assess the state of information needs of the population and its provision by local governments on the safety of nuclear energy facilities and community preparedness for emergencies at nuclear power plants (NNP). MATERIALS AND METHODS: To determine the information needs of the population, a survey of the working population of the surveillance zone (SZ) of the NPP was conducted using unique probability sampling, where the sample was 322 people and the sampling error was 5.4 % with a confidence interval of 95.0 %. The issues of population behavior in case of emergencies at NPPs were studied. The assessment of the quality of the information content of the official websites of the executive authorities and local governments of various levels on radiation safety issues was carried out. RESULTS: The population of the SZ NPP considers the most effective information at the place of work, through neighbors, friends, from State Emergency Service specialists. Among information channels, the first place in terms of efficiency is occupied by Internet resources and social networks; the press and television occupy the second position, but remain convenient for the majority of the population. The most popular information related to NPP activities are: radiation status, environmental impact, benefits and subventions, such as compensation for the risk of living near NPPs, conditions of storage and disposal of radioactive waste. The preparedness of communities and the behavior of the population, in case of an emergency at the nuclear power plant, has been practiced in the satellite city and partially in the cities, but the rural population understands the sequence of actions much worse. CONCLUSION: Information support in NPP satellite cities is significantly better compared to rural areas of SZ. Bodies of executive power and local selfgovernment of the NPP SZ do not perform their function of informing the population on radiation safety and community readiness for emergencies through their official websites. The problem of information support of territorial communities is one of the most important to prevent the consequences of emergencies.

Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN.

BACKGROUND: In the phase III CASPIAN study, first-line durvalumab in combination with etoposide plus either cisplatin or carboplatin (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small-cell lung cancer (ES-SCLC). Durvalumab plus tremelimumab plus EP numerically improved OS versus EP, but did not reach statistical significance. Here we report updated OS in censored patients after median follow-up of >3 years. PATIENTS AND METHODS: 805 patients with treatment-naïve ES-SCLC were randomized 1 : 1 : 1 to durvalumab plus EP, durvalumab plus tremelimumab plus EP, or EP. The two primary endpoints were OS for durvalumab plus EP versus EP and for durvalumab plus tremelimumab plus EP versus EP. RESULTS: As of 22 March 2021 (median follow-up 39.4 months, 86% maturity), durvalumab plus EP continued to demonstrate improved OS versus EP: hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.60-0.86; nominal P = 0.0003]; median OS was 12.9 versus 10.5 months, and 36-month OS rate was 17.6% versus 5.8%. Durvalumab plus tremelimumab plus EP continued to numerically improve OS versus EP: HR 0.81 (95% CI: 0.67-0.97; nominal P = 0.0200); median OS was 10.4 months, and 36-month OS rate was 15.3%. Twenty-seven and nineteen patients in the durvalumab plus EP and durvalumab plus tremelimumab plus EP arms, respectively, remained on durvalumab treatment at data cut-off. CONCLUSIONS: Three times more patients were estimated to be alive at 3 years when treated with durvalumab plus EP versus EP, with the majority still receiving durvalumab at data cut-off, further establishing durvalumab plus EP as first-line standard of care for ES-SCLC.

HEALTH IN THE SYSTEM OF VALUES OF THE POPULATION OF THE SURVEILLANCE ZONES NUCLEAR POWER PLANTSS. / ZDOROV'Ia V SYSTEMI TsINNOSTEI NASELENNIa ZON SPOSTEREZhENNIa ATOMNYKh ELEKTROSTANTsII.

OBJECTIVE: to determine the place of health in the system of values of the population of the surveillance zone (SZ)of nuclear power plants (NPPs) and its importance in the perception of emergency risks (ER). MATERIALS AND METHODS: To determine the place of health in the value system, a survey of the able-bodied popula-tion of satellite cities of Rivne (RNPP) and South Ukrainian (SUNPP) nuclear power plants was conducted using non-repetitive sampling, where the sampling error does not exceed 7,0 %. The motivational and behavioral componentthat determined health in the individual hierarchy of values of the subject according to the questionnaireBerezovskaya R. A. was studied. Statistical and mathematical methods were used in the research process. RESULTS: The array of respondents was conditionally divided into 4 groups according to their attitude to humanhealth. And the group where a person's life position is focused exclusively on health is the most common - 77,0 %.Group IV, which wants to live without limiting itself, is 8,1 %. The component integrity of values-goals and values-means among the urban population of the SZ of both nuclear power plants is the same: the main goal in life is health,happy family life, and as a means - perseverance, diligence and health. Goal values in groups I and IV have somedifferences: in the first group of respondents the main goal in life is health, and in the fourth, where a person's lifeguidelines exclude any restrictions - a happy family life. Values for these populations have some differences, but inboth groups health appears to be the main means to an end. There is a close correlation between the core of termi-nal values and the average indicators of the state of concern about the risk of emergencies. CONCLUSIONS: Identified hierarchy of values: a group of stable dominant values; average status values; group of leastsignificant values. The values of the highest status among the values-goals are - health, happy family life and inte-resting work. Most respondents plan to achieve them through values such as «health¼, «perseverance and hardwork¼. There is a close correlation between the core of terminal values and the average indicators of the state ofconcern about the risk of emergencies.

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication.

BACKGROUND: The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. PATIENTS AND METHODS: Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. RESULTS: Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). CONCLUSIONS: Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

THE ROLE OF HIGH-RESOLUTION ULTRASOUND IN THE DIAGNOSTICS OF FACIAL AND NECK SKIN AFTER LASER RESURFACING.

High-resolution ultrasound (US) was used to examine 25 patients before the procedure and at the 2nd, 7th, 21st days and in 1.5 months after combined exposure to the skin of the face and neck with the Er:YAG laser in cold ablation mode and with the neodymium (Nd:YAG) laser in long pulse mode. The maximum dermis thickness was noted in the middle third (the standard measurement point along the mid-pupillary line in the projection of the infraorbital foramen) and composed 1,75±0,29 mm, the minimum on the neck and in infraorbital area - 1,2 (1,15; 1,3) mm and 1,15±0,15 mm, respectively. On the second day after the procedure, there was a significant increase up to 2,63±0,33 mm in the dermal thickness in the middle third in the projection of the infraobital foramen and up to 1,57±0,23 mm in the submental area of the neck due to all its layers in comparison with the values given ​​before the procedure (p=0.005, p<0.0001). Visualization of the dermis layers was difficult in B-mode during ultrasound, the toughness of the tissues decreased at compression elastography, pronounced vascularization was detected in the CDI mode in comparison with the initial one before the procedure and persisted up to 6 weeks. The ultrasound image in B-mode corresponded to the initial parameters starting from the 7th day.

Regulatory Resources and Emotional States in Overcoming Difficulties of Self-organization During Lockdown.

The research aimed to study the characteristics of the joint influence of conscious self-regulation and emotional states on life self-organization during a lockdown and identify the factors that contribute to overcoming emerging difficulties. It was conducted online, using the block site builder Tilda Publishing (tilda.ws) and a Google Forms survey administration application. The empirical structural model of regulatory and emotional predictors of self-organization during the lockdown shows that conscious self-regulation in conditions of imposed self-isolation acts as a universal resource for successful self-organization, managing the difficulties of reorganizing one's life, and coping with the anxiety of uncertainty. Positive and negative emotional states affect these processes differently. Optimism significantly contributes to conscious self-regulation, indirectly supporting successful self-organization of life and preventing the development of accomplishments. We identified the regulatory factor ("Cito-resource of self-regulation"), which plays a crucial role in overcoming self-organization difficulties during a lockdown. This factor is represented by the regulatory indicators of modeling significant conditions for achieving goals and reliability. The higher its development, the easier it is for a person to manage the difficulties of self-organization and cope with anxiety caused by uncertainty. Conscious self-regulation acts as a resource for the self-organization of human life in the lockdown conditions, providing a flexible adjustment of behavior to new challenges. High self-regulation and successful self-organization, acting as a resource of stress protection, increases the ability to maintain health. An optimistic attitude, in its turn, positively affects the conscious self-regulation of human activity.

SONOGRAPHY OF THE FACE AND NECK REGION SOFT TISSUES IN ASSESSMENT OF THE COMPLICATIONS CAUSES AFTER FACIAL CONTOURING.

132 women after facial contouring on terms from 2 weeks to 15 years after filler injection were examined by sonography (US). They had complaints of the edema, hypercorrection, asymmetry, discomfort and anxiety about the excess of the terms that filler had spent into the soft tissues. HA fillers were injected in 111 cases (84.1%), silicon agents - in 13 cases (9.8%), CaHA - in 6 (4.5%), PMMA - on 1 (0.8%) and one patient have had non-hyalouronic filler with unknown origin (0.8%). According to the US data, nasolacrimal and palpebromar fissures were the most common location of fillers or the echo signs of fibrotic changes in the projection of their injection - 54 patients, just like the lips region and nasolabial folds - 52 cases. The US of the skin and the soft tissues of the face and neck region prescribed to the patients in order to carry out the differential diagnosis of complaints' causes, to determine the treatment tactics and for planning cosmetic procedures.

FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma.

BACKGROUND: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

[Methotrexate-induced lung damage in a patient with rheumatoid arthritis].

We herein report a case of interstitial lung disease secondary to the use of methotrexate in a patient with rheumatoid arthritis. Differential diagnosis between pneumonitis caused by methotrexate in patients treated with basic methotrexate therapy and interstitial pulmonary disease associated with rheumatoid arthritis is based on the clinical examination and instrumental data. The main condition for favorable clinical outcome in all drug-induced lung disease is drug withdrawal, what was proven in our report.

ECOLOGICAL DETERMINANTS IN THE FORMATION OF THE POPULATION'S ATTITUDE TO THE DEVELOPMENT OF NUCLEAR ENERGY. / EKOLOGIChNI DETERMINANTY U FORMUVANNI STAVLENNIa NASELENNIa DO ROZVYTKU ATOMNOÏ ENERGETYKY.

OBJECTIVE: Evaluation of the key environmental determinants that shape the response of the social environment tothe activities of nuclear power plants. MATERIALS AND METHODS: The poll was conducted in the observation zone (OZ) of the South-Ukrainian NPP (SUNPP).A repetition-free probabilistic selection was used in the population survey. The sample of respondents from the population of the SUNPP OZ was 322 people with the sampling error of 5.4 % and confidence interval of 95.0%. An ordinal 5-point measurement scale was used to assess the quality of life and anxiety, and nominal measurement scaleswere used for other issues. All the age groups of population from 20 to 65 years were taken into account. The sociohygienic, sociological, statistical and mathematical research methods were applied in the process of work (relativevalues, averages, reliability of paired differences according to Student's t test). RESULTS: The level of perception of radiation risk by the population of the NPP OZ was the lowest among respondentsof satellite cities of Rivne NPP (RNPP) and SUNPP compared to the population of rural settlements and cities of theOZ. Storage and shipment of radioactive waste are the determinant among the factors that form an environmentalthreat to the population of OZ as a result of NPP activities. Social factors that determine the assessment of environmental safety of NPP activities are employment at the NPP, place of residence, gender, age, level of education of thepopulation, etc. The «Ch-image¼ of the ecological catastrophe formed in the population of Ukraine as a result of theChNPP accident , regardless of the place of residence on the territory of Ukraine, influences behavior, formation ofplans and assessments, especially in population living near the ionizing radiation sources. CONCLUSION: The current legislation governing the relationship between functioning NPPs and the communities inwhich they are located needs to be improved, guided by the basic principle of environmental public health - socialjustice, i.e. the human right to a healthy environment. It means that the settlements of the OZ (communities)receive funds to compensate for risk living in compliance with certain safety rules to maintain health. Legal regulation and constant awareness of population are the main directions for the formation of adequate assessments.

Prognostic impact of baseline tumour immune infiltrate on disease-free survival in patients with completely resected, BRAFv600 mutation-positive melanoma receiving adjuvant vemurafenib.

BACKGROUND: We conducted a retrospective exploratory analysis to evaluate the effects of baseline tumour immune infiltrate on disease-free survival (DFS) outcomes in patients with fully resected stage IIC-IIIC melanoma receiving adjuvant vemurafenib monotherapy or placebo in the BRIM8 study. PATIENTS AND METHODS: BRIM8 was a phase III, international, double-blind, randomised, placebo-controlled study. Eligible patients with BRAFV600 mutation-positive, completely resected melanoma were randomly assigned to oral vemurafenib (960 mg twice daily) or matching placebo for 52 weeks. The primary end point was DFS. The association of CD8+ T-cell infiltration and programmed death ligand 1 (PD-L1) expression with DFS, as measured by immunohistochemistry, was explored retrospectively. RESULTS: Four hundred ninety-eight patients were randomly assigned to receive adjuvant vemurafenib (n = 250) or placebo (n = 248); tumour samples were available for biomarker analysis for approximately 60% of patients. In the pooled biomarker population, placebo-treated patients with <1% CD8+ T cells in the tumour centre had shorter median DFS than those with ≥1% CD8+ T cells (7.7 versus 47.8 months). DFS benefit from vemurafenib versus placebo was greater in patients with <1% CD8+ T cells [hazard ratio (HR) 0.56; 95% confidence interval (CI) 0.34-0.92) than in patients with ≥1% CD8+ T cells (HR 0.77; 95% CI 0.48-1.22). Likewise, median DFS was shorter among placebo-treated patients with <5% versus ≥5% PD-L1+ immune cells (IC) in the tumour (7.2 versus 47.8 months). A greater DFS benefit with vemurafenib versus placebo was observed in patients with <5% PD-L1+IC (HR 0.36; 95% CI 0.24-0.56) than in patients with ≥5% PD-L1+IC (HR 0.99; 95% CI 0.58-1.69). CONCLUSIONS: The presence of CD8+ T cells and PD-L1+IC are favourable prognostic factors for DFS. Treatment with adjuvant vemurafenib may overcome the poor DFS prognosis associated with low CD8+ T-cell count or PD-L1 expression. CLINICALTRIALS. GOV IDENTIFIER: NCT01667419.

[Risk factors for the early development of septic shock in patients with severe COVID-19].

AIM: In a retrospective study, we evaluated factors associated with the early development of septic shock in patients with severe COVID-19. MATERIALS AND METHODS: We collected medical records of the intensive care unit patients submitted by the local COVID-19 hospitals across Russia to the Federal Center for the Critical Care at the Sechenov First Moscow State Medical University (Sechenov University). Septic shock in crticially ill patients requiring mechanical ventilation was defined as a need in vasopressors to maintain blood pressure. RESULTS: We studied 1078 patients with severe COVID-19 who were admitted to the intensive care units for respiratory support. There were 611 males and 467 females. The mean age was 61.013.7 years. Five hundred twenty five medical records (48.7%) were received from the Moscow hospitals, 159 (14.7%) from the Moscow region, and 394 (36.5%) from the hospitals located in 58 regions of the Russian Federation. In 613 (56.9%) patients, diagnosis of SARS-CoV-2 infection was confirmed by PCR, and in the other cases it was established on the basis of the clinical picture and the results of the chest CT scan. Septic shock developed in 214 (19.9%) of 1078 patients. In the logistic regression model, the risk of septic shock in patients older than 50 years was higher than in patients of a younger age (OR 2.34; 95% CI 1.533.67; p0.0001). In patients with more severe SARS-CoV-2 infection, there was an increase in the prevalence of cardiovascular diseases, including coronary heart disease and atrial fibrillation, type 2 diabetes and malignant tumors. The risk of septic shock in patients with three or more concomitant diseases was higher than in patients without any concomitant chronic diseases (OR 1.76; 95% CI 1.762.70). CONCLUSION: The risk of septic shock in patients with acute respiratory distress syndrome induced by SARS-CoV-2 is higher in patients older than 50 years with concomitant diseases, although a severe course of the disease is also possible in younger patients without any concomitant disorders.

IMPACT OF THE RIVNE NPP ACTIVITY ON NATURAL AND SOCIAL ENVIRONMENT OF THE CONTROL AREA. / VPLYV DIIaL'NOSTI RIVNENS'KOÏ AES NA PRYRODNE TA SOTsIAL'NE SEREDOVYShchE ZONY SPOSTEREZhENNIa.

OBJECTIVE: To assess an impact of the Rivne Nuclear Power Plant (RNPP) activity on the control area (CA) environ- ment according to environmental and radiation monitoring data over time of 2011-2017 as a component of the radiation safety system. MATERIALS AND METHODS: Review of geographical and natural features of the territory of the «Rivne NPP¼ manufac- turing facility was carried out to assess its CA environment. Assessment of environmental and radiation situation of the CA was carried out according to the data of RNPP monitoring systems and a number of state institutions of Rivne oblast over time of 2011-2017. Opinion of the CA population about the RNPP environmental impact was studied. The sampled population of respondents was calculated based on the total population living in CA. The sampling error no more that 7.0%. Data from sociological survey of population were calculated using the statistical programs. RESULTS: The radiation impact of RNPP on environment is related to emissions and discharges of radioactive sub- stances generated in the production cycle. Over time the total index of radionuclide discharge to the Styr River since 2011 is of a marked downward trend from 2.11 % to 0.18 %. The maximum concentrations of 60Co and 137Cs radionuclides at the three sampling points along the Styr River over time of 2011-2016 were about one thousandth of a percent, and of 131I - one hundredth of a permissible value according to the Radiation Safety Standards of Ukraine (RSSU). Emissions of inert radioactive gases and long-lived nuclides into the atmosphere were less than 0.2 % and iodine emissions were 0.01 % to the emission limit. Average radionuclide concentrations in the natural air of the RNPP CA settlements did not exceed the admissible concentration limit (ACL). Concentrations of chem- ical pollutants in discharges of the RNPP to the Styr River over time of 2012-2017 did not exceed the ACL. Integral wastewaters of municipal enterprises of the CA and RNPP result in an increased index of biochemical oxygen uti- lization and ammonium salt content in the Styr River, exceeding the ACL in fishery reservoir water. No exceedance of ACL of repugnant substances in the open air of settlements was observed regarding the pollutants under study. According to population survey the radiation contamination of territories as a result of the ChNPP accident and RNPP activities, which cause anxiety, are the key factors determining an environmental situation at the place of residence. The correlation coefficients between anxiety index and public estimates of environmental situation are established. CONCLUSIONS: Content of radionuclides in emissions and discharges generated in the RNPP production cycle under everyday conditions does not exceed the allowed RSSU-97 values. The combined discharges of collective enterpri- ses and RNPP are the main sources of chemical pollution of surface waters in CA. There is a higher correlation coef- ficient between the anxiety and somatization rates and environmental sphere parameter in rural population com- pared to urban one. The combined effect of environmental, radiation and psychological factors on the RNPP CA population makes the health studies necessary in the latter.

Autoimmune liver disease (primary biliary cholangitis/autoimmune hepatitis-overlap) associated with sarcoidosis (clinical cases and literature review).

Clinical features of overlap autoimmune hepatitis/primary biliary cholangitis and morphological-proved sarcoid lesions (lungs, lymph nodes, skin) were performed. Data of long-term clinical observation presented in comparison with the results of laboratory datas, instrumental and morphological studies of liver tissue, lungs, skin. The modern aspects of pathogenesis of association autoimmune and granulomatous diseases arediscussed on the example of clinical cases of combination of cholestatic variants of autoimmune hepatitis and generalized sarcoidosis. Keywords: sarcoidosis, autoimmune hepatitis, primary biliary cholangitis, primary biliary cholangitis-autoimmune hepatitis-overlap, extrahepatic manifestations.

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE).

BACKGROUND: Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. PATIENTS AND METHODS: In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). RESULTS: Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9-22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%-82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). CONCLUSIONS: Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. CLINICALTRIALS.GOV: NCT01572038.