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Abstract Background With the advent of direct acting antivirals (DAAs) the World Health Organisation (WHO) adopted global strategy to eliminate hepatitis C virus (HCV) infection by 2030. In Europe, people who inject drugs (PWID) account for the majority of new cases, however testing and treatment remain suboptimal. The aim was to monitor progress in HCV policy and cascade-of-care for PWID, led by the civil society organisations (CSO) that provide harm reduction services for PWID across Europe. Methods In period 2020–2023, CSOs representing focal points of Correlation-European Harm Reduction Network were annually invited to complete online questionnaire on use/impact of HCV test-and-treat guidelines for PWID, availability/functioning of continuum-of-care, and role/limitations of harm reduction services for PWID. A retrospective longitudinal analysis of responses to questions answered each year by the same respondents was performed, and a comparison among the studied years was made. Results Twenty-five CSOs from cities in 25 European countries were included and responded to 25 questions. Between 2020 and 2023, there was positive trend in number of HCV treatment guidelines, separate guidelines for PWID, and their positive impact on acess to testing/treatment (24/25, 5/25, and 16/25 in 2023, respectively). DAAs were available in all countries, predominantly prescribed by specialist physicians only (slight increase at primary care), with restrictions including active drug use, stage of liver fibrosis or/and reimbursement policies (2/25, 4/25, and 3/25 in 2023, respectively). A decrease in HCV testing sites was noted. Treatment was consistently most common at clinical settings, however an increase outside the specialist settings was detected, particularly in prisons (12/25 and 15/25 in 2020–2021, respectively). Comparing 2022–2023, number of HCV-testing services increased in many cities with positive dynamic in nearly all the settings; increase in treatment at harm reduction services/community centres was noted (6/25 to 8/25, respectively). Between 2020 and 2023 the frequency of various limitations to CSOs addressing HCV was oscillating, presenting an increase between 2022 and 2023 (9/25 to 14/25, respectively). Conclusion The overall progress towards WHO HCV elimination goals across Europe remains insufficient, most probably also due to the influence of Covid-19 pandemic. Further improvements are needed, also by including CSOs for PWID in continuum-of-care services, and in monitoring progress.

ObjectivesTo conduct mental health surveillance in adults in Ukraine and Ukrainian refugees (Canton of Zurich, Switzerland) as an actionable scientific foundation for public mental health and mental healthcare.MethodsMental Health Assessment of the Population (MAP) is a research program including prospective, population-based, digital cohort studies focused on mental health monitoring. The study aims to include 17,400 people from the general population of Ukraine, 1,220 Ukrainians with refugee status S residing in the canton of Zurich, and 1,740 people from the Zurich general population. The primary endpoints are prevalence and incidence of symptoms of: posttraumatic stress disorder (measured by PCL-5), depression (PHQ-9), anxiety (GAD-7), and alcohol use disorder (AUDIT). Secondary endpoints include participants’ health-related quality of life (EQ-5D-5L and EQ-VAS), experiences of somatic distress syndrome (PHQ-15), social isolation, social integration, and mental wellbeing (SWEMWBS).ResultsBaseline assessment starts in March 2024 with follow-ups occurring every 3 months for at least 2 years.ConclusionMAP will generate reliable, comparable, and high-quality epidemiological data to inform public mental health and healthcare policies in the Ukrainian population.ISRCTN Registryhttps://www.isrctn.com/ISRCTN17240415.

Introduction: Doxorubicin (DOX) is an anthracycline antibiotic with considerable significance in clinics as an anticancer agent, which is limited by its cardiotoxicity, though. A large number of possible therapeutic strategies for reducing cardiotoxicity with doxorubicin have been studied. However, none of them fully meets the requirements of clinical practice. The aim of the study: to evaluate the cardioprotective effects of a new original heterocyclic compound, a pyridine-3-carboxylic acid derivative potassium 5-hydroxynicotinate. Materials and Methods: Cardiac injury was induced by intraperitoneal administration of doxorubicin (DOX) at a dose of 20 mg/kg. After 48 hours, the parameters of left ventricular contractility and StTTI coefficient were assessed on isolated heart in the Langendorff system under the conditions of 480 beats per minute for 11 seconds. Additionally, specific markers of myocardial injury were determined. The lipid peroxidation products and SOD activity were measured as well to challenge whether the compound is able to reduce oxidative stress. Results: The study showed that pretreatment by potassium 5-hydroxynicotinate (35 mg/kg, 48 h) attenuated DOX-induced damage, resulting in a significant decrease in the StТТI coefficient to 3.3 values and in the restoration of the antioxidant activity of enzymes. Conclusion: The obtained data totally demonstrate the protective effects of potassium 5-hydroxynicotinate in DOX-induced cardiomyopathy. A significant role in potassium 5-hydroxynicotinate-mediated cardioprotection is, apparently, related to the reduction of oxidative stress and down-regulation of the level of intracellular calcium.

The relevance of the study is dictated by the need to preserve the water resources of southern Ukraine and ensure their good environmental condition. In the context of military operations, Odesa Region plays a key role in providing the country with agricultural products because of significant damage incurred to agricultural lands of Mykolaiv and Kherson Regions in the course of military actions. Hence the role of irrigation and the need to restore and modernize irrigation systems are growing. One of fresh water reservoirs of Odesa Region is Sasyk reservoir (artificially created as part of the estuary) which accumulates fresh water supplied from the Danube. The Kogylnyk and the Sarata rivers flow into the northern part of the reservoir and can worsen its hydroecological condition. The subject of the study: pollution of the rivers across North-Western Black Sea Coast by chemicals. The object of the study: the environmental state of the Sarata River. The study is aimed at assessing the environmental state and environmental risks of chemical pollution of the Sarata River. The water quality assessment was performed based on a modified version of water pollution index (WPI). Biogenic substances (ammonium nitrogen, nitrite nitrogen, nitrate nitrogen) were identified as the main pollutants. The content of chlorides and sulfates is also significant. The assessment of the pollution risks by biogenic substances is based on calculations of the statistical probit function. The source materials of the research include hydrochemical observations made by the State Agency of Water Resources of Ukraine for the period from 2007 to 2023 in the upper reaches of the Sarata River - village of Miniailivka (94 km from the mouth, near the border with Moldova) and in the lower reaches of the Sarata River - village of Bilolissya (14.3 km from the mouth). The analysis of probability of exceeding the MPC for fishery use indicated that, in terms of nitrite ions and nitrate ions, such probability is higher in the upper basin than in the lower one. According to other indicators, the probability of exceeding the MPC by pollutants is either almost the same or slightly increased in the lower reaches. The assessment of water quality according to the modified WPI (dissolved oxygen, BOD5, ammonium, nitrite and nitrate ions, phosphates) showed that the water quality in the Sarata River mainly belongs to the "moderately polluted" and "polluted" classes. According to the environmental risk indicators, it was established that the possibility of a "high" risk of contamination by biogenic substances does prevail. Its probability is 52.9% for the upper reaches and 60% for the lower reaches. The "high" level of class IV pollution (ER=0.60-0.79) corresponds to an "unsatisfactory" environmental condition. The probability of achieving the class of a "good" environmental condition (class II, ER=0.20-0.39) is quite small: 17.6% in the upper reaches and only 6.67% in the lower reaches. Thus, the Sarata River belongs to such rivers, the natural properties of which underwent significant changes as a result of sewage delivery from "Sarata Komunservis" utility enterprise, settlement of Sarata. Contaminated waters are unsuitable for drinking, household and sports purposes, as well as for fish farming. The quality of the Sarata River's water has a negative impact on the environmental state of Sasyk reservoir.

The relevance of the work is determined by the necessity of quantitative assessment of the risks of water resources changes occurring in the early 21st century due to the greenhouse effect and corresponding climate changes. To evaluate climate risks the authors used a probabilistic approach which involves multiplying the indicator of water resource reduction by the probability of such event occurrence. Reduction of water resources caused by warming characterizes their "depletion". The study utilized the results of calculations of the average long-term annual "climate" runoff, determined through the "climate-runoff" model based on meteorological data of the averaged model trajectory of the EURO-CORDEX project for the climate change scenarios RCP4.5 and RCP8.5. The calculation period extends from 2021 to 2050, while the baseline period continues from the beginning of observations until 1989. The comparison of the calculated climatic runoff and the baseline runoff was performed across meteorological stations. The assessment of the changes was carried out by calculating the relative deviation between the baseline and calculated runoff values. The probability of the "depletion" stage for water resources was determined as the ratio of the number of meteorological stations (grid nodes) where changes reached certain magnitudes to the total number of stations considered. The threshold indicators for the degree of depletion of water resources included changes exceeding 10% (statistically significant changes in water resources), 50% (water resources destruction), and 70% (irreversible destruction of water resources). The objective of the study consists in developing criteria for calculating climate risks and establishing the risks of formation of a tense, critical, and catastrophic state of water resources, taking Ukraine as an example. A detailed examination of the intervals of changes in water resources showed that the highest risk of their depletion over the period from 2020 to 2050 will be observed in the range from -20 to -40% (tense state) for the RCP4.5 scenario and from -30 to -60% (tense state) for the RCP8.5 scenario. It was established that the climate risks of depletion and irreversible depletion of water resources for the territory of Ukraine from 2020 to 2050 remain quite small, which is confirmed by the low probability of their occurrence. However, the risk values increase by 1.5 to 2.0 times for the RCP8.5 scenario compared to the RCP4.5 scenario. Additionally, for calculating the climate risks, it was proposed to use a relative area subject to depletion as an indirect indicator of losses (a larger area implies higher costs of restoration). This approach allowed for having more differentiated risk assessments. The developed methodology for assessing the climate risks of water resources depletion in the context of global warming can be applied for various models and countries.

The relevance of the chosen topic is based on the goals and objectives of the Water Strategy of Ukraine until 2050 that provides for promotion of studies on the impact of climate change on the water content of Ukrainian rivers. The Dniester River is a transboundary river. It supplies water to Moldova and several regions of Ukraine. Predicting possible changes in the Dniester River's runoff due to global warming will help our society adapt to new climate conditions and take preventive measures. The research of the mountainous part of the watershed is of particular importance, as it is the area of runoff formation. Warming can change contribution of the snow component to the river's feed pattern and affect the total river flow. The object of the study: changes in air temperature due to global warming. The subject of the study: assessment of changes in the temperature regime within the Dniester watershed and impact of such changes on formation of its mountainous part's runoff. The study is aimed at assessing the changes in the air temperature regime within the Dniester River watershed at the beginning of the 21st century and assessing the impact of warming during winter season on formation of mountain rivers' spring floods. The main research methods include the method of difference integral curves and the method of regression analysis. The research materials include average monthly and annual air temperatures at 13 meteorological stations located within the Dniester watershed for the period of 1947-2021. The research indicated that the Dniester watershed is subject to warming. Statistically significant changes in air temperature began in 1988. Fluctuations in average annual air temperatures occur synchronously. Positive statistically significant trends over the entire observation period (1947-2021) were found for average annual air temperatures, average monthly temperatures of both warm and cold periods, and for the winter season. When considering two measurement periods (before 1989 and after), it was found that no statistically significant trends were observed before 1989. They were formed after 1989. It was also discovered that mountainous watersheds of the Ukrainian Carpathians respond to warming by forming negative trends in the fluctuations of average monthly runoff of spring floods.

Studies in recent decades have shown strong evidence of physical and biological changes in the Arctic tundra, largely in response to rapid rates of warming. Given the important implications of these changes for ecosystem services, hydrology, surface energy balance, carbon budgets, and climate feedbacks, research on the trends and patterns of these changes is becoming increasingly important and can help better constrain estimates of local, regional, and global impacts as well as inform mitigation and adaptation strategies. Despite this great need, scientific understanding of tundra ecology and change remains limited, largely due to the inaccessibility of this region and less intensive studies compared to other terrestrial biomes. A synthesis of existing datasets from past field studies can make field data more accessible and open up possibilities for collaborative research as well as for investigating and informing future studies. Here, we synthesize field datasets of vegetation and active-layer properties from the Alaskan tundra, one of the most well-studied tundra regions. Given the potentially increasing intensive fire regimes in the tundra, fire history and severity attributes have been added to data points where available. The resulting database is a resource that future investigators can employ to analyze spatial and temporal patterns in soil, vegetation, and fire disturbance-related environmental variables across the Alaskan tundra. This database, titled the Synthesized Alaskan Tundra Field Database (SATFiD), can be accessed at the Oak Ridge National Laboratory Distributed Active Archive Center (ORNL DAAC) for Biogeochemical Dynamics (Chen et al., 2023: https://doi.org/10.3334/ORNLDAAC/2177).

Light alloys based on magnesium are widely used in most areas of science and technology. However, magnesium powder alloys are quite difficult to sinter due to the stable film of oxides that counteracts diffusion. Therefore, finding a method to activate magnesium sintering is urgent. This study examines the effect of adding 5 wt. % and 10 wt. % zinc to the sintering pattern of magnesium powders at 430 °C; a dwell of 30 min was used to homogenize at the densification’s temperature. Scanning electron microscopy (SEM) was used to characterize the alloy’s microstructure, while the phase composition was characterized using X-ray diffraction (XRD) and energy dispersion spectroscopy (EDS). The sintering densities of Mg–5Zn and Mg–10Zn were found to be 88% and 92%, respectively. The results show that after sintering, a heterophase structure of the alloy is formed based on a solid solution and phases MgZn and Mg50Zn21. To establish the sintering mechanism, the interaction at the MgO and Zn melt phase interface was analyzed using the sessile drop method. The minimum contact angle—65°—was discovered at 500 °C with a 20 min holding time. It was demonstrated that the sintering process in the Mg–Zn system proceeds through the following stages: (1) penetration of zinc into oxide-free surfaces; (2) crystallization of a solid solution, intermetallics; and (3) the removal of magnesium oxide from the particle surface, with oxide particles deposited on the surface of the sample.

BACKGROUND: In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial. METHODS: Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (TcellinfGEP) and 10 non-TcellinfGEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-β, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for TcellinfGEP (prespecified α=0.05) and the 10 non-TcellinfGEP signatures (multiplicity-adjusted; prespecified α=0.10). RESULTS: RNA sequencing data were available for 137 patients in each treatment group. TcellinfGEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the TcellinfGEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel. CONCLUSIONS: This exploratory analysis of tumor TcellinfGEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. TcellinfGEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis. TRIAL REGISTRATION NUMBER: NCT02370498.

The necessary information on the formation of high manganese silicide (Mn4Si7) coating by magnetron sputtering method is presented in this work. The technology and basic modes of creating the necessary targets for a magnetron sputtering device are presented. Targets were created by adding silicon and manganese powders in the required amount and heating them under vacuum conditions at high temperature and pressure. Thin silicide films (thin coatings) of different thicknesses were formed on the surface of silicon dioxide from the produced targets using the method of magnetron sputtering. The electrophysical and thermoelectric properties of the produced films were studied using physical and optical methods.Due to the change in the structure of the coatings during subsequent heat treatment, the Seebeck coefficient noticeably increases.

Background The global demographic situation has been significantly impacted by the COVID-19 pandemic. The objective of this study was to develop a model that predicts the risk of COVID-associated mortality using clinical and laboratory data collected within 72 h of hospital admission. Materials and methods A total of 3024 subjects with PCR-confirmed COVID-19 were admitted to Almazov National Research Medical Center between May 2020 and August 2021. Among them, 6.25% ( n = 189) of patients had a fatal outcome. Five machine learning models and the Boruta-SHAP feature selection method were utilized to assess the risk of mortality during COVID-19 hospitalization. Results All methods demonstrated high efficacy, with ROC AUC (Receiver Operating Characteristic Area Under the Curve) values exceeding 80%. The selected Boruta-SHAP features, when incorporated into the random forest model, achieved an ROC AUC of 93.1% in the validation. Conclusion Throughout the study, close collaboration with healthcare professionals ensured that the developed tool met their practical needs. The success of our model validates the potential of machine learning techniques as decision support systems in clinical practice.

Abstract Cathepsin‐K (CTSK) is an osteoclast‐secreted cysteine protease that efficiently cleaves extracellular matrices and promotes bone homeostasis and remodeling, making it an excellent therapeutic target. Detection of CTSK activity in complex biological samples using tailored tools such as activity‐based probes (ABPs) will aid tremendously in drug development. Here, potent and selective CTSK probes are designed and created, comparing irreversible and reversible covalent ABPs with improved recognition components and electrophiles. The newly developed CTSK ABPs precisely detect active CTSK in mouse and human cells and tissues, from diseased and healthy states such as inflamed tooth implants, osteoclasts, and lung samples, indicating changes in CTSK's activity in the pathological samples. These probes are used to study how acidic pH stimulates mature CTSK activation, specifically, its transition from pro‐form to mature form. Furthermore, this study reveals for the first time, why intact cells and cell lysate exhibit diverse CTSK activity while having equal levels of mature CTSK enzyme. Interestingly, these tools enabled the discovery of active CTSK in human osteoclast nuclei and in the nucleoli. Altogether, these novel probes are excellent research tools and can be applied in vivo to examine CTSK activity and inhibition in diverse diseases without immunogenicity hazards.

Next-generation sequencing technologies have not only defined a breakthrough in medical genetics, but also been able to enter routine clinical practice to determine individual genetic susceptibilities. Modern technological developments are routinely introduced to genetic analysis overtaking the established approaches, potentially raising a number of challenges. To what extent is the advantage of new methodologies in synthetic metrics, such as precision and recall, more important than stability and reproducibility? Could differences in the technical protocol for calling variants be crucial to the diagnosis and, by extension, the patient’s treatment strategy? A regulatory review process may delay the incorporation of potentially beneficial technologies, resulting in missed opportunities to make the right medical decisions. On the other hand, a blind adoption of new technologies based solely on synthetic metrics of precision and recall can lead to incorrect conclusions and adverse outcomes for the specific patient. Here, we use the example of a patient with a WHO-diagnosed desmoplastic/nodular SHH-medulloblastoma to explore how the choice of DNA variant search protocol affects the genetic diagnostics outcome.

By the finite-element method, we study the stress-strain state of an interface crack in a piezoelectric bimaterial polarized in the direction perpendicular to the crack faces and subjected at infinity to the action of an electric field parallel to the crack and stresses parallel to the axis of polarization. On the crack faces, we consider the main versions of electrostatic boundary conditions, namely, impermeability (insulation), electric permeability, electric conductivity, and also a version of mixed boundary conditions, i.e., electric conductivity of a middle part of the top face and insulation of the remaining part of the crack. The formation of zones of mechanical contact between the faces is possible. The problem is considered in the statement of plane deformation. The energy release rates are found with the help of the virtual crack closure integral method. It is shown that the type of boundary conditions strongly affects the parameters of fracture. Keywords: piezoelectric bimaterial, interface crack, finite-element method, fracture parameters, virtual crack closure integral method., Introduction Piezoelectric materials are widely used in contemporary microelectronic devices, such as piezoresonators, piezoelectric transformers, actuators, etc. In the process of operation, these products are subjected to the action of [...]

Permafrost-affected ecosystems of the Arctic–boreal zone in northwestern North America are undergoing profound transformation due to rapid climate change. NASA's Arctic Boreal Vulnerability Experiment (ABoVE) is investigating characteristics that make these ecosystems vulnerable or resilient to this change. ABoVE employs airborne synthetic aperture radar (SAR) as a powerful tool to characterize tundra, taiga, peatlands, and fens. Here, we present an annotated guide to the L-band and P-band airborne SAR data acquired during the 2017, 2018, 2019, and 2022 ABoVE airborne campaigns. We summarize the ∼80 SAR flight lines and how they fit into the ABoVE experimental design (Miller et al., 2023; https://doi.org/10.3334/ORNLDAAC/2150). The Supplement provides hyperlinks to extensive maps, tables, and every flight plan as well as individual flight lines. We illustrate the interdisciplinary nature of airborne SAR data with examples of preliminary results from ABoVE studies including boreal forest canopy structure from TomoSAR data over Delta Junction, AK, and the Boreal Ecosystem Research and Monitoring Sites (BERMS) area in northern Saskatchewan and active layer thickness and soil moisture data product validation. This paper is presented as a guide to enable interested readers to fully explore the ABoVE L- and P-band airborne SAR data (https://uavsar.jpl.nasa.gov/cgi-bin/data.pl).

Spinalna mišična atrofija (SMA) je redka genetska bolezen, ki prizadene motorične nevrone, zaradi česar propadajo mišice ter se slabša splošno stanje bolnika. Do nedavnega vzročnega zdravljenja za SMA ni bilo, zato so bili bolniki popolnoma odvisni od podpornega zdravljenja in zgolj od vzdrževanja življenjskih funkcij. Danes so na voljo 3 zdravila: nusinersen, risdiplam in onasemnogen abeparvovek. Ker genska nadomestna terapija z zdravilom onasemnogen abeparvovek (Zolgensma®) pomeni nov mejnik v zdravljenju SMA, jo bo članek bolj podrobno predstavil, prav tako pa tudi prva dva bolnika s SMA, ki sta se z gensko nadomestno terapijo zdravila v Sloveniji. To gre hkrati tudi za prva dva primera uporabe genske nadomestne terapije za zdravljenje katere koli bolezni pri nas. S tem tudi dokazujemo, da je možno v Sloveniji bolnike varno in uspešno zdraviti z naprednimi terapijami, kar tudi zahteva ustrezno izobražen multidisciplinarni tim, ki zna prepoznati in zdraviti vse morebitne zaplete zdravljenja.